Label: PFIZERPEN- penicillin g potassium powder, for solution

Microbiology

Penicillin G exerts a bactericidal action against penicillin-susceptible microorganisms during the stage of active multiplication. It acts through the inhibition of biosynthesis of cell wall peptidoglycan rendering the cell wall osmotically unstable. It is not active against the penicillinase-producing bacteria, which include many strains of staphylococci or against organisms resistant to beta-lactams because of alterations in the penicillin-binding proteins, such as methicillin-resistant staphylococci. Penicillin G is highly active in vitro against streptococci (groups A, B, C, G, H, L and M) and Neisseria meningitidis.

Other organisms susceptible to penicillin G are N. gonorrhoeae, Corynebacterium diphtheriae, Bacillus anthracis, Clostridium spp., Actinomyces species, "Spirillum minus", Streptobacillus moniliformis, Listeria monocytogenes and Leptospira spp.; Treponema pallidum is extremely sensitive to the bactericidal action of penicillin G.

Some species of gram-negative bacilli were previously considered susceptible to very high intravenous doses of penicillin G (up to 80 million units/day) including some strains of Escherichia coli, Proteus mirabilis, Salmonella spp. and Shigella spp.; Enterobacter aerogenes (formerly Aerobacter aerogenes) and Alcaligenes faecalis. Penicillin G is no longer considered a drug of choice for infections caused by these organisms.

Therapy

Penicillin G Potassium for Injection is indicated in the treatment of serious infections caused by susceptible strains of the designated microorganisms in the conditions listed below.

Appropriate culture and susceptibility tests should be done before treatment in order to isolate and identify organisms causing infection and to determine their susceptibility to penicillin G.

Therapy with Penicillin G Potassium for Injection may be initiated before results of such tests are known when there is reason to believe the infection may involve any of the organisms listed below; however, once these results become available, appropriate therapy should be continued.

To reduce the development of drug-resistant bacteria and maintain effectiveness of Penicillin G Potassium and other antibacterial drugs, Penicillin G Potassium should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Anaphylaxis

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients on penicillin therapy. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and/or a history of sensitivity to multiple allergens. There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe reactions when treated with cephalosporins. Before initiating therapy with penicillin G, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens. If an allergic reaction occurs, penicillin G should be discontinued and appropriate therapy instituted.

Severe cutaneous adverse reactions

Severe cutaneous adverse reactions (SCAR), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported in patients taking beta-lactam antibiotics. When SCAR is suspected, Penicillin G Potassium for Injection should be discontinued immediately and an alternative treatment should be considered.

Clostridioides difficile associated diarrhea

Clostridioides difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Penicillin G Potassium for Injection and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

General

Penicillin should be used with caution in individuals with histories of significant allergies and/or asthma (see Warnings). 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. Penicillin G Potassium for Injection by the intravenous route in high doses (above 10 million units) should be administered slowly because of the potential adverse effects of electrolyte imbalance from the potassium content of the penicillin. Penicillin G Potassium for Injection contains 1.68 mEq potassium and 0.3 mEq of sodium per million units. The use of antibiotics may promote overgrowth of nonsusceptible organisms, including fungi. Indwelling intravenous catheters encourage superinfections. Should superinfection occur, appropriate measures should be taken. When indicated, incision and drainage or other surgical procedures should be performed in conjunction with antibiotic therapy.

Prescribing Penicillin G Potassium for Injection in the absence of 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.

Intramuscular and Intravenous Therapy

Care should be taken to avoid intravenous or accidental intraarterial administration, or injection into or near major peripheral nerves or blood vessels, since such injections may produce neurovascular damage. Particular care should be taken with IV administration because of the possibility of thrombophlebitis.

Information for Patients

Patients should be counseled that antibacterial drugs including Penicillin G Potassium for Injection should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Penicillin G Potassium 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 Penicillin G Potassium 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.

Laboratory Tests

Periodic assessment of organ system function, including frequent evaluation of electrolyte balance, hepatic, renal and hematopoietic systems, and cardiac and vascular status should be performed during prolonged therapy with high doses of intravenous penicillin G (see Adverse Reactions). If any impairment of function is suspected or known to exist, a reduction in the total dosage should be considered (see Dosage and Administration). In suspected staphylococcal infections, proper laboratory studies, including susceptibility tests should be performed. All infections due to Group A beta-hemolytic streptococci should be treated for at least 10 days.

Patients being treated for gonococcal infection should have a serologic test for syphilis before receiving penicillin. All cases of penicillin treated syphilis should receive adequate follow-up including clinical and serological examinations. The recommended follow-up varies with the stage of syphilis being treated.

Drug Interactions

Bacteriostatic antibacterials (i.e., chloramphenicol, erythromycins, sulfonamides or tetracyclines) may antagonize the bactericidal effect of penicillin, and concurrent use of these drugs should be avoided. This has been documented in vitro; however, the clinical significance of this interaction is not well-documented.

Penicillin blood levels may be prolonged by concurrent administration of probenecid which blocks the renal tubular secretion of penicillins. Other drugs may compete with penicillin G for renal tubular secretion and thus prolong the serum half-life of penicillin. These drugs include: aspirin, phenylbutazone, sulfonamides, indomethacin, thiazide diuretics, furosemide and ethacrynic acid.

Drug/Laboratory Test Interactions

After treatment with penicillin G, a false-positive reaction for glucose in the urine may occur with Benedict's solution, Fehling's solution or Clinitest® tablet, but not with the enzyme-based tests, such as Clinistix® and Tes-Tape®.

Penicillin G has been associated with pseudoproteinuria by certain test methods.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No long term animal studies have been conducted with this drug.

Pregnancy

Nursing Mothers

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

Pediatric Use

Incompletely developed renal function in newborns may delay elimination of penicillin; therefore, appropriate reductions in the dosage and frequency of administration should be made in these patients. All newborns treated with penicillins should be monitored closely for clinical and laboratory evidence of toxic or adverse effects (see Precautions).

Pediatric doses are generally determined on a weight basis and should be calculated for each patient individually. Recommended guidelines for pediatric dosages are presented in Dosage and Administration.

Geriatric Use

Clinical studies of penicillin G 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.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Penicillin G Potassium for Injection contains 6.8 mg (0.3 mEq) of sodium per million units. At the usual recommended doses of 10 to 20 million units per day patients would receive between 68 and 136 mg/day (3 and 6 mEq) of sodium per day. 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.

Body as a whole

The Jarisch-Herxheimer reaction is a systemic reaction that may occur after the initiation of penicillin therapy in patients with syphilis or other spirochetal infections (i.e., Lyme disease and Relapsing fever). The reaction begins one or two hours after initiation of therapy and disappears within 12 to 24 hours. It is characterized by fever, chills, myalgias, headache, exacerbation of cutaneous lesions, tachycardia, hyperventilation, vasodilation with flushing and mild hypotension. The pathogenesis of the Herxheimer reaction may be due to the release from the spirochetes of heat-stable pyrogen.

Hypersensitivity reactions

The reported incidence of allergic reactions to all penicillins ranges from 0.7 to 10 percent in different studies (see Warnings). Sensitization is usually the result of previous treatment with a penicillin, but some individuals have had immediate reactions when first treated. In such cases, it is postulated that prior exposure to penicillin may have occurred via trace amounts present in milk or vaccines.

Two types of allergic reactions to penicillin are noted clinically – immediate and delayed.

Immediate reactions usually occur within 20 minutes of administration and range in severity from urticaria and pruritus to angioneurotic edema, laryngospasm, bronchospasm, hypotension, vascular collapse and death (see Warnings). Such immediate anaphylactic reactions are very rare and usually occur after parenteral therapy, but a few cases of anaphylaxis have been reported following 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, fever and, occasionally, laryngeal edema.

Delayed reactions to penicillin therapy usually occur within 1–2 weeks after initiation of therapy. Manifestations include serum sickness-like symptoms, i.e., fever, malaise, urticaria, myalgia, arthralgia, abdominal pain and various skin rashes, ranging from maculopapular eruptions to exfoliative dermatitis.

Contact dermatitis has been observed in individuals who prepare penicillin solutions.

Gastrointestinal system

Pseudomembranous colitis has been reported with the onset occurring during or after penicillin G treatment. Nausea, vomiting, stomatitis, black or hairy tongue, and other symptoms of gastrointestinal irritation may occur, especially during oral therapy.

Hematologic system

Reactions include neutropenia, which resolves after penicillin therapy is discontinued; Coombs-positive hemolytic anemia, an uncommon reaction, occurs in patients treated with intravenous penicillin G in doses greater than 10 million units/day and who have previously received large doses of the drug; and with large doses of penicillin, a bleeding diathesis can occur secondary to platelet dysfunction.

Metabolic

Penicillin G Potassium for Injection (1 million units contains 1.68 mEq of potassium ion) may cause serious and even fatal electrolyte disturbances, i.e., hyperkalemia, when given intravenously in large doses.

Nervous system

Neurotoxic reactions including hyperreflexia, myoclonic twitches, seizures and coma have been reported following the administration of massive intravenous doses, and are more likely in patients with impaired renal function.

Urogenital system

Renal tubular damage and interstitial nephritis have been associated with large intravenous doses of penicillin G. Manifestations of this reaction may include fever, rash, eosinophilia, proteinuria, eosinophiluria, hematuria and a rise in serum urea nitrogen.

Discontinuation of penicillin G results in resolution in the majority of patients.

Local reactions

Phlebitis and thrombophlebitis may occur, and pain at the injection site has been reported with intravenous administration.

To report SUSPECTED ADVERSE EVENTS, contact (insert name of manufacturer) at (insert manufacturer's phone number) or FDA at 1-800-FDA-1088 or http://www.fda.gov/ for voluntary reporting of adverse reactions.

Adult patients

Pediatric patients

This product should not be administered to patients requiring less than one million units per dose (see Precautions-Pediatric Use).

Renal Impairment

Penicillin G is relatively nontoxic, and dosage adjustments are generally required only in cases of severe renal impairment. The recommended dosage regimens are as follows:

Creatinine clearance less than 10 mL/min/1.73m2; administer a full loading dose (see recommended dosages in the tables above) followed by one-half of the loading dose every 8–10 hours.

Uremic patients with a creatinine clearance greater than 10 mL/min/1.73m2; administer a full loading dose (see recommended dosages in the tables above) followed by one-half of the loading dose every 4–5 hours. Additional dosage modification should be made in patients with hepatic disease and renal impairment.

For most acute infections, treatment should be continued for at least 48 to 72 hours after the patient becomes asymptomatic. Antibiotic therapy for Group A β-hemolytic streptococcal infections should be maintained for at least 10 days to reduce the risk of rheumatic fever.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Reconstitution

The following table shows the amount of solvent required for solution of various concentrations:

When the required volume of solvent is greater than the capacity of the vial, the penicillin can be dissolved by first injecting only a portion of the solvent into the vial, then withdrawing the resultant solution and combining it with the remainder of the solvent in a larger sterile container.

Buffered Pfizerpen (Penicillin G Potassium for Injection, USP) is highly water soluble. It may be dissolved in small amounts of Water for Injection, or Sterile Isotonic Sodium Chloride Solution for Parenteral Use. All solutions should be stored in a refrigerator. When refrigerated, penicillin solutions may be stored for seven days without significant loss of potency.

Buffered Pfizerpen for Injection may be given intramuscularly or by continuous intravenous infusion for dosages of 500,000, 1,000,000, or 5,000,000 units. It is also suitable for intrapleural, intraarticular, and other local instillations.

THE 20,000,000 UNIT DOSAGE MAY BE ADMINISTERED BY INTRAVENOUS INFUSION ONLY.

Store the dry powder below 86°F (30°C).