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  • CLASSES

    Vasopressin Antagonists

    DEA CLASS

    Rx

    DESCRIPTION

    Non-peptide dual V1A and V2 vasopressin receptor antagonist; available IV; indicated for the treatment of euvolemic and hyprevolemic hyponatremia in hospitalized patients; increases serum sodium concentrations and increases free water clearance; prominent ADRs include injection site reactions, hypokalemia, thirst, and hypotension; efficacy and safety is being investigated for CHF.

    COMMON BRAND NAMES

    Vaprisol

    HOW SUPPLIED

    Vaprisol Intravenous Inj Sol: 0.2-5%

    DOSAGE & INDICATIONS

    For the treatment of hospitalized patients with euvolemic hyponatremia (e.g., syndrome of inappropriate secretion of antidiuretic hormone (SIADH), hypothyroidism, adrenal insufficiency, pulmonary disorders) or hypervolemic hyponatremia (e.g., cirrhosis, nephrotic syndrome).
    NOTE: Conivaptan is not indicated for the treatment of heart failure and has not been shown to be effective for the treatment of the signs and symptoms of heart failure.
    NOTE: Conivaptan should be administered only in settings where serum sodium concentrations, volume status, and blood pressure can be closely monitored.
    NOTE: It has not been established that utilizing conivaptan to raise serum sodium concentrations provides a symptomatic benefit to patients.
    Intravenous dosage
    Adults, including the Geriatric

    Initially, 20 mg IV loading dose administered over 30 minutes, followed by a maintenance dose of 20 mg IV continuous infusion over 24 hours. Following the initial day of treatment, conivaptan may be administered for an additional 1 to 3 days as an IV continuous infusion of 20 mg/day. If serum sodium is not rising at the desired rate, titrate up to 40 mg/day IV continuous infusion. The total duration of infusion (after the loading dose) should not exceed 4 days. Monitor serum sodium concentrations and volume status frequently. An overly rapid rise in serum sodium (greater than 12 mEq/L over 24 hours) may result in serious neurologic sequelae. For patients who develop an excessively fast rise in serum sodium concentration, discontinue conivaptan and carefully monitor serum sodium and neurologic status. If the serum sodium continues to rise, conivaptan should not be resumed. If hyponatremia persists or recurs, and the patient has had no evidence of neurologic sequelae or rapid rise in serum sodium, conivaptan may be resumed at a reduced dosage. For patients who develop hypovolemia or hypotension, the drug should be discontinued, followed by frequent monitoring of volume status and vital signs. Once the patient attains euvolemia and is normotensive again, conivaptan may be restarted at a reduced dosage to treat hyponatremia.

    For the treatment of increased intracranial pressure†.
    Intravenous dosage
    Adults

    Dosage not established. A single dose of 20 mg IV over 30 minutes has been reported in a case report and small (n = 10) prospective trial.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    20 mg IV loading dose; 40 mg/day IV continuous infusion; maximum duration of IV infusion is 4 days.

    Elderly

    20 mg IV loading dose; 40 mg/day IV continuous infusion; maximum duration of IV infusion is 4 days.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Moderate (Child-Pugh Class B) and severe (Child-Pugh Class C) hepatic impairment: 10 mg IV loading dose over 30 minutes followed by a continuous IV infusion of 10 mg over 24 hours for 2 to 4 days. Dosage may be titrated upward to 20 mg/day if serum sodium is not increasing at the desired rate.

    Renal Impairment

    CrCl 30 mL/minute or more: No dosage adjustment needed.
    CrCl less than 30 mL/minute: Not recommended.

    ADMINISTRATION

     
    NOTE: Conivaptan should be administered only in settings where serum sodium concentrations, volume status, and blood pressure can be monitored closely. Neurologic status should also be monitored closely to avoid overly rapid correction of serum sodium concentration (> 12 mEq/L over 24 hours) during treatment of hyponatremia.
     
    NOTE: Vascular irritation and injection site reaction may occur frequently (> 50%) despite appropriate preparation and administration of IV conivaptan. Monitor closely for injection-related reactions which may include edema, erythema, phlebitis, or pain at the infusion site.

    Injectable Administration

    For intravenous (IV) administration only.
    Do not mix or administer with other IV fluids or medications.
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Available as concentrated ampules (20 mg/4 mL) and as premixed 5% dextrose flexible containers (20 mg/100 mL).
    Proper dilution and preparation of the concentrated ampules are required to reduce the risk of injection site reactions. Each ampule is for single use only. Discard any unused content of the ampule.
    Administer via a large vein and change the infusion site every 24 hours to minimize the risk of vascular irritation.
     
    Preparation and administration of intravenous (IV) loading dose from concentrated ampule:
    Withdraw 4 mL (20 mg) of conivaptan from one ampule and add to an infusion bag containing 100 mL of 5% Dextrose for injection. Gently invert the bag several times to ensure complete mixing of the solution.
    Dilute only with 5% Dextrose for injection; conivaptan is physically and/or chemically incompatible with Lactated Ringer's injection and 0.9% Sodium Chloride for injection. After diluting with 5% Dextrose for injection, the solution is stable for up to 24 hours. The diluted solution should be used immediately and administration completed within 24 hours of mixing.
    Infuse the loading dose over 30 minutes.
     
    Preparation and administration of continuous intravenous (IV) infusion maintenance dose from concentrated ampule:
    Following the loading dose, the recommended initial maintenance dose is 20 mg IV continuous infusion over 24 hours. To prepare a continuous IV infusion bag containing 20 mg, withdraw 4 mL (20 mg) of conivaptan from one ampule and add to an infusion bag containing 250 mL of 5% Dextrose for injection. Gently invert the bag several times to ensure complete mixing of the solution.
    After appropriate titration, the maximum maintenance dose is 40 mg IV continuous infusion over 24 hours. To prepare a continuous IV infusion bag containing 40 mg, withdraw 8 mL (40 mg) of conivaptan from two ampules and add to an infusion bag containing 250 mL of 5% Dextrose for injection. Gently invert the bag several times to ensure complete mixing of the solution.
    Dilute only with 5% Dextrose for injection; conivaptan is physically and/or chemically incompatible with  Lactated Ringer's injection and 0.9% Sodium Chloride for injection. After diluting with 5% Dextrose for injection, the solution is stable for up to 24 hours. The diluted solution should be used immediately and administration completed within 24 hours of mixing.
     
    Administration of IV loading dose and maintenance continuous IV infusion dose from premixed flexible container:
    Loading dose: Administer one 20 mg/100 mL premixed flexible container over 30 minutes.
    Maintenance dose: For patients who require a maintenance dose of 20 mg/day, administer one 20 mg/100 mL premixed flexible container over 24 hours. For patients requiring a maintenance dose of 40 mg/day, administer two consecutive 20 mg/100 mL premixed flexible containers over 24 hours.
    Do not use premixed flexible containers in series connections. This practice may result in the formation of air embolism resulting from residual air being drawn from the primary container before completion of fluid drawn from the secondary container.
    Conivaptan is compatible with 0.9% Sodium Chloride injection for up to 22 hours when the two solutions are coadministered via a Y-site connection at a rate of 4.2 mL/hr for conivaptan and 2.1 mL/hr or 6.3 mL/hr for Sodium Chloride. Do not coadminister with Lactated Ringer's injection.

    STORAGE

    Vaprisol:
    - Avoid excessive heat (above 104 degrees F)
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Protect from freezing
    - Protect from light
    - Store at 77 degrees F; brief exposure up to 104 degrees F does not adversely affect product

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Coadministration of conivaptan with potent CYP3A4 inhibitors such as clarithromycin, ketoconazole, itraconazole, ritonavir, and indinavir, is contraindicated, and coadministration of conivaptan with CYP3A4 substrates should be avoided.

    Corn hypersensitivity
    Heart failure, hyponatremia

    The number of patients with underlying heart failure treated with conivaptan for hypervolemic hyponatremia is too small to establish safety in this population. Conivaptan should only be used in patients with underlying heart failure if the benefits of raising the serum sodium outweigh the risks of increased side effects.

    Hypotension, hypovolemia

    Conivaptan is contraindicated in patients with hypovolemic hyponatremia. Intravenous infusion of conivaptan has been associated with hypotension, including orthostatic hypotension. Conivaptan should be discontinued if hypovolemia or hypotension develops; monitor volume status and vital signs frequently. Once the patient attains euvolemia and is normotensive again, conivaptan may be restarted at a reduced dosage if needed for further treatment of euvolemic hyponatremia.

    Alcoholism, malnutrition

    Proper dilution, preparation, and administration of IV conivaptan are required to reduce the risk of injection site reactions. An overly rapid increase in serum sodium concentration during drug administration (> 12 mEq/L/24 hours) can result in serious neurologic sequelae. In controlled clinical trials, 9% of patients receiving conivaptan at doses of 20 to 40 mg/day had an overly rapid correction of serum sodium. However, none of these patients had permanent neurologic sequelae. Although not observed in conivaptan clinical studies, osmotic demyelination syndrome has been reported following the rapid correction of low serum sodium concentrations. Symptoms of osmotic demyelination include dysarthria, mutism, dysphagia, lethargy, changes in affect, spastic quadriparesis, seizures, coma, or death. Slower rates of serum sodium correction should be considered in patients more susceptible to the deleterious effects of too rapid a rise in serum sodium concentrations such as patients with severe malnutrition, alcoholism, advanced liver disease, SIADH or those very low baseline serum sodium concentrations (hyponatremia). Serum sodium and neurological status should be monitored during conivaptan administration. Conivaptan should be discontinued if the patient develops an undesirable rapid rise in serum sodium concentrations. If serum sodium concentrations continue to rise, do not resume conivaptan. If hyponatremia persists or recurs (assuming it is after an initial discontinuation of conivaptan due to a rapid rise in serum sodium) and the patients has no evidence of neurological sequelae from the rapid rise in serum sodium, conivaptan may be resumed at a reduced dose.

    Anuria, renal disease, renal failure, renal impairment

    Conivaptan is contraindicated in patients with anuria, as no clinical benefit can be expected in patients unable to make urine. Use of conivaptan in patients with severe renal impairment (i.e., severe renal disease or renal failure, CrCl < 30 mL/minute) is not recommended due to high incidence of infusion site phlebitis and unlikely benefit.

    Hepatic disease

    Use conivaptan with caution in patients with hepatic disease. The effects of hepatic impairment on the pharmacokinetics of intravenous conivaptan have not been systematically evaluated. Increased systemic exposure after administration of oral conivaptan has been observed in patients with stable cirrhosis and moderate hepatic impairment. Dosage adjustments are recommended in patients with hepatic impairment.

    Geriatric

    Although a nearly 2-fold higher drug exposure is reported for geriatric male subjects receiving 60 mg of oral conivaptan, drug exposure is reported to be similar for lower oral doses (15 to 30 mg). Though not compared directly to younger patients, the median conivaptan plasma concentrations following recommended IV dosage and maintenance infusion regimens appear to be similar for elderly hyponatremic patients and the general study population. In clinical trials of intravenous conivaptan, 52% of patients were >= 65 years and 34% were >= 75 years. No overall differences in adverse events were observed in elderly patients when compared with the general study population.

    Pregnancy

    There are no available data with conivaptan in human pregnancy to inform a drug-associated risk for major birth defects and miscarriage. When pregnant rats were given conivaptan at doses producing systemic exposures less than those achieved with a therapeutic human dose based on AUC comparisons, the offspring showed decreased neonatal viability, weaning indices, and body weight and delayed reflex and physical development, including sexual maturation. No maternal adverse effects were seen. However, when pregnant rabbits were given conivaptan at doses about twice the human exposure, no adverse maternal or fetal effects were noted. Pharmacokinetic data demonstrate that conivaptan that is taken up by fetal tissue is slowly cleared, suggesting that fetal accumulation is possible. Delayed delivery was observed when conivaptan was administered orally to rats at a dose providing systemic exposure equivalent to the human therapeutic exposure.

    Breast-feeding

    There are no data regarding conivaptan or its metabolites in human milk or the effects of conivaptan on the breast-fed infant or milk production. Conivaptan is present in rat milk. The maximum concentrations of conivaptan in rat milk were reached 1 hour after intravenous administration and were up to 3 times the maternal plasma concentrations after a dose that produced a systemic exposure less than human therapeutic exposure. Because of potential for serious adverse effects, including electrolyte abnormalities, hypotension, and volume depletion, in the breast-fed infant, avoid breast-feeding during treatment with conivaptan.

    Infertility, reproductive risk

    Discuss reproductive risk with female patients. Based on animal data, conivaptan may impair fertility or cause infertility in females of reproductive potential. It is not known whether these effects on fertility are reversible.

    ADVERSE REACTIONS

    Severe

    atrial fibrillation / Early / 2.0-5.0
    heart failure / Delayed / Incidence not known
    osmotic demyelination syndrome / Early / Incidence not known

    Moderate

    phlebitis / Rapid / 32.0-51.0
    hypokalemia / Delayed / 10.0-22.0
    orthostatic hypotension / Delayed / 6.0-14.0
    hypernatremia / Delayed / 9.0-9.0
    peripheral edema / Delayed / 3.0-8.0
    hypotension / Rapid / 5.0-8.0
    hypertension / Early / 6.0-8.0
    hyponatremia / Delayed / 6.0-8.0
    constipation / Delayed / 6.0-8.0
    erythema / Early / 6.0-6.0
    anemia / Delayed / 5.0-6.0
    confusion / Early / 0-5.0
    hypomagnesemia / Delayed / 2.0-5.0
    edema / Delayed / Incidence not known

    Mild

    injection site reaction / Rapid / 63.0-73.0
    fever / Early / 5.0-11.0
    headache / Early / 8.0-10.0
    diarrhea / Early / 0-7.0
    vomiting / Early / 5.0-7.0
    polydipsia / Early / 3.0-6.0
    pruritus / Rapid / 1.0-5.0
    insomnia / Early / 4.0-5.0
    nausea / Early / 3.0-5.0
    infection / Delayed / 2.0-5.0

    DRUG INTERACTIONS

    Abacavir; Dolutegravir; Lamivudine: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with conivaptan. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a CYP3A and P-gp substrate and conivaptan is a moderate CYP3A and P-gp inhibitor.
    Abemaciclib: (Moderate) Monitor for an increase in abemaciclib-related adverse reactions if coadministration with conivaptan is necessary; consider reducing the dose of abemaciclib in 50-mg decrements if toxicities occur. Discontinue abemaciclib for patients unable to tolerate 50 mg twice daily. Abemaciclib is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor. Coadministration with other moderate CYP3A inhibitors is predicted to increase the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by approximately 1.6- to 2.4-fold.
    Acalabrutinib: (Major) Decrease the acalabrutinib dose to 100 mg PO once daily if coadministered with conivaptan. Coadministration may result in increased acalabrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Acalabrutinib is a CYP3A substrate; conivaptan is a moderate CYP3A inhibitor. In physiologically based pharmacokinetic (PBPK) simulations, the Cmax and AUC values of acalabrutinib were increased by 2- to almost 3-fold when acalabrutinib was coadministered with moderate CYP3A inhibitors.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Consider a reduced dose of dihydrocodeine with frequent monitoring for respiratory depression and sedation if concurrent use of conivaptan is necessary. If conivaptan is discontinued, consider increasing the dihydrocodeine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Concomitant use of dihydrocodeine with conivaptan may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If conivaptan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Conivaptan is a moderate inhibitor of CYP3A, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with conivaptan may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of conivaptan could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If conivaptan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Conivaptan is a moderate inhibitor of CYP3A.
    Acetaminophen; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of conivaptan is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like conivaptan can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If conivaptan is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Acetaminophen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of conivaptan is necessary. If conivaptan is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A substrate, and coadministration with moderate CYP3A inhibitors like conivaptan can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If conivaptan is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    Afatinib: (Moderate) If the concomitant use of conivaptan and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of conivaptan. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and conivaptan is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Alfentanil: (Moderate) Consider a reduced dose of alfentanil with frequent monitoring for respiratory depression and sedation if concurrent use of conivaptan is necessary. If conivaptan is discontinued, consider increasing the alfentanil dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Alfentanil is a sensitive CYP3A substrate, and coadministration with CYP3A inhibitors like conivaptan can increase alfentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of alfentanil. If conivaptan is discontinued, alfentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to alfentanil.
    Alfuzosin: (Moderate) Monitor for evidence of alfuzosin-related adverse effects including hypotension and QT prolongation if coadministered with conivaptan. Increased alfuzosin exposure may occur. Alfuzosin is a CYP3A substrate; conivaptan is a moderate CYP3A inhibitor. Coadministration of another moderate CYP3A inhibitor increased the alfuzosin overall exposure by 1.3-fold.
    Aliskiren; Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with conivaptan is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate; conivaptan is a moderate CYP3A inhibitor. Concomitant use of amlodipine and oral conivaptan doubled amlodipine's overall exposure in a drug interaction study.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with conivaptan is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate; conivaptan is a moderate CYP3A inhibitor. Concomitant use of amlodipine and oral conivaptan doubled amlodipine's overall exposure in a drug interaction study.
    Alprazolam: (Major) Avoid coadministration of alprazolam and conivaptan due to the potential for elevated alprazolam concentrations, which may cause prolonged sedation and respiratory depression. If coadministration is necessary, consider reducing the dose of alprazolam as clinically appropriate and monitor for an increase in alprazolam-related adverse reactions. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with conivaptan, as these benzodiazepines are not oxidatively metabolized. Alprazolam is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor. Coadministration with other moderate CYP3A inhibitors increased alprazolam exposure by 1.6- to 1.98-fold.
    Amiodarone: (Moderate) If concomitant use of conivaptan with amiodarone is necessary, consider serial measurement of amiodarone serum concentrations. Coadministration may increase amiodarone concentrations resulting in amiodarone-related adverse events. Amiodarone is a CYP3A substrate; conivaptan is a moderate CYP3A inhibitor.
    Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with conivaptan is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate; conivaptan is a moderate CYP3A inhibitor. Concomitant use of amlodipine and oral conivaptan doubled amlodipine's overall exposure in a drug interaction study.
    Amlodipine; Atorvastatin: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with conivaptan is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp substrate; conivaptan is a P-gp inhibitor. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with conivaptan is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate; conivaptan is a moderate CYP3A inhibitor. Concomitant use of amlodipine and oral conivaptan doubled amlodipine's overall exposure in a drug interaction study.
    Amlodipine; Benazepril: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with conivaptan is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate; conivaptan is a moderate CYP3A inhibitor. Concomitant use of amlodipine and oral conivaptan doubled amlodipine's overall exposure in a drug interaction study.
    Amlodipine; Celecoxib: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with conivaptan is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate; conivaptan is a moderate CYP3A inhibitor. Concomitant use of amlodipine and oral conivaptan doubled amlodipine's overall exposure in a drug interaction study.
    Amlodipine; Olmesartan: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with conivaptan is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate; conivaptan is a moderate CYP3A inhibitor. Concomitant use of amlodipine and oral conivaptan doubled amlodipine's overall exposure in a drug interaction study.
    Amlodipine; Valsartan: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with conivaptan is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate; conivaptan is a moderate CYP3A inhibitor. Concomitant use of amlodipine and oral conivaptan doubled amlodipine's overall exposure in a drug interaction study.
    Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with conivaptan is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate; conivaptan is a moderate CYP3A inhibitor. Concomitant use of amlodipine and oral conivaptan doubled amlodipine's overall exposure in a drug interaction study.
    Amoxicillin; Clarithromycin; Omeprazole: (Contraindicated) Coadministration of conivaptan and clarithromycin is contraindicated due to the potential for increased conivaptan exposure. Conivaptan is a sensitive CYP3A substrate; clarithromycin is a strong CYP3A inhibitor. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the exposure of oral conivaptan by 11-fold.
    Aprepitant, Fosaprepitant: (Major) Avoid coadministration of conivaptan and aprepitant/fosaprepitant due to substantially increased exposure of aprepitant. Fosaprepitant is rapidly converted to aprepitant; therefore, a similar interaction is likely. Aprepitant is a CYP3A substrate; conivaptan is a moderate CYP3A inhibitor. Administration of a moderate CYP3A inhibitor increased overall aprepitant exposure by 2-fold.
    Aripiprazole: (Major) Monitor for aripiprazole-related adverse reactions during concurrent use of conivaptan. Reduce the oral aripiprazole dosage to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response in patients also receiving a CYP2D6 inhibitor. Adults receiving a combination of a CYP2D6 inhibitor and conivaptan for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada or Aristada Initio during use of a weak or moderate CYP3A inhibitor alone. Aripiprazole is a substrate for CYP2D6 and CYP3A; conivaptan is a moderate CYP3A inhibitor.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Concomitant use of codeine with conivaptan may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of conivaptan could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If conivaptan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Conivaptan is a moderate inhibitor of CYP3A.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Consider a reduced dose of dihydrocodeine with frequent monitoring for respiratory depression and sedation if concurrent use of conivaptan is necessary. If conivaptan is discontinued, consider increasing the dihydrocodeine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Concomitant use of dihydrocodeine with conivaptan may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If conivaptan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Conivaptan is a moderate inhibitor of CYP3A, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with conivaptan may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of conivaptan could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If conivaptan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Conivaptan is a moderate inhibitor of CYP3A.
    Aspirin, ASA; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of conivaptan is necessary. If conivaptan is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A substrate, and coadministration with moderate CYP3A inhibitors like conivaptan can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If conivaptan is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    Atazanavir: (Contraindicated) Coadministration of conivaptan and atazanavir is contraindicated due to the potential for increased conivaptan exposure. Conivaptan is a sensitive CYP3A substrate; atazanavir is a strong CYP3A inhibitor. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the exposure of oral conivaptan by 11-fold.
    Atazanavir; Cobicistat: (Contraindicated) Coadministration of conivaptan and atazanavir is contraindicated due to the potential for increased conivaptan exposure. Conivaptan is a sensitive CYP3A substrate; atazanavir is a strong CYP3A inhibitor. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the exposure of oral conivaptan by 11-fold. (Contraindicated) Coadministration of conivaptan and cobicistat is contraindicated due to the potential for increased conivaptan exposure. Concomitant use may also increase cobicistat exposure and risk for cobicistat-related adverse effects. Conivaptan is a CYP3A substrate and moderate CYP3A inhibitor; cobicistat is a CYP3A substrate and strong CYP3A inhibitor. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the exposure of oral conivaptan by 11-fold.
    Atorvastatin: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with conivaptan is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp substrate; conivaptan is a P-gp inhibitor.
    Atorvastatin; Ezetimibe: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with conivaptan is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp substrate; conivaptan is a P-gp inhibitor.
    Avanafil: (Major) Do not exceed an avanafil dose of 50 mg once every 24 hours in patients receiving conivaptan. Coadministration may increase avanafil exposure. Avanafil is a sensitive CYP3A substrate; conivaptan is a moderate CYP3A inhibitor. Administration of another moderate CYP3A inhibitor increased the avanafil AUC by 3-fold and prolonged the half-life to approximately 8 hours.
    Avapritinib: (Major) Avoid coadministration of avapritinib with conivaptan due to the increased risk of avapritinib-related adverse reactions. If concurrent use is unavoidable, reduce the starting dose of avapritinib from 300 mg PO once daily to 100 mg PO once daily in patients with gastrointestinal stromal tumor or from 200 mg PO once daily to 50 mg PO once daily in patients with advanced systemic mastocytosis. Avapritinib is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor. Coadministration of avapritinib 300 mg PO once daily with a moderate CYP3A inhibitor is predicted to increase the overall exposure of avapritinib by 210%.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Moderate) Monitor for an increase in ergotamine-related adverse effects and adjust the ergot alkaloid dosage as necessary if concomitant use of conivaptan is required. Concomitant use may increase the systemic exposure of ergot alkaloids and increase the risk for adverse reactions such as vasospasm which may lead to cerebral ischemia and ischemia of the extremities. Ergot alkaloids are CYP3A substrates and conivaptan is a moderate CYP3A inhibitor.
    Benzhydrocodone; Acetaminophen: (Moderate) Consider a reduced dose of benzhydrocodone with frequent monitoring for respiratory depression and sedation if concomitant use of conivaptan is necessary. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a CYP3A substrate, and coadministration with moderate CYP3A inhibitors like conivaptan can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of benzhydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If conivaptan is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to benzhydrocodone.
    Berotralstat: (Major) Reduce the berotralstat dose to 110 mg PO once daily in patients chronically taking conivaptan. Concurrent use may increase berotralstat exposure and the risk of adverse effects. Berotralstat is a P-gp substrate and conivaptan is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased berotralstat exposure by 69%.
    Betamethasone: (Moderate) Monitor for corticosteroid-related adverse effects if coadministration is necessary. Conivaptan is a strong CYP3A4 inhibitor and betamethasone is a CYP3A4 substrate. Another strong CYP3A4 inhibitor has been reported to decrease the metabolism of certain corticosteroids by up to 60%, leading to increased risk of corticosteroid side effects. Conivaptan has been associated with hypokalemia (9.8%). Although not studied, consider the potential for additive hypokalemic effects if conivaptan is coadministered with drugs known to induce hypokalemia, such as corticosteroids.
    Betrixaban: (Major) Avoid betrixaban use in patients with severe renal impairment receiving conivaptan. Reduce betrixaban dosage to 80 mg PO once followed by 40 mg PO once daily in all other patients receiving conivaptan. Bleeding risk may be increased; monitor patients closely for signs and symptoms of bleeding. Betrixaban is a substrate of P-gp; conivaptan inhibits P-gp.
    Bosentan: (Moderate) Use caution if coadministration of conivaptan with bosentan is necessary, as the systemic exposure of bosentan may be increased resulting in an increase in treatment-related adverse reactions; however, a bosentan dose adjustment is not necessary. Administration of bosentan with both conivaptan and a strong or moderate CYP2C9 inhibitor is not recommended. Bosentan is a CYP3A and CYP2C9 substrate; conivaptan is a moderate CYP3A inhibitor.
    Bosutinib: (Major) Avoid concomitant use of bosutinib and conivaptan as bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor. The bosutinib peak and overall exposure were increased 1.5-fold and 2-fold, respectively, when bosutinib 500 mg PO was administered with a single dose of a moderate CYP3A inhibitor.
    Brexpiprazole: (Moderate) Use caution if coadministration of conivaptan with brexpiprazole is necessary, as the systemic exposure of brexpiprazole may be increased resulting in an increase in brexpiprazole-related adverse reactions. Reduce the dose of brexpiprazole to one-quarter (25%) of the usual dose if brexpiprazole and conivaptan are coadministered with a moderate to strong inhibitor of CYP2D6 or if the patient is a poor metabolizer of CYP2D6. If conivaptan is discontinued, adjust the brexpiprazole dosage to its original level. Brexpiprazole is a CYP3A and CYP2D6 substrate; conivaptan is a moderate CYP3A inhibitor. Concomitant use of moderate CYP3A inhibitors with a strong or moderate CYP2D6 inhibitor increased the exposure of brexpiprazole compared to use of brexpiprazole alone.
    Brigatinib: (Major) Avoid coadministration of brigatinib with conivaptan if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 40% without breaking tablets (i.e., from 180 mg to 120 mg; from 120 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of conivaptan, resume the brigatinib dose that was tolerated prior to initiation of conivaptan. Brigatinib is a CYP3A substrate; conivaptan is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase the overall exposure of brigatinib by approximately 40%.
    Bromocriptine: (Major) When bromocriptine is used for diabetes, do not exceed a dose of 1.6 mg once daily during concomitant use of conivaptan. Use this combination with caution in patients receiving bromocriptine for other indications. Concurrent use may increase bromocriptine concentrations. Bromocriptine is extensively metabolized in the liver via CYP3A; conivaptan is a moderate inhibitor of CYP3A. Coadministration with another moderate CYP3A inhibitor increased bromocriptine exposure by 2.8-fold.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of conivaptan is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like conivaptan can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If conivaptan is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of conivaptan is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like conivaptan can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If conivaptan is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Budesonide: (Moderate) Avoid coadministration of systemic budesonide with conivaptan due to increased budesonide exposure; use caution with inhaled budesonide, as systemic exposure may increase. Budesonide is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor.
    Budesonide; Formoterol: (Moderate) Avoid coadministration of systemic budesonide with conivaptan due to increased budesonide exposure; use caution with inhaled budesonide, as systemic exposure may increase. Budesonide is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor.
    Budesonide; Glycopyrrolate; Formoterol: (Moderate) Avoid coadministration of systemic budesonide with conivaptan due to increased budesonide exposure; use caution with inhaled budesonide, as systemic exposure may increase. Budesonide is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor.
    Bupivacaine Liposomal: (Major) According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as bupivacaine, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with bupivacaine. Treatment with bupivacaine may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Bupivacaine: (Major) According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as bupivacaine, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with bupivacaine. Treatment with bupivacaine may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Bupivacaine; Lidocaine: (Major) According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as bupivacaine, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with bupivacaine. Treatment with bupivacaine may be initiated no sooner than 1 week after completion of conivaptan therapy. (Moderate) Monitor for lidocaine toxicity if coadministration with conivaptan is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor.
    Bupivacaine; Meloxicam: (Major) According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as bupivacaine, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with bupivacaine. Treatment with bupivacaine may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Buprenorphine: (Moderate) Concomitant use of buprenorphine and conivaptan can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when conivaptan is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping conivaptan, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If conivaptan is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A and conivaptan is a CYP3A inhibitor.
    Buprenorphine; Naloxone: (Moderate) Concomitant use of buprenorphine and conivaptan can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when conivaptan is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping conivaptan, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If conivaptan is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A and conivaptan is a CYP3A inhibitor.
    Buspirone: (Moderate) Monitor for an increase in buspirone-related adverse reactions if coadministration with conivaptan is necessary; the effect may be more pronounced if the patient has been titrated to a stable dose of buspirone and conivaptan is added or removed from therapy. Buspirone is a sensitive CYP3A substrate and conivaptan is a moderate CYP3A inhibitor. Coadministration with other moderate CYP3A inhibitors increased buspirone exposure by 3.4 to 6-fold and was accompanied by increased buspirone-related adverse reactions.
    Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Concomitant use of codeine with conivaptan may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of conivaptan could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If conivaptan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Conivaptan is a moderate inhibitor of CYP3A.
    Cabotegravir; Rilpivirine: (Moderate) Coadministration of rilpivirine with conivaptan may result in increased plasma concentrations of rilpivirine, leading to an increase in rilpivirine-related adverse effects. Rilpivirine is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor.
    Cannabidiol: (Moderate) Consider a dose reduction of cannabidiol if coadministered with conivaptan. Coadministration may increase cannabidiol plasma concentrations increasing the risk of adverse reactions. Cannabidiol is metabolized by CYP3A; conivaptan is a moderate inhibitor of CYP3A.
    Carbamazepine: (Moderate) Monitor carbamazepine concentrations closely during coadministration of conivaptan; carbamazepine dose adjustments may be needed. Concomitant use may increase carbamazepine concentrations. Carbamazepine is a CYP3A substrate and conivaptan is a CYP3A inhibitor.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of conivaptan is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like conivaptan can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If conivaptan is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of conivaptan is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like conivaptan can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If conivaptan is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Ceritinib: (Contraindicated) Coadministration of conivaptan and ceritinib is contraindicated due to the potential for increased conivaptan exposure. Conivaptan is a sensitive CYP3A substrate; ceritinib is a strong CYP3A inhibitor. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the exposure of oral conivaptan by 11-fold.
    Chloramphenicol: (Contraindicated) Coadministration of conivaptan and chloramphenicol is contraindicated due to the potential for increased conivaptan exposure. Conivaptan is a sensitive CYP3A substrate; chloramphenicol is a strong CYP3A inhibitor. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the exposure of oral conivaptan by 11-fold.
    Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with conivaptan may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of conivaptan could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If conivaptan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Conivaptan is a moderate inhibitor of CYP3A.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Consider a reduced dose of dihydrocodeine with frequent monitoring for respiratory depression and sedation if concurrent use of conivaptan is necessary. If conivaptan is discontinued, consider increasing the dihydrocodeine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Concomitant use of dihydrocodeine with conivaptan may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If conivaptan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Conivaptan is a moderate inhibitor of CYP3A, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Consider a reduced dose of dihydrocodeine with frequent monitoring for respiratory depression and sedation if concurrent use of conivaptan is necessary. If conivaptan is discontinued, consider increasing the dihydrocodeine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Concomitant use of dihydrocodeine with conivaptan may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If conivaptan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Conivaptan is a moderate inhibitor of CYP3A, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of conivaptan is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like conivaptan can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If conivaptan is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Chlorpheniramine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of conivaptan is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like conivaptan can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If conivaptan is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of conivaptan is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like conivaptan can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If conivaptan is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of conivaptan is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like conivaptan can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If conivaptan is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Cilostazol: (Major) Reduce the dose of cilostazol to 50 mg twice daily when coadministered with conivaptan and monitor for an increase in cilostazol-related adverse reactions. Concurrent use may increase cilostazol exposure. Cilostazol is a CYP3A substrate; conivaptan is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased the AUC of cilostazol (single dose) by 73%; the AUC of 4-trans-hydroxycilostazol increased by 141%.
    Cisapride: (Contraindicated) Post-marketing surveillance reports have documented QT prolongation and ventricular arrhythmias, including torsade de pointes and death, when known and potent inhibitors of CYP3A4 are coadministered with cisapride. Because of the potential severity of these drug interactions (increased plasma cisapride concentrations and QT prolongation), cisapride should not be used with conivaptan, which may inhibit the metabolism of cisapride through CYP3A4.
    Clarithromycin: (Contraindicated) Coadministration of conivaptan and clarithromycin is contraindicated due to the potential for increased conivaptan exposure. Conivaptan is a sensitive CYP3A substrate; clarithromycin is a strong CYP3A inhibitor. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the exposure of oral conivaptan by 11-fold.
    Clonazepam: (Moderate) Monitor for increased sedation and respiratory depression if clonazepam is coadministered with conivaptan; adjust the dose of clonazepam if necessary. The systemic exposure of clonazepam may be increased resulting in an increase in treatment-related adverse reactions. Clonazepam is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor.
    Clozapine: (Moderate) Consider a clozapine dose reduction if coadministered with conivaptan and monitor for adverse reactions. If conivaptan is discontinued, monitor for lack of clozapine effect and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP3A. Conivaptan is a moderate CYP3A inhibitor.
    Cobicistat: (Contraindicated) Coadministration of conivaptan and cobicistat is contraindicated due to the potential for increased conivaptan exposure. Concomitant use may also increase cobicistat exposure and risk for cobicistat-related adverse effects. Conivaptan is a CYP3A substrate and moderate CYP3A inhibitor; cobicistat is a CYP3A substrate and strong CYP3A inhibitor. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the exposure of oral conivaptan by 11-fold.
    Cobimetinib: (Major) Avoid using cobimetinib and conivaptan together for more than 14 days due to the risk of cobimetinib toxicity. If short-term use of conivaptan is necessary, reduce the dose of cobimetinib to 20 mg once daily for patients normally taking cobimetinib 60 mg per day. After discontinuation of conivaptan, resume cobimetinib 60 mg per day. Use alternative therapy in patients who are already taking a reduced dose of cobimetinib (20 or 40 mg daily). Cobimetinib is a CYP3A and P-gp substrate and conivaptan is a moderate CYP3A and P-gp inhibitor. Simulations suggest that a short course of cobimetinib 20 mg once daily taken with a moderate CYP3A inhibitor produces similar concentrations to cobimetinib 60 mg per day alone.
    Codeine: (Moderate) Concomitant use of codeine with conivaptan may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of conivaptan could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If conivaptan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Conivaptan is a moderate inhibitor of CYP3A.
    Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with conivaptan may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of conivaptan could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If conivaptan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Conivaptan is a moderate inhibitor of CYP3A.
    Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of codeine with conivaptan may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of conivaptan could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If conivaptan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Conivaptan is a moderate inhibitor of CYP3A.
    Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of codeine with conivaptan may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of conivaptan could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If conivaptan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Conivaptan is a moderate inhibitor of CYP3A.
    Codeine; Promethazine: (Moderate) Concomitant use of codeine with conivaptan may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of conivaptan could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If conivaptan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Conivaptan is a moderate inhibitor of CYP3A.
    Colchicine: (Major) Coadministration of colchicine and conivaptan is contraindicated in patients with renal or hepatic impairment because colchicine accumulation may be greater in these populations. Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and conivaptan in patients with normal renal and hepatic function unless the use of both agents is imperative. Concomitant use may increase colchicine exposure; colchicine is a CYP3A and P-gp substrate and conivaptan is a moderate CYP3A and P-gp inhibitor. If coadministration in patients with normal renal and hepatic function cannot be avoided, adjust the dose of colchicine by either reducing the daily dose or the dosage frequency, and carefully monitor for colchicine toxicity. Specific dosage adjustment recommendations are available for the Colcrys product for patients who have taken conivaptan in the past 14 days or require concurrent use: for prophylaxis of gout flares, if the original dose is 0.6 mg twice daily, decrease to 0.3 mg once daily or if the original dose is 0.6 mg once daily, decrease to 0.3 mg once every other day; for treatment of gout flares, give 0.6 mg as a single dose, then 0.3 mg 1 hour later, and do not repeat for at least 3 days; for familial Mediterranean fever, do not exceed a 0.6 mg/day.
    Conjugated Estrogens: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as conivaptan may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Conjugated Estrogens; Bazedoxifene: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as conivaptan may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Conjugated Estrogens; Medroxyprogesterone: (Moderate) Use caution if coadministration of conivaptan with medroxyprogesterone is necessary, as the systemic exposure of medroxyprogesterone may be increased resulting in an increase in treatment-related adverse reactions. Conivaptan is a moderate CYP3A inhibitor. Medroxyprogesterone is metabolized primarily by hydroxylation via a CYP3A. (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as conivaptan may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Crizotinib: (Moderate) Monitor for an increase in crizotinib-related adverse reactions if coadministration with conivaptan is necessary; crizotinib exposure may increase. Crizotinib is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor.
    Cyclosporine: (Moderate) Closely monitor cyclosporine whole blood trough concentrations as appropriate and watch for cyclosporine-related adverse reactions if coadministration with conivaptan is necessary. The dose of cyclosporine may need to be adjusted. Concurrent use may increase cyclosporine exposure causing an increased risk for cyclosporine-related adverse events. Cyclosporine is a CYP3A and P-gp substrate and conivaptan is a moderate CYP3A and P-gp inhibitor.
    Dabigatran: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with conivaptan, a P-gp inhibitor. Patients should be monitored for increased adverse effects of dabigatran. When dabigatran is administered for treatment or reduction in risk of recurrence of deep venous thrombosis (DVT) or pulmonary embolism (PE) or prophylaxis of DVT or PE following hip replacement surgery, avoid coadministration with P-gp inhibitors like conivaptan in patients with CrCl less than 50 mL/minute. When dabigatran is used in patients with non-valvular atrial fibrillation and severe renal impairment (CrCl less than 30 mL/minute), avoid coadministration with conivaptan, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Darifenacin: (Moderate) Monitor for increased toxicity of darifenacin if coadministered with conivaptan. Coadministration may increase the exposure of darifenacin. Darifenacin is a sensitive CYP3A substrate; conivaptan is a moderate CYP3A inhibitor.
    Darunavir: (Contraindicated) Coadministration of conivaptan and darunavir is contraindicated due to the potential for increased conivaptan exposure. Concomitant use may also increase darunavir exposure and risk for darunavir-related adverse effects. Conivaptan is a CYP3A substrate and moderate CYP3A inhibitor; darunavir is a CYP3A substrate and strong CYP3A inhibitor. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the exposure of oral conivaptan by 11-fold.
    Darunavir; Cobicistat: (Contraindicated) Coadministration of conivaptan and cobicistat is contraindicated due to the potential for increased conivaptan exposure. Concomitant use may also increase cobicistat exposure and risk for cobicistat-related adverse effects. Conivaptan is a CYP3A substrate and moderate CYP3A inhibitor; cobicistat is a CYP3A substrate and strong CYP3A inhibitor. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the exposure of oral conivaptan by 11-fold. (Contraindicated) Coadministration of conivaptan and darunavir is contraindicated due to the potential for increased conivaptan exposure. Concomitant use may also increase darunavir exposure and risk for darunavir-related adverse effects. Conivaptan is a CYP3A substrate and moderate CYP3A inhibitor; darunavir is a CYP3A substrate and strong CYP3A inhibitor. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the exposure of oral conivaptan by 11-fold.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Contraindicated) Coadministration of conivaptan and cobicistat is contraindicated due to the potential for increased conivaptan exposure. Concomitant use may also increase cobicistat exposure and risk for cobicistat-related adverse effects. Conivaptan is a CYP3A substrate and moderate CYP3A inhibitor; cobicistat is a CYP3A substrate and strong CYP3A inhibitor. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the exposure of oral conivaptan by 11-fold. (Contraindicated) Coadministration of conivaptan and darunavir is contraindicated due to the potential for increased conivaptan exposure. Concomitant use may also increase darunavir exposure and risk for darunavir-related adverse effects. Conivaptan is a CYP3A substrate and moderate CYP3A inhibitor; darunavir is a CYP3A substrate and strong CYP3A inhibitor. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the exposure of oral conivaptan by 11-fold.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Contraindicated) Coadministration of conivaptan and ritonavir is contraindicated due to the potential for increased conivaptan exposure. Conivaptan is a CYP3A substrate; ritonavir is a strong CYP3A inhibitor. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the exposure of oral conivaptan by 11-fold.
    Deflazacort: (Major) Decrease deflazacort dose to one third of the recommended dosage when coadministered with conivaptan. Concurrent use may significantly increase concentrations of 21-desDFZ, the active metabolite of deflazacort, resulting in an increased risk of toxicity. Deflazacort is a CYP3A substrate; conivaptan is a moderate CYP3A inhibitor.
    Delavirdine: (Contraindicated) Coadministration of conivaptan and delavirdine is contraindicated due to the potential for increased conivaptan exposure. Conivaptan is a sensitive CYP3A substrate; delavirdine is a strong CYP3A inhibitor. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the exposure of oral conivaptan by 11-fold.
    Dextromethorphan; Quinidine: (Moderate) Monitor ECG and for quinidine-related adverse reactions if coadministration with conivaptan is necessary. Concomitant use may result in increased plasma concentrations of quinidine. Quinidine is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor.
    Diazepam: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with conivaptan is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A substrate and conivaptan is a CYP3A inhibitor.
    Dienogest; Estradiol valerate: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as conivaptan may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Digoxin: (Moderate) Increase monitoring of serum digoxin concentrations and watch for potential signs and symptoms of clinical toxicity when starting, adjusting, or discontinuing conivaptan. Concurrent use may increase digoxin exposure. Digoxin is a P-gp substrate with a narrow therapeutic index and conivaptan is a P-gp inhibitor. Coadministration of digoxin with conivaptan resulted in a 1.8- and 1.4-fold increase in digoxin peak and overall exposure, respectively.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Consider a reduced dose of dihydrocodeine with frequent monitoring for respiratory depression and sedation if concurrent use of conivaptan is necessary. If conivaptan is discontinued, consider increasing the dihydrocodeine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Concomitant use of dihydrocodeine with conivaptan may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If conivaptan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Conivaptan is a moderate inhibitor of CYP3A, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Dihydroergotamine: (Moderate) Monitor for an increase in ergotamine-related adverse effects and adjust the ergot alkaloid dosage as necessary if concomitant use of conivaptan is required. Concomitant use may increase the systemic exposure of ergot alkaloids and increase the risk for adverse reactions such as vasospasm which may lead to cerebral ischemia and ischemia of the extremities. Ergot alkaloids are CYP3A substrates and conivaptan is a moderate CYP3A inhibitor.
    Diltiazem: (Moderate) Monitor blood pressure and heart rate if coadministration of diltiazem with conivaptan is necessary. Concurrent use may result in elevated diltiazem concentrations and additive risk for hypotension. Diltiazem is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of conivaptan is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like conivaptan can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If conivaptan is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Disopyramide: (Moderate) Monitor for an increase in disopyramide-related adverse reactions if coadministration with conivaptan is necessary as concurrent use may increase disopyramide exposure. Disopyramide is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor. Although specific drug interaction studies have not been done for disopyramide, cases of life-threatening interactions have been reported when disopyramide was coadministered with other moderate CYP3A inhibitors.
    Dofetilide: (Moderate) Monitor for an increase in dofetilide-related adverse reactions, including QT prolongation, if coadministration with conivaptan is necessary as concurrent use may increase dofetilide exposure. Conivaptan is a moderate CYP3A inhibitor. Dofetilide is a minor CYP3A substrate; however, because there is a linear relationship between dofetilide plasma concentration and QTc prolongation, concomitant administration of CYP3A inhibitors may increase the risk of arrhythmias such as torsade de pointes.
    Dolutegravir: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with conivaptan. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a CYP3A and P-gp substrate and conivaptan is a moderate CYP3A and P-gp inhibitor.
    Dolutegravir; Lamivudine: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with conivaptan. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a CYP3A and P-gp substrate and conivaptan is a moderate CYP3A and P-gp inhibitor.
    Dolutegravir; Rilpivirine: (Moderate) Coadministration of rilpivirine with conivaptan may result in increased plasma concentrations of rilpivirine, leading to an increase in rilpivirine-related adverse effects. Rilpivirine is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor. (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with conivaptan. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a CYP3A and P-gp substrate and conivaptan is a moderate CYP3A and P-gp inhibitor.
    Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Use caution when administering conivaptan and tenofovir concurrently. Conivaptan is an inhibitor of P-glycoprotein (P-gp). Co-administration of conivaptan with P-gp substrates, such as tenofovir, PMPA, can increase tenofovir exposure leading to increased or prolonged therapeutic effects and adverse events.
    Doxorubicin Liposomal: (Major) Avoid coadministration of doxorubicin with conivaptan due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Doxorubicin is a substrate of CYP3A and P-gp and conivaptan is a moderate CYP3A and P-gp inhibitor.
    Doxorubicin: (Major) Avoid coadministration of doxorubicin with conivaptan due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Doxorubicin is a substrate of CYP3A and P-gp and conivaptan is a moderate CYP3A and P-gp inhibitor.
    Dronabinol: (Moderate) Monitor for increased toxicity (e.g., feeling high, dizziness, confusion, somnolence) of dronabinol if coadministered with conivaptan. Coadministration may increase the exposure of dronabinol. Dronabinol is a CYP3A substrate; conivaptan is a moderate CYP3A inhibitor.
    Dronedarone: (Moderate) Monitor for increased toxicity of dronedarone during coadministration of conivaptan as concomitant use may increase the exposure of dronedarone. Dronedarone is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor.
    Drospirenone; Estradiol: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as conivaptan may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Dutasteride; Tamsulosin: (Moderate) Use caution if coadministration of conivaptan with tamsulosin is necessary, especially at a tamsulosin dose higher than 0.4 mg, as the systemic exposure of tamsulosin may be increased resulting in increased treatment-related adverse reactions including hypotension, dizziness, and vertigo. Tamsulosin is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor.
    Duvelisib: (Moderate) Monitor for increased toxicity if duvelisib is coadministered with conivaptan. Coadministration may increase the exposure of duvelisib, increasing the risk of toxicity. Duvelisib is a CYP3A substrate; conivaptan is a moderate CYP3A inhibitor.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Use caution when administering conivaptan and tenofovir concurrently. Conivaptan is an inhibitor of P-glycoprotein (P-gp). Co-administration of conivaptan with P-gp substrates, such as tenofovir, PMPA, can increase tenofovir exposure leading to increased or prolonged therapeutic effects and adverse events.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Use caution when administering conivaptan and tenofovir concurrently. Conivaptan is an inhibitor of P-glycoprotein (P-gp). Co-administration of conivaptan with P-gp substrates, such as tenofovir, PMPA, can increase tenofovir exposure leading to increased or prolonged therapeutic effects and adverse events.
    Elagolix; Estradiol; Norethindrone acetate: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as conivaptan may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Eletriptan: (Moderate) Monitor for increased eletriptan-related adverse effects if coadministered with conivaptan. Systemic concentrations of eletriptan may be increased. Eletriptan is a substrate for CYP3A, and conivaptan is a moderate CYP3A inhibitor. Coadministration of other moderate CYP3A inhibitors increased the eletriptan over all exposure by 2 to 4-fold.
    Elexacaftor; tezacaftor; ivacaftor: (Major) Adjust the elexacaftor; tezacaftor; ivacaftor dosing schedule when coadministered with conivaptan; coadministration may increase elexacaftor; tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 2 elexacaftor; tezacaftor; ivacaftor combination tablets every other day in the morning and 1 ivacaftor tablet every other day in the morning on alternate days (i.e., elexacaftor/tezacaftor/ivacaftor tablet on Day 1 and ivacaftor tablet on Day 2). The evening dose of ivacaftor should not be taken. Elexacaftor, tezacaftor, and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); conivaptan is a moderate CYP3A inhibitor. Coadministration of a moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold. Simulation suggests a moderate inhibitor may increase elexacaftor and tezacaftor exposure by 2.3-fold and 2-fold, respectively. (Major) Adjust the tezacaftor; ivacaftor dosing schedule when coadministered with conivaptan; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 1 tezacaftor; ivacaftor combination tablet every other day in the morning and 1 ivacaftor tablet every other day in the morning on alternate days (i.e., tezacaftor/ivacaftor tablet on Day 1 and ivacaftor tablet on Day 2). The evening dose of ivacaftor should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); conivaptan is a moderate CYP3A inhibitor. Coadministration of a moderate CYP3A inhibitor increased ivacaftor exposure 3-fold. Simulation suggests a moderate inhibitor may increase tezacaftor exposure 2-fold. (Major) If conivaptan and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Ivacaftor is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
    Eliglustat: (Major) Avoid coadministration of eliglustat with conivaptan in intermediate or poor CYP2D6 metabolizers (IMs or PMs). In extensive CYP2D6 metabolizers (EMs), coadministration of these agents requires dosage reduction of eliglustat to 84 mg PO once daily. Concurrent use is contraindicated in EMs and IMs also receiving a strong or moderate CYP2D6 inhibitor. Eliglustat is a CYP3A and CYP2D6 substrate. conivaptan is a moderate inhibitor of CYP3A. Concurrent use may result in unexpectedly high plasma concentrations of eliglustat, further increasing the risk of serious adverse events (e.g., cardiac arrhythmias).
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Contraindicated) Coadministration of conivaptan and cobicistat is contraindicated due to the potential for increased conivaptan exposure. Concomitant use may also increase cobicistat exposure and risk for cobicistat-related adverse effects. Conivaptan is a CYP3A substrate and moderate CYP3A inhibitor; cobicistat is a CYP3A substrate and strong CYP3A inhibitor. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the exposure of oral conivaptan by 11-fold.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Contraindicated) Coadministration of conivaptan and cobicistat is contraindicated due to the potential for increased conivaptan exposure. Concomitant use may also increase cobicistat exposure and risk for cobicistat-related adverse effects. Conivaptan is a CYP3A substrate and moderate CYP3A inhibitor; cobicistat is a CYP3A substrate and strong CYP3A inhibitor. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the exposure of oral conivaptan by 11-fold. (Moderate) Use caution when administering conivaptan and tenofovir concurrently. Conivaptan is an inhibitor of P-glycoprotein (P-gp). Co-administration of conivaptan with P-gp substrates, such as tenofovir, PMPA, can increase tenofovir exposure leading to increased or prolonged therapeutic effects and adverse events.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Coadministration of rilpivirine with conivaptan may result in increased plasma concentrations of rilpivirine, leading to an increase in rilpivirine-related adverse effects. Rilpivirine is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Moderate) Coadministration of rilpivirine with conivaptan may result in increased plasma concentrations of rilpivirine, leading to an increase in rilpivirine-related adverse effects. Rilpivirine is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor. (Moderate) Use caution when administering conivaptan and tenofovir concurrently. Conivaptan is an inhibitor of P-glycoprotein (P-gp). Co-administration of conivaptan with P-gp substrates, such as tenofovir, PMPA, can increase tenofovir exposure leading to increased or prolonged therapeutic effects and adverse events.
    Emtricitabine; Tenofovir disoproxil fumarate: (Moderate) Use caution when administering conivaptan and tenofovir concurrently. Conivaptan is an inhibitor of P-glycoprotein (P-gp). Co-administration of conivaptan with P-gp substrates, such as tenofovir, PMPA, can increase tenofovir exposure leading to increased or prolonged therapeutic effects and adverse events.
    Enalapril; Felodipine: (Moderate) Concomitant use of felodipine and conivaptan should be approached with caution and conservative dosing of felodipine due to the potential for significant increases in felodipine exposure. Monitor for evidence of increased felodipine effects including decreased blood pressure and increased heart rate. Felodipine is a sensitive CYP3A substrate and conivaptan is a moderate CYP3A inhibitor. Concurrent use of another moderate CYP3A inhibitor increased felodipine over all exposure and half-life by approximately 2.5-fold and 2-fold, respectively.
    Encorafenib: (Major) Avoid coadministration of encorafenib and conivaptan due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of conivaptan. If conivaptan is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of conivaptan. Encorafenib is a CYP3A substrate; conivaptan is a moderate CYP3A inhibitor. Coadministration of a moderate CYP3A inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively.
    Entrectinib: (Major) Avoid coadministration of entrectinib with conivaptan due to increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 200 mg PO once daily. If conivaptan is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of conivaptan. Entrectinib is a CYP3A substrate; conivaptan is a moderate CYP3A inhibitor. Coadministration of a moderate CYP3A inhibitor is predicted to increase the AUC of entrectinib by 3-fold.
    Eplerenone: (Major) Do not exceed an eplerenone dose of 25 mg PO once daily if given concurrently with conivaptan in a post-myocardial infarction patient with heart failure. In patients with hypertension receiving conivaptan, initiate eplerenone at 25 mg PO once daily; the dose may be increased to a maximum of 25 mg PO twice daily for inadequate blood pressure response. Measure serum creatinine and serum potassium within 3 to 7 days of initiating conivaptan and periodically thereafter. Eplerenone is a CYP3A substrate; conivaptan is a moderate CYP3A inhibitor. Coadministration with moderate CYP3A inhibitors increased eplerenone exposure by 100% to 190%. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    Ergoloid Mesylates: (Moderate) Monitor for an increase in ergotamine-related adverse effects and adjust the ergot alkaloid dosage as necessary if concomitant use of conivaptan is required. Concomitant use may increase the systemic exposure of ergot alkaloids and increase the risk for adverse reactions such as vasospasm which may lead to cerebral ischemia and ischemia of the extremities. Ergot alkaloids are CYP3A substrates and conivaptan is a moderate CYP3A inhibitor.
    Ergonovine: (Moderate) Monitor for an increase in ergotamine-related adverse effects and adjust the ergot alkaloid dosage as necessary if concomitant use of conivaptan is required. Concomitant use may increase the systemic exposure of ergot alkaloids and increase the risk for adverse reactions such as vasospasm which may lead to cerebral ischemia and ischemia of the extremities. Ergot alkaloids are CYP3A substrates and conivaptan is a moderate CYP3A inhibitor.
    Ergot alkaloids: (Moderate) Monitor for an increase in ergotamine-related adverse effects and adjust the ergot alkaloid dosage as necessary if concomitant use of conivaptan is required. Concomitant use may increase the systemic exposure of ergot alkaloids and increase the risk for adverse reactions such as vasospasm which may lead to cerebral ischemia and ischemia of the extremities. Ergot alkaloids are CYP3A substrates and conivaptan is a moderate CYP3A inhibitor.
    Ergotamine: (Moderate) Monitor for an increase in ergotamine-related adverse effects and adjust the ergot alkaloid dosage as necessary if concomitant use of conivaptan is required. Concomitant use may increase the systemic exposure of ergot alkaloids and increase the risk for adverse reactions such as vasospasm which may lead to cerebral ischemia and ischemia of the extremities. Ergot alkaloids are CYP3A substrates and conivaptan is a moderate CYP3A inhibitor.
    Ergotamine; Caffeine: (Moderate) Monitor for an increase in ergotamine-related adverse effects and adjust the ergot alkaloid dosage as necessary if concomitant use of conivaptan is required. Concomitant use may increase the systemic exposure of ergot alkaloids and increase the risk for adverse reactions such as vasospasm which may lead to cerebral ischemia and ischemia of the extremities. Ergot alkaloids are CYP3A substrates and conivaptan is a moderate CYP3A inhibitor.
    Erythromycin: (Moderate) Caution is warranted with concomitant use of conivaptan, a CYP3A4 substrate, and erythromycin, a moderate CYP3A4 inhibitor. Coadministration may result in elevated concentrations of conivaptan.
    Erythromycin; Sulfisoxazole: (Moderate) Caution is warranted with concomitant use of conivaptan, a CYP3A4 substrate, and erythromycin, a moderate CYP3A4 inhibitor. Coadministration may result in elevated concentrations of conivaptan.
    Esterified Estrogens: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as conivaptan may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Esterified Estrogens; Methyltestosterone: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as conivaptan may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Estradiol Cypionate; Medroxyprogesterone: (Moderate) Use caution if coadministration of conivaptan with medroxyprogesterone is necessary, as the systemic exposure of medroxyprogesterone may be increased resulting in an increase in treatment-related adverse reactions. Conivaptan is a moderate CYP3A inhibitor. Medroxyprogesterone is metabolized primarily by hydroxylation via a CYP3A. (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as conivaptan may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Estradiol: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as conivaptan may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Estradiol; Levonorgestrel: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as conivaptan may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Estradiol; Norethindrone: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as conivaptan may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Estradiol; Norgestimate: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as conivaptan may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Estradiol; Progesterone: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as conivaptan may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Estropipate: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4, such as conivaptan, may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Etravirine: (Moderate) Monitor for an increase in etravirine-related adverse reactions if concomitant use of conivaptan is necessary. Etravirine is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor.
    Everolimus: (Major) Coadministration of everolimus with conivaptan requires a dose reduction for some indications and close monitoring for others. For patients with oncology indications and tuberous sclerosis complex (TSC)-associated renal angiomyolipoma, reduce the initial dose of everolimus to 2.5 mg PO once daily; the dose may be increased to 5 mg PO once daily if the 2.5 mg dose is tolerated. For patients with TSC-associated subependymal giant cell astrocytoma (SEGA) and TSC-associated partial-onset seizures, reduce the daily dose of everolimus by 50%, changing to every-other-day dosing if the reduced dose is lower than the lowest available strength; assess the everolimus whole blood trough concentration 2 weeks after initiation of conivaptan and adjust the dose as necessary to remain in the recommended therapeutic range. Also monitor everolimus whole blood trough concentrations for patients receiving everolimus for either kidney or liver transplant and adjust the dose as necessary to remain in the recommended therapeutic range. Everolimus is a sensitive CYP3A substrate and a P-gp substrate; conivaptan is a moderate CYP3A and P-gp inhibitor. Coadministration with other moderate CYP3A/P-gp inhibitors increased the overall exposure of everolimus by 3.5 to 4.4-fold.
    Ezetimibe; Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with conivaptan is necessary. Simvastatin is a CYP3A and P-gp substrate and conivaptan is a moderate CYP3A and P-gp inhibitor.
    Felodipine: (Moderate) Concomitant use of felodipine and conivaptan should be approached with caution and conservative dosing of felodipine due to the potential for significant increases in felodipine exposure. Monitor for evidence of increased felodipine effects including decreased blood pressure and increased heart rate. Felodipine is a sensitive CYP3A substrate and conivaptan is a moderate CYP3A inhibitor. Concurrent use of another moderate CYP3A inhibitor increased felodipine over all exposure and half-life by approximately 2.5-fold and 2-fold, respectively.
    Fentanyl: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of conivaptan is necessary. If conivaptan is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A substrate, and coadministration with CYP3A inhibitors like conivaptan can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If conivaptan is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
    Finerenone: (Moderate) Monitor serum potassium during initiation or dose adjustment of either finerenone or conivaptan; a finerenone dosage reduction may be necessary. Concomitant use may increase finerenone exposure and the risk of hyperkalemia. Finerenone is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased overall exposure to finerenone by 248%.
    Flibanserin: (Contraindicated) The concomitant use of flibanserin and conivaptan is contraindicated due to increased flibanserin exposure, which can result in severe hypotension and syncope. If initiating flibanserin following use of conivaptan, start flibanserin at least 2 weeks after the last dose of conivaptan. If initiating conivaptan following flibanserin use, start conivaptan at least 2 days after the last dose of flibanserin. Flibanserin is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor.
    Flurazepam: (Moderate) Monitor for an increase in flurazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with conivaptan is necessary. Concurrent use may increase flurazepam exposure. Flurazepam is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor.
    Food: (Moderate) The incidence of marijuana associated adverse effects may change following coadministration with conivaptan. Conivaptan is an inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of marijuana's most psychoactive compound, delta-9-tetrahydrocannabinol (Delta-9-THC). When given concurrently with conivaptan, the amount of Delta-9-THC converted to the active metabolite 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC) may be reduced. These changes in Delta-9-THC and 11-OH-THC plasma concentrations may result in an altered marijuana adverse event profile.
    Fosamprenavir: (Moderate) Monitor for increased toxicity of fosamprenavir if coadministered with conivaptan. Concurrent use may increase the plasma concentrations of fosamprenavir. Fosamprenavir is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor.
    Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of glecaprevir and conivaptan as coadministration may increase serum concentrations of glecaprevir and increase the risk of adverse effects. Glecaprevir is a substrate of P-glycoprotein (P-gp); conivaptan is a P-gp inhibitor. (Moderate) Caution is advised with the coadministration of pibrentasvir and conivaptan as coadministration may increase serum concentrations of pibrentasvir and increase the risk of adverse effects. Pibrentasvir is a substrate of P-glycoprotein (P-gp); conivaptan is an inhibitor of P-gp.
    Glyburide: (Moderate) Glyburide is a substrate of drug transporter P-glycoprotein (P-gp). Conivaptan is a P-gp inhibitor and may theoretically increase concentrations of glyburide. Patients should be monitored for changes in glycemic control.
    Glyburide; Metformin: (Moderate) Glyburide is a substrate of drug transporter P-glycoprotein (P-gp). Conivaptan is a P-gp inhibitor and may theoretically increase concentrations of glyburide. Patients should be monitored for changes in glycemic control.
    Grapefruit juice: (Major) Advise patients to avoid grapefruit and grapefruit juice during conivaptan treatment due to the risk of increased conivaptan exposure and adverse reactions. Conivaptan is a CYP3A substrate and grapefruit juice is a strong CYP3A inhibitor.
    Guaifenesin; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of conivaptan is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like conivaptan can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If conivaptan is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of conivaptan is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like conivaptan can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If conivaptan is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Guanfacine: (Major) Decrease the dose of extended-release guanfacine by 50% if coadministration with conivaptan is necessary; if conivaptan is discontinued, the dose of extended-release guanfacine may be increased to the recommended level. Monitor patients closely for adverse effects including hypotension, drowsiness, lethargy, and bradycardia. Recommendations for immediate-release guanfacine are not available. Guanfacine is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor.
    Homatropine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of conivaptan is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like conivaptan can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If conivaptan is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of conivaptan is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like conivaptan can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If conivaptan is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone; Ibuprofen: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of conivaptan is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like conivaptan can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If conivaptan is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone; Phenylephrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of conivaptan is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like conivaptan can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If conivaptan is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of conivaptan is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like conivaptan can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If conivaptan is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of conivaptan is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like conivaptan can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If conivaptan is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of conivaptan is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like conivaptan can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If conivaptan is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Ibrutinib: (Major) If coadministered with conivaptan, reduce the ibrutinib dose to 280 mg/day PO for the treatment of B-cell malignancies. Resume ibrutinib at the previous dose if conivaptan is discontinued. Initiate ibrutinib at the recommended dose of 420 mg/day PO for the treatment of chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); interruption of ibrutinib therapy or a dose reduction may be necessary in patients who develop severe toxicity. Ibrutinib is a CYP3A substrate; conivaptan is a moderate CYP3A inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A inhibitor, the Cmax and AUC values of ibrutinib were increased by 3.4-fold and 3-fold, respectively.
    Ibuprofen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of conivaptan is necessary. If conivaptan is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A substrate, and coadministration with moderate CYP3A inhibitors like conivaptan can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If conivaptan is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    Idelalisib: (Contraindicated) Coadministration of conivaptan and idelalisib is contraindicated due to the potential for increased conivaptan exposure. Conivaptan is a CYP3A substrate; idelalisib is a strong CYP3A inhibitor. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the exposure of oral conivaptan by 11-fold.
    Ifosfamide: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with conivaptan is necessary. Ifosfamide is metabolized by CYP3A to its active alkylating metabolites. Conivaptan is a moderate CYP3A inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Indinavir: (Contraindicated) Coadministration of conivaptan and indinavir is contraindicated due to the potential for increased conivaptan exposure. Conivaptan is a CYP3A substrate; indinavir is a strong CYP3A inhibitor. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the exposure of oral conivaptan by 11-fold.
    Infigratinib: (Major) Avoid concomitant use of infigratinib and conivaptan. Coadministration may increase infigratinib exposure, increasing the risk for adverse effects. Infigratinib is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor.
    Isradipine: (Moderate) Monitor for an increase in isradipine-related adverse reactions including hypotension if coadministration with conivaptan is necessary. Concomitant use may increase isradipine exposure. Isradipine is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor.
    Itraconazole: (Contraindicated) Coadministration of conivaptan and itraconazole is contraindicated due to the potential for increased conivaptan exposure. Conivaptan is a sensitive CYP3A substrate; itraconazole is a strong CYP3A inhibitor. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the exposure of oral conivaptan by 11-fold.
    Ivabradine: (Major) Avoid coadministration of ivabradine and conivaptan as increased concentrations of ivabradine are possible, which may result in bradycardia exacerbation and conduction disturbances. Ivabradine is primarily metabolized by CYP3A and conivaptan is a moderate CYP3A inhibitor. Coadministration with other moderate CYP3A inhibitors increased the AUC of ivabradine by 2- to 3-fold.
    Ivacaftor: (Major) If conivaptan and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Ivacaftor is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
    Ivosidenib: (Major) Avoid coadministration of ivosidenib with conivaptan due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is necessary, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. Ivosidenib is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase the ivosidenib overall exposure 152-190%.
    Ixabepilone: (Moderate) Frequently monitor peripheral blood counts between cycles of ixabepilone and for other acute ixabepilone-related adverse reactions if coadministration with conivaptan is necessary; consider the use of an alternative agent to conivaptan that does not inhibit CYP3A. Ixabepilone is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor. The effect of moderate CYP3A inhibitors on exposure to ixabepilone has not been studied.
    Ketoconazole: (Contraindicated) Coadministration of conivaptan and ketoconazole is contraindicated due to the potential for increased conivaptan exposure. Conivaptan is a CYP3A substrate; ketoconazole is a strong CYP3A inhibitor. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the exposure of oral conivaptan by 11-fold.
    Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Use caution when administering conivaptan and tenofovir concurrently. Conivaptan is an inhibitor of P-glycoprotein (P-gp). Co-administration of conivaptan with P-gp substrates, such as tenofovir, PMPA, can increase tenofovir exposure leading to increased or prolonged therapeutic effects and adverse events.
    Lansoprazole; Amoxicillin; Clarithromycin: (Contraindicated) Coadministration of conivaptan and clarithromycin is contraindicated due to the potential for increased conivaptan exposure. Conivaptan is a sensitive CYP3A substrate; clarithromycin is a strong CYP3A inhibitor. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the exposure of oral conivaptan by 11-fold.
    Lapatinib: (Moderate) Monitor for an increase in lapatinib-related adverse reactions if coadministration with conivaptan is necessary. Lapatinib is a P-gp substrate and conivaptan is a P-gp inhibitor. Increased plasma concentrations of lapatinib are likely.
    Ledipasvir; Sofosbuvir: (Moderate) Caution is warranted when conivaptan is administered with ledipasvir; sofosbuvir as there is a potential for elevated concentrations of ledipasvir and sofosbuvir. Conivaptan is P-glycoprotein (P-gp) inhibitor. Both ledipasvir and sofosbuvir are substrates of P-gp. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp inhibitors; however, if these drugs are given together, consider increased monitoring for potential adverse effects. (Moderate) Caution is warranted when conivaptan is administered with sofosbuvir as there is a potential for elevated concentrations of sofosbuvir. Conivaptan is P-glycoprotein (P-gp) inhibitor. Sofosbuvir is a substrate of P-gp. According to the manufacturer, no dosage adjustments are required when sofosbuvir is administered concurrently with P-gp inhibitors; however, if these drugs are given together, consider increased monitoring for potential adverse effects.
    Lefamulin: (Moderate) Monitor for lefamulin-related adverse effects if oral lefamulin is administered with conivaptan as concurrent use may increase exposure from lefamulin tablets; an interaction is not expected with intravenous lefamulin. Lefamulin is a CYP3A and P-gp substrate; conivaptan is a moderate CYP3A and P-gp inhibitor.
    Lemborexant: (Major) Avoid coadministration of lemborexant and conivaptan as concurrent use may increase lemborexant exposure and the risk of adverse effects. Lemborexant is a CYP3A substrate; conivaptan is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased the lemborexant AUC by up to 4.5-fold.
    Letermovir: (Moderate) A clinically relevant increase in the plasma concentration of conivaptan may occur during concurrent administration with letermovir. Concurrent use is contraindicated if the patient is also receiving cyclosporine because the magnitude of the interaction may be amplified. Conivaptan is a sensitive CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when letermovir is given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Coadministration of oral conivaptan with another strong CYP3A inhibitor increased conivaptan maximum concentration and exposure by 4- and 11-fold, respectively.
    Levamlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with conivaptan is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate; conivaptan is a moderate CYP3A inhibitor. Concomitant use of amlodipine and oral conivaptan doubled amlodipine's overall exposure in a drug interaction study.
    Lidocaine: (Moderate) Monitor for lidocaine toxicity if coadministration with conivaptan is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor.
    Lidocaine; Prilocaine: (Moderate) Monitor for lidocaine toxicity if coadministration with conivaptan is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor.
    Lomitapide: (Contraindicated) Concomitant use of conivaptan and lomitapide is contraindicated due to increased lomitapide exposure. If treatment with conivaptan is unavoidable, lomitapide should be stopped. Lomitapide is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor. Although concomitant use of moderate CYP3A inhibitors with lomitapide has not been studied, a significant increase in lomitapide exposure is likely during concurrent use based on the 27-fold increase in exposure observed with coadministration of a strong CYP3A inhibitor.
    Lonafarnib: (Contraindicated) Coadministration of conivaptan and lonafarnib is contraindicated due to the potential for increased conivaptan and lonafarnib exposure. Conivaptan is a CYP3A substrate and moderate CYP3A inhibitor; lonafarnib is a CYP3A substrate and strong CYP3A inhibitor. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the exposure of oral conivaptan by 11-fold.
    Loperamide: (Moderate) Monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest), if coadministered with conivaptan. Concurrent use may increase loperamide exposure. Loperamide is a P-gp substrate and conivaptan is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased loperamide plasma concentrations be 2- to 3-fold.
    Loperamide; Simethicone: (Moderate) Monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest), if coadministered with conivaptan. Concurrent use may increase loperamide exposure. Loperamide is a P-gp substrate and conivaptan is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased loperamide plasma concentrations be 2- to 3-fold.
    Lopinavir; Ritonavir: (Contraindicated) Coadministration of conivaptan and ritonavir is contraindicated due to the potential for increased conivaptan exposure. Conivaptan is a CYP3A substrate; ritonavir is a strong CYP3A inhibitor. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the exposure of oral conivaptan by 11-fold.
    Lovastatin: (Moderate) Monitor for an increase in lovastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with conivaptan is necessary. Coadministration may increase the exposure of lovastatin. Lovastatin is a CYP3A and P-gp substrate and conivaptan is a moderate CYP3A and P-gp inhibitor.
    Lovastatin; Niacin: (Moderate) Monitor for an increase in lovastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with conivaptan is necessary. Coadministration may increase the exposure of lovastatin. Lovastatin is a CYP3A and P-gp substrate and conivaptan is a moderate CYP3A and P-gp inhibitor.
    Lumacaftor; Ivacaftor: (Major) If conivaptan and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Ivacaftor is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
    Lumateperone: (Major) Avoid coadministration of lumateperone and conivaptan as concurrent use may increase lumateperone exposure and the risk of adverse effects. Lumateperone is a CYP3A substrate; conivaptan is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor increased lumateperone exposure by approximately 2-fold.
    Lurasidone: (Major) The recommended starting dose of lurasidone is 20 mg daily (maximum, 80 mg daily) if coadministration with conivaptan is necessary. Reduce lurasidone to half of its original dose if conivaptan is added to existing lurasidone therapy. Lurasidone is a sensitive CYP3A substrate and conivaptan is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased lurasidone exposure by 116%.
    Lurbinectedin: (Major) Avoid coadministration of lurbinectedin and conivaptan due to the risk of increased lurbinectedin exposure which may increase the incidence of lurbinectedin-related adverse reactions. If concomitant use is unavoidable, consider reducing the dose of lurbinectedin if clinically indicated. Lurbinectedin is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor.
    Maraviroc: (Moderate) Monitor for an increase in maraviroc-related adverse reactions if coadministration with conivaptan is necessary. Concomitant use may increase maraviroc exposure. Maraviroc is a CYP3A and P-gp substrate and conivaptan is a moderate CYP3A and P-gp inhibitor.
    Medroxyprogesterone: (Moderate) Use caution if coadministration of conivaptan with medroxyprogesterone is necessary, as the systemic exposure of medroxyprogesterone may be increased resulting in an increase in treatment-related adverse reactions. Conivaptan is a moderate CYP3A inhibitor. Medroxyprogesterone is metabolized primarily by hydroxylation via a CYP3A.
    Mefloquine: (Moderate) Use mefloquine with caution if coadministration with conivaptan is necessary as concurrent use may increase mefloquine exposure and mefloquine-related adverse events. Mefloquine is a substrate of CYP3A and P-gp and conivaptan is a moderate CYP3A and P-gp inhibitor.
    Meperidine: (Moderate) Consider a reduced dose of meperidine with frequent monitoring for respiratory depression and sedation if concurrent use of conivaptan is necessary. If conivaptan is discontinued, meperidine plasma concentrations can decrease resulting in reduced efficacy and potential withdrawal syndrome in a patient who has developed physical dependence to meperidine. Meperidine is a substrate of CYP3A and conivaptan is a moderate CYP3A inhibitor. Concomitant use with conivaptan can increase meperidine exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of meperidine.
    Meperidine; Promethazine: (Moderate) Consider a reduced dose of meperidine with frequent monitoring for respiratory depression and sedation if concurrent use of conivaptan is necessary. If conivaptan is discontinued, meperidine plasma concentrations can decrease resulting in reduced efficacy and potential withdrawal syndrome in a patient who has developed physical dependence to meperidine. Meperidine is a substrate of CYP3A and conivaptan is a moderate CYP3A inhibitor. Concomitant use with conivaptan can increase meperidine exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of meperidine.
    Metformin; Repaglinide: (Moderate) A dose reduction of repaglinide and increased frequency of blood glucose monitoring may be required if coadministration with conivaptan is necessary. Repaglinide is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor.
    Methadone: (Moderate) Consider a reduced dose of methadone with frequent monitoring for respiratory depression and sedation if concurrent use of conivaptan is necessary. If conivaptan is discontinued, methadone plasma concentrations can decrease resulting in reduced efficacy and potential withdrawal syndrome in a patient who has developed physical dependence to methadone. Methadone is a substrate of CYP3A, CYP2B6, CYP2C19, CYP2C9, and CYP2D6; conivaptan is a moderate CYP3A inhibitor. Concomitant use with conivaptan can increase methadone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of methadone.
    Methylergonovine: (Moderate) Monitor for an increase in ergotamine-related adverse effects and adjust the ergot alkaloid dosage as necessary if concomitant use of conivaptan is required. Concomitant use may increase the systemic exposure of ergot alkaloids and increase the risk for adverse reactions such as vasospasm which may lead to cerebral ischemia and ischemia of the extremities. Ergot alkaloids are CYP3A substrates and conivaptan is a moderate CYP3A inhibitor.
    Methysergide: (Moderate) Monitor for an increase in ergotamine-related adverse effects and adjust the ergot alkaloid dosage as necessary if concomitant use of conivaptan is required. Concomitant use may increase the systemic exposure of ergot alkaloids and increase the risk for adverse reactions such as vasospasm which may lead to cerebral ischemia and ischemia of the extremities. Ergot alkaloids are CYP3A substrates and conivaptan is a moderate CYP3A inhibitor.
    Midazolam: (Major) Avoid coadministration of midazolam with conivaptan. Concomitant use may increase midazolam exposure leading to prolonged sedation. Midazolam is a sensitive CYP3A substrate and conivaptan is a CYP3A inhibitor. In a drug interaction study, concomitant use increase midazolam overall exposure by 100% to 200%.
    Mifepristone: (Contraindicated) Coadministration of conivaptan and mifepristone is contraindicated due to the potential for increased conivaptan exposure. Conivaptan is a CYP3A substrate; mifepristone is a strong CYP3A inhibitor. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the exposure of oral conivaptan by 11-fold.
    Mobocertinib: (Major) Avoid concomitant use of mobocertinib and conivaptan; reduce the dose of mobocertinib by approximately 50% and monitor the QT interval more frequently if use is necessary. Concomitant use may increase mobocertinib exposure and the risk for adverse reactions. Mobocertinib is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor. Use of a moderate CYP3A inhibitor is predicted to increase the overall exposure of mobocertinib and its active metabolites by 100% to 200%.
    Morphine: (Moderate) Use caution when administering conivaptan and morphine concurrently. Conivaptan is an inhibitor of P-glycoprotein (P-gp). Co-administration of conivaptan with P-gp substrates, such as morphine, can increase morphine exposure leading to increased or prolonged therapeutic effects and adverse events.
    Morphine; Naltrexone: (Moderate) Use caution when administering conivaptan and morphine concurrently. Conivaptan is an inhibitor of P-glycoprotein (P-gp). Co-administration of conivaptan with P-gp substrates, such as morphine, can increase morphine exposure leading to increased or prolonged therapeutic effects and adverse events.
    Naldemedine: (Moderate) Monitor for potential naldemedine-related adverse reactions if coadministered with conivaptan. The plasma concentrations of naldemedine may be increased during concomitant use. Naldemedine is a CYP3A and P-gp substrate; conivaptan is a moderate CYP3A and P-gp inhibitor.
    Naloxegol: (Major) Avoid concomitant administration of naloxegol and conivaptan due to the potential for increased naloxegol exposure. If coadministration cannot be avoided, decrease the naloxegol dosage to 12.5 mg once daily and monitor for adverse reactions including opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. Naloxegol is a CYP3A substrate; conivaptan is a moderate CYP3A inhibitor. Coadministration of another moderate CYP3A inhibitor increased naloxegol exposure by approximately 3.4-fold.
    Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for an increase in paclitaxel-related adverse reactions if coadministration of nab-paclitaxel with conivaptan is necessary due to the risk of increased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor. In vitro, coadministration with moderate CYP3A inhibitors increased paclitaxel exposure; however, the concentrations used exceeded those found in vivo following normal therapeutic doses. The pharmacokinetics of paclitaxel may also be altered in vivo as a result of interactions with CYP3A inhibitors.
    Nanoparticle Albumin-Bound Sirolimus: (Moderate) Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions if coadministration with conivaptan is necessary. The dose of sirolimus may need to be reduced. Sirolimus is a sensitive CYP3A and P-gp substrate with a narrow therapeutic range; conivaptan is a moderate CYP3A and P-gp inhibitor.
    Nefazodone: (Contraindicated) Coadministration of conivaptan and nefazodone is contraindicated due to the potential for increased conivaptan exposure. Conivaptan is a sensitive CYP3A substrate; nefazodone is a strong CYP3A inhibitor. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the exposure of oral conivaptan by 11-fold.
    Nelfinavir: (Contraindicated) Coadministration of conivaptan and nelfinavir is contraindicated due to the potential for increased conivaptan exposure. Concomitant use may also increase nelfinavir exposure and risk for nelfinavir-related adverse effects. Conivaptan is a CYP3A substrate and moderate CYP3A inhibitor; nelfinavir is a CYP3A substrate and strong CYP3A inhibitor. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the exposure of oral conivaptan by 11-fold.
    Neratinib: (Major) Avoid concomitant use of conivaptan with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A substrate and conivaptan is a dual moderate CYP3A/P-gp inhibitor. Simulations using physiologically based pharmacokinetic (PBPK) models suggest that another dual moderate CYP3A/P-gp inhibitor may increase neratinib exposure by 299%.
    Niacin; Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with conivaptan is necessary. Simvastatin is a CYP3A and P-gp substrate and conivaptan is a moderate CYP3A and P-gp inhibitor.
    Nifedipine: (Moderate) Careful monitoring and dose adjustment of nifedipine may be necessary if administered with conivaptan as nifedipine exposure and adverse effects may be increased. Consider initiating nifedipine at the lowest dose. Nifedipine is a CYP3A substrate; conivaptan is a moderate CYP3A inhibitor.
    Nimodipine: (Moderate) Monitor blood pressure and reduce the dose of nimodipine as clinically appropriate if coadministration with conivaptan is necessary. Concurrent use may increase nimodipine exposure. Nimodipine is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor.
    Nintedanib: (Moderate) Monitor for nintedanib-related adverse reactions if concomitant use of conivaptan is necessary. Concomitant use may increase nintedanib exposure. Nintedanib is a P-gp substrate, and a minor substrate of CYP3A and conivaptan is a dual P-gp and CYP3A inhibitor. Coadministration with another dual P-gp and CYP3A inhibitor increased nintedanib AUC by 60%.
    Nisoldipine: (Major) Avoid coadministration of nisoldipine with conivaptan due to increased plasma concentrations of nisoldipine. If coadministration is unavoidable, monitor blood pressure closely during concurrent use of these medications. Nisoldipine is a CYP3A substrate and conivaptan is a CYP3A inhibitor. Coadministration with another CYP3A inhibitor increased the AUC of nisoldipine by 30% to 45%.
    Olaparib: (Major) Avoid coadministration of olaparib with conivaptan due to the risk of increased olaparib-related adverse reactions. If concomitant use is necessary, reduce the dose of olaparib to 150 mg twice daily; the original dose may be resumed 3 to 5 elimination half-lives after conivaptan is discontinued. Olaparib is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor; concomitant use may increase olaparib exposure. Coadministration with a moderate CYP3A inhibitor is predicted to increase the olaparib peak by 14% and the overall exposure by 121%.
    Oliceridine: (Moderate) Monitor patients closely for respiratory depression and sedation at frequent intervals and base subsequent doses on the patient's severity of pain and response to treatment if concomitant administration of oliceridine and conivaptan is necessary; less frequent dosing of oliceridine may be required. Concomitant use of oliceridine and conivaptan may increase the plasma concentration of oliceridine, resulting in increased or prolonged opioid effects. If conivaptan is discontinued, consider increasing the oliceridine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oliceridine is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor.
    Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with conivaptan is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate; conivaptan is a moderate CYP3A inhibitor. Concomitant use of amlodipine and oral conivaptan doubled amlodipine's overall exposure in a drug interaction study.
    Ombitasvir; Paritaprevir; Ritonavir: (Contraindicated) Coadministration of conivaptan and ritonavir is contraindicated due to the potential for increased conivaptan exposure. Conivaptan is a CYP3A substrate; ritonavir is a strong CYP3A inhibitor. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the exposure of oral conivaptan by 11-fold.
    Oxybutynin: (Minor) Monitor for oxybutynin-related adverse reactions if coadministration with conivaptan is necessary. Oxybutynin is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor. Concomitant use with moderate CYP3A inhibitors may alter the mean pharmacokinetic parameters of oxybutynin, although the clinical relevance of these potential interactions is unknown.
    Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of conivaptan is necessary. If conivaptan is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A substrate, and coadministration with moderate CYP3A inhibitors like conivaptan can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If conivaptan is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    Paclitaxel: (Moderate) Monitor for an increase in paclitaxel-related adverse reactions if coadministration of paclitaxel with conivaptan is necessary due to the risk of increased plasma concentrations of paclitaxel. Paclitaxel is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor. In vitro, coadministration with moderate CYP3A inhibitors increased paclitaxel exposure; however, the concentrations used exceeded those found in vivo following normal therapeutic doses. The pharmacokinetics of paclitaxel may also be altered in vivo as a result of interactions with CYP3A inhibitors.
    Pazopanib: (Major) Avoid coadministration of pazopanib and conivaptan due to the potential for increased pazopanib exposure. Pazopanib is a P-gp substrate; conivaptan is a P-gp inhibitor. Consider selection of an alternative concomitant medication with no or minimal potential to inhibit P-gp.
    Pemigatinib: (Major) Avoid coadministration of pemigatinib and conivaptan due to the risk of increased pemigatinib exposure which may increase the risk of adverse reactions. If coadministration is necessary, reduce the dose of pemigatinib to 9 mg PO once daily if original dose was 13.5 mg per day and to 4.5 mg PO once daily if the original dose was 9 mg per day. If conivaptan is discontinued, resume the original pemigatinib dose after 3 elimination half-lives of conivaptan. Pemigatinib is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase pemigatinib exposure by approximately 50% to 80%.
    Pergolide: (Moderate) Monitor for an increase in ergotamine-related adverse effects and adjust the ergot alkaloid dosage as necessary if concomitant use of conivaptan is required. Concomitant use may increase the systemic exposure of ergot alkaloids and increase the risk for adverse reactions such as vasospasm which may lead to cerebral ischemia and ischemia of the extremities. Ergot alkaloids are CYP3A substrates and conivaptan is a moderate CYP3A inhibitor.
    Perindopril; Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with conivaptan is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate; conivaptan is a moderate CYP3A inhibitor. Concomitant use of amlodipine and oral conivaptan doubled amlodipine's overall exposure in a drug interaction study.
    Pexidartinib: (Major) Avoid coadministration of pexidartinib with conivaptan as concomitant use may increase pexidartinib exposure. If concurrent use cannot be avoided, reduce the dose of pexidartinib. If conivaptan is discontinued, increase the pexidartinib dose to the original dose after three plasma half-lives of conivaptan. Dose adjustments are as follows: 800 mg/day or 600 mg/day of pexidartinib, reduce to 200 mg twice daily; 400 mg/day of pexidartinib, reduce to 200 mg once daily. Pexidartinib is a CYP3A substrate; conivaptan is a moderate CYP3A inhibitor. Coadministration with moderate CYP3A inhibitors is predicted to increase pexidartinib exposure by 67% at steady state.
    Pimozide: (Major) Avoid concomitant use of pimozide and conivaptan. Concomitant use may result in elevated pimozide concentrations resulting in QT prolongation, ventricular arrhythmias, and sudden death. Pimozide is CYP3A substrate, and conivaptan is a moderate CYP3A inhibitor.
    Posaconazole: (Contraindicated) Coadministration of conivaptan and posaconazole is contraindicated due to the potential for increased conivaptan exposure. Concomitant use may also increase posaconazole exposure and risk for posaconazole-related adverse effects. Conivaptan is a CYP3A substrate and P-gp inhibitor; posaconazole is a P-gp substrate and strong CYP3A inhibitor. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the exposure of oral conivaptan by 11-fold.
    Probenecid; Colchicine: (Major) Coadministration of colchicine and conivaptan is contraindicated in patients with renal or hepatic impairment because colchicine accumulation may be greater in these populations. Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and conivaptan in patients with normal renal and hepatic function unless the use of both agents is imperative. Concomitant use may increase colchicine exposure; colchicine is a CYP3A and P-gp substrate and conivaptan is a moderate CYP3A and P-gp inhibitor. If coadministration in patients with normal renal and hepatic function cannot be avoided, adjust the dose of colchicine by either reducing the daily dose or the dosage frequency, and carefully monitor for colchicine toxicity. Specific dosage adjustment recommendations are available for the Colcrys product for patients who have taken conivaptan in the past 14 days or require concurrent use: for prophylaxis of gout flares, if the original dose is 0.6 mg twice daily, decrease to 0.3 mg once daily or if the original dose is 0.6 mg once daily, decrease to 0.3 mg once every other day; for treatment of gout flares, give 0.6 mg as a single dose, then 0.3 mg 1 hour later, and do not repeat for at least 3 days; for familial Mediterranean fever, do not exceed a 0.6 mg/day.
    Propafenone: (Moderate) Monitor for increased propafenone toxicity if coadministered with conivaptan; concurrent use may increase propafenone exposure and therefore increase the risk of proarrhythmias. Avoid simultaneous use of propafenone and conivaptan with a CYP2D6 inhibitor or in patients with CYP2D6 deficiency. Propafenone is a CYP3A and CYP2D6 substrate; conivaptan is a moderate CYP3A inhibitor.
    Quinidine: (Moderate) Monitor ECG and for quinidine-related adverse reactions if coadministration with conivaptan is necessary. Concomitant use may result in increased plasma concentrations of quinidine. Quinidine is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor.
    Quinine: (Moderate) Monitor for quinine-related adverse reactions if coadministration with conivaptan is necessary. Concurrent use may increase quinine exposure. Quinine is a substrate of CYP3A and conivaptan is a moderate CYP3A inhibitor.
    Ranolazine: (Major) Limit the dose of ranolazine to 500 mg twice daily if coadministration with conivaptan is necessary. Coadministration may increase the exposure of ranolazine. Ranolazine is a CYP3A and P-gp substrate and conivaptan is a moderate CYP3A and P-gp inhibitor. Coadministration with another moderate CYP3A inhibitor increased plasma levels of ranolazine by 50% to 130%.
    Relugolix: (Major) Avoid concomitant use of relugolix and oral conivaptan. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is unavoidable, administer conivaptan at least 6 hours after relugolix and monitor for adverse reactions. Alternatively, relugolix therapy may be interrupted for up to 14 days if a short course of conivaptan is required; if treatment is interrupted for more than 7 days, resume relugolix with a 360 mg loading dose followed by 120 mg once daily. Relugolix is a P-gp substrate and conivaptan is a P-gp inhibitor.
    Relugolix; Estradiol; Norethindrone acetate: (Major) Avoid concomitant use of relugolix and oral conivaptan. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is unavoidable, administer conivaptan at least 6 hours after relugolix and monitor for adverse reactions. Alternatively, relugolix therapy may be interrupted for up to 14 days if a short course of conivaptan is required; if treatment is interrupted for more than 7 days, resume relugolix with a 360 mg loading dose followed by 120 mg once daily. Relugolix is a P-gp substrate and conivaptan is a P-gp inhibitor. (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as conivaptan may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Repaglinide: (Moderate) A dose reduction of repaglinide and increased frequency of blood glucose monitoring may be required if coadministration with conivaptan is necessary. Repaglinide is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor.
    Ribociclib: (Contraindicated) Coadministration of conivaptan and ribociclib is contraindicated due to the potential for increased conivaptan exposure. Conivaptan is a CYP3A substrate; ribociclib is a strong CYP3A inhibitor. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the exposure of oral conivaptan by 11-fold.
    Ribociclib; Letrozole: (Contraindicated) Coadministration of conivaptan and ribociclib is contraindicated due to the potential for increased conivaptan exposure. Conivaptan is a CYP3A substrate; ribociclib is a strong CYP3A inhibitor. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the exposure of oral conivaptan by 11-fold.
    Rifaximin: (Moderate) Use caution when administering conivaptan and rifaximin concurrently. Conivaptan is an inhibitor of P-glycoprotein (P-gp). Co-administration of conivaptan with P-gp substrates, such as rifaximin, can increase rifaximin exposure leading to increased or prolonged therapeutic effects and adverse events.
    Rilpivirine: (Moderate) Coadministration of rilpivirine with conivaptan may result in increased plasma concentrations of rilpivirine, leading to an increase in rilpivirine-related adverse effects. Rilpivirine is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor.
    Rimegepant: (Major) Avoid concomitant use of rimegepant and conivaptan; use may increase rimegepant exposure and the risk for rimegepant-related adverse effects. Rimegepant is a CYP3A and P-gp substrate and conivaptan is a moderate CYP3A and P-gp inhibitor.
    Ritonavir: (Contraindicated) Coadministration of conivaptan and ritonavir is contraindicated due to the potential for increased conivaptan exposure. Conivaptan is a CYP3A substrate; ritonavir is a strong CYP3A inhibitor. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the exposure of oral conivaptan by 11-fold.
    Rivaroxaban: (Major) Avoid coadministration of rivaroxaban and conivaptan in patients with renal impairment (CrCl 15 to 79 mL/minute) unless the potential benefit justifies the risk. Rivaroxaban is a CYP3A and P-gp substrate and conivaptan is a moderate CYP3A and P-gp inhibitor. In a pharmacokinetic trial, coadministration with another combined moderate CYP3A/P-gp inhibitor increased the overall exposure of rivaroxaban by 76% in patients with mild renal impairment (CrCl 50 to 79 mL/minute) and by 99% in patients with moderate renal impairment (CrCl 30 to 49 mL/minute) compared to patients with normal renal function (CrCl greater than 80 mL/minute); similar trends in pharmacodynamic effects were also observed.
    Roflumilast: (Moderate) Monitor for an increase in roflumilast-related adverse reactions if concomitant use with conivaptan is necessary. Concurrent use may increase roflumilast exposure. Roflumilast is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased the exposure of roflumilast by 70%.
    Saquinavir: (Contraindicated) Coadministration of conivaptan and saquinavir is contraindicated due to the potential for increased conivaptan exposure. Concomitant use may also increase saquinavir exposure and risk for saquinavir-related adverse effects. Conivaptan is a CYP3A substrate and moderate CYP3A and P-gp inhibitor; saquinavir is a CYP3A and P-gp substrate and strong CYP3A inhibitor. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the exposure of oral conivaptan by 11-fold.
    Segesterone Acetate; Ethinyl Estradiol: (Minor) Coadministration of segesterone and strong CYP3A4 inhibitors such as conivaptan may increase the serum concentration of segesterone.
    Selpercatinib: (Major) Avoid coadministration of selpercatinib and conivaptan due to the risk of increased selpercatinib exposure which may increase the risk of adverse reactions, including QT prolongation. If coadministration is unavoidable, reduce the dose of selpercatinib to 80 mg PO twice daily if original dose was 120 mg twice daily, and to 120 mg PO twice daily if original dose was 160 mg twice daily. Monitor ECGs for QT prolongation more frequently. If conivaptan is discontinued, resume the original selpercatinib dose after 3 to 5 elimination half-lives of conivaptan. Selpercatinib is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor. Coadministration with other moderate CYP3A inhibitors is predicted to increase selpercatinib exposure by 60% to 99%.
    Selumetinib: (Major) Avoid coadministration of selumetinib and conivaptan due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If conivaptan is discontinued, resume the original selumetinib dose after 3 elimination half-lives of conivaptan. Selumetinib is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase selumetinib exposure by 41%.
    Sildenafil: (Moderate) Monitor for an increase in sildenafil-related adverse reactions if coadministration with conivaptan is necessary; consider a starting dose of 25 mg of sildenafil when prescribed for erectile dysfunction. Sildenafil is a sensitive CYP3A substrate and conivaptan is a moderate CYP3A inhibitor. In a drug interaction study, coadministration with a moderate CYP3A inhibitor increased the peak and overall exposure of sildenafil by 160% and 182%, respectively. Predictions based on a pharmacokinetic model suggest that drug-drug interactions with CYP3A inhibitors will be less for sildenafil injection than those observed after oral sildenafil administration.
    Silodosin: (Major) Avoid coadministration of silodosin and conivaptan due to the potential for increased silodosin exposure. Silodosin is a CYP3A and P-gp substrate; conivaptan is a moderate CYP3A and P-gp inhibitor.
    Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with conivaptan is necessary. Simvastatin is a CYP3A and P-gp substrate and conivaptan is a moderate CYP3A and P-gp inhibitor.
    Simvastatin; Sitagliptin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with conivaptan is necessary. Simvastatin is a CYP3A and P-gp substrate and conivaptan is a moderate CYP3A and P-gp inhibitor.
    Siponimod: (Moderate) Concomitant use of siponimod and conivaptan may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A substrate; conivaptan is a moderate CYP3A inhibitor. Coadministration with a moderate CYP2C9/CYP3A dual inhibitor led to a 2-fold increase in the overall exposure of siponimod.
    Sirolimus: (Moderate) Monitor sirolimus serum concentrations as appropriate and watch for sirolimus-related adverse reactions if coadministration with conivaptan is necessary. The dose of sirolimus may need to be reduced. Sirolimus is a sensitive CYP3A and P-gp substrate with a narrow therapeutic range; conivaptan is a moderate CYP3A and P-gp inhibitor.
    Sofosbuvir: (Moderate) Caution is warranted when conivaptan is administered with sofosbuvir as there is a potential for elevated concentrations of sofosbuvir. Conivaptan is P-glycoprotein (P-gp) inhibitor. Sofosbuvir is a substrate of P-gp. According to the manufacturer, no dosage adjustments are required when sofosbuvir is administered concurrently with P-gp inhibitors; however, if these drugs are given together, consider increased monitoring for potential adverse effects.
    Sofosbuvir; Velpatasvir: (Moderate) Caution is warranted when conivaptan is administered with sofosbuvir as there is a potential for elevated concentrations of sofosbuvir. Conivaptan is P-glycoprotein (P-gp) inhibitor. Sofosbuvir is a substrate of P-gp. According to the manufacturer, no dosage adjustments are required when sofosbuvir is administered concurrently with P-gp inhibitors; however, if these drugs are given together, consider increased monitoring for potential adverse effects. (Moderate) Use caution when administering velpatasvir with conivaptan. Taking these drugs together may increase the plasma concentrations of velpatasvir, potentially resulting in adverse events. Velpatasvir is a substrate of the drug transporter P-glycoprotein (P-gp); conivaptan is an inhibitor of P-gp. Conivaptan is also a potent inhibitor of the hepatic enzyme CYP3A4. Velpatasvir is a CYP3A4 substrate.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Caution is warranted when conivaptan is administered with sofosbuvir as there is a potential for elevated concentrations of sofosbuvir. Conivaptan is P-glycoprotein (P-gp) inhibitor. Sofosbuvir is a substrate of P-gp. According to the manufacturer, no dosage adjustments are required when sofosbuvir is administered concurrently with P-gp inhibitors; however, if these drugs are given together, consider increased monitoring for potential adverse effects. (Moderate) Use caution when administering velpatasvir with conivaptan. Taking these drugs together may increase the plasma concentrations of velpatasvir, potentially resulting in adverse events. Velpatasvir is a substrate of the drug transporter P-glycoprotein (P-gp); conivaptan is an inhibitor of P-gp. Conivaptan is also a potent inhibitor of the hepatic enzyme CYP3A4. Velpatasvir is a CYP3A4 substrate.
    Sonidegib: (Major) Avoid the concomitant use of sonidegib and conivaptan as concurrent use may increase sonidegib exposure. If concomitant use is necessary, administer conivaptan for less than 14 days and monitor for an increased risk of sonidegib-related adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor. Physiologic-based pharmacokinetic (PBPK) simulations indicate a moderate 3A inhibitor would increase sonidegib overall exposure by 1.8-fold if administered for 14 days and by 2.8-fold if the moderate CYP3A inhibitor is administered with sonidegib for more than 14 days.
    Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if conivaptan must be administered. Consider a reduced dose of sufentanil injection with frequent monitoring for respiratory depression and sedation if concurrent use of conivaptan is necessary. If conivaptan is discontinued, consider increasing the sufentanil injection dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Sufentanil is a CYP3A substrate, and coadministration with a moderate CYP3A inhibitor like conivaptan can increase sufentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of sufentanil. If conivaptan is discontinued, sufentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to sufentanil.
    Suvorexant: (Major) A dose reduction to 5 mg of suvorexant is recommended during concurrent use with conivaptan. The suvorexant dose may be increased to 10 mg if needed for efficacy. Suvorexant is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor increased the suvorexant overall exposure by 2-fold.
    Tacrolimus: (Moderate) Monitor tacrolimus serum concentrations as appropriate and watch for tacrolimus-related adverse reactions if coadministration with conivaptan is necessary. The dose of tacrolimus may need to be reduced. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range; conivaptan is a moderate CYP3A inhibitor.
    Tadalafil: (Moderate) Monitor for an increase in tadalafil-related adverse reactions if coadministration with conivaptan is necessary. Tadalafil is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor. Although specific interactions have not been studied, moderate CYP3A inhibitors would likely increase tadalafil exposure.
    Talazoparib: (Moderate) Monitor for an increase in talazoparib-related adverse reactions if coadministration with conivaptan is necessary. Talazoparib is a P-glycoprotein (P-gp) substrate and conivaptan is a P-gp inhibitor. Coadministration with other P-gp inhibitors increased talazoparib exposure by 8% to 45%.
    Tamsulosin: (Moderate) Use caution if coadministration of conivaptan with tamsulosin is necessary, especially at a tamsulosin dose higher than 0.4 mg, as the systemic exposure of tamsulosin may be increased resulting in increased treatment-related adverse reactions including hypotension, dizziness, and vertigo. Tamsulosin is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor.
    Tazemetostat: (Major) Avoid coadministration of tazemetostat with conivaptan as concurrent use may increase tazemetostat exposure and the frequency and severity of adverse reactions. If concomitant use is unavoidable, decrease current tazemetostat daily dosage by 50% (e.g., decrease 800 mg PO twice daily to 400 mg PO twice daily; 600 mg PO twice daily to 400 mg PO for first dose and 200 mg PO for second dose; 400 mg PO twice daily to 200 mg PO twice daily). If conivaptan is discontinued, wait at least 3 half-lives of conivaptan before increasing the dose of tazemetostat to the previous tolerated dose. Tazemetostat is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor. Coadministration of another moderate CYP3A inhibitor increased tazemetostat exposure by 3.1-fold.
    Telithromycin: (Contraindicated) Coadministration of conivaptan and telithromycin is contraindicated due to the potential for increased conivaptan exposure. Conivaptan is a CYP3A substrate; telithromycin is a strong CYP3A inhibitor. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the exposure of oral conivaptan by 11-fold.
    Telmisartan; Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with conivaptan is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate; conivaptan is a moderate CYP3A inhibitor. Concomitant use of amlodipine and oral conivaptan doubled amlodipine's overall exposure in a drug interaction study.
    Temsirolimus: (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with conivaptan is necessary due to the risk of increased temsirolimus exposure. Temsirolimus is a P-gp substrate and conivaptan is a P-gp inhibitor. Coadministration is likely to increase plasma concentrations of temsirolimus.
    Teniposide: (Major) Avoid coadministration of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and teniposide, a CYP3A4/P-gp substrate. Concurrent use may result in elevated teniposide serum concentrations. According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as teniposide, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with teniposide. Treatment with teniposide may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Tenofovir Alafenamide: (Moderate) Coadministration of conivaptan and tenofovir alafenamide may result in elevated tenofovir concentrations. Conivaptan is an inhibitor of the drug transporter P-glycoprotein (P-gp). Tenofovir alafenamide is a substrate for P-gp. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Tenofovir, PMPA: (Moderate) Use caution when administering conivaptan and tenofovir concurrently. Conivaptan is an inhibitor of P-glycoprotein (P-gp). Co-administration of conivaptan with P-gp substrates, such as tenofovir, PMPA, can increase tenofovir exposure leading to increased or prolonged therapeutic effects and adverse events.
    Tezacaftor; Ivacaftor: (Major) Adjust the tezacaftor; ivacaftor dosing schedule when coadministered with conivaptan; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 1 tezacaftor; ivacaftor combination tablet every other day in the morning and 1 ivacaftor tablet every other day in the morning on alternate days (i.e., tezacaftor/ivacaftor tablet on Day 1 and ivacaftor tablet on Day 2). The evening dose of ivacaftor should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); conivaptan is a moderate CYP3A inhibitor. Coadministration of a moderate CYP3A inhibitor increased ivacaftor exposure 3-fold. Simulation suggests a moderate inhibitor may increase tezacaftor exposure 2-fold. (Major) If conivaptan and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Ivacaftor is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
    Ticagrelor: (Moderate) Monitor for increased bleeding if ticagrelor is coadministered with conivaptan. Coadministration may increase the exposure of ticagrelor. Ticagrelor is a sensitive substrate of CYP3A and P-gp; conivaptan is a moderate CYP3A and P-gp inhibitor.
    Tinidazole: (Moderate) Monitor for an increase in tinidazole-related adverse reactions if coadministration with conivaptan is necessary. Concurrent use may increase the exposure of tinidazole. Tinidazole is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor.
    Tipranavir: (Contraindicated) Coadministration of conivaptan and tipranavir is contraindicated due to the potential for increased conivaptan exposure. Concomitant use may also increase tipranavir exposure and risk for tipranavir-related adverse effects. Conivaptan is a CYP3A substrate and moderate CYP3A and P-gp inhibitor; tipranavir is a CYP3A and P-gp substrate and strong CYP3A inhibitor. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the exposure of oral conivaptan by 11-fold.
    Tolvaptan: (Major) Avoid concomitant use of conivaptan and tolvaptan. Coadministration represents therapeutic duplication and could cause deleterious effects. If concomitant use is necessary in patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage. In ADPKD patients receiving tolvaptan 90mg every morning and 30 mg every evening, reduce the dose to 45 mg every morning and 15 mg every evening; for those receiving tolvaptan 60 mg every morning and 30 mg every evening, reduce the dose to 30 mg every morning and 15 mg every evening; for those receiving tolvaptan 45 mg every morning and 15 mg every evening, reduce the dose to 15 mg every morning and 15 mg every evening. Consider additional dosage reduction if the reduced dose is not tolerated. Tolvaptan is a sensitive CYP3A substrate; conivaptan is a moderate CYP3A inhibitor. Coadministration of another moderate CYP3A inhibitor increased the tolvaptan AUC by 200%.
    Topotecan: (Major) Avoid coadministration of conivaptan with oral topotecan due to increased topotecan exposure; conivaptan may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and conivaptan is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Tramadol: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with conivaptan is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of conivaptan, a moderate CYP3A inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
    Tramadol; Acetaminophen: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with conivaptan is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of conivaptan, a moderate CYP3A inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
    Trandolapril; Verapamil: (Moderate) Monitor blood pressure and heart rate during coadministration of verapamil with conivaptan. Coadministration may increase the exposure of verapamil. Conivaptan is a moderate inhibitor of CYP3A; verapamil is a substrate of CYP3A.
    Triazolam: (Moderate) Monitor for signs of triazolam toxicity during coadministration with conivaptan and consider appropriate dose reduction of triazolam if clinically indicated. Coadministration may increase triazolam exposure. Triazolam is a sensitive CYP3A substrate and conivaptan is a moderate CYP3A inhibitor.
    Tucatinib: (Contraindicated) Coadministration of conivaptan and tucatinib is contraindicated due to the potential for increased conivaptan exposure. Conivaptan is a sensitive CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration of a strong CYP3A4 inhibitor increased the exposure of oral conivaptan by 11-fold. The effect on the pharmacokinetics of intravenous conivaptan was not evaluated.
    Ubrogepant: (Major) Limit the initial dose of ubrogepant to 50 mg and avoid a second dose within 24 hours if coadministered with conivaptan. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a CYP3A and P-gp substrate; conivaptan is a moderate CYP3A and P-gp inhibitor. Coadministration with another moderate CYP3A inhibitor resulted in a 3.5-fold increase in the exposure of ubrogepant.
    Vardenafil: (Major) Do not use vardenafil orally disintegrating tablets with conivaptan due to increased vardenafil exposure; do not exceed a single dose of 5 mg per 24-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A; conivaptan is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased the AUC of vardenafil by 4-fold.
    Venetoclax: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with conivaptan due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of conivaptan. Venetoclax is a CYP3A and P-gp substrate; conivaptan is a moderate CYP3A and P-gp inhibitor. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Verapamil: (Moderate) Monitor blood pressure and heart rate during coadministration of verapamil with conivaptan. Coadministration may increase the exposure of verapamil. Conivaptan is a moderate inhibitor of CYP3A; verapamil is a substrate of CYP3A.
    Viloxazine: (Moderate) Monitor for an increase in conivaptan-related adverse effects if concomitant use of viloxazine is necessary. Concomitant use may increase conivaptan exposure; viloxazine is a weak CYP3A inhibitor and conivaptan is a CYP3A substrate.
    Vinblastine: (Moderate) Monitor for an earlier onset and/or increased severity of vinblastine-related adverse reactions, including myelosuppression, constipation, and peripheral neuropathy, if coadministration with conivaptan is necessary. Vinblastine is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor. Enhanced vinblastine toxicity was reported with coadministration of another moderate CYP3A inhibitor.
    Vincristine Liposomal: (Moderate) Monitor for vincristine-related adverse reactions if coadministration of conivaptan is necessary as concurrent use may increase vincristine exposure. Vincristine is a P-gp substrate and conivaptan is a P-gp inhibitor.
    Vincristine: (Moderate) Monitor for vincristine-related adverse reactions if coadministration of conivaptan is necessary as concurrent use may increase vincristine exposure. Vincristine is a P-gp substrate and conivaptan is a P-gp inhibitor.
    Vinorelbine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with conivaptan is necessary. Vinorelbine is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor.
    Voclosporin: (Major) Reduce the voclosporin dosage to 15.8 mg PO in the morning and 7.9 mg PO in the evening if coadministered with conivaptan. Concomitant use may increase voclosporin exposure and the risk of voclosporin-related adverse effects such as nephrotoxicity, hypertension, and QT prolongation. Voclosporin is a sensitive CYP3A substrate and conivaptan is a moderate CYP3A inhibitor. Coadministration with moderate CYP3A inhibitors is predicted to increase voclosporin exposure by 3-fold.
    Voriconazole: (Contraindicated) Coadministration of conivaptan and voriconazole is contraindicated due to the potential for increased conivaptan exposure. Concomitant use may also increase voriconazole exposure and risk for voriconazole-related adverse effects. Conivaptan is a CYP3A substrate and moderate CYP3A inhibitor; voriconazole is a CYP3A substrate and strong CYP3A inhibitor. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the exposure of oral conivaptan by 11-fold. Coadministration with another moderate CYP3A inhibitor increased voriconazole exposure by 79%.
    Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with conivaptan is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. The R-enantiomer of warfarin is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
    Zanubrutinib: (Major) Decrease the zanubrutinib dose to 80 mg PO twice daily if coadministered with conivaptan. Coadministration may result in increased zanubrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Further decrease the zanubrutinib dose as recommended if adverse reactions occur. After discontinuation of conivaptan, resume the previous dose of zanubrutinib. Zanubrutinib is a CYP3A substrate; conivaptan is a moderate CYP3A inhibitor. The AUC of zanubrutinib is predicted to increase by 157% to 317% when coadministered with other moderate CYP3A inhibitors.

    PREGNANCY AND LACTATION

    Pregnancy

    There are no available data with conivaptan in human pregnancy to inform a drug-associated risk for major birth defects and miscarriage. When pregnant rats were given conivaptan at doses producing systemic exposures less than those achieved with a therapeutic human dose based on AUC comparisons, the offspring showed decreased neonatal viability, weaning indices, and body weight and delayed reflex and physical development, including sexual maturation. No maternal adverse effects were seen. However, when pregnant rabbits were given conivaptan at doses about twice the human exposure, no adverse maternal or fetal effects were noted. Pharmacokinetic data demonstrate that conivaptan that is taken up by fetal tissue is slowly cleared, suggesting that fetal accumulation is possible. Delayed delivery was observed when conivaptan was administered orally to rats at a dose providing systemic exposure equivalent to the human therapeutic exposure.

    There are no data regarding conivaptan or its metabolites in human milk or the effects of conivaptan on the breast-fed infant or milk production. Conivaptan is present in rat milk. The maximum concentrations of conivaptan in rat milk were reached 1 hour after intravenous administration and were up to 3 times the maternal plasma concentrations after a dose that produced a systemic exposure less than human therapeutic exposure. Because of potential for serious adverse effects, including electrolyte abnormalities, hypotension, and volume depletion, in the breast-fed infant, avoid breast-feeding during treatment with conivaptan.

    MECHANISM OF ACTION

    Arginine vasopressin (AVP) is a peptide hormone consisting of 9 amino acids produced in the hypothalamus-neurohypophysis system. The actions of AVP are mediated by 3 types of vasopressin receptor subtypes: V1A, V1B, and V2 receptors. Conivaptan is a dual vasopressin antagonist with nanomolar affinity for human vasopressin receptors (V1A and V2) in vitro. Vasopressin receptors are found on the vascular smooth muscle cells, the myocardium and the distal tubule of the kidney. The primary pharmacodynamic effect of conivaptan in hyponatremia is mediated by antagonizing the V2 receptors found in the renal collecting ducts. The V2 receptors are functionally coupled to aquaporin channels in the apical membrane of the collecting ducts. These receptors help to maintain plasma osmolality within the normal range. The predominant pharmacodynamic effect of V2 antagonism results in 'aquaresis', or excretion of free water. The pharmacodynamic effects of conivaptan include increased free water excretion (i.e., effective water clearance or EWC) generally accompanied by increased net fluid loss, increased urine output, and decreased urine osmolality. Conivaptan also constricts blood vessels via vascular V1A receptors. Conivaptan is selective for the V1A/V2 receptors in a 10:1 ratio. As an antagonist of the V1A and V2 vasopressin receptors, conivaptan helps rid the body of excess fluid by acting as an 'aquaretic' (urine output is increased while urine osmolality is decreased).
    •Hyponatremia: Conivaptan is currently FDA-approved for euvolemic and hypervolemic hyponatremia. Euvolemic states associated with hyponatremia may occur in patients with the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) , hypothyroidism, adrenal insufficiency, and certain pulmonary disorders. Hypervolemic states associated with hyponatremia include patients with heart failure, cirrhosis, and nephrotic syndrome. Arginine vasopressin (AVP), otherwise known as antidiuretic hormone, plays a critical role in regulating water and electrolyte balance. The levels of AVP are usually elevated in both euvolemic and hypervolemic hyponatremia. Excessive vasopressin results in impairment of free water excretion and contributes to the development of hyponatremia. At recommended doses, IV conivaptan increases serum sodium concentrations and increases free water clearance in euvolemic hyponatremic patients. Following a 20 mg IV loading dose and 40 mg/day IV continuous infusion, 52% of patients achieved an increase of >= 4 mEq/L in serum sodium concentration. The mean change from baseline in serum sodium concentration at the end of 2 or 4 days of 40 mg/day IV infusion was 5.8 mEq/L or 6.4 mEq/L, respectively. The mean serum sodium concentration achieved was 129.4 mEq/L after 2 days and 130 mEq/L after 4 days of conivaptan therapy. Following 40 mg/day IV infusion, 39% (after 2 days) and 67% (after 4 days) of patients achieved either a normal serum sodium concentration of >= 135 mEq/L or an increase in serum sodium > 6 mEq/L. After 4 days, conivaptan IV infusion produced a baseline-corrected cumulative increase in EFW of over 2900 mL compared to approximately 1800 mL with placebo. Studies in animal models of hyponatremia have shown that conivaptan prevents the occurrence of hyponatremia-related physical signs in rats with SIADH.
    •Congestive Heart Failure: Although patients with hyponatremia associated with heart failure have significantly and chronically elevated plasma concentrations of vasopressin, the use of conivaptan for heart failure is currently not indicated. Several clinical trials are underway to further evaluate the safety, efficacy, and hemodynamics of conivaptan for the treatment of heart failure patients. Excessive arginine vasopressin activity has been proposed to contribute to the development of hyponatremia and edema in heart failure. Elevated vasopressin activity may significantly increase pulmonary capillary wedge pressure and systemic vascular resistance while decreasing stroke volume and cardiac output in heart failure patients. Physiologic actions associated with stimulation the V1A receptor include arteriolar vasoconstriction, increased systemic vascular resistance, increased afterload, and myocardial hypertrophy. Physiologic actions associated with V2 receptor stimulation include sodium and water retention, increased preload, increased pulmonary capillary wedge pressure, and increased left ventricular filling pressure. Therefore, it has been proposed that antagonism of V1A and V2 receptors may attenuate the adverse hemodynamic effects from heart failure. Based on preliminary hemodynamic data, conivaptan appears to significantly reduce pulmonary capillary wedge pressure without affecting systemic vascular resistance, heart rate, or cardiac output. Conivaptan has been studied using doses of 10, 20, and 40 mg IV given over 30 minutes in patients with advanced heart failure (NYHA Class III or IV); doses of 20 and 40 mg have resulted in significantly reduced capillary wedge pressure, right atrial pressure, and increased urinary output in the 3—6 hour period following drug administration.

    PHARMACOKINETICS

    Conivaptan is administered intravenously.
     
    Intersubject variability of conivaptan pharmacokinetics is high (94% CV for clearance). It is extensively bound to human plasma proteins, being 99% bound over the concentration range of approximately 10 to 1000 ng/mL. CYP3A4 has been identified as the sole cytochrome P450 isozyme responsible for metabolism. Four metabolites have been identified. The pharmacological activity of the metabolites at V1A and V2 receptors range from approximately 3% to 50% and 50% to 100% that of conivaptan, respectively. The combined exposure of the metabolites following intravenous administration of conivaptan is approximately 7% that of the parent drug. Therefore, the contribution of the metabolites to clinical effects is expected to be minimal.
     
    Affected cytochrome P450 isoenzymes and transporters: CYP3A4 and P-gp
    Conivaptan is a potent inhibitor, and a substrate of, of CYP3A4. Conivaptan is also a P-gp inhibitor.

    Intravenous Route

    The pharmacokinetic parameters of conivaptan following intravenous infusion (40 to 80 mg/day) are non-linear; inhibition of its own metabolism seems to be the major factor for the non-linearity. The absolute bioavailability of conivaptan has not been established due its nonlinear pharmacokinetic properties. One study has estimated the bioavailability to be approximately 44% when comparing the systemic exposure of 60 mg oral conivaptan to 50 mg IV conivaptan. In healthy male subjects, the mean terminal elimination half-life after conivaptan IV infusion is 5 hours, and the mean clearance is 15.2 L/hour. A mass balance study conducted over several days has indicated that approximately 83% of an intravenous or oral dose is excreted in feces, while approximately 12% is excreted in the urine. Over the first 24 hours after dosing, approximately 1% of an intravenous dose is excreted unchanged in the urine.