PHARMACOKINETICS

Intramuscular injections of nafcillin sodium, USP 1 gram produced peak serum levels in 0.5 to 1 hour of 7.61 mcg/mL. The degree of protein binding reported has been 89.9 +/-1.5%. With normal doses nafcillin is found in therapeutic concentrations in the pleural, bile, and amniotic fluids. Insignificant concentrations are found in the cerebrospinal fluid and aqueous humor. Blood concentrations may be tripled by the concurrent use of probenecid. Clinical studies with nafcillin sodium in infants under three days of age and prematures have revealed higher blood levels and slower rates of urinary excretion than in older children and adults. A high concentration of nafcillin sodium is excreted via the bile. About 30% of an intramuscular dose is excreted in the urine.

MICROBIOLOGY

Penicillinase-resistant penicillins exert a bactericidal action against penicillin-susceptible microorganisms during the state of active multiplication. All penicillins inhibit the biosynthesis of the bacterial cell wall. Nafcillin sodium has been shown to be active against most isolates of the following microorganism, both in vitroand in clinical infections as described in the INDICATIONS AND USAGE section.

Gram-Positive Bacteria

Staphylococcus aureus(Methicillin-susceptible isolates only)

Susceptibility Test Methods

For specific information regarding susceptibility test interpretive criteria, and associated test methods and quality control standards recognized by FDA for nafcillin for injection, please see: https://www.fda.gov/STIC.

General

Nafcillin should generally not be administered to patients with a history of sensitivity to any penicillin.

Penicillin should be used with caution in individuals with histories of significant allergies and/or asthma. Whenever allergic reactions occur, penicillin should be withdrawn unless, in the opinion of the physician, the condition being treated is life-threatening and amenable only to penicillin therapy. The use of antibiotics may result in overgrowth of nonsusceptible organisms. If new infections due to bacteria or fungi occur, the drug should be discontinued and appropriate measures taken.

The liver/biliary tract is the primary route of nafcillin clearance. Caution should be exercised when patients with concomitant hepatic insufficiency and renal dysfunction are treated with nafcillin.

Prescribing Nafcillin for Injection in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Laboratory Tests

Bacteriologic studies to determine the causative organisms and their susceptibility to the penicillinase-resistant penicillins should be performed (See CLINICAL PHARMACOLOGY- MICROBIOLOGY). In the treatment of suspected staphylococcal infections, therapy should be changed to another active agent if culture tests fail to demonstrate the presence of staphylococci.

Periodic assessment of organ system function including renal, hepatic, and hematopoietic should be made during prolonged therapy with nafcillin. White blood cell and differential cell counts should be obtained prior to initiation of therapy and periodically during therapy with nafcillin. Urinalysis, serum blood urea nitrogen, and creatinine determinations should be performed at baseline and during therapy with nafcillin. Serum bilirubin, SGOT, SGPT, alkaline phosphatase, and gamma glutamyl transferase should be obtained at baseline and periodically during therapy, especially when using high nafcillin doses. In patients with worsening hepatic function, the risk versus benefit of continued nafcillin use should be re-evaluated.

Drug Interactions

Tetracycline, a bacteriostatic antibiotic, may antagonize the bactericidal effect of penicillin, and concurrent use of these drugs should be avoided.

Nafcillin in high dosage regimens, i.e ., 2 grams every 4 hours, has been reported to decrease the effects of warfarin. When nafcillin and warfarin are used concomitantly, the prothrombin time should be closely monitored and the dose of warfarin adjusted as necessary. This effect may persist for up to 30 days after nafcillin has been discontinued.

Nafcillin when administered concomitantly with cyclosporine has been reported to result in subtherapeutic cyclosporine levels. The nafcillin-cyclosporine interaction was documented in a patient during two separate courses of therapy. When cyclosporine and nafcillin are used concomitantly in organ transplant patients, the cyclosporine levels should be monitored.

Drug/LaboratoryTest Interactions

Nafcillin in the urine can cause a false-positive urine reaction for protein when the sulfosalicyclic acid test is used, but not with the dipstick.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No long term animal studies have been conducted with these drugs. Studies on reproduction (nafcillin) in rats and mice reveal no fetal or maternal abnormalities before conception and continuously through weaning (one generation).

Pregnancy

Teratogenic Effects

Pregnancy Category B

Reproduction studies have been performed in the mouse with oral doses up to 20 times the human dose and orally in the rat at doses up to 40 times the human dose and have revealed no evidence of impaired fertility or harm to the rodent fetus due to nafcillin. There are, however, no adequate or well- controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, nafcillin should be used during pregnancy only if clearly needed.

Nursing Mothers

Penicillins are excreted in human milk. Caution should be exercised when penicillins are administered to a nursing woman.

Pediatric Use

The liver/biliary tract is the principal route of nafcillin elimination. Because of immature hepatic and renal function in pediatric patients, nafcillin excretion may be impaired. Safety and effectiveness in pediatric patients have not been established for the use of intravenous nafcillin. Safety and effectiveness in pediatric patients have been established for the use of intramuscular nafcillin.

Geriatric Use

Clinical studies of Nafcillin for Injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly 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.

Nafcillin for Injection contains 63.39 mg [2.76 mEq] of sodium per gram. At the usual recommended doses, patients would receive between 126.8 and 380.3 mg/day (5.52 and 16.56 mEq) of sodium. The geriatric population may respond with a blunted natriuresis to salt loading. This may be clinically important with regard to such diseases as congestive heart failure.

Information for Patients

Patients should be counseled that antibacterial drugs including Nafcillin for Injection should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Nafcillin for Injection is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Nafcillin for Injection or other antibacterial drugs in the future.

Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.

Body as a Whole

The reported incidence of allergic reactions to penicillin ranges from 0.7 to 10 percent (see WARNINGS). Sensitization is usually the result of treatment, but some individuals have had immediate reactions to penicillin when first treated. In such cases, it is thought that the patients may have had prior exposure to the drug via trace amounts present in milk or vaccines. Two types of allergic reactions to penicillins are noted clinically, immediate and delayed.

Immediate reactions usually occur within 20 minutes of administration and range in severity from urticaria and pruritus to angioedema, laryngospasm, bronchospasm, hypotension, vascular collapse, and death. Such immediate anaphylactic reactions are very rare (see WARNINGS) and usually occur after parenteral therapy but have occurred in patients receiving oral therapy. Another type of immediate reaction, an accelerated reaction, may occur between 20 minutes and 48 hours after administration and may include urticaria, pruritus, and fever.

Although laryngeal edema, laryngospasm, and hypotension occasionally occur, fatality is uncommon. Delayed allergic reactions to penicillin therapy usually occur after 48 hours and sometimes as late as 2 to 4 weeks after initiation of therapy. Manifestations of this type of reaction include serum sickness-like symptoms ( i.e., fever, malaise, urticaria, myalgia, arthralgia, abdominal pain) and various skin rashes. Nausea, vomiting, diarrhea, stomatitis, black or hairy tongue, and other symptoms of gastrointestinal irritation may occur, especially during oral penicillin therapy.

Local Reactions

Pain, swelling, inflammation, phlebitis, thrombophlebitis, and occasional skin sloughing at the injection site have occurred with intravenous administration of nafcillin. (See DOSAGE AND ADMINISTRATION) Severe tissue necrosis with sloughing secondary to subcutaneous extravasation of nafcillin has been reported.

Nervous System Reactions

Neurotoxic reactions similar to those observed with penicillin G could occur with large intravenous or intraventricular doses of nafcillin especially in patients with concomitant hepatic insufficiency and renal dysfunction. (See PRECAUTIONS).

Urogenital Reactions

Renal tubular damage and interstitial nephritis have been associated with the administration of nafcillin. Manifestations of this reaction may include rash, fever, eosinophilia, hematuria, proteinuria, and renal insufficiency.

Hepatic Reactions

Elevation of liver transaminases and/or cholestasis may occur, especially with administration of high doses of nafcillin.

Gastrointestinal Reactions

Pseudomembranous colitis has been reported with the use of nafcillin. The onset of pseudomembranous colitis symptoms may occur during or after antibiotic treatment (see WARNINGS).

Metabolic Reactions

Agranulocytosis, neutropenia, and bone marrow depression have been associated with the use of nafcillin.

To report SUSPECTED ADVERSE EVENTS, contact FDA at 1-800-FDA-1088 or www.fda.gov.

OVERDOSAGE

Neurotoxic reactions similar to those observed with penicillin G may arise with intravenous doses of nafcillin especially in patients with concomitant hepatic insufficiency and renal dysfunction (see PRECAUTIONS).

In the case of overdosage, discontinue nafcillin, treat symptomatically and institute supportive measures as required. Hemodialysis does not increase the rate of clearance of nafcillin from the blood.

DIRECTIONS FOR USE

For Intramuscular Use

Reconstitute with Sterile Water for Injection, USP, 0.9% Sodium Chloride Injection, USP or Bacteriostatic Water for Injection, USP (with benzyl alcohol or parabens); add 3.4 mL to the 1 g vial for 4 mL resulting solution and 6.6 mL to the 2 g vial for 8 mL resulting solution. All reconstituted vials have a concentration of 250 mg per mL.

The clear solution should be administered by deep intragluteal injection immediately after reconstitution.

Reconstituted Stability

Reconstitute with the required amount of Sterile Water for Injection, USP, 0.9% Sodium Chloride Injection, USP or Bacteriostatic Water for Injection, USP (with benzyl alcohol or parabens). The resulting solutions are stable for 3 days at room temperature or 7 days under refrigeration and 90 days frozen.

For Direct Intravenous Use

The required amount of drug should be diluted in 15 to 30 mL of Sterile Water for Injection, USP or Sodium Chloride Injection, USP and injected over a 5- to 10- minute period. This may be accomplished through the tubing of an intravenous infusion if desirable.

For Administration by Intravenous Drip

Reconstitute as directed above (For Intravenous Use) prior to diluting with intravenous solution.

Only those solutions listed above should be used for the intravenous infusion of nafcillin sodium, USP. The concentration of the antibiotic should fall within the range specified. The drug concentration and the rate and volume of the infusion should be adjusted so that the total dose of nafcillin is administered before the drug loses its stability in the solution in use.

There is no clinical experience available on the use of this agent in neonates or infants for this route of administration.

This route of administration should be used for relatively short-term therapy (24 to 48 hours) because of the occasional occurrence of thrombophlebitis particularly in elderly patients.

If another agent is used in conjunction with nafcillin therapy, it should not be physically mixed with nafcillin but should be administered separately.