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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 150 mg/kg/day IV divided every 6 hours (Max: 1 g/dose) for mild to moderate infections and 150 to 200 mg/kg/day IV divided every 4 to 6 hours (Max: 12 g/day) for severe infections.

    Neonates older than 7 days weighing more than 2 kg†

    25 mg/kg/dose IV every 6 hours.

    Neonates older than 7 days weighing 1 to 2 kg†

    25 mg/kg/dose IV every 8 hours.

    Neonates older than 7 days weighing less than 1 kg†

    25 mg/kg/dose IV every 12 hours until 2 weeks postnatal age (PNA), followed by 25 mg/kg/dose IV every 8 hours.

    Neonates 0 to 7 days weighing more than 2 kg†

    25 mg/kg/dose IV every 8 hours.

    Neonates 0 to 7 days weighing 2 kg or less†

    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 150 mg/kg/day IM divided every 6 hours (Max: 1 g/dose) for mild to moderate infections and 150 to 200 mg/kg/day IM divided every 4 to 6 hours (Max: 12 g/day) for severe infections is suggested. 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 or IV every 4 hours for severe infections.

    Neonates older than 7 days weighing more than 2 kg

    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 7 days weighing 1 to 2 kg

    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. NOTE: In general, IM administration of drugs 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.

    Neonates older than 7 days weighing less than 1 kg

    25 mg/kg/dose IM every 12 hours until 2 weeks postnatal age (PNA), followed by 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. NOTE: In general, IM administration of drugs 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.

    Neonates 0 to 7 days weighing more than 2 kg

    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 0 to 7 days weighing 2 kg or less

    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. NOTE: In general, IM administration of drugs 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.

    For the treatment of infective endocarditis.
    Intravenous dosage
    Adults

    12 g/day IV divided every 4 to 6 hours is recommended by clinical practice guidelines. The FDA-approved dosage for severe infections is 1 g IV every 4 hours. Clinical practice 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 clinical practice guidelines. Nafcillin is as 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†

    150 to 200 mg/kg/day IV divided every 4 to 6 hours is recommended by the American Academy of Pediatrics (AAP) for severe infections.

    Neonates older than 7 days weighing more than 2 kg†

    25 mg/kg/dose IV every 6 hours is the general dosage recommended by the American Academy of Pediatrics (AAP).

    Neonates older than 7 days weighing 1 to 2 kg†

    25 mg/kg/dose IV every 8 hours is the general dosage recommended by the American Academy of Pediatrics (AAP).

    Neonates older than 7 days weighing less than 1 kg†

    25 mg/kg/dose IV every 12 hours until 2 weeks postnatal age (PNA), followed by 25 mg/kg/dose IV every 8 hours is the general dosage recommended by the American Academy of Pediatrics (AAP).

    Neonates 0 to 7 days weighing more than 2 kg†

    25 mg/kg/dose IV every 8 hours is the general dosage recommended by the American Academy of Pediatrics (AAP).

    Neonates 0 to 7 days weighing 2 kg or less†

    25 mg/kg/dose IV every 12 hours is the general dosage recommended by the American Academy of Pediatrics (AAP).

    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 (e.g., pneumonia, community-acquired pneumonia).
    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. Clinical practice guidelines recommend nafcillin as preferred therapy for community-acquired pneumonia (CAP) due to methicillin-susceptible S. aureus.

    Infants†, Children†, and Adolescents†

    150 to 200 mg/kg/day IV divided every 4 to 6 hours (Max: 2 g/dose). Clinical practice guidelines recommend a semisynthetic penicillin (e.g., nafcillin) for 10 days for hospitalized children with community-acquired pneumonia (CAP) due to methicillin-susceptible S. aureus.

    Neonates older than 7 days weighing more than 2 kg†

    25 mg/kg/dose IV every 6 hours.

    Neonates older than 7 days weighing 1 to 2 kg†

    25 mg/kg/dose IV every 8 hours.

    Neonates older than 7 days weighing less than 1 kg†

    25 mg/kg/dose IV every 12 hours until 2 weeks postnatal age (PNA), followed by 25 mg/kg/dose IV every 8 hours.

    Neonates 0 to 7 days weighing more than 2 kg†

    25 mg/kg/dose IV every 8 hours.

    Neonates 0 to 7 days weighing 2 kg or less†

    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. Clinical practice guidelines recommend nafcillin as preferred therapy for community-acquired pneumonia (CAP) due to methicillin-susceptible S. aureus.

    Infants, Children, and Adolescents

    150 to 200 mg/kg/day IM divided every 4 to 6 hours (Max: 2 g/dose) is suggested. Clinical practice guidelines recommend a semisynthetic penicillin (e.g., nafcillin) for 10 days for hospitalized children with community-acquired pneumonia (CAP) due to methicillin-susceptible S. aureus. 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 or IV every 4 hours for severe infections.

    Neonates older than 7 days weighing more than 2 kg

    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 7 days weighing 1 to 2 kg

    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. NOTE: In general, IM administration of drugs 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.

    Neonates older than 7 days weighing less than 1 kg

    25 mg/kg/dose IM every 12 hours until 2 weeks postnatal age (PNA), followed by 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. NOTE: In general, IM administration of drugs 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.

    Neonates 0 to 7 days weighing more than 2 kg

    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 0 to 7 days weighing 2 kg or less

    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. NOTE: In general, IM administration of drugs 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.

    MAXIMUM DOSAGE

    Adults

    6 g/day IV/IM; however, 12 g/day IV/IM has been used off-label.

    Geriatric

    6 g/day IV/IM; however, 12 g/day IV/IM has been used.

    Adolescents

    >= 40 kg: 6 g/day IM; safety and efficacy of IV route have not been established; 12 g/day IV/IM has been used.
    < 40 kg: 100 mg/kg/day IM; safety and efficacy of IV route have not been established; up to 200 mg/kg/day IV/IM (not to exceed 12 g/day IV/IM) has been used.

    Children

    >= 40 kg: 6 g/day IM; safety and efficacy of IV route have not been established; 12 g/day IV/IM has been used.
    < 40 kg: 100 mg/kg/day IM; safety and efficacy of IV route have not been established; up to 200 mg/kg/day IV/IM (not to exceed 12 g/day IV/IM) has been used.

    Infants

    100 mg/kg/day IM; safety and efficacy of IV route have not been established; up to 200 mg/kg/day IV/IM (not to exceed 12 g/day IV/IM) has been used.

    Neonates

    20 mg/kg/day IM is the FDA-approved dosage for all neonates. Safety and efficacy of IV route have not been established; however, the following doses have been used off-label:
    > 7 days and > 2000 g: up to 200 mg/kg/day IV/IM.
    > 7 days and 1201—2000 g: up to 150 mg/kg/day IV/IM.
    <= 7 days and > 2000 g: up to 150 mg/kg/day IV/IM.
    <= 7 days and 1201— 2000 g: up to 100 mg/kg/day IV/IM.
    >= 29 days and <= 1200 g: up to 150 mg/kg/day IV.
    < 29 days and <= 1200 g: up to 100 mg/kg/day IV.

    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.
     
    Intramuscular Injection
    Inject deeply into a large muscle (i.e., upper outer quadrant of the gluteus maximus or lateral part of the thigh). Aspirate prior to injection to avoid injection into a blood vessel. 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.

    STORAGE

    Generic:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Store reconstituted product in accordance with package insert instructions
    - 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.

    Colitis, diarrhea, GI disease, inflammatory bowel disease, pseudomembranous colitis, ulcerative colitis

    Almost all antibacterial agents have been associated with pseudomembranous colitis (antibiotic-associated colitis) which may range in severity from mild to life-threatening. In the colon, overgrowth of Clostridia may exist when normal flora is altered subsequent to antibacterial administration. The toxin produced by Clostridium difficile is a primary cause of pseudomembranous colitis. It is known that systemic use of antibiotics predisposes patients to development of pseudomembranous colitis. Consideration should be given to the diagnosis of pseudomembranous colitis in patients presenting with diarrhea following nafcillin administration. Systemic antibiotics should be prescribed with caution to patients with inflammatory bowel disease such as ulcerative colitis or other GI disease. If diarrhea develops during therapy, the drug should be discontinued. Following diagnosis of pseudomembranous colitis, therapeutic measures should be instituted. In milder cases, the colitis may respond to discontinuation of the offending agent. In moderate to severe cases, fluids and electrolytes, protein supplementation, and treatment with an antibacterial effective against Clostridium difficile may be warranted. Products inhibiting peristalsis are contraindicated in this clinical situation. Practitioners should be aware that antibiotic-associated colitis has been observed to occur over two months or more following discontinuation of systemic antibiotic therapy; a careful medical history should be taken.

    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
    proteinuria / Delayed / Incidence not known
    eosinophilia / Delayed / Incidence not known
    hematuria / 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 (unspecified) / 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

    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; 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; Hydrocodone: (Moderate) Hydrocodone is metabolized by CYP3A4. Nafcillin, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with nafcillin.
    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; Hydrochlorothiazide, HCTZ; 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; Hydrochlorothiazide, HCTZ; 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; 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; Telmisartan: (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.
    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: (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: (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: (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: (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.
    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 substrate and nafcillin is a moderate CYP3A4 inducer in vitro. Coadministration with a strong CYP3A4/5 inducer, rifampin, significantly decreased the plasma exposure of axitinib in healthy volunteers.
    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.
    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.
    Bosutinib: (Major) Avoid concomitant use of bosutinib, a CYP3A4 substrate, with a moderate CYP3A4 inducer such as nafcillin, as a decrease in bosutinib plasma exposure may occur.
    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) Hydrocodone is metabolized by CYP3A4. Nafcillin, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with nafcillin.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Hydrocodone is metabolized by CYP3A4. Nafcillin, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with nafcillin.
    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.
    Cabazitaxel: (Moderate) Cabazitaxel is a CYP3A4 substrate and concomitant use with CYP3A4 inducers such as nafcillin may lead to reduced concentrations of cabazitaxel. Caution should be utilized when CYP3A4 inducers are coadministered with cabazitaxel, and alternative therapies with low enzyme induction potential should be considered.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Hydrocodone is metabolized by CYP3A4. Nafcillin, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with nafcillin.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Hydrocodone is metabolized by CYP3A4. Nafcillin, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with nafcillin.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Hydrocodone is metabolized by CYP3A4. Nafcillin, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with nafcillin.
    Chlorpheniramine; Hydrocodone: (Moderate) Hydrocodone is metabolized by CYP3A4. Nafcillin, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with nafcillin.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Hydrocodone is metabolized by CYP3A4. Nafcillin, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with nafcillin.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Hydrocodone is metabolized by CYP3A4. Nafcillin, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with nafcillin.
    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.
    Clindamycin: (Moderate) Concomitant use of clindamycin and nafcillin may increase clindamycin clearance and result in loss of efficacy of clindamycin. Clindamycin is a CYP3A4 substrate; nafcillin is a moderate inducer of CYP3A4. Caution and close monitoring are advised if these drugs are used together.
    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.
    Cobicistat; Elvitegravir; 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.
    Cobicistat; Elvitegravir; 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.
    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.
    Cyclophosphamide: (Minor) Use caution if cyclophosphamide is used concomitantly with nafcillin, and monitor for a possible increase in cyclophosphamide-related adverse events. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are inactivated by aldehyde dehydrogenase-mediated oxidation. Nafcillin is a moderate CYP3A4 inducer in vitro. It is not yet clear what effects CYP450 inducers have on the activation and/or toxicity of cyclophosphamide; the production of active or neurotoxic metabolites may be increased.
    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) The metabolism of dapsone may be accelerated when administered concurrently with nafcillin, a known inducer of CYP3A4. Coadministration is expected to decrease the plasma concentration of dapsone and increase the formation of dapsone hydroxylamine (a metabolite associated with hemolysis). If these drugs must be administered together, closely monitor for a reduction in dapsone efficacy and signs of hemolytic anemia.
    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.
    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 penicillins together with caution. Dichlorphenamide increases potassium excretion and can cause hypokalemia and should be used cautiously with other drugs that may cause hypokalemia including penicillins. 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.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Hydrocodone is metabolized by CYP3A4. Nafcillin, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with nafcillin.
    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, THC: (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.
    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.
    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.
    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, to a maximum of 450 mg. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Nafcillin is a CYP3A4 inducer in vitro. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days; coadministration with nafcillin may also decrease erlotinib exposure.
    Erythromycin; Sulfisoxazole: (Minor) Sulfonamides may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. These combinations should be used with caution and patients monitored for increased side effects.
    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.
    Etoposide, VP-16: (Major) Monitor for clinical efficacy of etoposide if used concomitantly with nafcillin. In vitro, nafcillin is an inducer of CYP3A4; etoposide, VP-16 is a CYP3A4 substrate. Coadministration of etoposide with a strong CYP3A4 inducer (phenytoin) resulted in increased etoposide clearance and reduced efficacy, as did coadministration with a weak inducer of CYP3A4 and P-glycoprotein (P-gp) (valproic acid).
    Exemestane: (Moderate) Use caution if coadministration of exemestane with nafcillin is necessary, and monitor for a possible decrease in the efficacy of exemestane. Exemestane is a CYP3A4 substrate; nafcillin is a moderate CYP3A4 inducer in vitro. In a pharmacokinetic interaction study (n = 10) with a strong CYP3A4 inducer, rifampicin (600 mg daily for 14 days), the mean Cmax and AUC of exemestane (single dose) decreased by 41% and 54%, respectively. The manufacturer of exemestane recommends a dose increase when concomitant use with a strong CYP3A4 inducer is necessary; recommendations are not available for moderate CYP3A4 inducers.
    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: (Severe) 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.
    Gefitinib: (Major) Monitor for clinical response of gefitinib if used concomitantly with nafcillin. Gefitinib is metabolized significantly by CYP3A4 and in vitro, nafcillin is a CYP3A4 inducer; coadministration may increase gefitinib metabolism and decrease gefitinib concentrations. While the manufacturer has provided no guidance regarding the use of gefitinib with mild or moderate CYP3A4 inducers, administration of a single 500 mg gefitinib dose with a concurrent strong CYP3A4 inducer (rifampin) resulted in reduced mean AUC of gefitinib by 83%.
    Guaifenesin; Hydrocodone: (Moderate) Hydrocodone is metabolized by CYP3A4. Nafcillin, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with nafcillin.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Hydrocodone is metabolized by CYP3A4. Nafcillin, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with nafcillin.
    Homatropine; Hydrocodone: (Moderate) Hydrocodone is metabolized by CYP3A4. Nafcillin, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with nafcillin.
    Hydrocodone: (Moderate) Hydrocodone is metabolized by CYP3A4. Nafcillin, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with nafcillin.
    Hydrocodone; Ibuprofen: (Moderate) Hydrocodone is metabolized by CYP3A4. Nafcillin, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with nafcillin.
    Hydrocodone; Phenylephrine: (Moderate) Hydrocodone is metabolized by CYP3A4. Nafcillin, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with nafcillin.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Hydrocodone is metabolized by CYP3A4. Nafcillin, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with nafcillin.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Hydrocodone is metabolized by CYP3A4. Nafcillin, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with nafcillin.
    Hydrocodone; Pseudoephedrine: (Moderate) Hydrocodone is metabolized by CYP3A4. Nafcillin, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with nafcillin.
    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.
    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.
    Irinotecan: (Major) In vitro, nafcillin is a moderate inducer of CYP3A4; irinotecan is a CYP3A4 substrate. Coadministration could potentially decrease irinotecan exposure, although coadministration of irinotecan with dexamethasone, a moderate CYP3A4 inducer, did not affect irinotecan pharmacokinetics. Monitor for efficacy of chemotherapy.
    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.
    Ivacaftor: (Moderate) Use caution when administering ivacaftor and nafcillin concurrently; the clinical impact of this interaction has not yet been determined. Administration of ivacaftor with strong CYP3A inducers is not recommended because sub-therapeutic ivacaftor exposure could result. Ivacaftor is a CYP3A substrate and nafcillin may induce CYP3A. Co-administration with rifampin, a strong CYP3A inducer, decreased the ivacaftor exposure by approximately 9-fold.
    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.
    Lapatinib: (Moderate) Lapatinib is metabolized by CYP3A4 and CYP3A5 enzymes. Drugs that are inducers of CYP3A4 activity, such as nafcillin, will decrease the plasma concentrations of lapatinib. If treatment with nafcillin is necessary, consider a lapatinib dose escalation. If nevirapine is discontinued, reduce the lapatinib dose to the indicated dose.
    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.
    Lumacaftor; Ivacaftor: (Moderate) Use caution when administering ivacaftor and nafcillin concurrently; the clinical impact of this interaction has not yet been determined. Administration of ivacaftor with strong CYP3A inducers is not recommended because sub-therapeutic ivacaftor exposure could result. Ivacaftor is a CYP3A substrate and nafcillin may induce CYP3A. Co-administration with rifampin, a strong CYP3A inducer, decreased the ivacaftor exposure by approximately 9-fold.
    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.
    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. The effect of moderate CYP3A4 induction on neratinib concentrations has not been studied; however, coadministration with a strong CYP3A4 inducer decreased neratinib exposure by 87% and decreased exposure to active metabolites M6 and M7 by 37% to 49%. Because of the significant impact on neratinib exposure from strong CYP3A4 induction, the potential impact on neratinib efficacy from concomitant use with moderate CYP3A4 inducers should be considered as they may also significantly decrease neratinib exposure.
    Nintedanib: (Major) In vitro, nafcillin is a CYP3A4 inducer and nintedanib is a minor CYP3A4 substrate. Coadministration of nintedanib with CYP3A4 inducers such as nafcillin should be avoided as these drugs may decrease exposure to nintedanib and compromise its efficacy.
    Olaparib: (Major) Avoid the coadministration of olaparib with nafcillin due to decreased olaparib exposure; if concomitant use is unavoidable, there is a potential for decreased efficacy of olaparib. Olaparib is a CYP3A4 substrate and nafcillin is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of olaparib by 60%.
    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.
    Palbociclib: (Major) Use caution and monitor patients for decreased palbociclib efficacy if nafcillin is used concomitantly with palbociclib. Palbociclib is a primary substrate of CYP3A and nafcillin is a moderate CYP3A inducer. In a drug interaction study, coadministration of multiple daily doses of a moderate CYP3A inducer, modafinil, decreased the plasma exposure of a single dose of palbociclib in healthy patients by 32% and the Cmax by 11% (n = 14).
    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.
    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.
    Phenytoin: (Minor) Penicillin G is 60% bound to albumin or moderately protein bound. Displacement of penicillins from plasma protein binding sites by highly protein bound drugs (e.g., phenytoin, fosphenytoin) 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.
    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.
    Pyrimethamine; Sulfadoxine: (Minor) Sulfonamides may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. These combinations should be used with caution and patients monitored for increased side effects.
    Ribociclib: (Moderate) Use caution if coadministration of ribociclib with nafcillin is necessary, as the systemic exposure of ribociclib may be decreased resulting in decreased efficacy. Ribociclib is extensively metabolized by CYP3A4 and nafcillin is a moderate CYP3A4 inducer.
    Ribociclib; Letrozole: (Moderate) Use caution if coadministration of ribociclib with nafcillin is necessary, as the systemic exposure of ribociclib may be decreased resulting in decreased efficacy. Ribociclib is extensively metabolized by CYP3A4 and nafcillin is a moderate CYP3A4 inducer.
    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.
    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.
    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 the sonidegib geometric mean steady-state AUC (0-24 hours) would decrease by 56% in cancer patients who received 14 days of sonidegib 200 mg/day with a moderate CYP3A inducer. Additionally, the PBPK model predicts that the sonidegib geometric mean steady-state AUC (0-24hours) would decrease by 69% in cancer patients who received sonidegib 200 mg/day with a moderate CYP3A inducer for 4 months.
    Sorafenib: (Major) Sorafenib is a CYP3A4 substrate, and concomitant use with a strong CYP3A4 inducer such as nafcillin may lead to reduced sorafenib concentrations. For example, concurrent use of sorafenib and the CYP3A4 inducer rifampicin resulted in an average 37% reduction in the sorafenib AUC. Avoid the use of sorafenib with a strong CYP3A4 inducer. If a strong CYP3A4 inducer must be coadministered with sorafenib, consider a sorafenib dose increase.
    Sulfadiazine: (Minor) Sulfonamides may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. These combinations should be used with caution and patients monitored for increased side effects.
    Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Minor) Sulfonamides may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. These combinations should be used with caution and patients monitored for increased side effects.
    Sulfasalazine: (Minor) Sulfonamides may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. These combinations should be used with caution and patients monitored for increased side effects.
    Sulfisoxazole: (Minor) Sulfonamides may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. These combinations should be used with caution and patients monitored for increased side effects.
    Sulfonamides: (Minor) Sulfonamides may compete with penicillin for renal tubular secretion, increasing penicillin serum concentrations. These combinations should be used with caution and patients monitored for increased side effects.
    Tamoxifen: (Major) In vitro, nafcillin is a CYP3A4 inducer. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Nafcillin may induce the CYP3A4 metabolism of tamoxifen to these metabolites, which can compromise efficacy; plasma concentrations of tamoxifen and its active metabolites have been reduced when coadministered other CYP3A4 inducers. If coadministration cannot be avoided, monitor for changes to the therapeutic effects of tamoxifen.
    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.
    Temsirolimus: (Moderate) Use caution if coadministration of temsirolimus with nafcillin is necessary, due to the risk of decreased efficacy of temsirolimus. Temsirolimus is a CYP3A4 substrate and nafcillin is a moderate inducer of CYP3A4 in vitro. The manufacturer of temsirolimus recommends a dose increase if coadministered with a strong CYP3A4 inducer, but recommendations are not available for concomitant use of moderate CYP3A4 inducers. Coadministration of temsirolimus with rifampin, a strong CYP3A4/5 inducer, had no significant effect on the AUC or Cmax of temsirolimus, but decreased the sirolimus AUC and Cmax by 56% and 65%, respectively.
    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.
    Tofacitinib: (Major) Nafcillin is a CYP3A4 inducer, and tofacitinib exposure is decreased when coadministered with potent CYP3A4 inducers. A loss of response or reduced clinical response to tofacitinib may occur.
    Tolvaptan: (Major) Tolvaptan is metabolized by CYP3A4. Nafcillin is an inducer of CYP3A4. Coadministration may result in reduced plasma concentration and subsequent reduced effectiveness of tolvaptan therapy and should be avoided. If coadministration is unavoidable, an increase in the tolvaptan dose may be necessary and patients should be monitored for decreased effectiveness of tolvaptan.
    Trabectedin: (Minor) Use caution if coadministration of trabectedin and nafcillin is necessary, due to the risk of decreased trabectedin exposure. Trabectedin is a CYP3A substrate and, in vitro, nafcillin is a moderate CYP3A inducer. Coadministration with rifampin (600 mg daily for 6 days), a strong CYP3A inducer, decreased the systemic exposure of a single dose of trabectedin by 31% and the Cmax by 21% compared to a single dose of trabectedin given alone. The manufacturer of trabectedin recommends avoidance of coadministration with strong CYP3A inducers; there are no recommendations for concomitant use of moderate or weak CYP3A inducers.
    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.
    Ulipristal: (Moderate) Ulipristal is a substrate of CYP3A4 and nafcillin is a CYP3A4 inducer. Concomitant use may decrease the plasma concentration and effectiveness of ulipristal.
    Vandetanib: (Moderate) Use caution if coadministration of vandetanib with nafcillin is necessary, due to a possibly unpredictable effect on vandetanib efficacy and toxicity. Nafcillin is a moderate inducer of CYP3A4 in vitro. In a crossover study (n = 12), coadministration of vandetanib with a strong CYP3A4 inducer, rifampicin, decreased the mean AUC of vandetanib by 40% (90% CI, 56% to 63%); a clinically meaningful change in the mean vandetanib Cmax was not observed. However, the AUC and Cmax of active metabolite, N-desmethyl-vandetanib, increased by 266% and 414%, respectively.
    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.
    Vinblastine: (Minor) Use caution when administering vinblastine concurrently with a CYP3A4 inducer such as nafcillin. Vinblastine is metabolized by CYP3A4 and nafcillin may decrease vinblastine plasma concentrations.
    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.
    Vinorelbine: (Moderate) Caution is warranted when nafcillin is administered with vinorelbine, as there is a potential for the metabolism of vinorelbine to be affected, decreasing drug efficacy. Patients receiving this drug concurrently with vincristine should be monitored for clinical effects. Vinorelbine is a substrate for cytochrome P450 (CYP) 3A4, and nafcillin is a CYP3A4 inducer in vitro.
    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.
    Warfarin: (Moderate) The addition of high-dose (e.g., 12 g/day IV) nafcillin to established warfarin therapy may decrease the hypoprothrombinemic response in patients previously stabilized on warfarin. A 2- to 5-fold increase in warfarin dosage may be required within 2 weeks of starting therapy. The dosage of warfarin may be reduced to pretreatment levels within 4 weeks of discontinuing nafcillin therapy. Although the mechanism of this drug interaction is unclear, enhanced warfarin hepatic metabolism by nafcillin has been proposed.

    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.