Clarithromycin extended-release tablets is a macrolide antimicrobial indicated for mild to moderate infections caused by designated, susceptible bacteria in the following: Acute Bacterial Exacerbation of Chronic Bronchitis in Adults (1.1) Acute Maxillary Sinusitis (1.2) Community-Acquired Pneumonia (1.3) Limitations of Use Clarithromycin extended-release tablets are indicated only for acute bacterial exacerbation of chronic bronchitis, acute maxillary sinusitis, and community-acquired pneumonia in adults.
(1.9) To reduce the development of drug-resistant bacteria and maintain the effectiveness of clarithromycin extended-release tablets and other antibacterial drugs, clarithromycin extended-release tablets should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. (1.9)
1.1Acute Bacterial Exacerbation of Chronic Bronchitis
Clarithromycin extended-release tablets are indicated in adults for the treatment of mild to moderate infections caused by susceptible isolates due to Haemophilus influenzae , Haemophilus parainfluenzae , Moraxella catarrhalis , or Streptococcus pneumoniae [see Indications and Usage (1.9) ] .
1.2Acute Maxillary Sinusitis
Clarithromycin extended-release tablets (in adults) are indicated for the treatment of mild to moderate infections caused by susceptible isolates due to Haemophilus influenzae , Moraxella catarrhalis , or Streptococcus pneumoniae [see Indications and Usage (1.9) ] .
1.3Community-Acquired Pneumonia
Clarithromycin extended-release tablets are indicated [see Indications and Usage (1.9) ] for the treatment of mild to moderate infections caused by susceptible isolates due to: Haemophilus influenzae (in adults) Haemophilus parainfluenzae (in adults) Moraxella catarrhalis (in adults) Mycoplasma pneumoniae , Streptococcus pneumoniae , Chlamydophila pneumoniae (in adults)
Clarithromycin extended-release tablets are indicated only for acute maxillary sinusitis, acute bacterial exacerbation of chronic bronchitis, and community-acquired pneumonia in adults. The efficacy and safety of clarithromycin extended-release tablets in treating other infections for which clarithromycin immediate release tablets and clarithromycin granules are approved have not been established. There is resistance to macrolides in certain bacterial infections caused by Streptococcus pneumoniae and Staphylococcus aureus .
Susceptibility testing should be performed when clinically indicated.
1.10Usage
To reduce the development of drug-resistant bacteria and maintain the effectiveness of clarithromycin extended-release tablets and other antibacterial drugs, clarithromycin extended-release tablets 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.
Contraindications
Hypersensitivity to clarithromycin or any macrolide drug (4.1) Cisapride and pimozide (4.2) History of cholestatic jaundice/hepatic dysfunction with use of clarithromycin (4.3) Colchicine in renal or hepatic impairment (4.4) Lomitapide, lovastatin, and simvastatin (4.5) Ergot alkaloids (ergotamine or dihydroergotamine) (4.6) Lurasidone (4.7)
4.1Hypersensitivity
Clarithromycin is contraindicated in patients with a known hypersensitivity to clarithromycin, erythromycin, or any of the macrolide antibacterial drugs [see Warnings and Precautions (5.1) ] .
4.2Cisapride and Pimozide
Concomitant administration of clarithromycin with cisapride and pimozide is contraindicated [see Drug Interactions (7) ] . There have been postmarketing reports of drug interactions when clarithromycin is co-administered with cisapride or pimozide, resulting in cardiac arrhythmias (QT prolongation, ventricular tachycardia, ventricular fibrillation, and torsades de pointes ) most likely due to inhibition of metabolism of these drugs by clarithromycin.
Fatalities have been reported.
4.3Cholestatic Jaundice/Hepatic Dysfunction
Clarithromycin is contraindicated in patients with a history of cholestatic jaundice or hepatic dysfunction associated with prior use of clarithromycin.
4.4Colchicine
Concomitant administration of clarithromycin and colchicine is contraindicated in patients with renal or hepatic impairment.
4.5Lomitapide, Lovastatin, and Simvastatin
Concomitant administration of clarithromycin with lomitapide is contraindicated due to potential for markedly increased transaminases [see Warnings and Precautions (5.4) and Drug Interactions (7) ] . Concomitant administration of clarithromycin with HMG-CoA reductase inhibitors (statins) that are extensively metabolized by CYP3A4 (lovastatin or simvastatin) is contraindicated, due to the increased risk of myopathy, including rhabdomyolysis [see Warnings and Precautions (5.4) and Drug Interactions (7) ] .
4.6Ergot Alkaloids
Concomitant administration of clarithromycin and ergotamine or dihydroergotamine is contraindicated [see Drug Interactions (7) ] .
4.7Lurasidone
Concomitant administration of clarithromycin and lurasidone is contraindicated since it may result in an increase in lurasidone exposure and the potential for serious adverse reactions [see Drug Interactions (7) ] .
4.8Contraindications for Co-administered Drugs
For information about contraindications of other drugs indicated in combination with clarithromycin, refer to their full prescribing information (contraindications section).
Warnings and precautions
Severe Acute Hypersensitivity Reactions : Discontinue clarithromycin if occurs (5.1) QT Prolongation : Avoid clarithromycin in patients with known QT prolongation or receiving drugs known to prolong the QT interval, ventricular arrhythmia ( torsades de pointes ), hypokalemia/hypomagnesemia, significant bradycardia, or taking Class IA or III antiarrhythmics (5.2) Hepatotoxicity : Discontinue if signs and symptoms of hepatitis occur (5.3) Serious adverse reactions can occur due to drug interactions of clarithromycin with colchicine, some lipid-lowering agents, some calcium channel blockers, and other drugs (5.4) Risk of all-cause mortality one year or more after the end of treatment in patients with coronary artery disease.
Balance this potential risk with the treatment benefits when prescribing clarithromycin tablets in these patients. (5.5) Clostridium difficile associated diarrhea (CDAD) : Evaluate if diarrhea occurs (5.6) Embryo-Fetal Toxicity: Based on animal findings, clarithromycin is not recommended for use in pregnant women except in clinical circumstances where no alternative therapy is appropriate (5.7) Exacerbation of myasthenia gravis has been reported in patients receiving clarithromycin therapy.
(5.8)
5.1 Severe Acute Hypersensitivity Reactions In the event of severe acute hypersensitivity reactions, such as anaphylaxis, Stevens-Johnson Syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS), Henoch-Schonlein purpura, and acute generalized exanthematous pustulosis, discontinue clarithromycin therapy immediately and institute appropriate treatment.
5.2QT 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. Avoid clarithromycin in the following patients: patients with known prolongation of the QT interval, ventricular cardiac arrhythmia, including torsades de pointes patients receiving drugs known to prolong the QT interval [see also Contraindications (4.2) ] patients with ongoing proarrhythmic conditions such as uncorrected hypokalemia or hypomagnesemia, clinically significant bradycardia and in patients receiving Class IA (e.g., quinidine, procainamide, disopyramide) or Class III (e.g., dofetilide, amiodarone, sotalol) antiarrhythmic agents.
Elderly patients may be more susceptible to drug-associated effects on the QT interval [see Use in Specific Populations (8.5) ] .
5.3Hepatotoxicity
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.
5.4Serious Adverse Reactions Due to Concomitant Use with Other Drugs
Drugs metabolized by CYP3A4: Serious adverse reactions have been reported in patients taking clarithromycin concomitantly with CYP3A4 substrates. These include colchicine toxicity with colchicine; markedly increased transaminases with lomitapide; rhabdomyolysis with simvastatin, lovastatin, and atorvastatin; hypoglycemia and cardiac arrhythmias (e.g., torsades de pointes ) with disopyramide; 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. Use clarithromycin with caution when administered concurrently with medications that induce the cytochrome CYP3A4 enzyme. The use of clarithromycin with lomitapide, simvastatin, lovastatin, ergotamine, or dihydroergotamine is contraindicated [see Contraindications (4.5, 4.6) and Drug Interactions (7) ] .
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 co-administration of clarithromycin and colchicine is necessary in patients with normal renal and hepatic function, reduce the dose of colchicine. Monitor patients for clinical symptoms of colchicine toxicity.
Concomitant administration of clarithromycin and colchicine is contraindicated in patients with renal or hepatic impairment [see Contraindications (4.4) and Drug Interactions (7) ] . Lomitapide: Concomitant use of clarithromycin with lomitapide is contraindicated [see Contraindications (4.5) ] . Lomitapide is metabolized by CYP3A4, and concomitant treatment with clarithromycin increases the plasma concentration of lomitapide, which increases the risk of elevation in transaminases [see Drug Interactions (7) ] .
If treatment with clarithromycin cannot be avoided, therapy with lomitapide must be suspended during the course of treatment. HMG-CoA Reductase Inhibitors (statins): Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated [see Contraindications (4.5) ] as these statins are extensively metabolized by CYP3A4, and concomitant treatment with clarithromycin increases their plasma concentration, which increases the risk of myopathy, including rhabdomyolysis.
Cases of rhabdomyolysis have been reported in patients taking clarithromycin concomitantly with these statins. If treatment with clarithromycin cannot be avoided, therapy with lovastatin or simvastatin must be suspended during the course of treatment. Exercise caution when prescribing clarithromycin with atorvastatin or pravastatin. In situations where the concomitant use of clarithromycin with atorvastatin or pravastatin cannot be avoided, atorvastatin dose should not exceed 20 mg daily and pravastatin dose should not exceed 40 mg daily.
5.5 All-Cause Mortality in Patie
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Interactions
Co-administration of clarithromycin is known to inhibit CYP3A, and a drug primarily metabolized by CYP3A may be associated with elevations in drug concentrations that could increase or prolong both therapeutic and adverse effects of the concomitant drug. Clarithromycin should be used with caution in patients receiving treatment with other drugs known to be CYP3A enzyme substrates, especially if the CYP3A substrate has a narrow safety margin (e.g., carbamazepine) and/or the substrate is extensively metabolized by this enzyme.
Adjust dosage when appropriate and monitor serum concentrations of drugs primarily metabolized by CYP3A closely in patients concurrently receiving clarithromycin. Table 8: Clinically Significant Drug Interactions with Clarithromycin Drugs That Are Affected By Clarithromycin Drug(s) with Pharmacokinetics Affected by Clarithromycin Recommendation Comments Antiarrhythmics: Disopyramide Quinidine Dofetilide Amiodarone Sotalol Procainamide Not Recommended Disopyramide, Quinidine: There have been postmarketing reports of torsades de pointes occurring with concurrent use of clarithromycin and quinidine or disopyramide.
Electrocardiograms should be monitored for QTc prolongation during coadministration of clarithromycin with these drugs [see Warnings and Precautions (5.3) ] . Serum concentrations of these medications should also be monitored. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with disopyramide and quinidine. There have been postmarketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide.
Therefore, blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide. Digoxin Use With Caution Digoxin: Digoxin is a substrate for P-glycoprotein (Pgp) and clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are co-administered, inhibition of Pgp by clarithromycin may lead to increased exposure of digoxin. Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have been reported in postmarketing surveillance.
Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Monitoring of serum digoxin concentrations should be considered, especially for patients with digoxin concentrations in the upper therapeutic range. Oral Anticoagulants: Warfarin Use With Caution Oral anticoagulants: Spontaneous reports in the postmarketing period suggest that concomitant administration of clarithromycin and oral anticoagulants may potentiate the effects of the oral anticoagulants.
Prothrombin times should be carefully monitored while patients are receiving clarithromycin and oral anticoagulants simultaneously [see Warnings and Precautions (5.4) ] . Antiepileptics: Carbamazepine Use With Caution Carbamazepine: 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.
Increased serum concentrations of carbamazepine were observed in clinical trials with clarithromycin. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with carbamazepine. Antifungals: Itraconazole Use With Caution Itraconazole: Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when administered concomitantly (see also Itraconazole under “Drugs That Affect Clarithromycin” in the table below).
Clarithromycin may increase the plasma concentrations of itraconazole. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions. Fluconazole No Dose Adjustment Fluconazole: [see Pharmacokinetics (12.3) ] Anti-Gout Agents: Colchicine (in patients with renal or hepatic impairment) Contraindicated Colchicine: Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp).
Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. The dose of colchicine should be reduced when co-administered with clarithromycin in patients with normal renal and hepatic function [see Contraindications (4.4) and Warnings and Precautions (5.4) ] . Colchicine (in patients with normal renal and hepatic function) Use With Caution Antipsychotics: Pimozide Contraindicated Pimozide: [See Contraindications (4.2) ] Quetiapine Quetiapine: Quetiapine is a substrate for CYP3A4, which is inhibited by clarithromycin.
Co-administration with clarithromycin could result in increased quetiapine exposure and possible quetiapine related toxicities. There have been postmarketing reports of somnolence, orthostatic hypotension, altered state of consciousness, neuroleptic malignant syndrome, and QT prolongation during concomitant administration. Refer to quetiapine prescribing information for recommendations on dose reduction if co-administered with CYP3A4 inhibitors such as clarithromycin.
Lurasidone Lurasidone: [See Contraindications (4.7) ] Antispasmodics: Tolterodine (patients deficient in CYP2D6 activity) Use With Caution Tolterodine: The primary route of metabolism for tolterodine is via CYP2D6. However, in a subset of the population devoid of CYP2D6, the identified pathway of metabolism is via CYP3A. In this population subset, inhibition of CYP3A results in significantly higher serum concentrations of tolterodine.
Tolterodine 1 mg twice daily is recommended in patients deficient in CYP2D6 activity (poor metabolizers) when co-administered with clarithromycin. Antivirals: Atazanavir Use With Caution Atazanavir: Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction (see Atazanavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3) ] .
Saquinavir (in patients with decreased renal function) Saquinavir: Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A and there is evidence of a bi-directional drug interaction (see Saquinavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3) ] . Ritonavir Etravirine Ritonavir, Etravirine: (see Ritonavir and Etravirine under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3) ] .
Maraviroc Maraviroc: Clarithromycin may result in increases in maraviroc exposures by inhibition of CYP3A metabolism. See Selzentry ® prescribing information for dose recommendation when given with strong CYP3A inhibitors such as clarithromycin. Boceprevir (in patients with normal renal function) Didanosine No Dose Adjustment Boceprevir: Both clarithromycin and boceprevir are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when co-administered.
No dose adjustments are necessary for patients with normal renal function (see Victrelis ® prescribing information). Zidovudine Zidovudine: Simultaneous oral administration of clarithromycin immediate-release tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations. Administration of clarithromycin and zidovudine should be separated by at least two hours [see Pharmacokinetics (12.3) ] .
The impact of co-administration of clarithromycin extended-release tablets or granules and zidovudine has not been evaluated. Calcium Channel Blockers: Verapamil Use With Caution Verapamil: Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent verapamil, [see Warnings and Precautions (5.4) ] . Amlodipine Diltiazem Amlodipine, Diltiazem: [see Warnings and Precautions (5.4) ] Nifedipine Nifedipine: Nifedipine is a substrate for CYP3A.
Clarithromycin and other macro
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Pregnancy and breastfeeding
8.1Pregnancy Risk Summary Based
on findings from animal studies, clarithromycin is not recommended for use in pregnant women except in clinical circumstances where no alternative therapy is appropriate. If pregnancy occurs while taking clarithromycin, the patient should be apprised of the potential hazard to the fetus [see Warnings and Precautions (5.7) ] . Limited data from a small number of published human studies with clarithromycin use during pregnancy are insufficient to inform drug-associated risks of major birth defects, miscarriage, or adverse maternal or fetal outcomes.
In animal reproduction studies, administration of oral clarithromycin to pregnant mice, rats, rabbits, and monkeys during the period of organogenesis produced malformations in rats (cardiovascular anomalies) and mice (cleft palate) at clinically relevant doses based on body surface area comparison. Fetal effects in mice, rats, and monkeys (e.g., reduced fetal survival, body weight, body weight gain) and implantation losses in rabbits were generally considered to be secondary to maternal toxicity (see Data).
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a 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. Data Animal Data Animal reproduction studies were conducted in mice, rats, rabbits, and monkeys with oral and intravenously administered clarithromycin.
In pregnant mice, clarithromycin was administered during organogenesis (gestation day [GD] 6 to 15) at oral doses of 15, 60, 250, 500, or 1000 mg/kg/day. Reduced body weight observed in dams at 1000 mg/kg/day (3 times the maximum recommended human dose [MRHD] based on body surface area comparison) resulted in reduced survival and body weight of the fetuses. At ≥ 500 mg/kg/day, increases in the incidence of post-implantation loss and cleft palate in the fetuses were observed.
No adverse developmental effects were observed in mice at ≤ 250 mg/kg/day (≤ 1 times MRHD based on body surface area comparison). In pregnant Sprague Dawley rats, clarithromycin was administered during organogenesis (GD 6 to 15) at oral doses of 15, 50, or 150 mg/kg/day. Reductions in body weight and food consumption was observed in dams at 150 mg/kg/day. Increased resorptions and reduced body weight of the fetuses at this dose were considered secondary to maternal toxicity.
Additionally, at 150 mg/kg/day (1 times MRHD based on body surface area comparison), a low incidence of cardiovascular anomalies (complete situs inversus, undivided truncus, IV septal defect) was observed in the fetuses. Clarithromycin did not cause adverse developmental effects in rats at 50 mg/kg/day (0.3 times MRHD based on body surface area comparison). Intravenous dosing of clarithromycin during organogenesis in rats (GD 6 to 15) at 15, 50, or 160 mg/kg/day was associated with maternal toxicity (reduced body weight, body-weight gain, and food consumption) at 160 mg/kg/day but no evidence of adverse developmental effects at any dose (≤ 1 times MRHD based on body surface area comparison).
In pregnant Wistar rat, clarithromycin was administered during organogenesis (GD 7 to 17) at oral doses of 10, 40, or 160 mg/kg/day. Reduced body weight and food consumption were observed in dams at 160 mg/kg/day but there was no evidence of adverse developmental effects at any dose (≤ 1 times MRHD based on body surface area comparison). In pregnant rabbits, clarithromycin administered during organogenesis (GD 6 to 18) at oral doses of 10, 35, or 125 mg/kg/day resulted in reduced maternal food consumption and decreased body weight at the highest dose, with no evidence of any adverse developmental effects at any dose (≤ 2 times MRHD based on body surface area comparison).
Intravenously administered clarithromycin to pregnant rabbits during organogenesis (GD 6 to 18) in rabbits at 20, 40, 80, or 160 mg/kg/day (≥ 0.3 times MRHD based on body surface area comparison) resulted in maternal toxicity and implantation losses at all doses. In pregnant monkeys, clarithromycin was administered (GD 20 to 50) at oral doses of 35 or 70 mg/kg/day. Dose-dependent emesis, poor appetite, fecal changes, and reduced body weight were observed in dams at all doses (≥ 0.5 times MRHD based on body surface area comparison).
Growth retardation in 1 fetus at 70 mg/kg/day was considered secondary to maternal toxicity. There was no evidence of primary drug related adverse developmental effects at any dose tested. In a reproductive toxicology study in rats administered oral clarithromycin late in gestation through lactation (GD 17 to post-natal day 21) at doses of 10, 40, or 160 mg/kg/day (≤ 1 times MRHD based on body surface area comparison), reductions in maternal body weight and food consumption were observed at 160 mg/kg/day.
Reduced body-weight gain observed in offspring at 160 mg/kg/day was considered secondary to maternal toxicity. No adverse developmental effects were observed with clarithromycin at any dose tested.
8.2Lactation Risk Summary Based
on limited human data, clarithromycin and its active metabolite 14-OH clarithromycin are present in human milk at less than 2% of the maternal weight-adjusted dose (see Data). In a separate observational study, reported adverse effects on breast-fed children (rash, diarrhea, loss of appetite, somnolence) were comparable to amoxicillin (see Data). No data are available to assess the effects of clarithromycin or 14-OH clarithromycin on milk production.
The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for clarithromycin and any potential adverse effects on the breast-fed child from clarithromycin or from the underlying maternal condition. Data Human Serum and milk samples were obtained after 3 days of treatment, at steady state, from one published study of 12 lactating women who were taking clarithromycin 250 mg orally twice daily.
Based on the limited data from this study, and assuming milk consumption of 150 mL/kg/day, an exclusively human milk fed infant would receive an estimated average of 136 mcg/kg/day of clarithromycin and its active metabolite, with this maternal dosage regimen. This is less than 2% of the maternal weight-adjusted dose (7.8 mg/kg/day, based on the average maternal weight of 64 kg), and less than 1% of the pediatric dose (15 mg/kg/day) for children greater than 6 months of age.
A prospective observational study of 55 breastfed infants of mothers taking a macrolide antibacterial (6 were exposed to clarithromycin) were compared to 36 breastfed infants of mothers taking amoxicillin. Adverse reactions were comparable in both groups. Adverse reactions occurred in 12.7% of infants exposed to macrolides and included rash, diarrhea, loss of appetite, and somnolence.
Adverse reactions
The following serious adverse reactions are described below and elsewhere in the labeling: Acute Hypersensitivity Reactions [see Warnings and Precautions (5.1) ] QT Prolongation [see Warnings and Precautions (5.2) ] Hepatotoxicity [see Warnings and Precautions (5.3) ] Serious Adverse Reactions Due to Concomitant Use with Other Drugs [see Warnings and Precautions (5.4) ] Clostridium difficile Associated Diarrhea [see Warnings and Precautions (5.6) ] Exacerbation of Myasthenia Gravis [see Warnings and Precautions (5.8) ] Most frequent adverse reactions for both adult and pediatric populations in clinical trials: abdominal pain, diarrhea, nausea, vomiting, dysgeusia (6.1) To report SUSPECTED ADVERSE REACTIONS, Lannett Company, Inc. at 1-844-834-0530 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1Clinical Trials Experience
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Based on pooled data across all indications, the most frequent adverse reactions for both adult and pediatric populations observed in clinical trials are abdominal pain, diarrhea, nausea, vomiting and dysgeusia.
Also reported were dyspepsia, liver function test abnormal, anaphylactic reaction, candidiasis, headache, insomnia, and rash. Less Frequent Adverse Reactions Observed During Clinical Trials of Clarithromycin Based on pooled data across all indications, 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 Gastrointestinal Adverse Reactions In the acute exacerbation of chronic bronchitis and acute maxillary sinusitis studies overall gastrointestinal adverse reactions 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 reactions compared to clarithromycin immediate-release tablets. All-Cause Mortality in Patients with Coronary Artery Disease 1 to 10 Years Following Clarithromycin Exposure In one clinical trial evaluating treatment with clarithromycin on outcomes in patients with coronary artery disease, an increase in risk of all-cause mortality was observed in patients randomized to clarithromycin.
Clarithromycin for treatment of coronary artery disease is not an approved indication. Patients were treated with clarithromycin or placebo for 14 days and observed for primary outcome events (e.g., all-cause mortality or non-fatal cardiac events) for several years. 1 A numerically higher number of primary outcome events in patients randomized to receive clarithromycin was observed with a hazard ratio of 1.06 (95% confidence interval 0.98 to 1.14).
However, at follow-up 10 years post-treatment, there were 866 (40%) deaths in the clarithromycin group and 815 (37%) deaths in the placebo group that represented a hazard ratio for all-cause mortality of 1.10 (95% confidence interval 1.00 to 1.21). The difference in the number of deaths emerged after one year or more after the end of treatment. The cause of the difference in all-cause mortality has not been established.
Other epidemiologic studies evaluating this risk have shown variable results [see Warnings and Precautions (5.5) ] .
6.2Postmarketing Experience
The following adverse reactions have been identified during post-approval use of clarithromycin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System: Thrombocytopenia, agranulocytosis Cardiac: Ventricular arrhythmia, ventricular tachycardia, torsades de pointes Ear and Labyrinth: Deafness was reported chiefly in elderly women and was usually reversible.
Gastrointestinal: Pancreatitis acute, tongue discoloration, tooth discoloration was reported and was usually reversible with professional cleaning upon discontinuation of the drug. There have been reports of clarithromycin extended-release tablets in the stool, many of which have occurred in patients with anatomic (including ileostomy or colostomy) or functional gastrointestinal disorders with shortened GI transit times.
In several reports, tablet residues have occurred in the context of diarrhea. It is recommended that patients who experience tablet residue in the stool and no improvement in their condition should be switched to a different clarithromycin formulation (e.g. suspension) or another antibacterial drug. Hepatobiliary: Hepatic failure, jaundice hepatocellular. Adverse reactions related to hepatic dysfunction have been reported with clarithromycin [see Warnings and Precautions (5.2) ] .
Infections and Infestations: Pseudomembranous colitis [see Warnings and Precautions (5.6) ] Immune System: Anaphylactic reactions, angioedema Investigations: Prothrombin time prolonged, white blood cell count decreased, international normalized ratio increased. Abnormal urine color has been reported, associated with hepatic failure. Metabolism and Nutrition: Hypoglycemia has been reported in patients taking oral hypoglycemic agents or insulin.
Musculoskeletal and Connective Tissue: Myopathy rhabdomyolysis was reported and in some of the reports, clarithromycin was administered concomitantly with statins, fibrates, colchicine or allopurinol [see Contraindications (4.5) and Warnings and Precautions (5.4) ] . Nervous System: Parosmia, anosmia, ageusia, paresthesia and convulsions Psychiatric : Abnormal behavior, confusional state, depersonalization, disorientation, hallucination, depression, manic behavior, abnormal dream, psychotic disorder.
These disorders usually resolve upon discontinuation of the drug. Renal and Urinary: Nephritis interstitial, renal failure Skin and Subcutaneous Tissue: Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS), Henoch-Schonlein purpura, acne, acute generalized exanthematous pustulosis Vascular: Hemorrhage 6.1
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Composition
Active ingredients
CLARITHROMYCIN 500MG
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
Use of a statin that is not dependent on CYP3A metabolism (e.g. fluvastatin) can be considered. It is recommended to prescribe the lowest registered dose if concomitant use cannot be avoided. 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 [see Drug Interactions (7) ] . Quetiapine: Use quetiapine and clarithromycin concomitantly with caution. Co-administration could result in increased quetiapine exposure and quetiapine related toxicities such as somnolence, orthostatic hypotension, altered state of consciousness, neuroleptic malignant syndrome, and QT prolongation. Refer to quetiapine prescribing information for recommendations on dose reduction if co-administered with CYP3A4 inhibitors such as clarithromycin [see Drug Interactions (7) ] .
Oral Anticoagulants: There is a risk of serious hemorrhage and significant elevations in INR and prothrombin time when clarithromycin is co-administered with warfarin. Monitor INR and prothrombin times frequently while patients are receiving clarithromycin and oral anticoagulants concurrently [see Drug Interactions (7) ] . Benzodiazepines: Increased sedation and prolongation of sedation have been reported with concomitant administration of clarithromycin and triazolobenzodiazepines, such as triazolam and midazolam [see Drug Interactions (7) ] .
