clarithromycin (Rx)

>10%

Gastrointestinal (GI) effects, general (13%)

1-10%

Abnormal taste (adults, 3-7%)

Diarrhea (3-6%)

Nausea (adults, 3-6%)

Vomiting (adults, 1%; children, 6%)

Elevated blood urea nitrogen (BUN; 4%)

Abdominal pain (adults, 2%; children, 3%)

Rash (children, 3%)

Dyspepsia (2%)

Heartburn (adults, 2%)

Headache (2%)

Elevated prothrombin time (PT; 1%)

<1%

Anaphylaxis

Anorexia

Anxiety

Clostridium difficile colitis

Dizziness

Dyspnea

Elevated liver function tests

Glossitis

Hallucinations

Hepatic dysfunction

Hepatitis

Hypoglycemia

Increased alkaline phosphatase

Increased aspartate aminotransferase

Increased bilirubin

Increased serum creatinine

Jaundice

Leukopenia

Manic behavior

Neuromuscular blockade

Neutropenia

Pancreatitis

Psychosis

QT prolongation

Seizures

Stevens-Johnson syndrome

Thrombocytopenia

Postmarketing Reports

Blood and lymphatic system disorders: Thrombocytopenia, agranulocytosis

Cardiac disorders: Torsades de pointes, ventricular tachycardia, ventricular arrhythmia

Ear and labyrinth disorders: Deafness was reported chiefly in elderly women and was usually reversible

Gastrointestinal disorders: Pancreatitis acute, tongue discoloration, tooth discoloration

Hepatobiliary disorders: Hepatic failure, jaundice hepatocellular

Immune system disorders: Anaphylactic reaction, angioedema

Infections and infestations: Pseudomembranous colitis

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 disorders: Hypoglycemia has been reported in patients taking oral hypoglycemic agents or insulin

Musculoskeletal and connective tissue disorders: Myopathy, rhabdomyolysis was reported and in some of the reports, clarithromycin was administered concomitantly with statins, fibrates, colchicine or allopurinol

Nervous system disorders: Convulsion, ageusia, parosmia, anosmia, paraesthesia Psychiatric disorders:

Psychotic disorder, confusional state, depersonalization, depression, disorientation, manic behavior, hallucination, abnormal behavior, abnormal dreams

Renal and urinary disorders: Nephritis interstitial, renal failure

Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, drug rash with eosinophilia and systemic symptoms (DRESS), Henoch-Schonlein purpura, acne

Vascular disorders: Hemorrhage

Other: Reports of colchicine toxicity, some resulting in death, with concomitant use of clarithromycin and colchicine, especially in the elderly, some of which occurred in patients with renal insufficiency

Use may result in fungal or bacterial superinfection

Decreased survival observed in HIV patients with mycobacterium avium complex treated with clarithromycin doses above maximum recommended dose; maximum recommended dosing should not be exceeded in this population; development of resistance to clarithromycin observed when used as prophylaxis and treatment of MAC infection

Contraindications

Documented hypersensitivity

Coadministration with pimozide, cisapride, ergotamine, and dihydroergotamine

History of cholestatic jaundice or hepatic dysfunction associated with previous use of clarithromycin

Coadministration with colchicine in patients with renal or hepatic impairment

Coadministration with HMG-CoA reductase inhibitors (statins) that are extensively metabolized by CYP3A4 (lovastatin, simvastatin), due to the increased risk of myopathy, including rhabdomyolysis

Cautions

Acute hypersensitivity reactions; discontinue immediately if severe hypersensitivity reactions occur (eg, anaphylaxis, Stevens-Johnson syndrome, TEN, drug reaction with eosinophilia and systemic symptoms [DRESS] syndrome, Henoch-Schonlein purpura)

Associated with QT interval prolongation and infrequent cases of arrhythmias, including torsade de pointes; avoid using with ongoing proarrhythmic conditions (eg, uncorrected hypokalemia or hypomagnesemia), clinically significant bradycardia; patients aged ≥65 yr may be more susceptible to drug-associated QT prolongation (also see Drug Interaction Overview)

Hepatic dysfunction, including increased liver enzyme activity and hepatocellular or cholestatic hepatitis, with or without jaundice, have been reported; this may be severe and is usually reversible

Discontinue clarithromycin immediately if signs and symptoms of hepatitis occur (eg, anorexia, jaundice, dark urine, pruritus, tender abdomen)

May increase morbidity among patients with coronary heart disease who received a 2-week course of clarithromycin; in an observational study, this risk became apparent after patients had been followed for ≥1 year; based on this study, the FDA added a warning to the prescribing information (CLARICOR trial; BMJ 2006;332:22-7)

Clostridium difficile associated diarrhea reported with use of nearly all antibacterial agents, including clarithromycin

Not for use in pregnancy, except when there is no alternative therapy; apprise patient about potential hazard to fetus if pregnancy occurs while in therapy

Exacerbation of myasthenia gravis or new onset of symptoms reported

Drug interaction overview

• Clarithromycin is a strong CYP3A4 inhibitor and also inhibits P-pg transport (ABCB1)

• CYP3A4

  • Clarithromycin is a strong CYP3A4 inhibitor; drugs primarily metabolized by CYP3A4 may result in higher exposure to these medications (also see Contraindications)
  • Reduce colchicine dose if coadministered with clarithromycin in patients with normal hepatic and renal function (contraindicated with hepatic and renal impairment)
  • Decrease dose of atorvastatin or pravastatin if coadministered with clarithromycin
  • Coadministration of clarithromycin with oral hypoglycemic agents and/or insulin can result in significant hypoglycemia; examples of or hypoglycemic agents that are CYP3A substrates include nateglinide, pioglitazone, repaglinide and rosiglitazone

• QT prolongation

  • Contraindicated with pimozide with cisapride (each are known to prolong QT interval and are also CYP3A4 substrates)
  • Avoid coadministration with drugs with known risk of QT prolongation
  • Coadministration with quetiapine may result in quetiapine related toxicities including neuroleptic malignant syndrome, QT prolongation, somnolence, orthostatic hypotension, altered state of consciousness
  • Cautiously monitor if coadministered with drugs that may prolong QT interval

• Other interactions

  • Macrolides may increase the serum concentration of vitamin K antagonists (eg, warfarin); monitor INR
  • Increased and prolonged sedation may occur when coadministered with benzodiazepines (eg, triazolam, midazolam)
  • May increase digoxin levels via P-gp inhibition

Pregnancy

Based on findings from animal studies, drug is not recommended for use in pregnant women except in clinical circumstances where no alternative therapy is appropriate; if pregnancy occurs while taking drug, patient should be apprised of potential hazard to fetus

Limited data from a small number of published human studies with therapy use during pregnancy are insufficient to inform drug-associated risks of major birth defects, miscarriage, or adverse maternal or fetal outcomes

Animal data

• 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

Lactation

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; in a separate observational study, reported adverse effects on breast-fed children (rash, diarrhea, loss of appetite, somnolence) were comparable to amoxicillin; no data are available to assess effects of clarithromycin or 14-OH clarithromycin on milk production

Development and health benefits of breastfeeding should be considered along with mother’s clinical need for drug and any potential adverse effects on breast-fed child from therapy or from underlying maternal condition

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Semisynthetic macrolide antibiotic that reversibly binds to P site of 50S ribosomal subunit of susceptible organisms and may inhibit RNA-dependent protein synthesis by stimulating dissociation of peptidyl t-RNA from ribosomes, thereby inhibiting bacterial growth

Absorption

Highly stable in presence of gastric acid (unlike erythromycin); food delays but does not affect extent of absorption

Bioavailability: 50%

Peak plasma time: 2-3 hr (immediate release); 5-8 hr (extended release)

Distribution

Distributed widely into most body tissues except central nervous system (CNS)

Protein bound: 42-50%

Metabolism

Partially metabolized by CYP3A4

Metabolites: 14-OH clarithromycin (active)

Elimination

Half-life: Immediate release, 3-7 hr; active metabolite, 5-9 hr

Renal clearance: Approximates normal glomerular filtration rate (GFR)

Excretion: Urine (30-55%)

Preparation of Oral Suspension

Add half the volume of water to the bottle containing granules and shake vigorously, THEN

Add the remainder of water to the bottle and shake

Shake well before each use

Volume of water to add

• 125 mg/5 mL (50-mL bottle): 27 mL
• 125 mg/5 mL (100-mL bottle): 55 mL
• 250 mg/5 mL (50-mL bottle): 27 mL
• 250 mg/5 mL (100-mL bottle): 55 mL

Oral Administration

Tablet or granules may be administered with or without food

Extended-release tablet

• Administer with food
• Swallow whole; do not chew, break, or crush

Storage

Tablets: Store at controlled room temperature of 20-25°C (68-77°F); excursions permitted to 15-30°C (59-86°F)

Granules for oral suspension

• Granules: Store below 25°C (77°F) in a well-closed container

• Reconstituted

  • Do not refrigerate after reconstituting granules
  • After mixing, store at 15-30°C (59-86°F) and use within 14 days