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    Penicillinase-Resistant Penicillin Antibiotics

    DEA CLASS

    Rx

    DESCRIPTION

    Oral/parenteral semisynthetic antistaphylococcal penicillin. Resists hydrolysis by penicillinase and active against penicillinase-producing S.aureus. Less risk of interstitial nephritis than with methicillin. Clinical uses of nafcillin include bacteremia, skin and soft-tissue infections, respiratory tract infections, bone and joint infections, and UTIs. Dicloxacillin preferred over nafcillin when oral therapy is desired due to more reliable gastrointestinal absorption.

    HOW SUPPLIED

    Nafcillin Sodium Intramuscular Inj Pwd F/Sol: 1g, 2g, 10g
    Nafcillin Sodium Intravenous Inj Pwd F/Sol: 1g, 2g, 10g
    Nafcillin Sodium Intravenous Inj Sol: 1g, 2g, 50mL, 100mL

    DOSAGE & INDICATIONS

    For the treatment of bacteremia, skin and skin structure infections (e.g., cellulitis), and bone and joint infections (e.g., osteomyelitis, infectious arthritis) caused by penicillinase-producing Staphylococcus sp..
    Intravenous dosage
    Adults

    500 mg IV every 4 hours for mild to moderate infections and 1 g IV every 4 hours for severe infections is the FDA-approved dosage. Alternately, 6 g/day IV divided every 4 hours for moderate infections and 9 to 12 g/day IV divided every 4 hours for severe infections is suggested.

    Infants,† Children†, and Adolescents†

    100 to 200 mg/kg/day IV divided every 4 to 6 hours (Max: 12 g/day).

    Neonates older than 34 weeks gestation and older than 7 days†

    25 mg/kg/dose IV every 6 hours.

    Neonates older than 34 weeks gestation and 0 to 7 days†

    25 mg/kg/dose IV every 8 hours.

    Neonates 34 weeks gestation and younger and older than 7 days†

    25 mg/kg/dose IV every 8 hours.

    Neonates 34 weeks gestation and younger and 0 to 7 days†

    25 mg/kg/dose IV every 12 hours.

    Intramuscular dosage
    Adults

    500 mg IM every 4 hours for mild to moderate infections and 1 g IM every 4 hours for severe infections is the FDA-approved dosage. Alternately, 6 g/day IM divided every 4 hours for moderate infections and 9 to 12 g/day IM divided every 4 hours for severe infections is suggested.

    Infants, Children, and Adolescents

    100 to 200 mg/kg/day IM divided every 4 to 6 hours (Max: 12 g/day) is recommended by the American Academy of Pediatrics (AAP). Alternately, for patients weighing less than 40 kg, the FDA-approved dosage is 25 mg/kg/dose IM every 12 hours. For patients weighing more than 40 kg, the FDA-approved dosage is 500 mg IM every 4 to 6 hours for most infections and up to 1 g IM every 4 hours for severe infections.
     

    Neonates older than 34 weeks gestation and older than 7 days

    25 mg/kg/dose IM every 6 hours is recommended by the American Academy of Pediatrics (AAP). The FDA-approved dosage is 10 mg/kg/dose IM every 12 hours.

    Neonates older than 34 weeks gestation and 0 to 7 days

    25 mg/kg/dose IM every 8 hours is recommended by the American Academy of Pediatrics (AAP). The FDA-approved dosage is 10 mg/kg/dose IM every 12 hours.

    Neonates 34 weeks gestation and younger and older than 7 days

    25 mg/kg/dose IM every 8 hours is recommended by the American Academy of Pediatrics (AAP). The FDA-approved dosage is 10 mg/kg/dose IM every 12 hours.

    Neonates 34 weeks gestation and younger and 0 to 7 days

    25 mg/kg/dose IM every 12 hours is recommended by the American Academy of Pediatrics (AAP). The FDA-approved dosage is 10 mg/kg/dose IM every 12 hours.

    For the treatment of infective endocarditis.
    Intravenous dosage
    Adults

    12 g/day IV divided every 4 to 6 hours is recommended by guidelines. The FDA-approved dosage for severe infections is 1 g IV every 4 hours. Guidelines recommend nafcillin for 6 weeks for uncomplicated left-sided native valve endocarditis (NVE) and for at least 6 weeks for complicated left-sided NVE due to methicillin-susceptible S. aureus. For MSSA prosthetic valve endocarditis (PVE), treat with nafcillin plus rifampin for at least 6 weeks; add gentamicin for the first 2 weeks.

    Children† and Adolescents†

    200 mg/kg/day IV divided every 4 to 6 hours (Max: 12 g/day) is recommended by guidelines. Nafcillin is an alternative therapy for penicillin-susceptible staphylococcal native valve endocarditis (NVE). Nafcillin is a preferred therapy for penicillin-resistant, methicillin-sensitive S. aureus (MSSA) NVE; may consider adding gentamicin for the first 3 to 5 days. Treat NVE for at least 4 to 6 weeks. For MSSA prosthetic valve endocarditis (PVE), treat with nafcillin plus rifampin for 6 weeks; add gentamicin for the first 2 weeks.

    Infants†

    100 to 200 mg/kg/day IV divided every 4 to 6 hours.

    Neonates older than 34 weeks gestation and older than 7 days†

    25 mg/kg/dose IV every 6 hours.

    Neonates older than 34 weeks gestation and 0 to 7 days†

    25 mg/kg/dose IV every 8 hours.

    Neonates 34 weeks gestation and younger and older than 7 days†

    25 mg/kg/dose IV every 8 hours.

    Neonates 34 weeks gestation and younger and 0 to 7 days†

    25 mg/kg/dose IV every 12 hours.

    For the treatment of bacterial meningitis.
    Intravenous dosage
    Adults

    2 g IV every 4 hours is recommended by clinical practice guidelines for methicillin-sensitive S. aureus meningitis. The FDA-approved dosage for severe infections is 1 g IV every 4 hours.

    Infants†, Children†, and Adolescents†

    200 mg/kg/day IV divided every 6 hours (Max: 12 g/day) is recommended for methicillin-sensitive S. aureus meningitis by clinical practice guidelines.

    Neonates older than 7 days weighing more than 2 kg†

    50 mg/kg/dose IV every 6 hours. Alternately, clinical practice guidelines recommend 100 to 150 mg/kg/day IV divided every 6 to 8 hours for methicillin-sensitive S. aureus meningitis.

    Neonates older than 7 days weighing 2 kg or less†

    50 mg/kg/dose IV every 8 hours.

    Neonates 0 to 7 days weighing more than 2 kg†

    50 mg/kg/dose IV every 8 hours. Alternately, clinical practice guidelines recommend 75 mg/kg/day IV divided every 8 to 12 hours for methicillin-sensitive S. aureus meningitis.

    Neonates 0 to 7 days weighing 2 kg or less†

    50 mg/kg/dose IV every 12 hours.

    For the treatment of lower respiratory tract infections (LRTIs), including community-acquired pneumonia (CAP).
    For the treatment of nonspecific lower respiratory tract infections (LRTIs).
    Intravenous dosage
    Adults

    500 mg IV every 4 hours for mild to moderate infections and 1 g IV every 4 hours for severe infections is the FDA-approved dose. Alternately, 6 g/day IV divided every 4 hours for moderate infections and 9 to 12 g/day IV divided every 4 hours for severe infections is suggested.

    Infants†, Children†, and Adolescents†

    150 to 200 mg/kg/day IV divided every 4 to 6 hours (Max: 2 g/dose).

    Neonates older than 34 weeks gestation and older than 7 days†

    25 mg/kg/dose IV every 6 hours.

    Neonates older than 34 weeks gestation and 0 to 7 days†

    25 mg/kg/dose IV every 8 hours.

    Neonates 34 weeks gestation and younger and older than 7 days†

    25 mg/kg/dose IV every 8 hours.

    Neonates 34 weeks gestation and younger and 0 to 7 days†

    25 mg/kg/dose IV every 12 hours.

    Intramuscular dosage
    Adults

    500 mg IM every 4 hours for mild to moderate infections and 1 g IM every 4 hours for severe infections is the FDA-approved dose.[53199] Alternately, 6 g/day IM divided every 4 hours for moderate infections and 9 to 12 g/day IM divided every 4 hours for severe infections is suggested.[49841] [60641] [60642]

    Children and Adolescents weighing 40 kg or more

    150 to 200 mg/kg/day IM divided every 4 to 6 hours (Max: 2 g/dose) is recommended by the American Academy of Pediatrics (AAP).[63245] The FDA-approved dose is 500 mg IM every 4 to 6 hours for mild to moderate infections and 1 g IM every 4 hours for severe infections.

    Infants, Children, and Adolescents weighing less than 40 kg

    150 to 200 mg/kg/day IM divided every 4 to 6 hours (Max: 2 g/dose) is recommended by the American Academy of Pediatrics (AAP).[63245] The FDA-approved dose is 25 mg/kg/dose IM every 12 hours.[53199]

    Neonates older than 34 weeks gestation and older than 7 days

    25 mg/kg/dose IM every 6 hours is recommended by the American Academy of Pediatrics (AAP). The FDA-approved dose is 10 mg/kg/dose IM every 12 hours.

    Neonates older than 34 weeks gestation and 0 to 7 days

    25 mg/kg/dose IM every 8 hours is recommended by the American Academy of Pediatrics (AAP). The FDA-approved dose is 10 mg/kg/dose IM every 12 hours.

    Neonates 34 weeks gestation and younger and older than 7 days

    25 mg/kg/dose IM every 8 hours is recommended by the American Academy of Pediatrics (AAP). The FDA-approved dose is 10 mg/kg/dose IM every 12 hours.

    Neonates 34 weeks gestation and younger and 0 to 7 days

    25 mg/kg/dose IM every 12 hours is recommended by the American Academy of Pediatrics (AAP). The FDA-approved dose is 10 mg/kg/dose IM every 12 hours.

    For the treatment of community-acquired pneumonia (CAP).
    Intravenous dosage†
    Infants 4 to 11 months, Children, and Adolescents

    150 to 200 mg/kg/day IV divided every 4 to 8 hours (Max: 2 g/dose) for 10 days.[46963] [63245] Guidelines recommend a semisynthetic penicillin for hospitalized patients with infections due to methicillin-susceptible S. aureus.[46963]

    Intramuscular dosage
    Infants 4 to 11 months, Children, and Adolescents

    150 to 200 mg/kg/day IM divided every 4 to 8 hours (Max: 2 g/dose) for 10 days.[46963] [63245] Guidelines recommend a semisynthetic penicillin for hospitalized patients with infections due to methicillin-susceptible S. aureus.[46963]

    For the treatment of mastitis.
    Intravenous dosage
    Adults

    1 to 2 g IV every 4 hours for 10 to 14 days.

    For the treatment of neonatal mastitis†.
    Intravenous dosage
    Infants 1 to 2 months

    100 to 200 mg/kg/day IV divided every 4 to 6 hours.

    Neonates older than 34 weeks gestation and older than 7 days

    25 mg/kg/dose IV every 6 hours. 

    64275

    Neonates older than 34 weeks gestation and 0 to 7 days

    25 mg/kg/dose IV every 8 hours. 

    64275

    Neonates 34 weeks gestation and younger and older than 7 days

    25 mg/kg/dose IV every 8 hours. 

    64275

    Neonates 34 weeks gestation and younger and 0 to 7 days

    25 mg/kg/dose IV every 12 hours. 

    64275

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    6 g/day IV/IM is the FDA-approved dosage; however, 12 g/day IV/IM has been used off-label.

    Geriatric

    6 g/day IV/IM is the FDA-approved dosage; however, 12 g/day IV/IM has been used off-label.

    Adolescents

    weight 40 kg or more:6 g/day IM is the FDA-approved dosage; up to 200 mg/kg/day (Max: 12 g/day) IV/IM has been used off-label.
    weight less than 40 kg:50 mg/kg/day IM is the FDA-approved dosage; up to 200 mg/kg/day IV/IM has been used off-label.

    Children

    weight 40 kg or more: 6 g/day IM is the FDA-approved dosage; up to 200 mg/kg/day (Max: 12 g/day) IV/IM has been used off-label.
    weight less than 40 kg:50 mg/kg/day IM is the FDA-approved dosage; up to 200 mg/kg/day IV/IM has been used off-label.

    Infants

    50 mg/kg/day IM is the FDA-approved dosage; up to 200 mg/kg/day IV/IM has been used off-label.

    Neonates

    20 mg/kg/day IM is the FDA-approved dosage for all neonates; however, this dose is not typically used in current clinical practice. Safety and efficacy of IV route have not been established; however, the following doses have been used off-label:
    older than 7 days weighing more than 2 kg: up to 200 mg/kg/day IV/IM.
    older than 7 days weighing 2 kg or less: up to 150 mg/kg/day IV/IM.
    0 to 7 days weighing more than 2 kg: up to 150 mg/kg/day IV/IM.
    0 to 7 days weighing 2 kg or less: up to 100 mg/kg/day IV/IM.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in patients with hepatic impairment are not available; however, nafcillin clearance is significantly decreased in patients with hepatic dysfunction.

    Renal Impairment

    No dosage adjustment needed.

    ADMINISTRATION

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Reconstitution
    Vials: Reconstitute with Sterile Water for Injection or 0.9% Sodium Chloride Injection. Review the reconstitution instructions for the particular product and package size, as the amount of diluent required for reconstitution may vary by manufacturer.
    Storage: Reconstituted solutions are stable for 3 days at room temperature or 7 days under refrigeration.
    Pharmacy bulk package: Reconstitute 10 g vial with 93 mL of Sterile Water for Injection or 0.9% Sodium Chloride Injection for a resultant concentration of 100 mg/mL.
    Storage: Use reconstituted pharmacy bulk package within 4 hours from initial entry.
     
    Dilution
    For Intermittent IV Injection: Further dilute the reconstituted solution in 15 to 30 mL of Sterile Water for Injection or 0.9% Sodium Chloride Injection.
    For Intermittent IV Infusion: Further dilute reconstituted solution in 0.9% Sodium Chloride Injection or 5% Dextrose Injection to a usual concentration of 10 to 40 mg/mL.
    For peripheral vein infusion, a concentration of 20 mg/mL or less is preferred to lessen the risk of phlebitis; however, some patients cannot tolerate the fluid load and need a more concentrated solution.
    For fluid restricted patients, higher concentrations may be used depending on the diluent (5% Dextrose Injection: up to 71 mg/mL; 0.9% Sodium Chloride Injection: up to 64 mg/mL; Sterile Water for Injection: up to 128 mg/mL). These higher concentrations may increase the risk of phlebitis.
    Storage:
    Solutions diluted in 0.9% Sodium Chloride Injection or Sterile Water for Injection to a concentration of 10 to 200 mg/mL are stable for 24 hours at room temperature (25 degrees C) or 7 days under refrigeration (4 degrees C).
    Solutions diluted in 5% Dextrose Injection to a concentration of 2 to 30 mg/mL are stable for 24 hours at room temperature (25 degrees C). Solutions diluted in 5% Dextrose Injection to a concentration of 10 to 30 mg/mL are stable for 7 days under refrigeration (4 degrees C).
    GALAXY bags: No further dilution is required.
     
    Thawing Frozen Pre-mixed Bags
    Frozen GALAXY bags: Thaw frozen container at room temperature or under refrigeration. Do not force thaw by immersion in water baths or by microwave irradiation.
    Components of the solution may precipitate in the frozen state and will dissolve upon reaching room temperature; potency is not affected. If the solution remains cloudy or if an insoluble precipitate remains after the solution has reached room temperature and has been agitated, discard the product.
    Storage: The thawed solution remains stable for 21 days under refrigeration or for 3 days at room temperature. Do not refreeze.
     
    Intermittent IV Injection
    Inject slowly over 5 to 10 minutes into the tubing of a free-flowing compatible IV solution. To minimize vein irritation, inject as slowly as possible. Compatible solutions include 5% Dextrose Injection, 0.9% Sodium Chloride Injection, 5% Dextrose and 0.45% Sodium Chloride Injection, and Lactated Ringer's Injection.
     
    Intermittent IV Infusion
    Infuse IV slowly over 30 to 60 minutes to reduce the risk for phlebitis and extravasation. For peripheral vein infusion, consider infusion over 60 minutes.

    Intramuscular Administration

    Reconstitution
    Vials: Reconstitute with Sterile Water for Injection, Bacteriostatic Water for Injection with Parabens or Benzyl Alcohol, or 0.9% Sodium Chloride Injection for a resultant concentration of 250 mg/mL. Review the reconstitution instructions for the particular product and package size, as the amount of diluent required for reconstitution may vary by manufacturer. For neonates, use Sterile Water for Injection or 0.9% Sodium Chloride Injection to avoid the administration of benzyl alcohol.
    Storage: Reconstituted solutions are stable for 3 days at room temperature or 7 days under refrigeration.[53199]
     
    Intramuscular Injection
    Inject deeply into a large muscle (i.e., upper outer quadrant of the gluteus maximus or lateral part of the thigh). Care should be taken to avoid sciatic nerve injury.
    In general, IM administration of antibiotics in very low birth weight premature neonates is not practical due to small muscle mass, and absorption is unreliable due to hemodynamic instability that is relatively common in this population.[53249]

    STORAGE

    Generic:
    - Store unreconstituted product at 68 to 77 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Interstitial nephritis has been associated with methicillin therapy. The risk for this adverse reaction appears to be lower with nafcillin, but interstitial nephritis has occurred after administration of both methicillin and nafcillin in a 6-year-old boy (see Adverse Reactions).

    Asthma, carbapenem hypersensitivity, cephalosporin hypersensitivity, eczema, penicillin hypersensitivity

    Nafcillin is a penicillin, and should not be used in patients with penicillin hypersensitivity. Nafcillin should be used cautiously in patients with carbapenem hypersensitivity, or cephalosporin hypersensitivity because its structural similarity to the cephalosporins and imipenem causes these patients to be more susceptible to hypersensitivity reactions. Patients with allergies or allergic conditions including asthma, eczema, hives, or hay fever may have a greater risk for hypersensitivity reactions to penicillins.

    Hepatic disease, jaundice

    Use nafcillin with caution in patients with hepatic disease (e.g., jaundice) because the drug is eliminated primarily via the bile. In patients with concomitant hepatic impairment and renal impairment, neurotoxic reactions may occur.

    C. difficile-associated diarrhea, diarrhea, pseudomembranous colitis

    Consider pseudomembranous colitis in patients presenting with diarrhea after antibacterial use. Careful medical history is necessary as pseudomembranous colitis has been reported to occur over 2 months after the administration of antibacterial agents. Almost all antibacterial agents, including nafcillin, have been associated with pseudomembranous colitis or C. difficile-associated diarrhea (CDAD) which may range in severity from mild to life-threatening. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

    Electrolyte imbalance, heart failure

    Use nafcillin with caution in patients with electrolyte imbalance and those who are particularly sensitive to sodium intake. The amount of sodium and/or potassium can vary between nafcillin products. For example, nafcillin injection by Baxter Healthcare contains 76.6 mg (3.33 mEq) of sodium per gram. At the usual recommended doses, patients would receive between 230 and 460 mg/day (10 and 20 mEq) of sodium. The elderly or other susceptible patients may respond to sodium loading with a blunted natriuresis which may be clinically important in regard to such diseases as congestive heart failure.

    Pregnancy

    Penicillin antibiotics cross the placenta. Use of penicillins in human pregnancy has not shown any evidence of harmful effects on the fetus. Animal data have also not demonstrated any evidence of impaired fertility or harmful fetal effects. However, there are no adequate and well-controlled studies in pregnant women to show conclusively that harmful effects of penicillins on the fetus can be excluded. Because animal reproduction studies are not always predictive of human response, nafcillin should be used in pregnant women only if clearly needed.

    Breast-feeding

    Penicillins, such as nafcillin, are excreted in human breast milk. Use caution when penicillins are administered to a breast-feeding woman. Penicillins may cause diarrhea (due to disruption of GI flora), candidiasis, and skin rash in breast-feeding infants. Unless the infant is allergic to penicillins, breast-feeding is generally safe during maternal penicillin therapy; the infant should be observed for potential effects.

    Extravasation

    Extravasation of nafcillin can be very painful and cause serious tissue damage, including local tissue necrosis. Do not exceed recommended infusion rates and monitor the administration site frequently. Hyaluronidase treatment (15 units in 1 mL of sodium chloride 0.9% injection) has been successfully used for nafcillin extravasation in pediatric case reports and has resulted in decreased tissue damage and destruction.

    Geriatric

    Reported clinical experience with nafcillin has not identified differences in responses between geriatric and younger adults. Consider the sodium load from nafcillin treatment in geriatric patients for whom sodium intake is of concern. In general, dose selection for a geriatric patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to OBRA, use of antibiotics should be limited to confirmed or suspected bacterial infections. Antibiotics are non-selective and may result in the eradication of beneficial microorganisms while promoting the emergence of undesired ones, causing secondary infections such as oral thrush, colitis, or vaginitis. Any antibiotic may cause diarrhea, nausea, vomiting, anorexia, and hypersensitivity reactions.

    ADVERSE REACTIONS

    Severe

    serum sickness / Delayed / 0-5.0
    bronchospasm / Rapid / 0-1.0
    laryngeal edema / Rapid / 0-1.0
    angioedema / Rapid / 0-1.0
    Stevens-Johnson syndrome / Delayed / 0-1.0
    exfoliative dermatitis / Delayed / 0-1.0
    anaphylactic shock / Rapid / 0-1.0
    laryngospasm / Rapid / 0-1.0
    toxic epidermal necrolysis / Delayed / 0-1.0
    tissue necrosis / Early / 0-1.0
    agranulocytosis / Delayed / Incidence not known
    interstitial nephritis / Delayed / Incidence not known
    renal tubular necrosis / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    seizures / Delayed / Incidence not known

    Moderate

    superinfection / Delayed / 1.0-10.0
    pseudomembranous colitis / Delayed / 1.0-10.0
    stomatitis / Delayed / 2.0-5.0
    hypotension / Rapid / 0-1.0
    phlebitis / Rapid / 10.0
    neutropenia / Delayed / Incidence not known
    hematuria / Delayed / Incidence not known
    eosinophilia / Delayed / Incidence not known
    proteinuria / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    cholestasis / Delayed / Incidence not known

    Mild

    fever / Early / 0-5.0
    malaise / Early / 0-5.0
    pruritus / Rapid / 0-5.0
    rash / Early / 0-5.0
    arthralgia / Delayed / 0-5.0
    myalgia / Early / 0-5.0
    urticaria / Rapid / 0-5.0
    nausea / Early / 2.0-5.0
    abdominal pain / Early / 2.0-5.0
    vomiting / Early / 2.0-5.0
    diarrhea / Early / 2.0-5.0
    tongue discoloration / Delayed / 2.0-5.0
    injection site reaction / Rapid / 10.0

    DRUG INTERACTIONS

    Abemaciclib: (Major) Avoid coadministration of nafcillin with abemaciclib due to decreased exposure to abemaciclib and its active metabolites, which may lead to reduced efficacy. Consider alternative treatments. Abemaciclib is a CYP3A4 substrate and nafcillin is a moderate CYP3A4 inducer. Coadministration with moderate CYP3A4 inducers is predicted to decrease the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by 53%, 41%, and 29% respectively.
    Acetaminophen; Aspirin, ASA; Caffeine: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with nafcillin can decrease dihydrocodeine levels, resulting in less metabolism by CYP2D6 and decreased dihydromorphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. If coadministration is necessary, monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal; consider increasing the dose of dihydrocodeine as needed. If nafcillin is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Nafcillin is a moderate inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as penicillins, and sulfonamides. An enhanced effect of the displaced drug may occur.
    Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with nafcillin can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If nafcillin is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Nafcillin is a moderate CYP3A4 inducer.
    Acetaminophen; Hydrocodone: (Moderate) Concomitant use of hydrocodone with nafcillin can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If nafcillin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and nafcillin is a moderate CYP3A4 inducer.
    Acetaminophen; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with nafcillin is necessary; consider increasing the dose of oxycodone as needed. If nafcillin is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and nafcillin is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Aliskiren; Amlodipine: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as nafcillin, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as nafcillin, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as nafcillin, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Atorvastatin: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as nafcillin, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Benazepril: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as nafcillin, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Celecoxib: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as nafcillin, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Olmesartan: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as nafcillin, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Valsartan: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as nafcillin, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as nafcillin, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Aprepitant, Fosaprepitant: (Major) Use caution if nafcillin and aprepitant are used concurrently and monitor for a possible decrease in the efficacy of aprepitant. After administration, fosaprepitant is rapidly converted to aprepitant and shares the same drug interactions. Nafcillin is a moderate CYP3A4 inducer in vitro, and aprepitant is a CYP3A4 substrate. When a single dose of aprepitant (375 mg, or 3 times the maximum recommended dose) was administered on day 9 of a 14-day rifampin regimen (a strong CYP3A4 inducer), the AUC of aprepitant decreased approximately 11-fold and the mean terminal half-life decreased by 3-fold. The manufacturer of aprepitant recommends avoidance of administration with strong CYP3A4 inducers, but does not provide guidance for weak-to-moderate inducers.
    Artemether; Lumefantrine: (Major) Nafcillin is an inducer and both components of artemether; lumefantrine are substrates of the CYP3A4 isoenzyme; therefore, coadministration may lead to decreased artemether; lumefantrine concentrations. Concomitant use warrants caution due to a possible reduction in antimalarial activity.
    Aspirin, ASA: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
    Aspirin, ASA; Butalbital; Caffeine: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Concomitant use of codeine with nafcillin can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If nafcillin is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Nafcillin is a moderate CYP3A4 inducer. (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
    Aspirin, ASA; Caffeine: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with nafcillin can decrease dihydrocodeine levels, resulting in less metabolism by CYP2D6 and decreased dihydromorphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. If coadministration is necessary, monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal; consider increasing the dose of dihydrocodeine as needed. If nafcillin is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Nafcillin is a moderate inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
    Aspirin, ASA; Caffeine; Orphenadrine: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
    Aspirin, ASA; Carisoprodol: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with nafcillin can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If nafcillin is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Nafcillin is a moderate CYP3A4 inducer. (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
    Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
    Aspirin, ASA; Dipyridamole: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
    Aspirin, ASA; Omeprazole: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
    Aspirin, ASA; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with nafcillin is necessary; consider increasing the dose of oxycodone as needed. If nafcillin is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and nafcillin is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
    Aspirin, ASA; Pravastatin: (Minor) Due to the high protein binding of aspirin, it could displace or be displaced from binding sites by other highly protein-bound drugs, such as penicillins. Also, aspirin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. Overall, this combination should be used with caution and patients monitored for increased side effects.
    Atazanavir: (Major) Caution is warranted when atazanavir is administered with nafcillin as there is a potential for decreased concentrations of atazanavir. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Nafcillin is an inducer of CYP3A4. Atazanavir is a CYP3A4 substrate.
    Atazanavir; Cobicistat: (Major) Caution is warranted when atazanavir is administered with nafcillin as there is a potential for decreased concentrations of atazanavir. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Nafcillin is an inducer of CYP3A4. Atazanavir is a CYP3A4 substrate. (Major) Caution is warranted when cobicistat is administered with nafcillin as there is a potential for decreased concentrations of cobicistat. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Nafcillin is an inducer of CYP3A4. Cobicistat is a CYP3A4 substrate.
    Atogepant: (Major) Use an atogepant dose of 30 or 60 mg PO once daily if coadministered with nafcillin. Concurrent use may decrease atogepant exposure and reduce efficacy. Atogepant is a CYP3A substrate and nafcillin is a moderate CYP3A inducer.
    Avacopan: (Major) Avoid concomitant use of avacopan and nafcillin due to the risk of decreased avacopan exposure which may reduce its efficacy. Avacopan is a CYP3A substrate and nafcillin is a moderate CYP3A inducer.
    Avapritinib: (Major) Avoid coadministration of avapritinib with nafcillin due to the risk of decreased avapritinib efficacy. Avapritinib is a CYP3A4 substrate and nafcillin is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer is predicted to decrease the AUC and Cmax of avapritinib by 62% and 55%, respectively.
    Axitinib: (Major) Avoid coadministration of axitinib with nafcillin if possible due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4/5 substrate and nafcillin is a moderate CYP3A4 inducer.
    Bedaquiline: (Major) Avoid concurrent use of nafcillin with bedaquiline. Nafcillin is a CYP3A4 inducer, which may result in decreased bedaquiline systemic exposure (AUC) and possibly reduced therapeutic effect.
    Benzhydrocodone; Acetaminophen: (Moderate) Concurrent use of benzhydrocodone with nafcillin may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. If concomitant use is necessary, consider increasing the benzhydrocodone dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Discontinuation of nafcillin may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. If nafcillin is discontinued, consider a benzhydrocodone dosage reduction and monitor patients for respiratory depression and sedation at frequent intervals. Benzhydrocodone is a prodrug of hydrocodone. Nafcillin is an in vitro inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of hydrocodone.
    Boceprevir: (Moderate) Close clinical monitoring is advised when administering nafcillin with boceprevir due to the potential for boceprevir treatment failure. If nafcillin 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 pathways of nafcillin and boceprevir. Nafcillin is an inducer of the hepatic isoenzyme CYP3A4; boceprevir is metabolized by this isoenzyme. When used in combination, the plasma concentrations of boceprevir may decrease, resulting in decreased boceprevir efficacy.
    Brigatinib: (Major) Avoid coadministration of brigatinib with nafcillin due to decreased plasma exposure to brigatinib which may result in decreased efficacy. If concomitant use is unavoidable, after 7 days of concomitant treatment with nafcillin, increase the dose of brigatinib as tolerated in 30 mg increments to a maximum of twice the original brigatinib dose. After discontinuation of nafcillin, resume the brigatinib dose that was tolerated prior to initiation of nafcillin. Brigatinib is a CYP3A4 substrate and nafcillin is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of brigatinib by approximately 50%.
    Bromocriptine: (Moderate) Caution and close monitoring are advised if bromocriptine and griseofulvin are used together. Concurrent use may decrease the plasma concentrations of bromocriptine resulting in loss of efficacy. Bromocriptine is extensively metabolized by the liver via CYP3A4; In vitro data suggest that nafcillin may induce the CYP3A4 isoenzyme.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with nafcillin can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If nafcillin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and nafcillin is a moderate CYP3A4 inducer.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with nafcillin can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If nafcillin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and nafcillin is a moderate CYP3A4 inducer.
    Budesonide: (Moderate) Theoretically, induction of the cytochrome P450 3A4 isoenzyme, such as nafcillin, may result in a lowering of budesonide plasma concentrations, reducing the clinical effect.
    Budesonide; Formoterol: (Moderate) Theoretically, induction of the cytochrome P450 3A4 isoenzyme, such as nafcillin, may result in a lowering of budesonide plasma concentrations, reducing the clinical effect.
    Budesonide; Glycopyrrolate; Formoterol: (Moderate) Theoretically, induction of the cytochrome P450 3A4 isoenzyme, such as nafcillin, may result in a lowering of budesonide plasma concentrations, reducing the clinical effect.
    Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Concomitant use of codeine with nafcillin can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If nafcillin is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Nafcillin is a moderate CYP3A4 inducer.
    Cabotegravir; Rilpivirine: (Moderate) Close clinical monitoring is advised when administering nafcillin with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Nafcillin is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
    Caffeine; Sodium Benzoate: (Moderate) Antibiotics that undergo tubular secretion such as penicillins may compete with phenylacetlyglutamine and hippuric acid for active tubular secretion. The overall usefulness of sodium benzoate; sodium phenylacetate is due to the excretion of its metabolites. An increase in metabolite concentrations could contribute to failed treatment and worsening of the patient's clinical status. This combination should be used with caution.
    Capmatinib: (Major) Avoid coadministration of capmatinib and nafcillin due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and nafcillin is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased capmatinib exposure by 44%.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with nafcillin can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If nafcillin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and nafcillin is a moderate CYP3A4 inducer.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with nafcillin can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If nafcillin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and nafcillin is a moderate CYP3A4 inducer.
    Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with nafcillin can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If nafcillin is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Nafcillin is a moderate CYP3A4 inducer.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of dihydrocodeine with nafcillin can decrease dihydrocodeine levels, resulting in less metabolism by CYP2D6 and decreased dihydromorphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. If coadministration is necessary, monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal; consider increasing the dose of dihydrocodeine as needed. If nafcillin is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Nafcillin is a moderate inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with nafcillin can decrease dihydrocodeine levels, resulting in less metabolism by CYP2D6 and decreased dihydromorphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. If coadministration is necessary, monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal; consider increasing the dose of dihydrocodeine as needed. If nafcillin is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Nafcillin is a moderate inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with nafcillin can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If nafcillin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and nafcillin is a moderate CYP3A4 inducer.
    Chlorpheniramine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with nafcillin can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If nafcillin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and nafcillin is a moderate CYP3A4 inducer.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with nafcillin can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If nafcillin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and nafcillin is a moderate CYP3A4 inducer.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with nafcillin can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If nafcillin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and nafcillin is a moderate CYP3A4 inducer.
    Choline Salicylate; Magnesium Salicylate: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as penicillins, and sulfonamides. An enhanced effect of the displaced drug may occur.
    Cobicistat: (Major) Caution is warranted when cobicistat is administered with nafcillin as there is a potential for decreased concentrations of cobicistat. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Nafcillin is an inducer of CYP3A4. Cobicistat is a CYP3A4 substrate.
    Cobimetinib: (Major) Avoid the concurrent use of cobimetinib with nafcillin due to decreased cobimetinib efficacy. Cobimetinib is a CYP3A substrate in vitro, and nafcillin is a moderate inducer of CYP3A. Based on simulations, cobimetinib exposure would decrease by 73% when coadministered with a moderate CYP3A inducer.
    Codeine: (Moderate) Concomitant use of codeine with nafcillin can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If nafcillin is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Nafcillin is a moderate CYP3A4 inducer.
    Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with nafcillin can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If nafcillin is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Nafcillin is a moderate CYP3A4 inducer.
    Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of codeine with nafcillin can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If nafcillin is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Nafcillin is a moderate CYP3A4 inducer.
    Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of codeine with nafcillin can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If nafcillin is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Nafcillin is a moderate CYP3A4 inducer.
    Codeine; Promethazine: (Moderate) Concomitant use of codeine with nafcillin can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If nafcillin is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Nafcillin is a moderate CYP3A4 inducer.
    Cyclosporine: (Moderate) Nafcillin can increase the clearance of cyclosporine by inducing cyclosporine metabolism. Cyclosporine concentrations should be monitored closely to avoid loss of clinical efficacy until a new steady-state cyclosporine concentration is achieved when nafcillin is added to an existing cyclosporine regimen.
    Daclatasvir: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be increased to 90 mg PO once daily when administered in combination with moderate CYP3A4 inducers, such as nafcillin. Taking these drugs together may decrease daclatasvir serum concentrations, potentially resulting in reduced antiviral efficacy and antimicrobial resistance.
    Dapsone: (Moderate) Closely monitor for a reduction in dapsone efficacy and signs of hemolytic anemia if coadministration with nafcillin is necessary. Dapsone is a CYP3A4 substrate and nafcillin is a moderate CYP3A4 inducer. Coadministration may decrease plasma concentrations of dapsone and increase the formation of dapsone hydroxylamine (a metabolite associated with hemolysis).
    Darunavir: (Major) Caution is warranted when darunavir is administered with nafcillin as there is a potential for decreased concentrations of darunavir. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Nafcillin is an inducer of CYP3A4. Darunavir is a CYP3A4 substrate.
    Darunavir; Cobicistat: (Major) Caution is warranted when cobicistat is administered with nafcillin as there is a potential for decreased concentrations of cobicistat. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Nafcillin is an inducer of CYP3A4. Cobicistat is a CYP3A4 substrate. (Major) Caution is warranted when darunavir is administered with nafcillin as there is a potential for decreased concentrations of darunavir. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Nafcillin is an inducer of CYP3A4. Darunavir is a CYP3A4 substrate.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Caution is warranted when cobicistat is administered with nafcillin as there is a potential for decreased concentrations of cobicistat. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Nafcillin is an inducer of CYP3A4. Cobicistat is a CYP3A4 substrate. (Major) Caution is warranted when darunavir is administered with nafcillin as there is a potential for decreased concentrations of darunavir. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Nafcillin is an inducer of CYP3A4. Darunavir is a CYP3A4 substrate.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Concurrent administration of nafcillin with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in decreased plasma concentrations of dasabuvir, paritaprevir, and ritonavir, which may affect antiviral efficacy. Nafcillin is an inducer of the hepatic isoenzyme CYP3A4; ritonavir, paritaprevir and dasabuvir (minor) are CYP3A4 substrates. Caution and close monitoring are advised if these drugs are administered together. (Major) Concurrent administration of nafcillin with ritonavir may result in decreased plasma concentrations of ritonavir, which may affect antiviral efficacy. Nafcillin is an inducer of the hepatic isoenzyme CYP3A4; ritonavir is a CYP3A4 substrate. Caution and close monitoring are advised if these drugs are administered together.
    Deflazacort: (Major) Avoid concomitant use of deflazacort and nafcillin. Concurrent use may significantly decrease concentrations of 21-desDFZ, the active metabolite of deflazacort, resulting in loss of efficacy. Deflazacort is a CYP3A4 substrate; nafcillin is a moderate inducer of CYP3A4. Administration of deflazacort with multiple doses of rifampin (a strong CYP3A4 inducer) resulted in geometric mean exposures that were approximately 95% lower compared to administration alone.
    Dichlorphenamide: (Moderate) Use dichlorphenamide and nafcillin together with caution. Dichlorphenamide increases potassium excretion and can cause hypokalemia and should be used cautiously with other drugs that may cause hypokalemia including nafcillin. Measure potassium concentrations at baseline and periodically during dichlorphenamide treatment. If hypokalemia occurs or persists, consider reducing the dose or discontinuing dichlorphenamide therapy.
    Digoxin: (Minor) Displacement of penicillins from plasma protein binding sites by highly protein bound drugs like digoxin will elevate the level of free penicillin in the serum. The clinical significance of this interaction is unclear. It is recommended to monitor these patients for increased adverse effects.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with nafcillin can decrease dihydrocodeine levels, resulting in less metabolism by CYP2D6 and decreased dihydromorphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. If coadministration is necessary, monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal; consider increasing the dose of dihydrocodeine as needed. If nafcillin is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Nafcillin is a moderate inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with nafcillin can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If nafcillin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and nafcillin is a moderate CYP3A4 inducer.
    Dolutegravir; Rilpivirine: (Moderate) Close clinical monitoring is advised when administering nafcillin with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Nafcillin is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
    Doravirine: (Moderate) Concurrent administration of doravirine and nafcillin may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; nafcillin is a moderate CYP3A4 inducer.
    Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Concurrent administration of doravirine and nafcillin may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; nafcillin is a moderate CYP3A4 inducer.
    Doxorubicin: (Major) In vitro, nafcillin is a CYP3A4 inducer; doxorubicin is a major substrate of CYP3A4. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of nafcillin and doxorubicin if possible. If not possible, monitor doxorubicin closely for efficacy.
    Dronabinol: (Moderate) Use caution if coadministration of dronabinol with nafcillin is necessary, and monitor for a decrease in the efficacy of dronabinol. Dronabinol is a CYP2C9 and 3A4 substrate; nafcillin is a moderate inducer of CYP3A4 in vitro. Concomitant use may result in decreased plasma concentrations of dronabinol.
    Dronedarone: (Major) The concomitant use of dronedarone and CYP3A4 inducers should be avoided. Dronedarone is metabolized by CYP3A. Nafcillin induces CYP3A4. Coadministration of CYP3A4 inducers, such as nafcillin, with dronedarone may result in reduced plasma concentration and subsequent reduced effectiveness of dronedarone therapy.
    Duvelisib: (Major) Avoid concomitant use of duvelisib with nafcillin. Coadministration may decrease the exposure of duvelisib, which may reduce the efficacy of duvelisib. If concomitant use is necessary, increase the dose of duvelisib on day 12 of coadministration from 25 mg PO twice daily to 40 mg PO twice daily; or from 15 mg PO twice daily to 25 mg PO twice daily. When nafcillin has been discontinued for at least 14 days, resume duvelisib at the dose taken prior to initiating treatment with nafcillin. Duvelisib is a CYP3A substrate; nafcillin is a moderate CYP3A inducer. Coadministration of duvelisib with another moderate CYP3A inducer for 12 days decreased duvelisib exposure by 35%.
    Elbasvir; Grazoprevir: (Major) Concurrent administration of elbasvir with nafcillin should be avoided if possible. Nafcillin is a moderate CYP3A inducer, while elbasvir is a substrate of CYP3A. Use of these drugs together is expected to decrease the plasma concentrations of elbasvir, and may result in decreased virologic response. (Major) Concurrent administration of grazoprevir with nafcillin should be avoided if possible. Nafcillin is a moderate CYP3A inducer, while grazoprevir is a substrate of CYP3A. Use of these drugs together is expected to decrease the plasma concentrations of grazoprevir, and may result in decreased virologic response.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Caution is warranted when cobicistat is administered with nafcillin as there is a potential for decreased concentrations of cobicistat. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Nafcillin is an inducer of CYP3A4. Cobicistat is a CYP3A4 substrate.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Caution is warranted when cobicistat is administered with nafcillin as there is a potential for decreased concentrations of cobicistat. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Nafcillin is an inducer of CYP3A4. Cobicistat is a CYP3A4 substrate.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Close clinical monitoring is advised when administering nafcillin with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Nafcillin is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Moderate) Close clinical monitoring is advised when administering nafcillin with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Nafcillin is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
    Encorafenib: (Major) Avoid coadministration of encorafenib and nafcillin due to decreased encorafenib exposure and potential loss of efficacy. Encorafenib is a CYP3A4 substrate; nafcillin is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
    Entrectinib: (Major) Avoid coadministration of entrectinib with nafcillin due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; nafcillin is a moderate CYP3A4 inducer. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
    Erdafitinib: (Major) If coadministration of erdafitinib and nafcillin is necessary at the initiation of erdafitinib therapy, administer the dose of erdafitinib as recommended (8 mg once daily with potential to increase the dose to 9 mg on days 14 to 21 based on phosphate levels and tolerability). If nafcillin must be added to erdafitinib therapy after the initial dose increase period (days 14 to 21), increase the dose of erdafitinib up to 9 mg. If nafcillin is discontinued, continue erdafitinib at the same dose in the absence of drug-related toxicity. Erdafitinib is a CYP3A4 substrate and nafcillin is a moderate CYP3A4 inducer.
    Erlotinib: (Major) Avoid the coadministration of erlotinib with nafcillin if possible due to the risk of decreased erlotinib efficacy. If concomitant use is unavoidable, increase the dose of erlotinib by 50 mg increments at 2-week intervals as tolerated, to a maximum of 450 mg. Erlotinib is a CYP3A4 substrate and nafcillin is a moderate CYP3A4 inducer. Coadministration may decrease plasma concentrations of erlotinib.
    Ethacrynic Acid: (Minor) Ethacrynic acid may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. This combination should be used with caution and patients monitored for increased side effects.
    Everolimus: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate if coadministration with nafcillin is necessary. The dose of everolimus may need to be increased. Everolimus is a sensitive CYP3A4 substrate and nafcillin is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers may increase the metabolism of everolimus and decrease everolimus blood concentrations.
    Fedratinib: (Major) Avoid coadministration of fedratinib with nafcillin as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; nafcillin is a moderate CYP3A4 inducer. The coadministration of fedratinib with a moderate CYP3A4 inducer has not been evaluated.
    Fentanyl: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if concurrent use of nafcillin is necessary. If nafcillin is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a CYP3A4 inducer like nafcillin with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
    Finerenone: (Major) Avoid concurrent use of finerenone and nafcillin due to the risk for decreased finerenone exposure which may reduce its efficacy. Finerenone is a CYP3A substrate and nafcillin is a moderate CYP3A inducer. Coadministration with another moderate CYP3A inducer decreased overall exposure to finerenone by 80%.
    Flibanserin: (Major) The concomitant use of flibanserin with CYP3A4 inducers significantly decreases flibanserin exposure compared to the use of flibanserin alone. Therefore, concurrent use of flibanserin and CYP3A4 inducers, such as nafcillin, is not recommended.
    Food: (Contraindicated) The incidence of marijuana associated adverse effects may change following coadministration with nafcillin. Nafcillin is an inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of marijuana's most psychoactive compound, delta-9-tetrahydrocannabinol (Delta-9-THC). When given concurrently with nafcillin, the amount of Delta-9-THC converted to the active metabolite 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC) may be increased. These changes in Delta-9-THC and 11-OH-THC plasma concentrations may result in an altered marijuana adverse event profile.
    Furosemide: (Minor) Furosemide may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. This combination should be used with caution and patients monitored for increased side effects.
    Glasdegib: (Major) Avoid coadministration of glasdegib and nafcillin due to the potential for decreased glasdegib exposure and risk of decreased efficacy. If concurrent use cannot be avoided, increase the glasdegib dosage (i.e., from 100 mg PO daily to 200 mg PO daily; or from 50 mg PO daily to 100 mg PO daily). Resume the previous dose of glasdegib after nafcillin has been discontinued for 7 days. Glasdegib is a CYP3A4 substrate; nafcillin is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer was predicted to decrease the glasdegib AUC value by 55%.
    Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with nafcillin can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If nafcillin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and nafcillin is a moderate CYP3A4 inducer.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with nafcillin can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If nafcillin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and nafcillin is a moderate CYP3A4 inducer.
    Homatropine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with nafcillin can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If nafcillin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and nafcillin is a moderate CYP3A4 inducer.
    Hydrocodone: (Moderate) Concomitant use of hydrocodone with nafcillin can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If nafcillin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and nafcillin is a moderate CYP3A4 inducer.
    Hydrocodone; Ibuprofen: (Moderate) Concomitant use of hydrocodone with nafcillin can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If nafcillin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and nafcillin is a moderate CYP3A4 inducer.
    Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with nafcillin can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If nafcillin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and nafcillin is a moderate CYP3A4 inducer.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Concomitant use of hydrocodone with nafcillin can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If nafcillin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and nafcillin is a moderate CYP3A4 inducer.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with nafcillin can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If nafcillin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and nafcillin is a moderate CYP3A4 inducer.
    Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with nafcillin can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If nafcillin is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and nafcillin is a moderate CYP3A4 inducer.
    Ibrexafungerp: (Major) Avoid concurrent administration of ibrexafungerp with nafcillin. Use of these drugs together is expected to significantly decrease ibrexafungerp exposure, which may reduce its efficacy. Ibrexafungerp is a CYP3A substrate and nafcillin is a moderate CYP3A inducer.
    Ibrutinib: (Moderate) Use ibrutinib and nafcillin together with caution; decreased ibrutinib levels may occur resulting in reduced ibrutinib efficacy. Monitor patients for signs of decreased ibrutinib efficacy if these agents are used together. Ibrutinib is a CYP3A4 substrate; nafcillin is a moderate CYP3A inducer. Simulations using physiologically-based pharmacokinetic (PBPK) models suggest that moderate CYP3A4 inducers may decrease ibrutinib exposure up to 3-fold.
    Ibuprofen; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with nafcillin is necessary; consider increasing the dose of oxycodone as needed. If nafcillin is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and nafcillin is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Ifosfamide: (Moderate) Closely monitor for increased ifosfamide-related toxicities (e.g., neurotoxicity, nephrotoxicity) if coadministration with nafcillin is necessary; consider adjusting the dose of ifosfamide as clinically appropriate. Ifosfamide is metabolized to its active alkylating metabolites by CYP3A4; nafcillin is a moderate CYP3A4 inducer. Concomitant use may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde.
    Indomethacin: (Minor) Indomethacin may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. This combination should be used with caution and patients monitored for increased side effects.
    Infigratinib: (Major) Avoid concurrent use of infigratinib and nafcillin. Coadministration may decrease infigratinib exposure resulting in decreased efficacy. Infigratinib is a CYP3A4 substrate and nafcillin is a moderate CYP3A4 inducer.
    Isavuconazonium: (Major) Caution and close monitoring are warranted when isavuconazonium is administered with nafcillin as there is a potential for decreased concentrations of isavuconazonium. Decreased isavuconazonium concentrations may lead to a reduction of antifungal efficacy and the potential for treatment failure. Isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate of the hepatic isoenzyme CYP3A4; nafcillin is an inducer of this enzyme.
    Ixabepilone: (Major) Ixabepilone is a CYP3A4 substrate and concomitant use with CYP3A4 inducers such as nafcillin may lead to reduced and subtherapeutic concentrations of ixabepilone. Caution should be utilized when CYP3A4 inducers are coadministered with ixabepilone, and alternative therapies with low enzyme induction potential should be considered.
    Lefamulin: (Major) Avoid coadministration of lefamulin with nafcillin unless the benefits outweigh the risks as concurrent use may decrease lefamulin exposure and efficacy. Lefamulin is a CYP3A4 substrate; nafcillin is a moderate CYP3A4 inducer.
    Lemborexant: (Major) Avoid coadministration of lemborexant and nafcillin as concurrent use may decrease lemborexant exposure which may reduce efficacy. Lemborexant is a CYP3A4 substrate; nafcillin is a moderate CYP3A4 inducer.
    Letermovir: (Major) Concurrent administration of letermovir and nafcillin is not recommended. Use of these drugs together may decrease letermovir plasma concentrations, resulting in a potential loss of letermovir efficacy.
    Levamlodipine: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as nafcillin, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Lonafarnib: (Contraindicated) Coadministration of lonafarnib and nafcillin is contraindicated; concurrent use may decrease lonafarnib exposure, which may reduce its efficacy. Lonafarnib is a sensitive CYP3A4 substrate and nafcillin is a moderate CYP3A4 inducer.
    Loperamide: (Moderate) The plasma concentration and efficacy of loperamide may be reduced when administered concurrently with nafcillin. Loperamide is metabolized by the hepatic enzyme CYP3A4; nafcillin is an inducer of this enzyme.
    Loperamide; Simethicone: (Moderate) The plasma concentration and efficacy of loperamide may be reduced when administered concurrently with nafcillin. Loperamide is metabolized by the hepatic enzyme CYP3A4; nafcillin is an inducer of this enzyme.
    Lopinavir; Ritonavir: (Major) Concurrent administration of nafcillin with ritonavir may result in decreased plasma concentrations of ritonavir, which may affect antiviral efficacy. Nafcillin is an inducer of the hepatic isoenzyme CYP3A4; ritonavir is a CYP3A4 substrate. Caution and close monitoring are advised if these drugs are administered together.
    Lorlatinib: (Major) Avoid concomitant use of lorlatinib and nafcillin due to decreased plasma concentrations of lorlatinib, which may reduce its efficacy. If concomitant use is necessary, increase the dose of lorlatinib to 125 mg PO once daily. Lorlatinib is a CYP3A substrate and nafcillin is a moderate CYP3A inducer. Administration with another moderate CYP3A inducer decreased lorlatinib exposure by 23%.
    Lumateperone: (Major) Avoid coadministration of lumateperone and nafcillin as concurrent use may decrease lumateperone exposure which may reduce efficacy. Lumateperone is a CYP3A4 substrate; nafcillin is a moderate CYP3A4 inducer.
    Lurbinectedin: (Major) Avoid coadministration of lurbinectedin and mitotane due to the risk of decreased lurbinectedin exposure which may reduce its efficacy. Lurbinectedin is a CYP3A substrate and mitotane is a moderate CYP3A inducer.
    Magnesium Salicylate: (Minor) Due to high protein binding, salicylates could be displaced from binding sites, or could displace other highly protein-bound drugs such as penicillins, and sulfonamides. An enhanced effect of the displaced drug may occur.
    Maraviroc: (Moderate) Use caution if coadministration of maraviroc with nafcillin is necessary, due to a possible decrease in maraviroc exposure. Maraviroc is a CYP3A substrate and nafcillin is a CYP3A4 inducer. Monitor for a decrease in maraviroc efficacy with concomitant use.
    Methotrexate: (Major) Penicillins may reduce the renal clearance of methotrexate. Increased serum concentrations of methotrexate with concomitant hematologic and gastrointestinal toxicity have been observed with concurrent administration of high or low doses of methotrexate and penicillins. Patients should be carefully monitored while receiving this combination.
    Mobocertinib: (Major) Avoid concomitant use of mobocertinib and nafcillin. Coadministration may decrease mobocertinib exposure resulting in decreased efficacy. Mobocertinib is a CYP3A substrate and nafcillin is a moderate CYP3A inducer. Use of a moderate CYP3A inducer is predicted to decrease the overall exposure of mobocertinib and its active metabolites by 58%.
    Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for decreased efficacy of nab-paclitaxel if coadministration with nafcillin is necessary due to the risk of decreased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A4 substrate and nafcillin is a moderate CYP3A4 inducer.
    Neratinib: (Major) Avoid concomitant use of nafcillin with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and nafcillin is a moderate CYP3A4 inducer. Simulations using physiologically based pharmacokinetic (PBPK) models suggest that another moderate CYP3A4 inducer may decrease neratinib exposure by 52%.
    Nisoldipine: (Major) Avoid coadministration of nisoldipine with nafcillin due to decreased plasma concentrations of nisoldipine. Alternative antihypertensive therapy should be considered. Nisoldipine is a CYP3A4 substrate and nafcillin is a CYP3A4 inducer in vitro. Coadministration with a strong CYP3A4 inducer lowered nisoldipine plasma concentrations to undetectable levels.
    Olaparib: (Major) Avoid coadministration of olaparib with nafcillin due to the risk of decreasing the efficacy of olaparib. Olaparib is a CYP3A substrate and nafcillin is a moderate CYP3A4 inducer; concomitant use may decrease olaparib exposure. Coadministration with a moderate CYP3A inducer is predicted to decrease the olaparib Cmax by 31% and the AUC by 60%.
    Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as nafcillin, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Concurrent administration of nafcillin with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in decreased plasma concentrations of dasabuvir, paritaprevir, and ritonavir, which may affect antiviral efficacy. Nafcillin is an inducer of the hepatic isoenzyme CYP3A4; ritonavir, paritaprevir and dasabuvir (minor) are CYP3A4 substrates. Caution and close monitoring are advised if these drugs are administered together. (Major) Concurrent administration of nafcillin with ritonavir may result in decreased plasma concentrations of ritonavir, which may affect antiviral efficacy. Nafcillin is an inducer of the hepatic isoenzyme CYP3A4; ritonavir is a CYP3A4 substrate. Caution and close monitoring are advised if these drugs are administered together.
    Oral Contraceptives: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with nafcillin is necessary; consider increasing the dose of oxycodone as needed. If nafcillin is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and nafcillin is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Pazopanib: (Moderate) Pazopanib is a substrate for CYP3A4. Plasma pazopanib concentrations may be decreased by concurrent administration with a CYP3A4 inducer such as nafcillin. Use caution if chronic use of CYP3A4 inducers and pazopanib can not be avoided.
    Pemigatinib: (Major) Avoid coadministration of pemigatinib and nafcillin due to the risk of decreased pemigatinib exposure which may reduce its efficacy. Pemigatinib is a CYP3A4 substrate and nafcillin is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A4 inducer is predicted to decrease pemigatinib exposure by more than 50%.
    Perampanel: (Major) Start perampanel at a higher initial dose of 4 mg once daily at bedtime when using concurrently with nafcillin due to a potential reduction in perampanel plasma concentration. If introduction or withdrawal of nafcillin occurs during perampanel therapy, closely monitor patient response; a dosage adjustment may be necessary. Nafcillin is a strong CYP3A4 inducer, and perampanel is a CYP3A4 substrate.
    Perindopril; Amlodipine: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as nafcillin, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Pimavanserin: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends avoiding concomitant use of pimavanserin with moderate CYP3A4 inducers, such as nafcillin. Moderate inducers of CYP3A4 can reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin.
    Praziquantel: (Major) In vitro and drug interactions studies suggest that the CYP3A4 isoenzyme is the major enzyme involved in praziquantel metabolism. Therefore, use of praziquantel with nafcillin, a CYP3A4 inducer in vitro, should be done with caution as concomitant use may produce therapeutically ineffective concentrations of praziquantel.
    Probenecid: (Minor) Probenecid competitively inhibits renal tubular secretion and causes higher, prolonged serum levels of penicillins. In general, this pharmacokinetic interaction is not harmful and can be used therapeutically if needed.
    Probenecid; Colchicine: (Minor) Probenecid competitively inhibits renal tubular secretion and causes higher, prolonged serum levels of penicillins. In general, this pharmacokinetic interaction is not harmful and can be used therapeutically if needed.
    Rilpivirine: (Moderate) Close clinical monitoring is advised when administering nafcillin with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Nafcillin is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
    Rimegepant: (Major) Avoid coadministration of rimegepant with nafcillin; concurrent use may significantly decrease rimegepant exposure which may result in loss of efficacy. Rimegepant is a CYP3A4 substrate and nafcillin is a moderate CYP3A4 inducer.
    Ripretinib: (Major) Avoid coadministration of ripretinib with nafcillin. If concomitant use is unavoidable, increase the frequency of ripretinib dosing from 150 mg once daily to 150 mg twice daily; monitor for clinical response and tolerability. Resume once daily dosing of ripretinib 14 days after discontinuation of nafcillin. Coadministration is predicted to decrease the exposure of ripretinib and its active metabolite (DP-5439), which may decrease ripretinib anti-tumor activity. Ripretinib and DP-5439 are metabolized by CYP3A and nafcillin is a moderate CYP3A inducer. Drug interaction modeling studies suggest coadministration with a moderate CYP3A inducer may decrease ripretinib exposure by 56%.
    Ritonavir: (Major) Concurrent administration of nafcillin with ritonavir may result in decreased plasma concentrations of ritonavir, which may affect antiviral efficacy. Nafcillin is an inducer of the hepatic isoenzyme CYP3A4; ritonavir is a CYP3A4 substrate. Caution and close monitoring are advised if these drugs are administered together.
    Rivaroxaban: (Minor) Coadministration of rivaroxaban and nafcillin may result in decreased rivaroxaban exposure and may decrease the efficacy of rivaroxaban. Nafcillin is an inducer of CYP3A4, and rivaroxaban is a substrate of CYP3A4. If these drugs are administered concurrently, monitor the patient for signs of lack of efficacy of rivaroxaban.
    Romidepsin: (Moderate) Romidepsin is a substrate for CYP3A4. Coadministration of a CYP3A4 inducer, like nafcillin, may decrease systemic concentrations of romidepsin. Use caution when concomitant administration of these agents is necessary.
    Ruxolitinib: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are CYP3A4 inducers such as nafcillin, a dose adjustment is not necessary, but closely monitor patients and titrate the ruxolitinib dose based on safety and efficacy. The Cmax and AUC of a single 50 mg dose of ruxolitinib was decreased by 32% and 61%, respectively, after rifampin 600 mg once daily was administered for 10 days. The relative exposure to ruxolitinib's active metabolites increased by about 100%, which may partially explain the reported disproportionate 10% reduction in the pharmacodynamic marker pSTAT3 inhibition.
    Salsalate: (Minor) Due to high protein binding, salicylates could be displaced from binding sites or could displace other highly protein-bound drugs such as penicillins. An enhanced effect of the displaced drug may occur.
    Selpercatinib: (Major) Avoid coadministration of selpercatinib and nafcillin due to the risk of decreased selpercatinib exposure which may reduce its efficacy. Selpercatinib is a CYP3A4 substrate and nafcillin is a moderate CYP3A4 inducer. Coadministration with other moderate CYP3A4 inducers is predicted to decrease selpercatinib exposure by 40% to 70%.
    Selumetinib: (Major) Avoid coadministration of selumetinib and nafcillin due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A4 substrate and nafcillin is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A4 inducer is predicted to decrease selumetinib exposure by 38%.
    Siponimod: (Moderate) Concomitant use of siponimod and nafcillin is not recommended for patients with CYP2C9*1/*3 and *2/*3 genotypes due to a significant decrease in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; nafcillin is a moderate CYP3A4 inducer. Across different CYP2C9 genotypes, a moderate CYP3A4 inducer decreased the exposure of siponimod by up to 52% according to in silico evaluation.
    Sodium Benzoate; Sodium Phenylacetate: (Moderate) Antibiotics that undergo tubular secretion such as penicillins may compete with phenylacetlyglutamine and hippuric acid for active tubular secretion. The overall usefulness of sodium benzoate; sodium phenylacetate is due to the excretion of its metabolites. An increase in metabolite concentrations could contribute to failed treatment and worsening of the patient's clinical status. This combination should be used with caution.
    Sodium picosulfate; Magnesium oxide; Anhydrous citric acid: (Major) Prior or concomitant use of antibiotics with sodium picosulfate; magnesium oxide; anhydrous citric acid may reduce efficacy of the bowel preparation as conversion of sodium picosulfate to its active metabolite bis-(p-hydroxy-phenyl)-pyridyl-2-methane (BHPM) is mediated by colonic bacteria. If possible, avoid coadministration. Certain antibiotics (i.e., tetracyclines and quinolones) may chelate with the magnesium in sodium picosulfate; magnesium oxide; anhydrous citric acid solution. Therefore, these antibiotics should be taken at least 2 hours before and not less than 6 hours after the administration of sodium picosulfate; magnesium oxide; anhydrous citric acid solution.
    Sofosbuvir; Velpatasvir: (Major) Avoid coadministration of velpatasvir with nafcillin. Taking these drugs together may significantly decrease velpatasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. Velpatasvir is a CYP3A4 substrate; nafcillin is an in vitro inducer of CYP3A4.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Avoid coadministration of velpatasvir with nafcillin. Taking these drugs together may significantly decrease velpatasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. Velpatasvir is a CYP3A4 substrate; nafcillin is an in vitro inducer of CYP3A4. (Major) Avoid coadministration of voxilaprevir (a CYP3A4 substrate) with moderate to strong inducers of CYP3A4, such as nafcillin. Taking these drugs together may significantly decrease voxilaprevir plasma concentrations, potentially resulting in loss of antiviral efficacy.
    Sonidegib: (Major) Avoid the concomitant use of sonidegib and nafcillin; sonidegib levels may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate and nafcillin is a moderate CYP3A4 inducer in vitro. Physiologic-based pharmacokinetics (PBPK) simulations indicate that a moderate CYP3A4 inducer would decrease the sonidegib AUC by 56% if administered for 14 days and by 69% if the moderate CYP3A inducer is administered for more than 14 days.
    Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if nafcillin must be administered. Monitor for reduced efficacy of sufentanil injection and signs of opioid withdrawal if coadministration with nafcillin is necessary; consider increasing the dose of sufentanil injection as needed. If nafcillin is discontinued, consider a dose reduction of sufentanil injection and frequently monitor for signs or respiratory depression and sedation. Sufentanil is a CYP3A4 substrate and nafcillin is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease sufentanil concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Tazemetostat: (Major) Avoid coadministration of tazemetostat with nafcillin as concurrent use may decrease tazemetostat exposure, which may reduce its efficacy. Tazemetostat is a CYP3A4 substrate and nafcillin is a moderate CYP3A4 inducer.
    Telaprevir: (Moderate) Close clinical monitoring is advised when administering nafcillin with telaprevir due to the potential for telaprevir treatment failure. If nafcillin dose adjustments are made, re-adjust the dose upon completion of telaprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathways of nafcillin and telaprevir. Nafcillin is an inducer of the hepatic isoenzyme CYP3A4; telaprevir is metabolized by this isoenzyme. When used in combination, the plasma concentrations of telaprevir may decrease, resulting in decreased telaprevir efficacy.
    Telmisartan; Amlodipine: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as nafcillin, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Terbinafine: (Moderate) Due to the risk for breakthrough fungal infections, caution is advised when administering terbinafine with nafcillin. Although this interaction has not been studied by the manufacturer, and published literature suggests the potential for interactions to be low, taking these drugs together may decrease the systemic exposure of terbinafine. Predictions about the interaction can be made based on the metabolic pathways of both drugs. Terbinafine is metabolized by at least 7 CYP isoenyzmes, with major contributions coming from CYP3A4; nafcillin induces this enzyme. Monitor patients for breakthrough fungal infections.
    Tetracyclines: (Major) Avoid the coadministration of tetracycline antibiotics with penicillins as tetracyclines may interfere with the bactericidal action of penicillins.
    Typhoid Vaccine: (Major) Antibiotics which possess bacterial activity against salmonella typhi organisms may interfere with the immunological response to the live typhoid vaccine. Allow 24 hours or more to elapse between the administration of the last dose of the antibiotic and the live typhoid vaccine.
    Ubrogepant: (Major) Increase the initial and second dose of ubrogepant to 100 mg if coadministered with nafcillin as concurrent use may decrease ubrogepant exposure and reduce its efficacy. Ubrogepant is a CYP3A4 substrate; nafcillin is a moderate CYP3A4 inducer.
    Venetoclax: (Major) Avoid the concomitant use of venetoclax and nafcillin; venetoclax levels may be decreased and its efficacy reduced. Venetoclax is a CYP3A4 substrate and nafcillin is a moderate CYP3A4 inducer. Consider alternative agents. In a drug interaction study (n = 11), the venetoclax Cmax and AUC values were decreased by 42% and 71%, respectively, following the co-administration of multiple doses of a strong CYP3A4 inducer. Use of venetoclax with a moderate CYP3A4 inducer has not been evaluated.
    Vincristine Liposomal: (Moderate) Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP3A4 may increase the metabolism of vincristine and decrease the efficacy of drug, including nafcillin (in vitro). Patients receiving these drugs concurrently with vincristine should be monitored for possible loss of vincristine efficacy.
    Vincristine: (Moderate) Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP3A4 may increase the metabolism of vincristine and decrease the efficacy of drug, including nafcillin (in vitro). Patients receiving these drugs concurrently with vincristine should be monitored for possible loss of vincristine efficacy.
    Voclosporin: (Major) Avoid coadministration of voclosporin with nafcillin. Coadministration may decrease voclosporin exposure resulting in decreased efficacy. Voclosporin is a sensitive CYP3A4 substrate and nafcillin is a moderate CYP3A4 inducer. Coadministration with moderate CYP3A4 inducers is predicted to decrease voclosporin exposure by 70%.
    Vorapaxar: (Moderate) Use caution during concurrent use of vorapaxar and nafcillin. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible when vorapaxar, a CYP3A4 substrate, is coadministered with nafcillin, an inducer of CYP3A4 in vitro.
    Voxelotor: (Major) Avoid coadministration of voxelotor and nafcillin as concurrent use may decrease voxelotor exposure and lead to reduced efficacy. If coadministration is unavoidable, increase voxelotor dosage to 2,500 mg PO once daily. Voxelotor is a substrate of CYP3A4; nafcillin is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer is predicted to decrease voxelotor exposure by up to 60%.
    Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with nafcillin is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Nafcillin is a moderate CYP3A4 inducer and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance. High-dose (e.g., 12 g/day IV) nafcillin added to established warfarin therapy may warrant a 2- to 5-fold increase in warfarin dosage within 2 weeks of starting therapy. The dosage of warfarin may be reduced to pretreatment levels within 4 weeks of discontinuing nafcillin therapy.
    Zanubrutinib: (Major) Avoid the concomitant use of zanubrutinib and nafcillin. Coadministration may result in decreased zanubrutinib exposure and reduced efficacy. Zanubrutinib is a CYP3A4 substrate; nafcillin is a moderate CYP3A4 inducer. The AUC of zanubrutinib is predicted to decrease by 60% when coadministered with another moderate CYP3A4 inducer.

    PREGNANCY AND LACTATION

    Pregnancy

    Penicillin antibiotics cross the placenta. Use of penicillins in human pregnancy has not shown any evidence of harmful effects on the fetus. Animal data have also not demonstrated any evidence of impaired fertility or harmful fetal effects. However, there are no adequate and well-controlled studies in pregnant women to show conclusively that harmful effects of penicillins on the fetus can be excluded. Because animal reproduction studies are not always predictive of human response, nafcillin should be used in pregnant women only if clearly needed.

    Penicillins, such as nafcillin, are excreted in human breast milk. Use caution when penicillins are administered to a breast-feeding woman. Penicillins may cause diarrhea (due to disruption of GI flora), candidiasis, and skin rash in breast-feeding infants. Unless the infant is allergic to penicillins, breast-feeding is generally safe during maternal penicillin therapy; the infant should be observed for potential effects.

    MECHANISM OF ACTION

    Mechanism of Action: Beta-lactam antibiotics such as nafcillin are mainly bactericidal. Nafcillin inhibits the third and final stage of bacterial cell wall synthesis by preferentially binding to specific penicillin-binding proteins (PBPs) that are located inside the bacterial cell wall. Like all beta-lactam antibiotics, nafcillin's ability to interfere with PBP-mediated cell wall synthesis ultimately leads to cell lysis. Lysis is mediated by bacterial cell wall autolytic enzymes (i.e., autolysins). The relationship between PBPs and autolysins is unclear, but it is possible that the beta-lactam antibiotic interferes with an autolysin inhibitor.Nafcillin, because of its side chain, resists destruction by beta-lactamases. This makes it useful for treating bacteria that resist penicillin due to the presence of penicillinase. Nafcillin is ineffective, however, against methicillin-resistant S.aureus (MRSA). These organisms appear to resist nafcillin and related antistaphylococcal penicillins due to the presence of a relatively insensitive PBP, although this mechanism is not fully understood.Nafcillin is extremely active against most strains of penicillinase-producing Staphylococcus aureus and some strains of Staphylococcus epidermidis. As mentioned above, methicillin-resistant strains of staphylococci are resistant. The antistaphylococcal penicillins are active against group A streptococci and Streptococcus viridans, although the natural penicillins are more potent against streptococci and are preferred. The antistaphylococcal penicillins have limited activity against gram-negative and anaerobic bacteria, so they are not recommended for treating these infections. Clinicians are advised to consult susceptibility data to determine nafcillin activity.

    PHARMACOKINETICS

    Nafcillin is administered orally and parenterally. Protein binding is approximately 70—90%. Nafcillin is distributed into liver; bone; bile; and pleural, pericardial, peritoneal, and synovial fluids. Although it reaches low levels within the CSF, higher concentrations are obtained when the meninges are inflamed, so nafcillin is effective in the treatment of meningitis. It does cross the placenta. Approximately 60% of a dose is metabolized in the liver to inactive metabolites. Unlike other penicillins, nafcillin is excreted primarily in the bile and undergoes enterohepatic circulation.  A small percentage can be excreted in breast milk. The elimination half-life of nafcillin is approximately 30—90 minutes.
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4
    In vitro data suggest that nafcillin may induce the CYP3A4 isoenzyme.

    Oral Route

    Only 10—20% of an oral nafcillin dose is absorbed. Peak serum levels occur within 30—120 minutes following an oral dose.

    Intramuscular Route

    Peak serum nafcillin levels occur within 30—60 minutes following an IM dose. Up to 30% of an IM dose is excreted in the urine.