USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. o Renal Impairment: Monitor patients longer for toxicity and drug interactions due to delayed clearance. (8.6). 8.1 Pregnancy. Risk SummaryAvailable data from published epidemiologic studies and pharmacovigilance case reports over several decades with cephalosporin use, including cephalexin capsules use in pregnant women have not established drug-associated risks of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data).Animal reproduction studies with mice and rats using oral doses of cephalexin that are 0.6- and 1.2-times the maximum recommended human dose (MRHD) based on body surface area during organogenesis revealed no evidence of harm to the fetus (see Data).The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.DataHuman DataWhile available studies cannot definitively establish the absence of risk, published data from epidemiologic studies and postmarketing case reports over several decades have not identified consistent association with cephalosporin use, including cephalexin capsules, during pregnancy, and major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Available studies have methodologic limitations, including small sample size, retrospective data collection, and inconsistent comparator groups.Animal DataIn animal reproduction studies, pregnant mice and rats administered oral cephalexin doses of 250 or 500 mg/kg/day (approximately 0.6 and 1.2 times the MRHD) based on body surface area, respectively during the period of organogenesis showed no adverse effects on embryofetal development.In pre-and post-natal developmental toxicity study, pregnant rats that received oral doses of 250 or 500 mg/kg/day of cephalexin from Day 15 of pregnancy to litter Day 21 showed no adverse effects on parturition, litter size, or growth of offspring.. 8.2 Lactation. Risk SummaryData from published clinical lactation study reports that cephalexin is present in human milk. The Relative Infant Dose (RID) is considered to be <1% of the maternal weight adjusted dose. There are no data on the effects of cephalexin on the breastfed child or on milk production.The development of health benefits of breastfeeding should be considered along with the mothers clinical need for cephalexin and any potential adverse effects on the breastfed child from cephalexin or from the underlying maternal condition.. 8.4 Pediatric Use. The safety and effectiveness of cephalexin capsules in pediatric patients was established in clinical trials for the dosages described in the dosage and administration section [see Dosage and Administration (2.2) ]. 8.5 Geriatric Use. Of the 701 subjects in 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 [see Warnings and Precautions (5.4) ].. 8.6 Renal Impairment. Cephalexin capsules should be administered with careful monitoring in the presence of renal impairment (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 [see Dosage and Administration (2.3)].Monitor patients longer for toxicity and drug interactions due to delayed clearance.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. o Serious hypersensitivity (anaphylactic) reactions: Prior to use, inquire regarding history of hypersensitivity to beta-lactam antibacterial drugs. Discontinue the drug if signs or symptoms of an allergic reaction occur and institute supportive measures. (5.1)o Clostridium difficile- associated diarrhea (CDAD): Evaluate if diarrhea occurs. (5.2) Direct Coombs Test Seroconversion: If anemia develops during or after cephalexin therapy, evaluate for drug-induced hemolytic anemia.(5.3) Seizure Potential: Use lower dose in patients with renal impairment. (5.4). 5.1 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 cephalexin capsules. Before therapy with cephalexin capsules is instituted, inquire whether the patient has 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 history of penicillin allergy.If an allergic reaction to cephalexin capsules occurs, discontinue the drug and institute appropriate treatment.. 5.2 Clostridium difficile-Associated Diarrhea. Clostridium difficile- associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including cephalexin capsules, 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 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.. 5.3 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 diagnostic work-up for drug-induced hemolytic anemia, discontinue cephalexin and institute appropriate therapy.. 5.4 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 cephalexin capsules. Anticonvulsant therapy can be given if clinically indicated.. 5.5 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 protracted course of antibacterial therapy, and patients receiving anticoagulant therapy. Monitor prothrombin time in patients at risk and manage as indicated.. 5.6 Development of Drug-Resistant Bacteria. Prescribing cephalexin capsules in the absence of 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 cephalexin capsules 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.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. o Metformin: increased metformin concentrations. Monitor for hypoglycemia. (7.1)o Probenecid- The renal excretion of cephalexin capsules is inhibited by probenecid. Co-administration of probenecid with cephalexin capsules is not recommended. (7.2)o Administration of cephalexin capsules may result in false-positive reaction for glucose in the urine (7.3).. 7.1 Metformin. Administration of cephalexin capsules with metformin results in increased plasma metformin concentrations and decreased renal clearance of metformin.Careful patient monitoring and dose adjustment of metformin is recommended in patients concomitantly taking cephalexin capsules and metformin [see Clinical Pharmacology (12.3)].. 7.2 Probenecid. The renal excretion of cephalexin capsules is inhibited by probenecid. Co-administration of probenecid with cephalexin capsules is not recommended.. 7.3 Interaction with Laboratory or Diagnostic Testing. false-positive reaction may occur when testing for the presence of glucose in the urine using Benedicts solution or Fehlings solution.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following serious events are described in greater detail in the Warning and Precautions section:o Hypersensitivity reactions [see Warning and Precautions (5.1) ]o Clostridium difficile-associated diarrhea [see Warnings and Precautions (5.2) ]o Direct Coombs Test Seroconversion [see Warnings and Precautions (5.3) ]o Seizure Potential [see Warnings and Precautions (5.4) ]o Effect on Prothrombin Activity [see Warnings and Precautions (5.5) ]o Development of Drug-Resistant Bacteria [see Warnings and Precautions (5.6) ]. The most common adverse reactions associated with cephalexin capsules include diarrhea, nausea, vomiting, dyspepsia and abdominal pain. (6)To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-877-233-2001, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 cephalexin capsules, 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.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Cephalexin is cephalosporin antibacterial drug [see Microbiology (12.4)].. 12.3 Pharmacokinetics. Absorption:Cephalexin is acid stable and may be given without regard to meals. Following doses of 250 mg, 500 mg, and g, average peak serum levels of approximately 9, 18, and 32 mcg/mL, respectively, were obtained at hour. Serum levels were detectable hours after administration (at 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 hours. During this period, peak urine concentrations following the 250 mg, 500 mg, and g doses were approximately 1000, 2200, and 5000 mcg/mL respectively.Drug Interactions: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.. 12.4 Microbiology. Mechanism of ActionCephalexin is bactericidal agent that acts by the inhibition of bacterial cell-wall synthesis.ResistanceMethicillin-resistant staphylococci and most isolates of enterococci are resistant to cephalexin. Cephalexin is not active against most isolates of Enterobacter spp., Morganella morganii, and Proteus vulgaris. Cephalexin has no activity against Pseudomonas spp., or Acinetobacter calcoaceticus. Penicillin-resistant Streptococcus pneumoniae is usually cross-resistant to beta-lactam antibacterial drugs.Antimicrobial ActivityCephalexin has been shown to be active against most isolates of the following bacteria both in vitro and in clinical infections [see Indications and Usage (1) ].Gram-positive bacteriaStaphylococcus aureus (methicillin-susceptible isolates only)Streptococcus pneumoniae (penicillin-susceptible isolates)Gram-negative bacteriaEscherichia coliHaemophilus influenzaeKlebsiella pneumoniaeMoraxella catarrhalisProteus mirabilisSusceptibility TestingFor specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Adults and patients at least 15 years of ageThe usual dose is 250 mg every hours, but dose of 500 mg every 12 hours may be administered (2.1)Pediatric patients (over year of age)o Otitis media: 75 to 100 mg/kg in equally divided doses every hours (2.2)o All other indications: 25 to 50 mg/kg given in equally divided doses (2.2)o In severe infections: 50 to 100 mg/kg may be administered in equally divided doses (2.2)o Duration of therapy ranges from to14 days depending on the infection type and severity. (2)o Dosage adjustment is required in patients with severe and end stage renal disease (ESRD) defined as creatinine clearance below 30 mL/min. (2.3). 2.1 Adults and Pediatric Patients at Least 15 Years of Age. The usual dose of oral cephalexin capsules is 250 mg every hours, but dose of 500 mg every 12 hours may be administered. Treatment is administered for to 14 days.For more severe infections larger doses of oral cephalexin capsules may be needed, up to grams daily in two to four equally divided doses.. 2.2 Pediatric Patients (over year of age). The recommended total daily dose of oral cephalexin capsules for pediatric patients is 25 to 50 mg/kg given in equally divided doses for to 14 days. In the treatment of -hemolytic streptococcal infections, duration of at least 10 days is recommended. In severe infections, 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.. 2.3 Dosage Adjustments in Adult and Pediatric Patients at Least 15 Years of Age with Renal Impairment. Administer the following dosing regimens for cephalexin capsules to patients with renal impairment [see Warnings and Precautions (5.4) and Use in Specific Populations (8.6) ].Table 1. Recommended Dose Regimen for Patients with Renal ImpairmentRenal functionDose regimen recommendationCreatinine clearance >= 60 mL/minNo dose adjustmentCreatinine clearance 30 to 59 mL/minNo dose adjustment; maximum daily dose should not exceed gCreatinine clearance 15 to 29 mL/min250 mg, every hours or every 12 hoursCreatinine clearance to 14 mL/min not yet on dialysis250 mg, every 24 hoursCreatinine clearance to mL/min not yet on dialysis250 mg, every 48 hours or every 60 hoursThere is insufficient information to make dose adjustment recommendations in patients on hemodialysis.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Cephalexin capsules are cephalosporin antibacterial drug indicated for the treatment of the following infections caused by susceptible isolates of designated bacteria:o Respiratory tract infection (1.1) Otitis media (1.2)o Skin and skin structure infections (1.3)o Bone infections (1.4)o Genitourinary tract infections (1.5)To reduce the development of drug-resistant bacteria and maintain the effectiveness of cephalexin capsules and other antibacterial drugs, cephalexin capsules should be used only to treat infections that are proven or strongly suspected to be caused by bacteria. (1.6). 1.1 Respiratory Tract Infections. Cephalexin capsules are indicated for the treatment of respiratory tract infections caused by susceptible isolates of Streptococcus pneumoniae and Streptococcus pyogenes. 1.2 Otitis Media. Cephalexin capsules are indicated for the treatment of otitis media caused by susceptible isolates of Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Streptococcus pyogenes, and Moraxella catarrhalis. 1.3 Skin and Skin Structure Infections. Cephalexin capsules are 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.. 1.4 Bone Infections. Cephalexin capsules are indicated for the treatment of bone infections caused by susceptible isolates of Staphylococcus aureus and Proteus mirabilis. 1.5 Genitourinary Tract Infections. Cephalexin capsules are indicated for the treatment of genitourinary tract infections, including acute prostatitis, caused by susceptible isolates of Escherichia coli, Proteus mirabilis, and Klebsiella pneumoniae.. 1.6 Usage. To reduce the development of drug-resistant bacteria and maintain the effectiveness of cephalexin capsules and other antibacterial drugs, cephalexin capsules 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.

PATIENT COUNSELING INFORMATION.

17 PATIENT COUNSELING INFORMATION. Allergic ReactionsAdvise patients that allergic reactions, including serious allergic reactions, could occur and that serious reactions require immediate treatment. Ask the patient about any previous hypersensitivity reactions to cephalexin capsules, other beta-lactams (including cephalosporins) or other allergens (5.1)DiarrheaAdvise patients that diarrhea is common problem caused by antibacterial drugs and usually resolves when the drug is discontinued. Sometimes, frequent watery or bloody diarrhea may occur and may be sign of more serious intestinal infection. If severe watery or bloody diarrhea develops, advise patients to contact their healthcare provider.Antibacterial ResistanceCounsel patients that antibacterial drugs including cephalexin capsules, should only be used to treat bacterial infections.They do not treat viral infections (e.g., the common cold). When cephalexin capsules are prescribed to treat bacterial infection, tell patients 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 cephalexin capsules or other antibacterial drugs in the future.Distributed by: West-Ward Pharmaceuticals Corp. Eatontown, NJ 07724 USAManufactured by:Jazeera Pharmaceutical Industries (JPI)Al- Kharj RoadP. O. Box 106229Riyadh 11666 Saudi ArabiaAn Affiliate of:HIKMA PharmaceuticalsP.O. Box 182400Amman 11118 JordanRevised October 2020.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Absorption:Cephalexin is acid stable and may be given without regard to meals. Following doses of 250 mg, 500 mg, and g, average peak serum levels of approximately 9, 18, and 32 mcg/mL, respectively, were obtained at hour. Serum levels were detectable hours after administration (at 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 hours. During this period, peak urine concentrations following the 250 mg, 500 mg, and g doses were approximately 1000, 2200, and 5000 mcg/mL respectively.Drug Interactions: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 SECTION.

8.1 Pregnancy. Risk SummaryAvailable data from published epidemiologic studies and pharmacovigilance case reports over several decades with cephalosporin use, including cephalexin capsules use in pregnant women have not established drug-associated risks of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data).Animal reproduction studies with mice and rats using oral doses of cephalexin that are 0.6- and 1.2-times the maximum recommended human dose (MRHD) based on body surface area during organogenesis revealed no evidence of harm to the fetus (see Data).The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.DataHuman DataWhile available studies cannot definitively establish the absence of risk, published data from epidemiologic studies and postmarketing case reports over several decades have not identified consistent association with cephalosporin use, including cephalexin capsules, during pregnancy, and major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Available studies have methodologic limitations, including small sample size, retrospective data collection, and inconsistent comparator groups.Animal DataIn animal reproduction studies, pregnant mice and rats administered oral cephalexin doses of 250 or 500 mg/kg/day (approximately 0.6 and 1.2 times the MRHD) based on body surface area, respectively during the period of organogenesis showed no adverse effects on embryofetal development.In pre-and post-natal developmental toxicity study, pregnant rats that received oral doses of 250 or 500 mg/kg/day of cephalexin from Day 15 of pregnancy to litter Day 21 showed no adverse effects on parturition, litter size, or growth of offspring.