Clarithromycin 500 mg Tablet, Film Coated, 60-count — NDC 63187-625-30 (Billing 63187-0625-30)

WARNINGS Use In Pregnancy CLARITHROMYCIN SHOULD NOT BE USED IN PREGNANT WOMEN EXCEPT IN CLINICAL CIRCUMSTANCES WHERE NO ALTERNATIVE THERAPY IS APPROPRIATE. IF PREGNANCY OCCURS WHILE TAKING THIS DRUG, THE PATIENT SHOULD BE APPRISED OF THE POTENTIAL HAZARD TO THE FETUS. CLARITHROMYCIN HAS DEMONSTRATED ADVERSE EFFECTS OF PREGNANCY OUTCOME AND/OR EMBRYO-FETAL DEVELOPMENT IN MONKEYS, RATS, MICE, AND RABBITS AT DOSES THAT PRODUCED PLASMA LEVELS 2 TO 17 TIMES THE SERUM LEVELS ACHIEVED IN HUMANS TREATED AT THE MAXIMUM RECOMMENDED HUMAN DOSES (see PRECAUTIONS - Pregnancy ).

Hepatotoxicity Hepatic dysfunction, including increased liver enzymes, and hepatocellular and/or cholestatic hepatitis, with or without jaundice, has been reported with clarithromycin. This hepatic dysfunction may be severe and is usually reversible. In some instances, hepatic failure with fatal outcome has been reported and generally has been associated with serious underlying diseases and/or concomitant medications.

Symptoms of hepatitis can include anorexia, jaundice, dark urine, pruritus, or tender abdomen. Discontinue clarithromycin immediately if signs and symptoms of hepatitis occur. QT Prolongation Clarithromycin has been associated with prolongation of the QT interval and infrequent cases of arrhythmia.

Cases of torsades de pointes have been spontaneously reported during postmarketing surveillance in patients receiving clarithromycin. Fatalities have been reported. Clarithromycin should be avoided in patients with ongoing proarrhythmic conditions such as uncorrected hypokalemia or hypomagnesemia, clinically significant bradycardia (see CONTRAINDICATIONS ) and in patients receiving Class IA (quinidine, procainamide) or Class III (dofetilide, amiodarone, sotalol) antiarrhythmic agents.

Elderly patients may be more susceptible to drug-associated effects on the QT interval. Drug Interactions Serious adverse reactions have been reported in patients taking clarithromycin concomitantly with CYP3A4 substrates. These include colchicine toxicity with colchicine; rhabdomyolysis with simvastatin, lovastatin, and atorvastatin; and hypotension and acute kidney injury with calcium channel blockers metabolized by CYP3A4 (e.g., verapamil, amlodipine, diltiazem, nifedipine).

Most reports of acute kidney injury with calcium channel blockers metabolized by CYP3A4 involved elderly patients 65 years of age or older (see CONTRAINDICATIONS and PRECAUTIONS - Drug Interactions ). Clarithromycin should be used with caution when administered concurrently with medications that induce the cytochrome CYP3A4 enzyme (see PRECAUTIONS - Drug Interactions ). Colchicine Life-threatening and fatal drug interactions have been reported in patients treated with clarithromycin and colchicine.

Clarithromycin is a strong CYP3A4 inhibitor and this interaction may occur while using both drugs at their recommended doses. If coadministration of clarithromycin and colchicine is necessary in patients with normal renal and hepatic function, the dose of colchicine should be reduced. Patients should be monitored for clinical symptoms of colchicine toxicity.

Concomitant administration of clarithromycin and colchicine is contraindicated in patients with renal or hepatic impairment (see CONTRAINDICATIONS and PRECAUTIONS - Drug Interactions ). Benzodiazepines Increased sedation and prolongation of sedation have been reported with concomitant administration of clarithromycin and triazolobenzodiazepines, such as triazolam, and midazolam. Oral Hypoglycemic Agents/Insulin The concomitant use of clarithromycin and oral hypoglycemic agents and/or insulin can result in significant hypoglycemia.

With certain hypoglycemic drugs such as nateglinide, pioglitazone, repaglinide and rosiglitazone, inhibition of CYP3A enzyme by clarithromycin may be involved and could cause hypoglycemia when used concomitantly. Careful monitoring of glucose is recommended. Oral Anticoagulants There is a risk of serious hemorrhage and significan…

ADVERSE REACTIONS The most frequent and common adverse reactions related to clarithromycin therapy for both adult and pediatric populations are abdominal pain, diarrhea, nausea, vomiting and dysgeusia. These adverse reactions are consistent with the known safety profile of macrolide antibiotics. There was no significant difference in the incidence of these gastrointestinal adverse reactions during clinical trials between the patient population with or without preexisting mycobacterial infections.

Adverse Reactions Observed During Clinical Trials of Clarithromycin The following adverse reactions were observed in clinical trials with clarithromycin at a rate greater than or equal to 1%: Gastrointestinal Disorders Diarrhea, vomiting, dyspepsia, nausea, abdominal pain Hepatobiliary Disorders Liver function test abnormal Immune System Disorders Anaphylactoid reaction Infection and Infestations Candidiasis Nervous System Disorders Dysgeusia, headache Psychiatric Disorders Insomnia Skin and Subcutaneous Tissue Disorders Rash Other Adverse Reactions Observed During Clinical Trials of Clarithromycin The following adverse reactions were observed in clinical trials with clarithromycin at a rate less than 1%: Blood and Lymphatic System Disorders Leukopenia, neutropenia, thrombocythemia, eosinophilia Cardiac Disorders Electrocardiogram QT prolonged, cardiac arrest, atrial fibrillation, extrasystoles, palpitations Ear and Labyrinth Disorders Vertigo, tinnitus, hearing impaired Gastrointestinal Disorders Stomatitis, glossitis, esophagitis, gastrooesophageal reflux disease, gastritis, proctalgia, abdominal distension, constipation, dry mouth, eructation, flatulence General Disorders and Administration Site Conditions Malaise, pyrexia, asthenia, chest pain, chills, fatigue Hepatobiliary Disorders Cholestasis, hepatitis Immune System Disorders Hypersensitivity Infections and Infestations Cellulitis, gastroenteritis, infection, vaginal infection Investigations Blood bilirubin increased, blood alkaline phosphatase increased, blood lactate dehydrogenase increased, albumin globulin ratio abnormal Metabolism and Nutrition Disorders Anorexia, decreased appetite Musculoskeletal and Connective Tissue Disorders Myalgia, muscle spasms, nuchal rigidity Nervous System Disorders Dizziness, tremor, loss of consciousness, dyskinesia, somnolence Psychiatric Disorders Anxiety, nervousness Renal and Urinary Disorders Blood creatinine increased, blood urea increased Respiratory, Thoracic and Mediastinal Disorders Asthma, epistaxis, pulmonary embolism Skin and Subcutaneous Tissue Disorders Urticaria, dermatitis bullous, pruritus, hyperhidrosis, rash maculo-papular In the acute exacerbation of chronic bronchitis and acute maxillary sinusitis studies overall gastrointestinal adverse events were reported by a similar proportion of patients taking either clarithromycin tablets or clarithromycin extended-release tablets; however, patients taking clarithromycin extended-release tablets reported significantly less severe gastrointestinal symptoms compared to patients taking clarithromycin tablets.

In addition, patients taking clarithromycin extended-release tablets had significantly fewer premature discontinuations for drug-related gastrointestinal or abnormal taste adverse events compared to clarithromycin tablets. In community-acquired pneumonia studies conducted in adults comparing clarithromycin to erythromycin base or erythromycin stearate, there were fewer adverse events involving the digestive system in clarithromycin-treated patients compared to erythromycin-treated patients (13% vs. 32%; p < 0.01).

Twenty percent of erythromycin-treated patients discontinued therapy due to adverse events compared to 4% of clarithromycin-treated patients. In two U.S. studies of acute otitis media comparing clarithromycin to amoxicillin/potassium clavulanate in pediatric patients, there were fewer adverse events involving the digestive system in clarithromycin-treated patients com…

Drug Interactions Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum theophylline concentrations. Monitoring of serum theophylline concentrations should be considered for patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range. In two studies in which theophylline was administered with clarithromycin (a theophylline sustained-release formulation was dosed at either 6.5 mg/kg or 12 mg/kg together with 250 or 500 mg q 12 h clarithromycin), the steady-state levels of C max , C min , and the area under the serum concentration time curve (AUC) of theophylline increased about 20%.

Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent verapamil, belonging to the calcium channel blockers drug class. Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in increased plasma concentrations of carbamazepine. Blood level monitoring of carbamazepine may be considered.

When clarithromycin and terfenadine were coadministered, plasma concentrations of the active acid metabolite of terfenadine were threefold higher, on average, than the values observed when terfenadine was administered alone. The pharmacokinetics of clarithromycin and the 14-OH-clarithromycin were not significantly affected by coadministration of terfenadine once clarithromycin reached steady-state conditions. Concomitant administration of clarithromycin with terfenadine is contraindicated (see CONTRAINDICATIONS ).

Clarithromycin 500 mg every 8 hours was given in combination with omeprazole 40 mg daily to healthy adult subjects. The steady-state plasma concentrations of omeprazole were increased (C max , AUC 0-24 , and t ½ increases of 30%, 89%, and 34%, respectively), by the concomitant administration of clarithromycin. The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when coadministered with clarithromycin.

Coadministration of clarithromycin with ranitidine bismuth citrate resulted in increased plasma ranitidine concentrations (57%), increased plasma bismuth trough concentrations (48%), and increased 14-hydroxy-clarithromycin plasma concentrations (31%). These effects are clinically insignificant. Simultaneous oral administration of clarithromycin tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations.

Following administration of clarithromycin 500 mg tablets twice daily with zidovudine 100 mg every 4 hours, the steady-state zidovudine AUC decreased 12% compared to administration of zidovudine alone (n=4). Individual values ranged from a decrease of 34% to an increase of 14%. When clarithromycin tablets were administered two to four hours prior to zidovudine, the steady-state zidovudine C max increased 100% whereas the AUC was unaffected (n=24).

Administration of clarithromycin and zidovudine should be separated by at least two hours. Simultaneous administration of clarithromycin tablets and didanosine to 12 HIV-infected adult patients resulted in no statistically significant change in didanosine pharmacokinetics. Following administration of fluconazole 200 mg daily and clarithromycin 500 mg twice daily to 21 healthy volunteers, the steady-state clarithromycin C min and AUC increased 33% and 18%, respectively.

Steady-state concentrations of 14-OH clarithromycin were not significantly affected by concomitant administration of fluconazole. No dosage adjustment of clarithromycin is necessary when coadministered with fluconazole. Ritonavir Concomitant administration of clarithromycin and ritonavir (n = 22) resulted in a 77% increase in clarithromycin AUC and a 100% decrease in the AUC of 14-OH clarithromycin.

Clarithromycin may be administered without dosage adjustment to patients with normal renal function taking ritonavir. Since concentrations of 14-OH clarithromycin are sig…