Clarithromycin warnings and precautions

# 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 with calcium channel blockers metabolized by CYP3A4 (e.g., verapamil, amlodipine, diltiazem) (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 co-administration 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 significant elevations in INR and prothrombin time when clarithromycin is co-administered with warfarin. INR and prothrombin times should be frequently monitored while patients are receiving clarithromycin and oral anticoagulants concurrently.

## HMG-CoA Reductase Inhibitors (statins)
Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated (see CONTRAINDICATIONS) 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.
Caution should be exercised when prescribing clarithromycin with statins. 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. 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.

## Clostridium difficile Associated Diarrhea
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including BIAXIN, 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.

## 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), and Henoch-Schonlein purpura clarithromycin therapy should be discontinued immediately and appropriate treatment should be urgently initiated.

## Combination Therapy with Other Drugs
For information about warnings of other drugs indicated in combination with BIAXIN, refer to the WARNINGS section of their package inserts.

# Precautions

## General
Prescribing BIAXIN in the absence of a 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.
Clarithromycin is principally excreted via the liver and kidney. Clarithromycin may be administered without dosage adjustment to patients with hepatic impairment and normal renal function. However, in the presence of severe renal impairment with or without coexisting hepatic impairment, decreased dosage or prolonged dosing intervals may be appropriate.
Clarithromycin in combination with ranitidine bismuth citrate therapy is not recommended in patients with creatinine clearance less than 25 mL/min (see Dosage And Administration).
Clarithromycin in combination with ranitidine bismuth citrate should not be used in patients with a history of acute porphyria.
Exacerbation of symptoms of myasthenia gravis and new onset of symptoms of myasthenic syndrome has been reported in patients receiving clarithromycin therapy.
For information about precautions of other drugs indicated in combination with BIAXIN, refer to the PRECAUTIONS section of their package inserts.

## Information to Patients
Patients should be counseled that antibacterial drugs including BIAXIN should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When BIAXIN 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 BIAXIN 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.
BIAXIN may interact with some drugs; therefore patients should be advised to report to their doctor the use of any other medications.
BIAXIN tablets and oral suspension can be taken with or without food and can be taken with milk; however, BIAXIN XL tablets should be taken with food. Do NOT refrigerate the suspension.