Keflex

Dosage Forms And Strengths

250 mg capsules: a white to light yellow powder filled into an opaque white and opaque dark green capsule that is imprinted with KEFLEX 250 mg in edible black ink on the white body.

500 mg capsules: a white to light yellow powder filled into an opaque light green and opaque dark green capsule that is imprinted with KEFLEX 500 mg in edible black ink on the light green body.

750 mg capsules: a white to light yellow powder filled into an elongated opaque dark green and opaque dark green capsule that is imprinted KEFLEX 750 mg in edible white ink on the dark green body.

Storage And Handling

KEFLEX (cephalexin) Capsules, USP, is supplied as follows:

250 mg Capsules, bottles of 100 – NDC 59630-112-10
500 mg Capsules, bottles of 100 – NDC 59630-113-10
750 mg Capsules, bottles of 50 – NDC 59630-115-05

KEFLEX should be stored at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).

Dispense in a tight, light-resistant container.

Manufactured for: Shionogi Inc. Florham Park, NJ 07932. Manufactured by: Sandoz GmbH Kundl, Austria. Revised: Oct 2015.

Respiratory Tract Infections

KEFLEX is indicated for the treatment of respiratory tract infections caused by susceptible isolates of Streptococcus pneumoniae and Streptococcus pyogenes.

Otitis Media

KEFLEX is indicated for the treatment of otitis media caused by susceptible isolates of Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Streptococcus pyogenes, and Moraxella catarrhalis.

Skin And Skin Structure Infections

KEFLEX is indicated for the treatment of skin and skin structure infections caused by susceptible isolates of the following Gram-positive bacteria: Staphylococcus aureus and Streptococcus pyogenes.

Bone Infections

KEFLEX is indicated for the treatment of bone infections caused by susceptible isolates of Staphylococcus aureus and Proteus mirabilis.

Genitourinary Tract Infections

KEFLEX is indicated for the treatment of genitourinary tract infections, including acute prostatitis, caused by susceptible isolates of Escherichia coli, Proteus mirabilis, and Klebsiella pneumoniae.

Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of KEFLEX and other antibacterial drugs, KEFLEX should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information is available, this information 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.

Adults And Pediatric Patients At Least 15 Years Of Age

The usual dose of oral KEFLEX is 250 mg every 6 hours, but a dose of 500 mg every 12 hours may be administered. Treatment is administered for 7 to 14 days.

For more severe infections larger doses of oral KEFLEX may be needed, up to 4 grams daily in two to four equally divided doses.

Pediatric Patients (over 1 year of age)

The recommended total daily dose of oral KEFLEX for pediatric patients is 25 to 50 mg/kg given in equally divided doses for 7 to 14 days. In the treatment of β-hemolytic streptococcal infections, duration of at least 10 days is recommended. In severe infections, a total daily dose of 50 to 100 mg/kg may be administered in equally divided doses.

For the treatment of otitis media, the recommended daily dose is 75 to 100 mg/kg given in equally divided doses.

Dosage Adjustments In Adult And Pediatric Patients At Least 15 Years Of Age With Renal Impairment

Administer the following dosing regimens for KEFLEX to patients with impaired renal function.

Table 1: Recommended Dose Regimen for Patients with Renal Impairment

KEFLEX is contraindicated in patients with known hypersensitivity to cephalexin or other members of the cephalosporin class of antibacterial drugs.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Hypersensitivity Reactions

Allergic reactions in the form of rash, urticaria, angioedema, anaphylaxis, erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis have been reported with the use of KEFLEX. Before therapy with KEFLEX is instituted, inquire whether the patient has a history of hypersensitivity reactions to cephalexin, cephalosporins, penicillins, or other drugs. Cross-hypersensitivity among beta-lactam antibacterial drugs may occur in up to 10% of patients with a history of penicillin allergy.

If an allergic reaction to KEFLEX occurs, discontinue the drug and institute appropriate treatment.

Clostridium Difficile-Associated Diarrhea

Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including KEFLEX, 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.

Direct Coombs' Test Seroconversion

Positive direct Coombs' tests have been reported during treatment with the cephalosporin antibacterial drugs including cephalexin. Acute intravascular hemolysis induced by cephalexin therapy has been reported. If anemia develops during or after cephalexin therapy, perform a diagnostic work-up for drug-induced hemolytic anemia, discontinue cephalexin and institute appropriate therapy.

Seizure Potential

Several cephalosporins have been implicated in triggering seizures, particularly in patients with renal impairment when the dosage was not reduced. If seizures occur, discontinue KEFLEX. Anticonvulsant therapy can be given if clinically indicated.

Prolonged Prothrombin Time

Cephalosporins may be associated with prolonged prothrombin time. Those at risk include patients with renal or hepatic impairment, or poor nutritional state, as well as patients receiving a protracted course of antibacterial therapy, and patients receiving anticoagulant therapy. Monitor prothrombin time in patients at risk and manage as indicated.

Development Of Drug-Resistant Bacteria

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

Prolonged use of KEFLEX may result in the overgrowth of nonsusceptible organisms. Careful observation of the patient is essential. If superinfection occurs during therapy, appropriate measures should be taken.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Lifetime studies in animals have not been performed to evaluate the carcinogenic potential of cephalexin. Tests to determine the mutagenic potential of cephalexin have not been performed. In male and female rats, fertility and reproductive performance were not affected by cephalexin oral doses up to 1.5 times the highest recommended human dose based upon body surface area.

Use In Specific Populations

Pregnancy

Pregnancy Category B

There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Reproduction studies have been performed on mice and rats using oral doses of cephalexin monohydrate 0.6 and 1.5 times the maximum daily human dose (66 mg/kg/day) based upon body surface area basis, and have revealed no evidence of impaired fertility or harm to the fetus.

Nursing Mothers

Cephalexin is excreted in human milk. Caution should be exercised when KEFLEX is administered to a nursing woman.

Pediatric Use

The safety and effectiveness of KEFLEX in pediatric patients was established in clinical trials for the dosages described in the dosage and administration section.

Geriatric Use

Of the 701 subjects in 3 published clinical studies of cephalexin, 433 (62%) were 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients.

This drug is 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.

Renal Impairment

KEFLEX should be administered with caution in the presence of impaired renal function (creatinine clearance < 30 mL/min, with or without dialysis). Under such conditions, careful clinical observation and laboratory studies renal function monitoring should be conducted because safe dosage may be lower than that usually recommended.

REFERENCES

1. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard - Tenth Edition. CLSI document M07-A10, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015.

2. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobials Susceptibility Tests; Twenty-Fifth Informational Supplement. CLSI document M100-S25, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015.

3. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard - Twelfth Edition. CLSI document M02-A12, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015.

In healthy subjects given single 500 mg doses of cephalexin and metformin, plasma metformin mean Cmax and AUC increased by an average of 34% and 24%, respectively, and metformin mean renal clearance decreased by 14%. No information is available about the interaction of cephalexin and metformin following multiple doses of either drug.

Pregnancy Category B

There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Reproduction studies have been performed on mice and rats using oral doses of cephalexin monohydrate 0.6 and 1.5 times the maximum daily human dose (66 mg/kg/day) based upon body surface area basis, and have revealed no evidence of impaired fertility or harm to the fetus.

The following serious events are described in greater detail in the Warning and Precautions section:

• Hypersensitivity reactions
• Clostridium difficile-associated diarrhea
• Direct Coombs' Test Seroconversion
• Seizure Potential
• Effect on Prothrombin Activity
• Development of Drug-Resistant Bacteria

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice

In clinical trials, the most frequent adverse reaction was diarrhea. Nausea and vomiting, dyspepsia, gastritis, and abdominal pain have also occurred. As with penicillins and other cephalosporins, transient hepatitis and cholestatic jaundice have been reported.

Other reactions have included hypersensitivity reactions, genital and anal pruritus, genital candidiasis, vaginitis and vaginal discharge, dizziness, fatigue, headache, agitation, confusion, hallucinations, arthralgia, arthritis, and joint disorder. Reversible interstitial nephritis has been reported. Eosinophilia, neutropenia, thrombocytopenia, hemolytic anemia, and slight elevations in aspartate transaminase (AST) and alanine transaminase (ALT) have been reported.

In addition to the adverse reactions listed above that have been observed in patients treated with KEFLEX, the following adverse reactions and other altered laboratory tests have been reported for cephalosporin class antibacterial drugs:

Other Adverse Reactions

Fever, colitis, aplastic anemia, hemorrhage, renal dysfunction, and toxic nephropathy.

Altered Laboratory Tests

Prolonged prothrombin time, increased blood urea nitrogen (BUN), increased creatinine, elevated alkaline phosphatase, elevated bilirubin, elevated lactate dehydrogenase (LDH), pancytopenia, leukopenia, and agranulocytosis.

Symptoms of oral overdose may include nausea, vomiting, epigastric distress, diarrhea, and hematuria. In the event of an overdose, institute general supportive measures.

Forced diuresis, peritoneal dialysis, hemodialysis, or charcoal hemoperfusion have not been established as beneficial for an overdose of cephalexin.

Absorption

Cephalexin is acid stable and may be given without regard to meals. Following doses of 250 mg, 500 mg, and 1 g, average peak serum levels of approximately 9, 18, and 32 mcg/mL, respectively, were obtained at 1 hour. Serum levels were detectable 6 hours after administration (at a level of detection of 0.2 mcg/mL).

Distribution

Cephalexin is approximately 10% to 15% bound to plasma proteins.

Excretion

Cephalexin is excreted in the urine by glomerular filtration and tubular secretion. Studies showed that over 90% of the drug was excreted unchanged in the urine within 8 hours. During this period, peak urine concentrations following the 250 mg, 500 mg, and 1 g doses were approximately 1000, 2200, and 5000 mcg/mL respectively.