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    Vasopressin Antagonists

    BOXED WARNING

    Alcoholism, malnutrition, requires a specialized care setting

    The initiation and reinitiation of tolvaptan for hyponatremia requires a specialized care setting where serum sodium concentrations and neurological status can be closely monitored during therapy. Consider slower rates of serum sodium correction 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, very low baseline serum sodium concentrations (hyponatremia), or those receiving a diuretic concomitantly. Discontinue or interrupt tolvaptan if the patient develops too rapid a rise in serum sodium concentrations, and consider the administration of hypotonic fluid. Avoid fluid restriction during the first 24 hours of tolvaptan therapy as this may increase the possibility of rapid correction of serum sodium.

    DEA CLASS

    Rx

    DESCRIPTION

    Oral selective vasopressin V2-receptor antagonist
    Used inpatient for hypervolemic and euvolemic hyponatremia, including in patients with heart failure and SIADH (Samsca)
    Also used to slow kidney function decline from rapidly progressing autosomal dominant polycystic kidney disease (Jynarque)
    Associated with serious and potentially fatal liver injury; must register with the Jynarque REMs program to monitor liver function

    COMMON BRAND NAMES

    JYNARQUE, Samsca

    HOW SUPPLIED

    JYNARQUE/Samsca/Tolvaptan Oral Tab: 15mg, 30mg, 15-45mg, 30-60mg, 30-90mg

    DOSAGE & INDICATIONS

    For the treatment of clinically significant hypervolemic and euvolemic hyponatremia, including in patients with heart failure and syndrome of inappropriate antidiuretic hormone (SIADH).
    Clinically significant hyponatremia is defined as serum sodium less than 125 mEq/L or hyponatremia that is symptomatic and has resisted correction with fluid restriction.
    Oral dosage
    Adults

    15 mg PO once daily, initially. May increase the dose by 30 mg/day after at least 24 hours up to a maximum of 60 mg/day to achieve the desired serum sodium concentration. Do not administer for more than 30 days to minimize the risk of liver injury.[35780]

    For the treatment of autosomal dominant polycystic kidney disease (ADPKD) to slow kidney function decline in patients at risk of developing rapidly progressing ADPKD.
    Oral dosage (Jynarque)
    Adults

    45 mg PO every morning upon wakening and 15 mg PO once daily 8 hours later, initially. Increase dose to 60 mg PO every morning upon wakening and 30 mg PO once daily 8 hours later, and then 90 mg PO every morning upon wakening and 30 mg PO once daily 8 hours later at a minimum of weekly intervals, if tolerated. May down-titrate based on tolerability.

    MAXIMUM DOSAGE

    Adults

    60 mg/day PO for up to 30 days for hyponatremia (Samsca); 120 mg/day PO for autosomal dominant polycystic kidney disease (Jynarque).

    Geriatric

    60 mg/day PO for up to 30 days for hyponatremia (Samsca); 120 mg/day PO for autosomal dominant polycystic kidney disease (Jynarque).

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Samsca: Avoid in patients with underlying hepatic disease.
    Jynarque: At the onset of signs or symptoms consistent with hepatic injury OR if ALT, AST, or bilirubin increase to more than 2 times upper limit of normal (ULN), immediately discontinue therapy and obtain repeat tests within 48 to 72 hours; continue testing, if appropriate. If laboratory abnormalities stabilize or resolve, reinitiate therapy with increased frequency of monitoring as long as ALT and AST remain below 3 times ULN. Do not restart therapy in patients who experience signs or symptoms of hepatic injury or whose ALT and AST ever exceed 3 times ULN during treatment, unless there is another explanation for liver injury and that injury has resolved. In patients with stable, low baseline ALT and AST, an increase above 2 times baseline, even if less than 2 times ULN, may indicate early liver injury. Suspension of treatment may be warranted; obtain repeat tests within 48 to 72 hours prior to reinitiating therapy and monitor more frequently.

    Renal Impairment

    CrCl 10 to 79 mL/minute: No dosage adjustment needed.
    CrCl less than 10 mL/minute and patients requiring hemodialysis: No information is available; tolvaptan is contraindicated in anuric patients.

    ADMINISTRATION

    For storage information, see specific product information within the How Supplied section.

    Oral Administration

    May administer with or without food.
     
    Samsca (for hyponatremia)
    Only initiate and reinitiate treatment in a hospital where serum sodium concentrations and volume status can be closely monitored.
    Avoid fluid restriction during the first 24 hours of therapy. Advise patients to drink fluid in response to thirst.
    Monitor for neurologic changes associated with rapid correction of serum sodium concentrations (more than 12 mEq/L over 24 hours).
    Limit duration to 30 days due to the risk of hepatic injury.
     
    Jynarque (for autosomal dominant polycystic kidney disease)
    Encourage patients to drink enough water to avoid thirst and dehydration.

    STORAGE

    JYNARQUE:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Samsca:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Tolvaptan is contraindicated in patients who have experienced hypersensitivity (e.g., generalized rash, anaphylactic shock) to tolvaptan or any component of the product.
     
    Concomitant use of Samsca and hypertonic saline is not recommended.

    Dehydration, hypernatremia, hyponatremia, hypovolemia

    Jynarque is contraindicated in patients with uncorrected hyponatremia or hypernatremia (i.e., abnormal blood sodium concentrations). Tolvaptan is contraindicated in patients with hypovolemia (including hypovolemic hyponatremia). The risks of developing hypotension and renal failure from worsening hypovolemia outweigh the possible benefits of therapy with tolvaptan. Dehydration or hypovolemia may occur during the course of tolvaptan therapy, particularly in patients who are fluid-restricted or those who are volume-depleted and receiving diuretics. Fluid restriction should be avoided during the first 24 hours of hyponatremia treatment. Tolvaptan is contraindicated in patients unable to sense or respond to thirst; such patients are at increased risk of incurring an overly rapid correction of serum sodium, hypernatremia, and hypovolemia. Encourage patients to drink enough water to avoid thirst and dehydration. Monitor for weight loss, tachycardia, and hypotension. If clinically significant dehydration or hypovolemia occurs, discontinue or interrupt tolvaptan therapy and provide supportive care with careful management of vital signs and fluid and electrolyte balance.

    Alcoholism, malnutrition, requires a specialized care setting

    The initiation and reinitiation of tolvaptan for hyponatremia requires a specialized care setting where serum sodium concentrations and neurological status can be closely monitored during therapy. Consider slower rates of serum sodium correction 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, very low baseline serum sodium concentrations (hyponatremia), or those receiving a diuretic concomitantly. Discontinue or interrupt tolvaptan if the patient develops too rapid a rise in serum sodium concentrations, and consider the administration of hypotonic fluid. Avoid fluid restriction during the first 24 hours of tolvaptan therapy as this may increase the possibility of rapid correction of serum sodium.

    Autosomal dominant polycystic kidney disease, hepatic disease, hepatotoxicity

    Samsca is contraindicated for use for the treatment of autosomal dominant polycystic kidney disease (ADPKD); only Jynarque should be prescribed for ADPKD. Tolvaptan can cause serious and potentially fatal liver injury. Jynarque is contraindicated for use in patients with a history of hepatic disease or in patients with signs or symptoms of significant liver impairment (hepatotoxicity), not including uncomplicated polycystic liver disease. Samsca should be avoided in patients with underlying hepatic disease. Acute liver failure requiring liver transplantation has been reported with the postmarketing use of tolvaptan for ADPKD. Discontinuing therapy in response to laboratory abnormalities or signs or symptoms of liver injury can reduce the risk of severe hepatotoxicity. Measure transaminases and bilirubin before ADPKD treatment, at 2 weeks and 4 weeks after initiation, monthly for the first 18 months, and then every 3 months thereafter. In patients receiving tolvaptan for hyponatremia, a slower rate of serum sodium correction should be considered in patients with advanced hepatic disease, as these patients are more susceptible to the serious neurological sequelae (e.g., osmotic demyelination syndrome) that is possible when too rapid a rise in serum sodium concentrations occurs.

    Anuria, prostatic hypertrophy, urinary tract obstruction

    Tolvaptan is contraindicated in patients with anuria since no clinical benefit is expected in patients unable to make urine. Due to the increased risk of acute urinary retention, Jynarque is contraindicated in patients with uncorrected urinary tract obstruction. Also do not administer Samsca in patients with uncorrected urinary outflow obstruction, and avoid Samsca in patients with partial obstruction of urinary outflow, such as patients with prostatic hypertrophy or micturition impairment.

    Hyperkalemia

    Use tolvaptan with caution in patients with hyperkalemia who are being treated for hyponatremia. Treatment of hyponatremia with tolvaptan is associated with an acute reduction of the extracellular fluid volume that could result in increased serum potassium. Monitor serum potassium concentrations after initiation of tolvaptan treatment in patients with a serum potassium more than 5 mEq/L as well as those who are receiving drugs known to increase serum potassium concentrations.

    Geriatric

    Reported clinical experience has not identified differences in safety or efficacy between geriatric patients and the general study population; however, greater sensitivity of some elderly persons to tolvaptan therapy cannot be ruled out. In general, dose selection for an elderly patient should be cautious, starting at the low end of the dosing range.

    Pregnancy

    There are insufficient data on the use of tolvaptan in pregnant women to determine if there is a drug associated risk of adverse developmental outcomes during pregnancy. Tolvaptan has been shown to have adverse effects on the fetus when given to pregnant animals at maternally toxic doses. At 17-times the human exposure, reduced fetal weights and delayed fetal ossification in rats were observed. In rabbits, increased abortions, embryo-fetal death, cleft palate, open eyelids, brachymelia, microphthalmia, and skeletal malformations were observed at 3-times the human exposure. Advise pregnant women of the potential risk to the fetus.

    Breast-feeding

    There are no data on the presence of tolvaptan in human milk, the effects on the breast-feeding infant, or the effects on milk production. Due to the potential for serious adverse reactions, including liver toxicity, electrolyte abnormalities, hypotension, and volume depletion in breast-fed infants, breast-feeding is not advised during treatment with tolvaptan.

    ADVERSE REACTIONS

    Severe

    diabetic ketoacidosis / Delayed / 0-2.0
    thrombosis / Delayed / 0-2.0
    stroke / Early / 0-2.0
    ventricular fibrillation / Early / 0-2.0
    pulmonary embolism / Delayed / 0-2.0
    rhabdomyolysis / Delayed / 0-2.0
    disseminated intravascular coagulation (DIC) / Delayed / 0-2.0
    hyperkalemia / Delayed / Incidence not known
    GI bleeding / Delayed / Incidence not known
    osmotic demyelination syndrome / Early / Incidence not known
    hepatic failure / Delayed / Incidence not known
    hepatotoxicity / Delayed / Incidence not known
    anaphylactic shock / Rapid / Incidence not known

    Moderate

    constipation / Delayed / 7.0-7.0
    hyperglycemia / Delayed / 6.0-6.0
    elevated hepatic enzymes / Delayed / 0-4.9
    hypernatremia / Delayed / 0.7-4.0
    hyperuricemia / Delayed / 3.9-3.9
    palpitations / Early / 3.5-3.5
    dehydration / Delayed / 2.1-3.3
    hypovolemia / Early / 2.1-2.3
    colitis / Delayed / 0-2.0
    prolonged bleeding time / Delayed / 0-2.0
    vaginal bleeding / Delayed / 0-2.0
    bleeding / Early / 0-2.0
    respiratory depression / Rapid / 0-2.0
    hyperbilirubinemia / Delayed / Incidence not known

    Mild

    polyuria / Early / 4.0-69.5
    polydipsia / Early / 12.0-63.7
    xerostomia / Early / 13.0-16.0
    fatigue / Early / 13.6-13.6
    diarrhea / Early / 13.3-13.3
    dizziness / Early / 11.3-11.3
    asthenia / Delayed / 9.0-9.0
    dyspepsia / Early / 7.9-7.9
    anorexia / Delayed / 4.0-7.2
    rash / Early / 4.2-4.2
    fever / Early / 4.0-4.0
    nausea / Early / Incidence not known

    DRUG INTERACTIONS

    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Aliskiren; Valsartan: (Moderate) Monitor serum potassium concentrations closely if tolvaptan and angiotensin II receptor blockers are used together. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with angiotensin II receptor blockers compared to administration of these medications with placebo.
    Amiloride: (Moderate) Monitor serum potassium concentrations closely if tolvaptan and potassium-sparing diuretics are used together. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with potassium-sparing diuretics compared to administration of these medications with placebo.
    Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations closely if tolvaptan and potassium-sparing diuretics are used together. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with potassium-sparing diuretics compared to administration of these medications with placebo. (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Amiodarone: (Major) Avoid coadministration of amiodarone when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with amiodarone. 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 CYP3A4 substrate; amiodarone is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200%.
    Amlodipine; Benazepril: (Moderate) Monitor serum potassium concentrations closely if tolvaptan and angiotensin-converting enzyme inhibitors (ACE inhibitors) are used together. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with ACE inhibitors compared to administration of these medications with placebo.
    Amlodipine; Olmesartan: (Moderate) Monitor serum potassium concentrations closely if tolvaptan and angiotensin II receptor blockers are used together. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with angiotensin II receptor blockers compared to administration of these medications with placebo.
    Amlodipine; Valsartan: (Moderate) Monitor serum potassium concentrations closely if tolvaptan and angiotensin II receptor blockers are used together. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with angiotensin II receptor blockers compared to administration of these medications with placebo.
    Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations closely if tolvaptan and angiotensin II receptor blockers are used together. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with angiotensin II receptor blockers compared to administration of these medications with placebo. (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Amoxicillin; Clarithromycin; Omeprazole: (Contraindicated) The concomitant use of tolvaptan and clarithromycin is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; clarithromycin is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Amprenavir: (Major) Tolvaptan is metabolized by CYP3A4. Amprenavir is a moderate inhibitor of CYP3A4. Coadministration of CYP3A4 inhibitors with tolvaptan may cause a marked increased in tolvaptan concentrations. Concomitant use of tolvaptan with moderate CYP3A4 inhibitors, such as amprenavir, should be avoided.
    Angiotensin II receptor antagonists: (Moderate) Monitor serum potassium concentrations closely if tolvaptan and angiotensin II receptor blockers are used together. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with angiotensin II receptor blockers compared to administration of these medications with placebo.
    Angiotensin-converting enzyme inhibitors: (Moderate) Monitor serum potassium concentrations closely if tolvaptan and angiotensin-converting enzyme inhibitors (ACE inhibitors) are used together. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with ACE inhibitors compared to administration of these medications with placebo.
    Apalutamide: (Major) Avoid concurrent use of tolvaptan and apalutamide due to the risk for decreased tolvaptan plasma concentrations and reduced efficacy. Tolvaptan is a sensitive CYP3A substrate and apalutamide is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased tolvaptan exposure by 85%.
    Aprepitant, Fosaprepitant: (Major) Avoid coadministration of multi-day regimens of oral aprepitant when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with multi-day regimens of oral aprepitant. 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. Interrupt tolvaptan in ADPKD patients if the recommended reduced doses are not available in patients requiring short-term therapy of aprepitant. Tolvaptan is a sensitive CYP3A4 substrate; aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200%. When administered as a single oral or single intravenous dose, the inhibitory effect of aprepitant on CYP3A4 is weak and did not result in a clinically significant increase in the AUC of a sensitive substrate.
    Argatroban: (Moderate) Coadministration of tolvaptan and hypertonic saline (e.g., 3% NaCl injection solution) is not recommended. The use of hypertonic sodium chloride in combination with tolvaptan may result in a too rapid correction of hyponatremia and increase the risk of osmotic demyelination (i.e., central pontine myelinolysis).
    Atazanavir: (Contraindicated) The concomitant use of tolvaptan and atazanavir is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; atazanavir is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Atazanavir; Cobicistat: (Contraindicated) The concomitant use of tolvaptan and atazanavir is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; atazanavir is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors. (Contraindicated) The concomitant use of tolvaptan and cobicistat is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; cobicistat is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Atenolol; Chlorthalidone: (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Azilsartan: (Moderate) Monitor serum potassium concentrations closely if tolvaptan and angiotensin II receptor blockers are used together. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with angiotensin II receptor blockers compared to administration of these medications with placebo.
    Azilsartan; Chlorthalidone: (Moderate) Monitor serum potassium concentrations closely if tolvaptan and angiotensin II receptor blockers are used together. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with angiotensin II receptor blockers compared to administration of these medications with placebo. (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Avoid concurrent use of tolvaptan and phenobarbital due to the risk for decreased tolvaptan plasma concentrations and reduced efficacy. Tolvaptan is a sensitive CYP3A substrate and phenobarbital is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased tolvaptan exposure by 85%.
    Benazepril: (Moderate) Monitor serum potassium concentrations closely if tolvaptan and angiotensin-converting enzyme inhibitors (ACE inhibitors) are used together. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with ACE inhibitors compared to administration of these medications with placebo.
    Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations closely if tolvaptan and angiotensin-converting enzyme inhibitors (ACE inhibitors) are used together. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with ACE inhibitors compared to administration of these medications with placebo. (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Bendroflumethiazide; Nadolol: (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Berotralstat: (Major) Avoid coadministration of berotralstat when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with berotralstat. 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. Additionally, reduce berotralstat dose to 110 mg/day PO in patients chronically taking tolvaptan; concurrent use may increase berotralstat exposure and risk of adverse effects. Tolvaptan is a sensitive CYP3A4 and P-gp substrate and P-gp inhibitor; berotralstat is a P-gp substrate and P-gp and moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200% and coadministration with another P-gp inhibitor increased berotralstat exposure by 69%.
    Bexarotene: (Major) Tolvaptan is metabolized by CYP3A4. Bexarotene is an inducer of CYP3A4. Coadministration may result in reduced plasma concentration and subsequent reduced effectiveness of tolvaptan therapy and should be avoided. If coadministration is unavoidable, an increase in the tolvaptan dose may be necessary and patients should be monitored for decreased effectiveness of tolvaptan.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Bivalirudin: (Moderate) Coadministration of tolvaptan and hypertonic saline (e.g., 3% NaCl injection solution) is not recommended. The use of hypertonic sodium chloride in combination with tolvaptan may result in a too rapid correction of hyponatremia and increase the risk of osmotic demyelination (i.e., central pontine myelinolysis).
    Boceprevir: (Moderate) Close clinical monitoring is advised when administering tolvaptan with boceprevir due to an increased potential for tolvaptan-related adverse events. If tolvaptan dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of tolvaptan. Tolvaptan is a substrate of the drug efflux transporter P-glycoprotein (PGP) and of the hepatic isoenzyme CYP3A4; boceprevir is an inhibitor of both the efflux protein and the isoenzyme. Coadministration may result in elevated tolvaptan plasma concentrations.
    Bumetanide: (Moderate) Monitor serum sodium closely if tolvaptan and bumetanide are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Candesartan: (Moderate) Monitor serum potassium concentrations closely if tolvaptan and angiotensin II receptor blockers are used together. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with angiotensin II receptor blockers compared to administration of these medications with placebo.
    Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations closely if tolvaptan and angiotensin II receptor blockers are used together. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with angiotensin II receptor blockers compared to administration of these medications with placebo. (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Captopril: (Moderate) Monitor serum potassium concentrations closely if tolvaptan and angiotensin-converting enzyme inhibitors (ACE inhibitors) are used together. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with ACE inhibitors compared to administration of these medications with placebo.
    Captopril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations closely if tolvaptan and angiotensin-converting enzyme inhibitors (ACE inhibitors) are used together. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with ACE inhibitors compared to administration of these medications with placebo. (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Carbamazepine: (Major) Avoid concurrent use of tolvaptan and carbamazepine due to the risk for decreased tolvaptan plasma concentrations and reduced efficacy. Tolvaptan is a sensitive CYP3A substrate and carbamazepine is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased tolvaptan exposure by 85%.
    Ceritinib: (Contraindicated) The concomitant use of tolvaptan and ceritinib is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; ceritinib is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Chloramphenicol: (Contraindicated) The concomitant use of tolvaptan and chloramphenicol is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; chloramphenicol is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Chlorothiazide: (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Chlorthalidone: (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Chlorthalidone; Clonidine: (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Cimetidine: (Moderate) Coadministration of tolvaptan and hypertonic saline (e.g., 3% NaCl injection solution) is not recommended. The use of hypertonic sodium chloride in combination with tolvaptan may result in a too rapid correction of hyponatremia and increase the risk of osmotic demyelination (i.e., central pontine myelinolysis).
    Ciprofloxacin: (Major) Avoid coadministration of ciprofloxacin when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with ciprofloxacin. 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. Interrupt tolvaptan in ADPKD patients if the recommended reduced doses are not available in patients requiring short-term therapy of ciprofloxacin. Tolvaptan is a sensitive CYP3A4 substrate; ciprofloxacin is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200%.
    Clarithromycin: (Contraindicated) The concomitant use of tolvaptan and clarithromycin is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; clarithromycin is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Clindamycin: (Moderate) Coadministration of tolvaptan and hypertonic saline (e.g., 3% NaCl injection solution) is not recommended. The use of hypertonic sodium chloride in combination with tolvaptan may result in a too rapid correction of hyponatremia and increase the risk of osmotic demyelination (i.e., central pontine myelinolysis).
    Cobicistat: (Contraindicated) The concomitant use of tolvaptan and cobicistat is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; cobicistat is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Conivaptan: (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%.
    Crizotinib: (Major) Avoid coadministration of crizotinib when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with crizotinib. 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 CYP3A4 substrate; crizotinib is a moderate CYP3A inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200%.
    Cyclosporine: (Major) Avoid coadministration of cyclosporine when tolvaptan is administered for hyponatremia; a reduction in the tolvaptan dose according to clinical response may be required if coadministration cannot be avoided. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with cyclosporine. 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 CYP3A4 substrate and a P-glycoprotein (P-gp) substrate; cyclosporine is a moderate CYP3A4 inhibitor and a P-gp inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200%.
    Danazol: (Major) Avoid coadministration of danazol when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with danazol. 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 CYP3A4 substrate; danazol is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200%.
    Darunavir: (Contraindicated) The concomitant use of tolvaptan and darunavir is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; darunavir is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Darunavir; Cobicistat: (Contraindicated) The concomitant use of tolvaptan and cobicistat is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; cobicistat is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors. (Contraindicated) The concomitant use of tolvaptan and darunavir is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; darunavir is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Contraindicated) The concomitant use of tolvaptan and cobicistat is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; cobicistat is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors. (Contraindicated) The concomitant use of tolvaptan and darunavir is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; darunavir is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Contraindicated) The concomitant use of tolvaptan and ritonavir is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; ritonavir is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Delavirdine: (Contraindicated) The concomitant use of tolvaptan and delavirdine is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; delavirdine is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Desmopressin: (Major) Coadministration of tolvaptan and desmopressin (DDAVP) is not recommended. Tolvaptan is a V2 receptor antagonist and may interfere with the V2 agonist activity of DDAVP. In a male subject with mild Von Willebrand (vW) disease, intravenous infusion of DDAVP 2 hours after administration of oral tolvaptan did not produce the expected increases in vW Factor Antigen or Factor VIII activity.
    Dextran: (Moderate) Coadministration of tolvaptan and hypertonic saline (e.g., 3% NaCl injection solution) is not recommended. The use of hypertonic sodium chloride in combination with tolvaptan may result in a too rapid correction of hyponatremia and increase the risk of osmotic demyelination (i.e., central pontine myelinolysis).
    Digoxin: (Moderate) Monitor serum digoxin concentrations and watch for potential signs and symptoms of clinical toxicity when starting, adjusting, or discontinuing tolvaptan. Concurrent use may increase digoxin exposure. Digoxin is a P-glycoprotein (P-gp) substrate with a narrow therapeutic index and tolvaptan is a P-gp inhibitor. Coadministration of digoxin and tolvaptan increased digoxin peaks by 30% and overall exposure by 20%.
    Diltiazem: (Major) Avoid coadministration of diltiazem when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with diltiazem. 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 CYP3A4 substrate; diltiazem is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200%.
    Dronedarone: (Major) Avoid coadministration of dronedarone when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with dronedarone. 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 CYP3A4 substrate; dronedarone is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200%.
    Duvelisib: (Major) Avoid coadministration of duvelisib when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with duvelisib. In ADPKD patients receiving tolvaptan 90 mg 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; duvelisib is a moderate CYP3A inhibitor. Coadministration of another moderate CYP3A inhibitor increased the tolvaptan AUC by 200%.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Contraindicated) The concomitant use of tolvaptan and cobicistat is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; cobicistat is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Contraindicated) The concomitant use of tolvaptan and cobicistat is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; cobicistat is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Enalapril, Enalaprilat: (Moderate) Monitor serum potassium concentrations closely if tolvaptan and angiotensin-converting enzyme inhibitors (ACE inhibitors) are used together. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with ACE inhibitors compared to administration of these medications with placebo.
    Enalapril; Felodipine: (Moderate) Monitor serum potassium concentrations closely if tolvaptan and angiotensin-converting enzyme inhibitors (ACE inhibitors) are used together. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with ACE inhibitors compared to administration of these medications with placebo.
    Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations closely if tolvaptan and angiotensin-converting enzyme inhibitors (ACE inhibitors) are used together. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with ACE inhibitors compared to administration of these medications with placebo. (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Enzalutamide: (Major) Avoid concurrent use of tolvaptan and enzalutamide due to the risk for decreased tolvaptan plasma concentrations and reduced efficacy. Tolvaptan is a sensitive CYP3A substrate and enzalutamide is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased tolvaptan exposure by 85%.
    Eprosartan: (Moderate) Monitor serum potassium concentrations closely if tolvaptan and angiotensin II receptor blockers are used together. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with angiotensin II receptor blockers compared to administration of these medications with placebo.
    Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations closely if tolvaptan and angiotensin II receptor blockers are used together. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with angiotensin II receptor blockers compared to administration of these medications with placebo. (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Erythromycin: (Major) Avoid coadministration of erythromycin when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with erythromycin. 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. Interrupt tolvaptan in ADPKD patients if the recommended reduced doses are not available in patients requiring short-term therapy of erythromycin. Tolvaptan is a sensitive CYP3A4 substrate; erythromycin is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200%.
    Erythromycin; Sulfisoxazole: (Major) Avoid coadministration of erythromycin when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with erythromycin. 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. Interrupt tolvaptan in ADPKD patients if the recommended reduced doses are not available in patients requiring short-term therapy of erythromycin. Tolvaptan is a sensitive CYP3A4 substrate; erythromycin is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200%.
    Ethacrynic Acid: (Moderate) Monitor serum sodium closely if ethacrynic acid and tolvaptan are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Everolimus: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with tolvaptan is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-glycoprotein (P-gp) substrate and tolvaptan is a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
    Fedratinib: (Major) Avoid coadministration of fedratinib when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with fedratinib. 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 CYP3A4 substrate; fedratinib is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200%.
    Finerenone: (Moderate) Monitor serum potassium concentrations closely if finerenone and tolvaptan are used together. Concomitant use may increase the risk of hyperkalemia. The risk for hyperkalemia may be greatest during and immediately following tolvaptan's peak aquaretic effect as a result of an acute reduction in extracellular fluid volume.
    Fluconazole: (Major) Avoid coadministration of fluconazole when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with fluconazole. 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. Interrupt tolvaptan in ADPKD patients if the recommended reduced doses are not available in patients requiring short-term therapy of fluconazole. Tolvaptan is a sensitive CYP3A4 substrate; fluconazole is a moderate CYP3A4 inhibitor. In a drug interaction study, coadministration of fluconazole increased the tolvaptan AUC by 200%. (Moderate) Coadministration of tolvaptan and hypertonic saline (e.g., 3% NaCl injection solution) is not recommended. The use of hypertonic sodium chloride in combination with tolvaptan may result in a too rapid correction of hyponatremia and increase the risk of osmotic demyelination (i.e., central pontine myelinolysis).
    Flutamide: (Major) Tolvaptan is metabolized by CYP3A4. Flutamide is an inducer of CYP3A4. Coadministration may result in reduced plasma concentration and subsequent reduced effectiveness of tolvaptan therapy and should be avoided. If coadministration is unavoidable, an increase in the tolvaptan dose may be necessary and patients should be monitored for decreased effectiveness of tolvaptan.
    Fluvoxamine: (Major) Avoid coadministration of fluvoxamine when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with fluvoxamine. 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 CYP3A4 substrate; fluvoxamine is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200%.
    Fosamprenavir: (Contraindicated) The concomitant use of tolvaptan and fosamprenavir is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a P-glycoprotein (P-gp) substrate and sensitive CYP3A4 substrate; fosamprenavir is a strong inhibitor of CYP3A4. Some data suggest that amprenavir, the active metabolite of fosamprenavir, can induce CYP3A4 and P-gp, therefore, the interaction with tolvaptan may be unpredictable. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Fosinopril: (Moderate) Monitor serum potassium concentrations closely if tolvaptan and angiotensin-converting enzyme inhibitors (ACE inhibitors) are used together. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with ACE inhibitors compared to administration of these medications with placebo.
    Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations closely if tolvaptan and angiotensin-converting enzyme inhibitors (ACE inhibitors) are used together. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with ACE inhibitors compared to administration of these medications with placebo. (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Fosphenytoin: (Major) Avoid concurrent use of tolvaptan and fosphenytoin due to the risk for decreased tolvaptan plasma concentrations and reduced efficacy. Tolvaptan is a sensitive CYP3A substrate and fosphenytoin is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased tolvaptan exposure by 85%.
    Furosemide: (Moderate) Monitor serum sodium closely if tolvaptan and furosemide are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Gemcitabine: (Moderate) Coadministration of tolvaptan and hypertonic saline (e.g., 3% NaCl injection solution) is not recommended. The use of hypertonic sodium chloride in combination with tolvaptan may result in a too rapid correction of hyponatremia and increase the risk of osmotic demyelination (i.e., central pontine myelinolysis).
    Gentamicin: (Moderate) Coadministration of tolvaptan and hypertonic saline (e.g., 3% NaCl injection solution) is not recommended. The use of hypertonic sodium chloride in combination with tolvaptan may result in a too rapid correction of hyponatremia and increase the risk of osmotic demyelination (i.e., central pontine myelinolysis).
    Grapefruit juice: (Major) Advise patients to avoid grapefruit juice while taking tolvaptan. Coadministration of grapefruit juice and tolvaptan has increased tolvaptan exposure by up to 1.8-fold.
    Heparin: (Moderate) Coadministration of tolvaptan and hypertonic saline (e.g., 3% NaCl injection solution) is not recommended. The use of hypertonic sodium chloride in combination with tolvaptan may result in a too rapid correction of hyponatremia and increase the risk of osmotic demyelination (i.e., central pontine myelinolysis).
    Hetastarch: (Moderate) Coadministration of tolvaptan and hypertonic saline (e.g., 3% NaCl injection solution) is not recommended. The use of hypertonic sodium chloride in combination with tolvaptan may result in a too rapid correction of hyponatremia and increase the risk of osmotic demyelination (i.e., central pontine myelinolysis).
    Hydralazine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Hydrochlorothiazide, HCTZ; Methyldopa: (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) Monitor serum potassium concentrations closely if tolvaptan and angiotensin-converting enzyme inhibitors (ACE inhibitors) are used together. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with ACE inhibitors compared to administration of these medications with placebo. (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Ibritumomab Tiuxetan: (Moderate) Coadministration of tolvaptan and hypertonic saline (e.g., 3% NaCl injection solution) is not recommended. The use of hypertonic sodium chloride in combination with tolvaptan may result in a too rapid correction of hyponatremia and increase the risk of osmotic demyelination (i.e., central pontine myelinolysis).
    Idelalisib: (Contraindicated) The concomitant use of tolvaptan and idelalisib is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; idelalisib is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Imatinib: (Major) Avoid coadministration of imatinib when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with imatinib. 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 CYP3A4 substrate; imatinib is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200%.
    Indinavir: (Contraindicated) The concomitant use of tolvaptan and indinavir is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; indinavir is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Irbesartan: (Moderate) Monitor serum potassium concentrations closely if tolvaptan and angiotensin II receptor blockers are used together. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with angiotensin II receptor blockers compared to administration of these medications with placebo.
    Irbesartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations closely if tolvaptan and angiotensin II receptor blockers are used together. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with angiotensin II receptor blockers compared to administration of these medications with placebo. (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Isavuconazonium: (Major) Avoid coadministration of isavuconazonium when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with isavuconazonium. 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. Interrupt tolvaptan in ADPKD patients if the recommended reduced doses are not available in patients requiring short-term therapy of isavuconazonium. Tolvaptan is a sensitive CYP3A4 substrate; isavuconazole, the active moiety of isavuconazonium, is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200%.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid concurrent use of tolvaptan and rifampin due to the risk for decreased tolvaptan plasma concentrations and reduced efficacy. Tolvaptan is a sensitive CYP3A substrate and rifampin is a strong CYP3A inducer. Coadministration with rifampin decreased tolvaptan exposure by 85%.
    Isoniazid, INH; Rifampin: (Major) Avoid concurrent use of tolvaptan and rifampin due to the risk for decreased tolvaptan plasma concentrations and reduced efficacy. Tolvaptan is a sensitive CYP3A substrate and rifampin is a strong CYP3A inducer. Coadministration with rifampin decreased tolvaptan exposure by 85%.
    Itraconazole: (Contraindicated) Tolvaptan is contraindicated for use during and for 2 weeks after itraconazole therapy due to increased exposure to tolvaptan. Tolvaptan is a P-glycoprotein (P-gp) substrate and sensitive CYP3A4 substrate; itraconazole is a strong inhibitor of CYP3A4 and a P-gp inhibitor. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Ketoconazole: (Contraindicated) The concomitant use of tolvaptan and ketoconazole is contraindicated due to increased tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; ketoconazole is a strong inhibitor of CYP3A4. In a drug interaction study, coadministration of ketoconazole 200 mg increased tolvaptan exposure 5-fold; larger ketoconazole doses are expected to produce larger increases in tolvaptan exposure. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Labetalol: (Moderate) Coadministration of tolvaptan and hypertonic saline (e.g., 3% NaCl injection solution) is not recommended. The use of hypertonic sodium chloride in combination with tolvaptan may result in a too rapid correction of hyponatremia and increase the risk of osmotic demyelination (i.e., central pontine myelinolysis).
    Lansoprazole; Amoxicillin; Clarithromycin: (Contraindicated) The concomitant use of tolvaptan and clarithromycin is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; clarithromycin is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Lefamulin: (Major) Avoid coadministration of oral lefamulin when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with oral lefamulin. 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 CYP3A4 substrate; oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200%.
    Letermovir: (Major) Concurrent use is contraindicated if the patient is also receiving cyclosporine, because the magnitude of the interaction may be increased. Otherwise, avoid coadministration of letermovir when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with letermovir. 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 CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200%.
    Levetiracetam: (Moderate) Coadministration of tolvaptan and hypertonic saline (e.g., 3% NaCl injection solution) is not recommended. The use of hypertonic sodium chloride in combination with tolvaptan may result in a too rapid correction of hyponatremia and increase the risk of osmotic demyelination (i.e., central pontine myelinolysis).
    Lisinopril: (Moderate) Monitor serum potassium concentrations closely if tolvaptan and angiotensin-converting enzyme inhibitors (ACE inhibitors) are used together. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with ACE inhibitors compared to administration of these medications with placebo.
    Lisinopril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations closely if tolvaptan and angiotensin-converting enzyme inhibitors (ACE inhibitors) are used together. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with ACE inhibitors compared to administration of these medications with placebo. (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Lonafarnib: (Contraindicated) The concomitant use of tolvaptan and lonafarnib is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 and P-gp substrate; lonafarnib is a P-gp and strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Lopinavir; Ritonavir: (Contraindicated) The concomitant use of tolvaptan and ritonavir is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; ritonavir is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Losartan: (Moderate) Monitor serum potassium concentrations closely if tolvaptan and angiotensin II receptor blockers are used together. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with angiotensin II receptor blockers compared to administration of these medications with placebo.
    Losartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations closely if tolvaptan and angiotensin II receptor blockers are used together. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with angiotensin II receptor blockers compared to administration of these medications with placebo. (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Lumacaftor; Ivacaftor: (Major) Avoid concurrent use of tolvaptan and lumacaftor; ivacaftor due to the risk for decreased tolvaptan plasma concentrations and reduced efficacy. Tolvaptan is a sensitive CYP3A substrate and lumacaftor; ivacaftor is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased tolvaptan exposure by 85%.
    Methotrexate: (Major) Avoid concomitant use of methotrexate with tolvaptan due to the increased risk of severe methotrexate-related adverse reactions; additive hepatotoxicity may also occur. If concomitant use is unavoidable, closely monitor for adverse reactions. Tolvaptan and methotrexate are both hepatotoxic drugs; concomitant use of methotrexate with hepatotoxic drugs may increase methotrexate plasma concentrations. The potential for increased hepatotoxicity when methotrexate is administered with other hepatotoxic drugs has not been evaluated; however, hepatotoxicity has been reported in such cases.
    Methyclothiazide: (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Metolazone: (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Metoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Midazolam: (Moderate) Coadministration of tolvaptan and hypertonic saline (e.g., 3% NaCl injection solution) is not recommended. The use of hypertonic sodium chloride in combination with tolvaptan may result in a too rapid correction of hyponatremia and increase the risk of osmotic demyelination (i.e., central pontine myelinolysis).
    Mifepristone: (Contraindicated) The concomitant use of tolvaptan and chronic mifepristone therapy is contraindicated. Concurrent use is expected to increase tolvaptan exposure. The clinical significance of this interaction with the short-term use of mifepristone for termination of pregnancy is unknown. Tolvaptan is a sensitive CYP3A4 substrate; mifepristone is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Mitotane: (Major) Avoid concurrent use of tolvaptan and mitotane due to the risk for decreased tolvaptan plasma concentrations and reduced efficacy. Tolvaptan is a sensitive CYP3A substrate and mitotane is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased tolvaptan exposure by 85%.
    Modafinil: (Major) Tolvaptan is metabolized by CYP3A4. Modafinil is an inducer of CYP3A4. Coadministration may result in reduced plasma concentration and subsequent reduced effectiveness of tolvaptan therapy and should be avoided. If coadministration is unavoidable, an increase in the tolvaptan dose may be necessary and patients should be monitored for decreased effectiveness of tolvaptan.
    Moexipril: (Moderate) Monitor serum potassium concentrations closely if tolvaptan and angiotensin-converting enzyme inhibitors (ACE inhibitors) are used together. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with ACE inhibitors compared to administration of these medications with placebo.
    Moxifloxacin: (Moderate) Coadministration of tolvaptan and hypertonic saline (e.g., 3% NaCl injection solution) is not recommended. The use of hypertonic sodium chloride in combination with tolvaptan may result in a too rapid correction of hyponatremia and increase the risk of osmotic demyelination (i.e., central pontine myelinolysis).
    Nebivolol; Valsartan: (Moderate) Monitor serum potassium concentrations closely if tolvaptan and angiotensin II receptor blockers are used together. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with angiotensin II receptor blockers compared to administration of these medications with placebo.
    Nefazodone: (Contraindicated) The concomitant use of tolvaptan and nefazodone is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; nefazodone is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Nelfinavir: (Contraindicated) The concomitant use of tolvaptan and nelfinavir is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; nelfinavir is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Netupitant, Fosnetupitant; Palonosetron: (Major) Avoid coadministration of netupitant when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with netupitant. 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. Interrupt tolvaptan in ADPKD patients if the recommended reduced doses are not available in patients requiring short-term therapy of netupitant. Tolvaptan is a sensitive CYP3A4 substrate; netupitant is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200%.
    Nicardipine: (Moderate) Coadministration of tolvaptan and hypertonic saline (e.g., 3% NaCl injection solution) is not recommended. The use of hypertonic sodium chloride in combination with tolvaptan may result in a too rapid correction of hyponatremia and increase the risk of osmotic demyelination (i.e., central pontine myelinolysis).
    Nilotinib: (Major) Avoid coadministration of nilotinib when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with nilotinib. 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 CYP3A4 substrate; nilotinib is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200%.
    Olmesartan: (Moderate) Monitor serum potassium concentrations closely if tolvaptan and angiotensin II receptor blockers are used together. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with angiotensin II receptor blockers compared to administration of these medications with placebo.
    Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations closely if tolvaptan and angiotensin II receptor blockers are used together. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with angiotensin II receptor blockers compared to administration of these medications with placebo. (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Olmesartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations closely if tolvaptan and angiotensin II receptor blockers are used together. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with angiotensin II receptor blockers compared to administration of these medications with placebo. (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Ombitasvir; Paritaprevir; Ritonavir: (Contraindicated) The concomitant use of tolvaptan and ritonavir is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; ritonavir is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Ondansetron: (Moderate) Coadministration of tolvaptan and hypertonic saline (e.g., 3% NaCl injection solution) is not recommended. The use of hypertonic sodium chloride in combination with tolvaptan may result in a too rapid correction of hyponatremia and increase the risk of osmotic demyelination (i.e., central pontine myelinolysis).
    Perindopril: (Moderate) Monitor serum potassium concentrations closely if tolvaptan and angiotensin-converting enzyme inhibitors (ACE inhibitors) are used together. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with ACE inhibitors compared to administration of these medications with placebo.
    Perindopril; Amlodipine: (Moderate) Monitor serum potassium concentrations closely if tolvaptan and angiotensin-converting enzyme inhibitors (ACE inhibitors) are used together. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with ACE inhibitors compared to administration of these medications with placebo.
    Phenobarbital: (Major) Avoid concurrent use of tolvaptan and phenobarbital due to the risk for decreased tolvaptan plasma concentrations and reduced efficacy. Tolvaptan is a sensitive CYP3A substrate and phenobarbital is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased tolvaptan exposure by 85%.
    Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid concurrent use of tolvaptan and phenobarbital due to the risk for decreased tolvaptan plasma concentrations and reduced efficacy. Tolvaptan is a sensitive CYP3A substrate and phenobarbital is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased tolvaptan exposure by 85%.
    Phenytoin: (Major) Avoid concurrent use of tolvaptan and phenytoin due to the risk for decreased tolvaptan plasma concentrations and reduced efficacy. Tolvaptan is a sensitive CYP3A substrate and phenytoin is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased tolvaptan exposure by 85%.
    Posaconazole: (Contraindicated) The concomitant use of tolvaptan and posaconazole is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; posaconazole is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Potassium Chloride: (Moderate) Coadministration of tolvaptan and hypertonic saline (e.g., 3% NaCl injection solution) is not recommended. The use of hypertonic sodium chloride in combination with tolvaptan may result in a too rapid correction of hyponatremia and increase the risk of osmotic demyelination (i.e., central pontine myelinolysis).
    Potassium-sparing diuretics: (Moderate) Monitor serum potassium concentrations closely if tolvaptan and potassium-sparing diuretics are used together. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with potassium-sparing diuretics compared to administration of these medications with placebo.
    Primidone: (Major) Avoid concurrent use of tolvaptan and primidone due to the risk for decreased tolvaptan plasma concentrations and reduced efficacy. Tolvaptan is a sensitive CYP3A substrate and primidone is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased tolvaptan exposure by 85%.
    Propranolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Quinapril: (Moderate) Monitor serum potassium concentrations closely if tolvaptan and angiotensin-converting enzyme inhibitors (ACE inhibitors) are used together. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with ACE inhibitors compared to administration of these medications with placebo.
    Quinapril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations closely if tolvaptan and angiotensin-converting enzyme inhibitors (ACE inhibitors) are used together. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with ACE inhibitors compared to administration of these medications with placebo. (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Quinine: (Major) Avoid coadministration of quinine when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with quinine. 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. Interrupt tolvaptan in ADPKD patients if the recommended reduced doses are not available in patients requiring short-term therapy of quinine. Tolvaptan is a sensitive CYP3A4 substrate; quinine is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200%.
    Ramipril: (Moderate) Monitor serum potassium concentrations closely if tolvaptan and angiotensin-converting enzyme inhibitors (ACE inhibitors) are used together. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with ACE inhibitors compared to administration of these medications with placebo.
    Regular Insulin: (Moderate) Coadministration of tolvaptan and hypertonic saline (e.g., 3% NaCl injection solution) is not recommended. The use of hypertonic sodium chloride in combination with tolvaptan may result in a too rapid correction of hyponatremia and increase the risk of osmotic demyelination (i.e., central pontine myelinolysis).
    Ribociclib: (Contraindicated) The concomitant use of tolvaptan and ribociclib is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; ribociclib is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Ribociclib; Letrozole: (Contraindicated) The concomitant use of tolvaptan and ribociclib is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; ribociclib is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Rifampin: (Major) Avoid concurrent use of tolvaptan and rifampin due to the risk for decreased tolvaptan plasma concentrations and reduced efficacy. Tolvaptan is a sensitive CYP3A substrate and rifampin is a strong CYP3A inducer. Coadministration with rifampin decreased tolvaptan exposure by 85%.
    Rifapentine: (Major) Avoid concurrent use of tolvaptan and rifapentine due to the risk for decreased tolvaptan plasma concentrations and reduced efficacy. Tolvaptan is a sensitive CYP3A substrate and rifapentine is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased tolvaptan exposure by 85%.
    Rimegepant: (Major) Avoid coadministration of rimegepant with tolvaptan; concurrent use may increase rimegepant exposure. Rimegepant is a substrate of P-gp and tolvaptan is a P-gp inhibitor.
    Ritonavir: (Contraindicated) The concomitant use of tolvaptan and ritonavir is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; ritonavir is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Sacubitril; Valsartan: (Moderate) Monitor serum potassium concentrations closely if tolvaptan and angiotensin II receptor blockers are used together. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with angiotensin II receptor blockers compared to administration of these medications with placebo.
    Saquinavir: (Contraindicated) The concomitant use of tolvaptan and saquinavir is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; saquinavir is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Sodium Chloride: (Moderate) Coadministration of tolvaptan and hypertonic saline (e.g., 3% NaCl injection solution) is not recommended. The use of hypertonic sodium chloride in combination with tolvaptan may result in a too rapid correction of hyponatremia and increase the risk of osmotic demyelination (i.e., central pontine myelinolysis).
    Spironolactone: (Moderate) Monitor serum potassium concentrations closely if tolvaptan and potassium-sparing diuretics are used together. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with potassium-sparing diuretics compared to administration of these medications with placebo.
    Spironolactone; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations closely if tolvaptan and potassium-sparing diuretics are used together. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with potassium-sparing diuretics compared to administration of these medications with placebo. (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    St. John's Wort, Hypericum perforatum: (Major) Avoid concurrent use of tolvaptan and St. John's Wort due to the risk for decreased tolvaptan plasma concentrations and reduced efficacy. Tolvaptan is a sensitive CYP3A substrate and St. John's Wort is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased tolvaptan exposure by 85%.
    Telithromycin: (Contraindicated) The concomitant use of tolvaptan and telithromycin is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; telithromycin is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Telmisartan: (Moderate) Monitor serum potassium concentrations closely if tolvaptan and angiotensin II receptor blockers are used together. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with angiotensin II receptor blockers compared to administration of these medications with placebo.
    Telmisartan; Amlodipine: (Moderate) Monitor serum potassium concentrations closely if tolvaptan and angiotensin II receptor blockers are used together. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with angiotensin II receptor blockers compared to administration of these medications with placebo.
    Telmisartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations closely if tolvaptan and angiotensin II receptor blockers are used together. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with angiotensin II receptor blockers compared to administration of these medications with placebo. (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Thiazide diuretics: (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Tipranavir: (Contraindicated) The concomitant use of tolvaptan and tipranavir is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; tipranavir is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Tobramycin: (Moderate) Coadministration of tolvaptan and hypertonic saline (e.g., 3% NaCl injection solution) is not recommended. The use of hypertonic sodium chloride in combination with tolvaptan may result in a too rapid correction of hyponatremia and increase the risk of osmotic demyelination (i.e., central pontine myelinolysis).
    Topotecan: (Major) Avoid coadministration of tolvaptan with oral topotecan due to increased topotecan exposure; tolvaptan may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and tolvaptan is a weak 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.
    Torsemide: (Moderate) Monitor serum sodium closely if torsemide and tolvaptan are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Trandolapril: (Moderate) Monitor serum potassium concentrations closely if tolvaptan and angiotensin-converting enzyme inhibitors (ACE inhibitors) are used together. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with ACE inhibitors compared to administration of these medications with placebo.
    Trandolapril; Verapamil: (Major) Avoid coadministration of verapamil when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with verapamil. 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 CYP3A4 substrate; verapamil is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200%. (Moderate) Monitor serum potassium concentrations closely if tolvaptan and angiotensin-converting enzyme inhibitors (ACE inhibitors) are used together. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with ACE inhibitors compared to administration of these medications with placebo.
    Tranexamic Acid: (Moderate) Coadministration of tolvaptan and hypertonic saline (e.g., 3% NaCl injection solution) is not recommended. The use of hypertonic sodium chloride in combination with tolvaptan may result in a too rapid correction of hyponatremia and increase the risk of osmotic demyelination (i.e., central pontine myelinolysis).
    Triamterene: (Moderate) Monitor serum potassium concentrations closely if tolvaptan and potassium-sparing diuretics are used together. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with potassium-sparing diuretics compared to administration of these medications with placebo.
    Triamterene; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations closely if tolvaptan and potassium-sparing diuretics are used together. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with potassium-sparing diuretics compared to administration of these medications with placebo. (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Tucatinib: (Contraindicated) The concomitant use of tolvaptan and tucatinib is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 and P-glycoprotein (P-gp) substrate; tucatinib is a strong CYP3A4 inhibitor and P-gp inhibitor. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Valsartan: (Moderate) Monitor serum potassium concentrations closely if tolvaptan and angiotensin II receptor blockers are used together. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with angiotensin II receptor blockers compared to administration of these medications with placebo.
    Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations closely if tolvaptan and angiotensin II receptor blockers are used together. In clinical studies, hyperkalemia was reported at a rate 1% to 2% higher when tolvaptan was administered with angiotensin II receptor blockers compared to administration of these medications with placebo. (Moderate) Monitor serum sodium closely if tolvaptan and thiazide diuretics are used together. Coadministration increases the risk of too rapid correction of serum sodium.
    Vancomycin: (Moderate) Coadministration of tolvaptan and hypertonic saline (e.g., 3% NaCl injection solution) is not recommended. The use of hypertonic sodium chloride in combination with tolvaptan may result in a too rapid correction of hyponatremia and increase the risk of osmotic demyelination (i.e., central pontine myelinolysis).
    Verapamil: (Major) Avoid coadministration of verapamil when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with verapamil. 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 CYP3A4 substrate; verapamil is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200%.
    Voriconazole: (Contraindicated) The concomitant use of tolvaptan and voriconazole is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; voriconazole is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.

    PREGNANCY AND LACTATION

    Pregnancy

    There are insufficient data on the use of tolvaptan in pregnant women to determine if there is a drug associated risk of adverse developmental outcomes during pregnancy. Tolvaptan has been shown to have adverse effects on the fetus when given to pregnant animals at maternally toxic doses. At 17-times the human exposure, reduced fetal weights and delayed fetal ossification in rats were observed. In rabbits, increased abortions, embryo-fetal death, cleft palate, open eyelids, brachymelia, microphthalmia, and skeletal malformations were observed at 3-times the human exposure. Advise pregnant women of the potential risk to the fetus.

    There are no data on the presence of tolvaptan in human milk, the effects on the breast-feeding infant, or the effects on milk production. Due to the potential for serious adverse reactions, including liver toxicity, electrolyte abnormalities, hypotension, and volume depletion in breast-fed infants, breast-feeding is not advised during treatment with tolvaptan.

    MECHANISM OF ACTION

    Tolvaptan is a selective vasopressin V2-receptor antagonist with an affinity for the V2-receptor that is 1.8 times that of native arginine vasopressin (AVP). Tolvaptan antagonizes the effect of vasopressin. Decreased binding of vasopressin to the V2-receptor in the kidney lowers adenylate cyclase activity, which results in a decrease in intracellular adenosine 3', 5'-cyclic monophosphate (cAMP) concentrations. Decreased cAMP concentrations prevent aquaporin 2-containing vesicles from fusing with the plasma membrane, which causes an increase in urine water excretion that results in an increase in free water clearance (aquaresis), a decrease in urine osmolality, and a resulting increase in serum sodium concentrations. In autosomal dominant polycystic kidney disease (ADPKD) cyst epithelial cells, tolvaptan inhibits AVP-stimulated cyst growth in vitro and chloride-dependent fluid secretion into cysts. In animal models, decreased cAMP concentrations are associated with decreases in the total kidney volume growth rate and the rate of formation and enlargement of kidney cysts.

    PHARMACOKINETICS

    Tolvaptan is administered orally. Tolvaptan is highly protein bound (99%) to albumin and alpha1-acid glycoprotein; binding is not affected by disease state. Vd is approximately 3 L/kg. The drug is metabolized almost exclusively by CYP3A. Of the 14 metabolites identified in plasma, urine, and feces, all but 1 were also metabolized by CYP3A; none are pharmacologically active. Approximately 40% of a dose is eliminated in the urine (less than 1% as unchanged tolvaptan) and 59% in the feces (19% as unchanged tolvaptan). Estimated half-life of tolvaptan increases from 3 hours (for a single 15 mg oral dose) to approximately 12 hours (for a single dose of 120 mg or more) due to prolonged absorption of tolvaptan at higher doses. Apparent clearance is approximately 4 mL/kg/minute and does not appear to change with increasing dose. Clearance is reduced to about 2 mL/kg/minute in patients with hyponatremia.
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP3A, BCRP, OATP1B1, OAT3, P-gp
    Tolvaptan is metabolized almost exclusively by CYP3A. Tolvaptan is a substrate and inhibitor of P-glycoprotein (P-gp) and an inhibitor of BCRP. The oxobutyric acid metabolite of tolvaptan is an inhibitor of OATP1B1 and OAT3.

    Oral Route

    The absolute bioavailability of tolvaptan is 56% (range: 42% to 80%) after a 30-mg dose; bioavailability decreases with increasing doses. Peak concentrations are observed 2 to 4 hours after administration. AUC increases proportionally with dose; however, after administration of doses of 60 mg or more, Cmax increases less than proportionally with dose. Food does not impact bioavailability. Coadministration with a high-fat meal doubles peak concentrations but has no effect on AUC.
     
    A peak increase in serum sodium and urine excretion of approximately 6 mEq and 9 mL/minute, respectively, is observed 4 to 8 hours after administration. Approximately 60% of the peak serum sodium effect is sustained at 24 hours post-dose, but the urinary excretion rate is no longer elevated at this time. Doses above 60 mg do not further increase aquaresis or serum sodium. When given as the recommended split-dose regimen for polycystic kidney disease, tolvaptan inhibits vasopressin from binding to the V2-receptor in the kidney for the entire day, as demonstrated by increased urine output and decreased urine osmolality. Change in mean daily urine volume was about 4 L for a mean total daily volume of about 7 L in patients with an eGFR more than 60 mL/minute/1.73m2. In patients with an eGFR less than 30 mL/minute/1.73m2, mean change was about 2 L for a total daily urine volume of 5 L.
     
    The pharmacokinetic properties of tolvaptan are stereospecific, with a steady-state ratio of the S(-) to the R(+) enantiomer of about 3. Tolvaptan's accumulation factor is less than 1.2 when administered as multiple once-daily 300 mg doses or as split dose regimens to patients with polycystic kidney disease. The accumulation factor is 1.3 with the once-daily hyponatremia regimen. There is marked intersubject variation in peak and average exposure to tolvaptan with a percent coefficient of variation ranging from 30% to 60%.