Biaxin: Indications, Dosage, Precautions, Adverse Effects
Россия
  • Россия
  • Украина

Biaxin - Product Information

Manufacture: Abbott
Country: Canada
Condition: Bacterial Endocarditis Prevention (Bacterial Endocarditis Prophylaxis), Bronchitis, Dental Abscess, Helicobacter Pylori Infection, Legionella Pneumonia, Mycoplasma Pneumonia, Mycobacterium avium-intracellulare, Treatment, Mycobacterium avium-intracellulare, Prophylaxis, Nongonococcal Urethritis, Otitis Media, Pertussis, Pertussis Prophylaxis, Pharyngitis, Pneumonia, Sinusitis, Skin and Structure Infection, Skin or Soft Tissue Infection, Strep Throat (Streptococcal Pharyngitis), Toxoplasmosis, Tonsillitis/Pharyngitis, Upper Respiratory Tract Infection
Class: Macrolides
Form: Tablets, Powder, Syrup
Ingredients: clarithromycin, cellulosic polymers, croscarmellose sodium, D&C Yellow No. 10, magnesium stearate, povidone, pregelatinized starch (250 mg only), propylene glycol, silicon dioxide, sorbic acid, sorbitan monooleate, stearic acid, talc, titanium dioxide, vanillin

BIAXIN BID

clarithromycin tablets USP, film-coated


BIAXIN XL

clarithromycin extended-release tablets

Abbott Standard


BIAXIN

clarithromycin for oral suspension USP

Summary Product Information

Route of
Administration
Dosage Form /
Strength
Clinically Relevant Non-medicinal
Ingredients
Oral film-coated tablets /
250 mg & 500 mg
cellulosic polymers, croscarmellose sodium, D&C Yellow No. 10, magnesium stearate, povidone, pregelatinized starch (250 mg only), propylene glycol, silicon dioxide, sorbic acid, sorbitan monooleate, stearic acid, talc, titanium dioxide and vanillin.
extended-release
tablets / 500 mg
cellulosic polymers, lactose monohydrate, magnesium stearate, propylene glycol, Quinoline Yellow Lake E104, sorbitan monooleate, talc, titanium dioxide and vanillin.
oral suspension /
125 mg / 5 mL and
250 mg / 5 mL
artificial and natural fruit flavour, citric acid, carbopol, castor oil, hydroxypropyl methylcellulose phthalate, maltodextrin, potassium sorbate, povidone, silicon dioxide, sucrose or sugar, titanium dioxide and xanthan gum.
For a complete listing see DOSAGE FORMS, COMPOSITION AND PACKAGING section.

Indications and Clinical Use

BIAXIN BID (clarithromycin tablets USP, film-coated)

BIAXIN BID (clarithromycin tablets USP, film-coated) may be indicated in the treatment of mild to moderate infections caused by susceptible strains of the designated microorganisms in the diseases listed below.

Upper Respiratory Tract

Pharyngitis/tonsillitis, caused by Streptococcus pyogenes (Group A beta-hemolytic streptococci).

Acute maxillary sinusitis caused by Streptococcus pneumoniae (S. pneumoniae), Haemophilus influenzae (H. influenzae), and Moraxella (Branhamella) catarrhalis [M. (Branhamella) catarrhalis].

Lower Respiratory Tract

Acute bacterial exacerbation of chronic bronchitis caused by S. pneumoniae, H. influenzae (including beta-lactamase producing strains), M. (Branhamella) catarrhalis (including beta-lactamase producing strains).

Pneumonia caused by S. pneumoniae and Mycoplasma. pneumoniae (M. pneumoniae).

Uncomplicated Skin and Skin Structure Infections

Uncomplicated Skin and Skin Structure Infections caused by Streptococcus pyogenes (S. pyogenes), Staphylococcus aureus (S. aureus).

Mycobacterial Infections

BIAXIN BID (clarithromycin tablets USP, film-coated) is indicated for the prevention of disseminated Mycobacterium avium complex (MAC) disease in patients with advanced HIV infection, and for the treatment of disseminated mycobacterial infections due to Mycobacterium avium (M. avium) and Mycobacterium intracellulare (M. intracellulare). See CLINICAL TRIALS, Mycobacterial Infections.

Eradication of Helicobacter pylori

BIAXIN BID (clarithromycin tablets USP, film-coated) in the presence of acid suppression (with omeprazole) with another antibiotic (amoxicillin) is indicated for the eradication of Helicobacter pylori (H. pylori) that may result in decreased recurrence of duodenal ulcer in patients with active duodenal ulcers and who are H. pylori positive. See CLINICAL TRIALS, Eradication of Helicobacter pylori, Triple Therapy: BIAXIN BID/omeprazole/amoxicillin.

(For additional information on the use of BIAXIN BID in triple therapy for the treatment of H. pylori infection and active duodenal ulcer recurrence, refer to the Hp-PAC Product Monograph.)

BIAXIN XL (clarithromycin extended-release tablets)

BIAXIN XL (clarithromycin extended-release tablets) may be indicated in the treatment of mild to moderate infections caused by susceptible strains of the designated microorganisms in the diseases listed below.

Upper Respiratory Tract

Acute maxillary sinusitis due to H. influenzae, M. catarrhalis, or S. pneumoniae.

Lower Respiratory Tract

Acute bacterial exacerbation of chronic bronchitis due to Haemophilus parainfluenzae (H. parainfluenzae), H. influenzae, M. catarrhalis, S. aureus, or S. pneumoniae.

Community-acquired pneumonia due to H. influenzae, H. parainfluenzae, M. catarrhalis, S. pneumoniae, Chlamydia pneumoniae (TWAR), or M. pneumoniae.

The efficacy and safety of BIAXIN XL in treating other infections for which BIAXIN BID and BIAXIN are approved have not been established.

BIAXIN (clarithromycin for oral suspension USP)

BIAXIN (clarithromycin for oral suspension USP) is indicated for the treatment of infections due to susceptible organisms, in the following conditions.

Upper Respiratory Tract

Pharyngitis caused by S. pyogenes (Group A ß-hemolytic streptococci).

Acute otitis media caused by H. influenzae, M. catarrhalis, or S. pneumoniae. See CLINICAL TRIALS, Otitis Media.

Lower Respiratory Tract

Mild to moderate community-acquired pneumonia caused by S. pneumoniae, C. pneumoniae, or M. pneumoniae.

Uncomplicated skin and skin structure infections

Uncomplicated skin and skin structure infections (i.e., impetigo and cellulitis) caused by S. aureus or S. pyogenes.

Mycobacterial Infections

Disseminated mycobacterial infections due to M. avium and M. intracellulare.

Pediatrics (6 months - 12 years of age)

Dosing recommendations for children are based on body weight. See WARNINGS AND PRECAUTIONS, Special Populations, Pediatrics and DOSAGE AND ADMINISTRATION, Table 15.

Geriatrics (> 65 years of age)

Dosage adjustment should be considered in elderly patients with severe renal impairment. See WARNINGS AND PRECAUTIONS, Special Populations, Geriatrics.

Contraindications

BIAXIN BID (clarithromycin tablets USP, film-coated), BIAXIN XL (clarithromycin extended-release tablets) and BIAXIN (clarithromycin for oral suspension USP) are contraindicated in:

  • patients with a known hypersensitivity to clarithromycin, erythromycin, other macrolide antibacterial agents or to any ingredient in this product. See DOSAGE FORMS, COMPOSITION AND PACKAGING.
  • patients with a history of cholestatic jaundice/hepatic dysfunction associated with prior use of clarithromycin.
  • patients who suffer from severe hepatic failure in combination with renal impairment. See WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic, WARNINGS AND PRECAUTIONS, Renal, DOSAGE AND ADMINISTRATION, Dosing Considerations and DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment.
  • patients with history of QT prolongation or ventricular cardiac arrhythmia, including torsades de pointes. See WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS, Drug-Drug Interactions.
  • patients with hypokalaemia due to the risk of prolongation of QT-time and torsades de pointes.
  • concomitant therapy with astemizole, cisapride, pimozide, terfenadine.

    There have been post-marketing reports of drug interactions when clarithromycin and/or erythromycin are co-administered with astemizole, cisapride, pimozide, or terfenadine resulting in cardiac arrhythmias (QT prolongation, ventricular tachycardia, ventricular fibrillation, and torsades de pointes) most likely due to inhibition of hepatic metabolism of these drugs by erythromycin and clarithromycin. Fatalities have been reported. See DRUG INTERACTIONS, Drug-Drug Interactions, Table 12.

  • concomitant therapy with HMG-CoA reductase inhibitors (statins) that are extensively metabolized by CYP3A4 (lovastatin or simvastatin), due to an increased risk of myopathy, including rhabdomyolysis. See DRUG INTERACTIONS, Drug-Drug Interactions, Table 12.
  • concomitant therapy with ergot alkaloids (e.g., ergotamine or dihydroergotamine) as this may result in ergot toxicity. See DRUG INTERACTIONS, Drug-Drug Interactions, Table 12.
  • concomitant administration with oral midazolam. See DRUG INTERACTIONS, Drug-Drug Interactions, Table 12.
  • concomitant therapy with colchicine due to the risk of life threatening and fatal colchicine toxiciy. This risk may be further increased with concomitant medications metabolized by P-glycoprotein or strong CYP3A inhibitors. See DRUG INTERACTIONS, Drug-Drug Interactions, Table 12.
  • concomitant therapy with ticagrelor or ranolazine*.

* Not marketed in Canada.

Serious Warnings and Precautions

  • Clarithromycin should not be used in pregnancy except where no alternative therapy is appropriate, particularly during the first 3 months of pregnancy. If pregnancy occurs while taking the drug, the patient should be apprised of the potential hazard to the fetus. See WARNINGS AND PRECAUTIONS, Special Populations, Pregnant Women.
  • The concomitant administration of clarithromycin and drugs metabolized by CYP3A and/or transported by P-gp may result in significant safety concerns. See WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS, Overview.

General

Clarithromycin should be administered with caution to any patient who has demonstrated some form of drug allergy, particularly to structurally related-drugs. If an allergic reaction to clarithromycin occurs, administration of the drug should be discontinued. Serious hypersensitivity reactions may require epinephrine, antihistamines, or corticosteroids. See WARNINGS AND PRECAUTIONS, Immune, Hypersensitivity.

Long-term use may, as with other antibiotics, result in colonization with increased numbers of non-susceptible bacteria and fungi. If superinfections occur, appropriate therapy should be instituted.

Patients Infected with Human Immunodeficiency Virus

Several studies of Human Immunodeficiency Virus (HIV)-positive patients receiving clarithromycin for treatment of MAC infection have shown poorer survival in those patients randomized to receive doses higher than 500 mg twice daily. The explanation for the poorer survival associated with doses higher than 500 mg twice daily has not been determined. Treatment or prophylaxis of MAC infection with clarithromycin should not exceed the approved dose of 500 mg twice daily.

Myasthenia Gravis

Exacerbation of symptoms of myasthenia gravis and new onset of symptoms of myasthenic syndrome has been reported in patients receiving clarithromycin therapy.

Use of Clarithromycin with Other Drugs

Use of clarithromycin with other drugs may lead to drug-drug interactions.

Oral Hypoglycemic Agents/Insulin

The concomitant use of clarithromycin and oral hypoglycaemic agents (such as sulphonylurias) and/or insulin can result in significant hypoglycaemia. Careful monitoring of glucose is recommended. See DRUG INTERACTIONS, Drug-Drug Interactions, Table 12.

Oral Anticoagulants

There is a risk of serious hemorrhage and significant elevations in International Normalized Ratio (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. See DRUG INTERACTIONS, Drug-Drug Interactions, Table 12.

HMG-CoA Reductase Inhibitors

Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated. See CONTRAINDICATIONS. Caution should be exercised when prescribing clarithromycin with other statins. Rhabdomyolysis has been reported in patients taking clarithromycin and statins. Patients should be monitored for signs and symptoms of myopathy. In situations where the concomitant use of clarithromycin with statins cannot be avoided, it is recommended to prescribe the lowest registered dose of the statin. Use of a statin that is not dependent on CYP3A metabolism (e.g., fluvastatin) can be considered. See DRUG INTERACTIONS, Drug-Drug Interactions, Table 12.

Triazolobenzodiazepines and Related Benzodiazepines

Caution is advised regarding the concomitant administration of clarithromycin with triazolobenzodiazepines (such as triazolam and alprazolam), or with other benzodiazepines (such as intravenous midazolam) due to the serious risk of central nervous system (CNS) effects (e.g., somnolence and confusion). See DRUG INTERACTIONS, Drug-Drug Interactions, Table 12.

Concomitant administration with oral midazolam is contraindicated. See CONTRAINDICATIONS.

Calcium Channel Blockers

Caution is advised regarding the concomitant administration of clarithromycin and calcium channel blockers metabolized by CYP3A4 (e.g., verapamil, amlodipine, diltiazem) due to the risk of hypotension. See DRUG INTERACTIONS, Drug-Drug Interactions, Table 12.

Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent verapamil, belonging to the calcium channel blockers drug class. See DRUG INTERACTIONS, Drug-Drug Interactions, Table 12.

Other Drugs

For other established or potential drug-drug interactions and their mechanisms, see CONTRAINDICATIONS and DRUG INTERACTIONS, Drug-Drug Interactions.

Carcinogenesis and Mutagenesis

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of clarithromycin.

The following in vitro mutagenicity tests have been conducted with clarithromycin: Salmonella/mammalian microsome test, bacterial induced mutation frequency test, in vitro chromosome aberration test, rat hepatocyte DNA synthesis assay, mouse lymphoma assay, mouse dominant lethal study, mouse micronucleus test. All tests had negative results except the in vitro chromosome aberration test which was weakly positive in one test and negative in another. In addition, a Bacterial Reverse-Mutation Test (Ames Test) has been performed on clarithromycin metabolites with negative results.

Cardiovascular

Clarithromycin should be used with caution in patients with coronary artery disease, severe cardiac insufficiency, hypomagnesemia, bradycardia (< 50 bpm), or when co-administered with other medicinal products associated with QT prolongation, due to the risk for QT prolongation and torsades de pointes. See DRUG INTERACTIONS, Drug-Drug Interactions.

Clarithromycin is contraindicated in patients with congenital or documented acquired QT prolongation or history of ventricular arrhythmia, including torsades de pointes. Clarithromycin is also contraindicated in patients with hypokalaemia due to the risk of QT prolongation and torsades de pointes. See CONTRAINDICATIONS.

Endocrine and Metabolism

BIAXIN (clarithromycin for oral suspension USP) contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucosegalactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

When prescribing to diabetic patients, the sucrose content should be taken into account. See DOSAGE FORMS, COMPOSITION AND PACKAGING.

BIAXIN XL (clarithromycin extended-release tablets) contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take these medicines. See DOSAGE FORMS, COMPOSITION AND PACKAGING.

Gastrointestinal

Clostridium difficile-Associated Disease

Clostridium difficile-associated disease (CDAD) has been reported with use of many antibacterial agents, including clarithromycin. CDAD may range in severity from mild diarrhea to fatal colitis. It is important to consider this diagnosis in patients who present with diarrhea, or symptoms of colitis, pseudomembranous colitis, toxic megacolon, or perforation of colon subsequent to the administration of any antibacterial agent. CDAD has been reported to occur over 2 months after the administration of antibacterial agents.

Treatment with antibacterial agents may alter the normal flora of the colon and may permit overgrowth of Clostridium difficile. Clostridium difficile produces toxins A and B, which contribute to the development of CDAD. CDAD may cause significant morbidity and mortality. CDAD can be refractory to antimicrobial therapy.

If the diagnosis of CDAD is suspected or confirmed, appropriate therapeutic measures should be initiated.Mild cases of CDAD usually respond to discontinuation of antibacterial agents not directed against Clostridium difficile. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against Clostridium difficile. Surgical evaluation should be instituted as clinically indicated, as surgical intervention may be required in certain severe cases. See ADVERSE REACTIONS.

Hepatic/Biliary/Pancreatic

Caution is advised in patients with impaired hepatic function.

Clarithromycin is principally excreted by the liver and kidney. In patients with a combination of hepatic (mild to moderate) and renal impairments, decreased dosage of clarithromycin or prolonged dosing intervals might be appropriate. See DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment.

Clarithromycin is contraindicated in patients with severe hepatic failure in combination with renal impairment. See CONTRAINDICATIONS.

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 outcomes has been reported and generally has been associated with serious underlying diseases and/or concomitant medications. Discontinue clarithromycin immediately if signs and symptoms of hepatitis occur, such as anorexia, jaundice, dark urine, pruritus, or tender abdomen.

Immune

Hypersensitivity Reactions

Severe acute hypersensitivity reactions, such as anaphylaxis, Stevens-Johnson syndrome, toxic epidermal necrolysis and DRESS have been reported. In the event of severe acute hypersensitivity reactions, clarithromycin therapy should be discontinued immediately and appropriate treatment should be urgently initiated.

Renal

Caution is advised in patients with severe renal insufficiency.

Clarithromycin is principally excreted by the liver and kidney. In patients with a combination of hepatic (mild to moderate) and renal impairments or in the presence of severe renal impairment, decreased dosage of clarithromycin or prolonged dosing intervals might be appropriate. See DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment.

Clarithromycin is contraindicated in patients with severe hepatic failure in combination with renal impairment. See CONTRAINDICATIONS.

For the eradication of H. pylori, amoxicillin and clarithromycin should not be administered to patients with renal impairment since the appropriate dosage in this patient population has not yet been established.

Sensitivity/Resistance

The development of resistance (11 out of 19 breakthrough isolates in 1 study) has been seen in HIV positive patients receiving clarithromycin for prophylaxis and treatment of MAC infection.

In view of the emerging resistance of Streptococcus pneumoniae, Staphylococcus aureus and Streptococcus pyogenes to macrolides, it is important that sensitivity testing be performed when prescribing clarithromycin for community-acquired pneumonia and uncomplicated skin and skin structure infections.

To avoid failure of the eradication treatment with a potential for developing antimicrobial resistance and a risk of failure with subsequent therapy, patients should be instructed to follow closely the prescribed regimen.

Antibiotic Resistance in Relation to Helicobacter pylori Eradication

Use of any antimicrobial therapy, such as clarithromycin, to treat H. pylori infection may select for drug-resistant organisms.

Triple Therapy with Omeprazole

Among the 113 triple therapy recipients with pretreatment H. pylori isolates susceptible to clarithromycin, 2/102 patients (2%) developed resistance after treatment with omeprazole, clarithromycin, and amoxicillin. Among patients who received triple therapy, 6/108 (5.6%) patients had pretreatment H. pylori isolates resistant to clarithromycin. Of these 6 patients, 3 (50%) had H. pylori eradicated at follow-up, and 3 (50%) remained positive after treatment. In 5/113 (4.4%) patients, no susceptibility data for clarithromycin pretreatment were available. Development of clarithromycin resistance should be considered as a possible risk especially when less efficient treatment regimens are used.

Special Populations

Pregnant Women

There are no adequate and well-controlled studies in pregnant women. The benefits against risk, particularly during the first 3 months of pregnancy should be carefully weighed by a physician. See WARNINGS AND PRECAUTIONS, Serious Warnings and Precautions.

Four teratogenicity studies in rats (3 with oral doses and 1 with intravenous doses up to 160 mg/kg/day administered during the period of major organogenesis) and 2 in rabbits (at oral doses up to 125 mg/kg/day or intravenous doses of 30 mg/kg/day administered during gestation days 6 to 18) failed to demonstrate any teratogenicity from clarithromycin. Two additional oral studies in a different rat strain at similar doses and similar conditions demonstrated a low incidence of cardiovascular anomalies at doses of 150 mg/kg/day administered during gestation days 6 to 15. Plasma levels after 150 mg/kg/day were 2 times the human serum levels.

Four studies in mice revealed a variable incidence of cleft palate following oral doses of 1000 mg/kg/day during gestation days 6 to 15. Cleft palate was also seen at 500 mg/kg/day. The 1000 mg/kg/day exposure resulted in plasma levels 17 times the human serum levels. In monkeys, an oral dose of 70 mg/kg/day produced fetal growth retardation at plasma levels that were 2 times the human serum levels.

Embryonic loss has been seen in monkeys and rabbits. See TOXICOLOGY, Reproduction and Teratology.

Nursing Women

The safety of clarithromycin for use during breast-feeding of infants has not been established. Clarithromycin is excreted in human milk.

Preweaned rats, exposed indirectly via consumption of milk from dams treated with 150 mg/kg/day for 3 weeks, were not adversely affected, despite data indicating higher drug levels in milk than in plasma.

Pediatrics (6 months to 12 years of age)

Use of BIAXIN BID (clarithromycin tablets USP, film-coated) and BIAXIN XL (clarithromycin extended-release tablets) in children under 12 years of age has not been studied.

Use of BIAXIN (clarithromycin for oral suspension USP) in children under 6 months has not been studied. In pneumonia, clarithromycin granules were not studied in children younger than 3 years.

The safety of clarithromycin has not been studied in MAC patients under the age of 20 months.

Neonatal and juvenile animals tolerated clarithromycin in a manner similar to adult animals. Young animals were slightly more intolerant to acute overdosage and to subtle reductions in erythrocytes, platelets and leukocytes, but were less sensitive to toxicity in the liver, kidney, thymus and genitalia.

Increased valproate and phenobarbital concentrations and extreme sedation were noted in a 3-year old patient coincident with clarithromycin therapy. Cause and effect relationship cannot be established. However, monitoring of valproate and phenobarbital concentrations may be considered.

Geriatrics (> 65 years of age)

Dosage adjustment should be considered in elderly patients with severe renal impairment. In a steady-state study in which healthy elderly subjects (age 65 to 81 years old) were given 500 mg every 12 hours, the maximum concentrations of clarithromycin and 14-OH-clarithromycin were increased. The AUC was also increased. These changes in pharmacokinetics parallel known age-related decreases in renal function. In clinical trials, elderly patients did not have an increased incidence of adverse events when compared to younger patients.

Adverse Reactions

Adverse Drug Reaction Overview

The majority of side effects observed in clinical trials involving 3563 patients treated with BIAXIN BID were of a mild and transient nature. Fewer than 3% of adult patients without mycobacterial infections discontinued therapy because of drug-related side-effects. The most common drug-related adverse reactions in adults taking BIAXIN BID were nausea, diarrhea, abdominal pain, dyspepsia, headache, taste perversion and vomiting. The most frequently reported events in adults taking BIAXIN XL were diarrhea, abnormal taste and nausea. In pediatric patients taking BIAXIN (oral suspension), the most frequently reported events were diarrhea, vomiting, abdominal pain, dyspepsia, taste perversion and infection.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

BIAXIN BID (clarithromycin tablets USP, film-coated)

Patients with Respiratory Tract or Skin Infections

Table 1 provides a listing of adverse reactions from clinical trials or post-marketing surveillance as well as adverse events reported during post-marketing surveillance. Adverse events reported during post-marketing surveillance may include patients treated for various infections and are not limited to patients with respiratory tract or skin infections.

Table 1 Adverse Events/Adverse Drug Reactions in Patients with Respiratory Tract or Skin Infections or Other Infections Treated with BIAXIN BID
System Organ Class Adverse Reaction/Adverse Event
General disorders and administration site conditionsAsthenia
Pain
Chest pain
Infections and infestationsInfection
Colitis pseudomembranous
Candidiasis
Rhinitis
Pharyngitis
Vaginal candidiasis
Vaginal infection
Musculoskeletal and connective tissue disordersBack pain
Myalgia
InvestigationsIncreased liver enzymes
Cardiac disorders*Electrocardiogram QT prolonged
Ventricular tachycardia
Torsades de pointes
Gastrointestinal disordersConstipation
Flatulence
Dry mouth
Glossitis
Stomatitis
Gastrointestinal disorder
Tongue discolouration
Tooth discolouration
Pancreatitis
Metabolism and nutrition disordersAnorexia
Hypoglycemia**
Hepatobiliary disordersHepatomegaly
Hepatic function abnormal
Hepatitis
Hepatitis cholestatic
Jaundice (cholestatic and hepatocellular)
Hepatic failure ***
Nervous system disordersDizziness
Somnolence
Convulsion
Parosmia
Dysgeusia
Ageusia
Ear and labyrinth disordersVertigo
Tinnitus
Ear disorder
Deafness****
Psychiatric disordersNervousness
Anxiety
Insomnia
Nightmare
Depression
Confusional state
Disorientation
Depersonalisation
Hallucination
Psychotic disorder
Respiratory, thoracic and mediastinal disordersCough
Dyspnea
Asthma
Skin and subcutaneous tissue disordersPruritus
Rash
Hyperhidrosis
Urticaria
Stevens-Johnson syndrome
Toxic epidermal necrosis
Immune system disordersAnaphylactic reaction
Myasthenia gravis
Eye disordersVisual disturbance
Conjunctivitis
Renal and urinary disordersHematuria
Nephritis interstitial
Reproductive system and breast disordersDysmenorrhea
Blood and lymphatic system disordersEosinophilia
Anemia
Leukopenia
Thrombocythemia
Thrombocytopenia

* As with other macrolides, QT prolongation, ventricular tachycardia, and torsades de pointes have been reported with clarithromycin.

** There have been reports of hypoglycemia, some of which have occurred in patients on concomitant oral hypoglycemic agents or insulin.

*** Hepatic dysfunction may be severe and is usually reversible. Hepatic failure with fatal outcome has been reported and generally has been associated with serious underlying diseases and/or concomitant medications.

**** There have been reports of hearing loss with clarithromycin which is usually reversible upon withdrawal of therapy.

In studies of adults with pneumonia comparing clarithromycin to erythromycin base or erythromycin stearate, there were significantly fewer adverse events involving the digestive system in patients treated with clarithromycin.

Abnormal Laboratory Values

Changes in laboratory values with possible clinical significance reported during clinical studies or during post-marketing surveillance are displayed in Table 2.

Table 2 Abnormal Hematologic and Clinical Chemistry Findings in Patients with Respiratory Tract or Skin Infections Treated with BIAXIN BID
System Organ
Class
Laboratory Values Frequency
Investigations Alanine aminotransferase increased
Aspartate aminotransferase increased
Gamma-glutamyltransferase increased
Blood alkaline phosphatase increased
Blood lactate dehydrogenase increased
Blood bilirubin increased
Blood creatinine increased
White blood cell count decreased
Uncommon
(Less than 1%)
Prothrombin time prolonged
Blood urea increased
1%
4%
Patients with Mycobacterial Infections

In patients with acquired immune deficiency syndrome (AIDS) and other immunocompromised patients treated with the higher doses of clarithromycin over long periods of time for prevention or treatment of mycobacterial infections, it was often difficult to distinguish adverse events possibly associated with clarithromycin administration from underlying signs of HIV disease or intercurrent illness.

Prophylaxis

Discontinuation due to adverse events was required in 18% of AIDS patients receiving clarithromycin 500 mg twice daily, compared to 17% of patients receiving placebo in a randomized, double-blind study. Primary reasons for discontinuation in the clarithromycin-treated patients include headache, nausea, vomiting, depression and taste perversion. The most frequently reported adverse events with an incidence of 2% or greater, excluding those due to the patient's concurrent condition, are listed in Table 3. Among these events, taste perversion was the only event that had significantly higher incidence in the clarithromycin-treated compared to the placebo-treated group.

Table 3 Percentage of Adverse Events* in Immunocompromised Adult Patients Receiving Prophylaxis Against M. avium Complex
System Organ Class‡ Adverse Reaction Clarithromycin
(n=339)
%
Placebo
(n = 339)
%
Gastrointestinal disordersAbdominal pain5.0%3.5%
Nausea11.2%7.1%
Diarrhea7.7%4.1%
Vomiting5.9%3.2%
Dyspepsia3.8%2.7%
Flatulence2.4%0.9%
Nervous system disordersDysgeusia8.0%0.3%
Headache2.7%0.9%
Skin and subcutaneous tissue
disorders
Rash3.2%3.5%

* Includes those events possibly or probably related to study drug and excludes concurrent conditions.

‡ ≥ 2% Adverse Event Incidence Rates for either treatment group.

Abnormal Laboratory Values

In immunocompromised patients receiving prophylaxis against M. avium, those laboratory values outside the extreme high or low limit for the specified test were analyzed (Table 4).

Table 4 Percentage of Patients* Exceeding Extreme Laboratory Value in Immunocompromised Patients Receiving Prophylaxis Against M. avium Complex
System Organ
Class
Laboratory Values Clarithromycin
500 mg b.i.d.
Placebo
Investigations Hemoglobin decreased
< 8 g/dL
4/118 3% 5/103 5%
Platelet count decreased
< 50 x 109/L
11/249 4% 12/250 5%
White blood cell count decreased
< 1 x 109/L
2/103 4% 0/95 0%
Aspartate aminotransferase
increased
> 5 x ULN
7/196 4% 5/208 2%
Alanine aminotransferase increased
> 5 x ULN
6/217 3% 4/232 2%
Blood alkaline phosphatase
increased
> 5 x ULN
5/220 2% 5/218 2%

* Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables).

Legend: b.i.d. = twice daily; ULN = Upper Limit of Normal

Treatment of Patients with Mycobacterial Infections

Excluding those patients who discontinued therapy due to complications of their underlying non-mycobacterial diseases (including death), approximately 14% of the patients discontinued therapy due to drug-related adverse events.

In adult patients, the most frequently reported adverse events with an incidence of 3% or greater, excluding those due to the patient’s concurrent condition, are listed in Table 5 by the total daily dose the patient was receiving at the time of the event. A total of 867 patients were treated with clarithromycin for mycobacterial infections. Of these, 43% reported one or more adverse events. Most of these events were described as mild to moderate in severity, although 14% were described as severe.

Incidence of adverse events was higher in patients taking 4000 mg total daily doses compared to lower doses (Table 5).

Table 5 Percentage of Adverse Events* in Immunocompromised Adult Patients Treated with Clarithromycin for Mycobacterial Infections
Presented by Total Daily Dose at Time of the Event
System Organ Class Adverse Reaction 1000 mg
(n=463)
2000 mg
(n=516)
4000 mg
(n=87)
Gastrointestinal disordersNausea11%16%40%
Vomiting7%9%24%
Abdominal Pain5%7%20%
Diarrhea4%6%17%
Flatulence1%2%7%
Constipation1%<1%5%
Dry Mouth<1%0%5%
Nervous system
disorders
Dysgeusia6%7%29%
Headache2%2%7%
Skin and subcutaneous tissue
disorders
Rash4%3%2%
InvestigationsAspartate aminotransferase
increased
2%2%11%
Alanine aminotransferase
increased
1%1%9%
Respiratory, thoracic and mediastinal disordersDyspnea<1%<1%7%
Psychiatric disordersInsomnia<1%<1%6%
Ear and labyrinth disordersHearing impaired**3%2%5%

* Related adverse events considered to be definitely, probably, possibly or remotely related to study events.

** Sum of patients with deafness, ear disorder, partial transitory deafness, and/or tinnitus.

n = Number of adverse events.

A limited number of pediatric AIDS patients have been treated with clarithromycin suspension for mycobacterial infections. The most frequently reported adverse events, excluding those due to the patient's concurrent condition, are listed in Table 6 by the total daily dose of clarithromycin the patient received.

Table 6 Number of Pediatric AIDS Patients Treated with Clarithromycin for Mycobacterial Infections Who Experienced Adverse Events
Presented by Total Daily Dose at Time of the Event
System Organ Class Adverse Event < 15 mg/kg/day
(n=19)
15 to < 25 mg/kg/day
(n=13)
≥ 25 mg/kg/day
(n=12)
Ear and labyrinth
disorders
Tinnitus 2 0 0
Deafness 1 1 0
Gastrointestinal
disorders
Vomiting 1 0 0
Nausea 1 0 0
Abdominal Pain 1 0 0
Pancreatitis 1 0 0
Skin and subcutaneous
tissue disorders
Purpuric Rash 1 0 0
Investigations Amylase Increased 0 0 1
Abnormal Laboratory Values

In immunocompromised patients treated with clarithromycin for mycobacterial infections, evaluations of laboratory values were made by analysing those values outside the seriously abnormal level (i.e., the extreme high or low limit) for the specified test (Table 7 and Table 8).

Table 7 Percentage of Immunocompromised Adult Patients Treated with Clarithromycin for Mycobacterial Infections who had On-Treatment Laboratory Values that Were Outside the Seriously Abnormal Level
Presented by Total Daily Dose
System Organ
Class
Laboratory Values Seriously Abnormal Level 1000 mg 2000 mg 4000 mg
InvestigationsAspartate aminotransferase
increased
> 5 x ULN3%2%4%
Alanine aminotransferase
increased
> 5 x ULN2%2%4%
Platelet count decreased< 50 x 109/L2%2%7%
White blood cell count
decreased
< 1 x 109/L0%2%0%
Blood urea increased> 50 mg/dL<1%<1%4%

Legend: ULN = Upper Limit of Normal.

Table 8 Number of Pediatric AIDS Patients Treated with Clarithromycin for Mycobacterial Infections who had On-Treatment Laboratory Values that Were Outside the Seriously Abnormal Level
Presented by Total Daily Dose
System Organ
Class
Laboratory
Values
Seriously
Abnormal
Level
< 15 mg/kg/day 15 to < 25 mg/kg/day ≥ 25 mg/kg/day
InvestigationsAlanine
aminotransferase
increased
> 5 x ULN010
Blood bilirubin
increased
> 12 mg/dL100
Platelet count
decreased
< 50 x 109/L010
Blood urea
increased
> 50 mg/dL010

Legend: ULN = Upper Limit of Normal.

Patients with Helicobacter pylori Infection
Triple Therapy: clarithromycin/omeprazole/amoxicillin

A summary of drug-related adverse event incidence rates is presented in Table 9.

Table 9 Summary of Drug-Related Adverse Event Incidence Rates by System Organ Class
Patients With Drug-Related Adverse Events
(% of Patients Treated)*
System Organ Class Omeprazole + Clarithromycin
+ Amoxicillin
(n=137)
Omeprazole +
Clarithromycin
(n=130)
Gastrointestinal disorders 24 (18%) 21 (16%)
General disorders and
administration site conditions
5 (4%) 0 (0%)
Nervous system disorders 15 (11%) 30 (23%)
Cardiac disorders 0 (0%) 1 (1%)
Investigations 9 (7%) 0 (0%)
Infections and infestations 1 (1%) 1 (1%)
Hepatobiliary disorders 2(1%) 0 (0%)
Psychiatric disorders 1(1%) 1(1%)
Ear and labyrinth disorders 1(1%) 2 (2%)
Respiratory, thoracic and
mediastinal disorders
1(1%) 0 (0%)
Skin and subcutaneous tissue
disorders
3 (2%) 1(1%)
Eye disorders 0 (0%) 1(1%)
Reproductive system and breast
disorders
1(1%) 0 (0%)

* Patients with more than 1 event within a system organ class are counted only once in the total for that system organ class.

Note: There is a statistical difference (Fisher’s exact two-sided, p-value = 0.009) between omeprazole + clarithromycin + amoxicillin (11%) versus omeprazole + clarithromycin (23%) in regard to nervous system disorders.

Less Common Clinical Trial Adverse Drug Reactions (<1%) for BIAXIN BID

The following adverse drug reactions are applicable to all indications approved for this formulation.

Blood and Lymphatic
System Disorders:
eosinophilia and neutropenia
Gastrointestinal Disorders: abdominal distension
General Disorders and
Administration Site
Conditions:
chest pain, chills, fatigue, influenza and malaise
Hepatobiliary Disorders: cholestasis, gamma-glutamyltransferase increased and hepatitis
Investigations: blood alkaline phosphatase increased and blood lactate dehydrogenase increased

BIAXIN XL (clarithromycin extended-release tablets)

Fewer than 2% of adult patients taking BIAXIN XL (clarithromycin extended-release tablets) discontinued therapy because of drug-related side effects. The most frequently reported adverse events in adults taking clarithromycin extended-release tablets were diarrhea (6%), abnormal taste (7%), and nausea (3%). Most of these events were described as mild or moderate in severity. Of the reported adverse events, less than 1% were described as severe.

There have been rare 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 antibiotic.

Less Common Clinical Trial Adverse Drug Reactions (<1%) for BIAXIN XL

The following adverse drug reactions are applicable to all indications approved for this formulation.

Gastrointestinal Disorders: gastrooesophageal reflux disease and proctalgia
Infections and Infestations: gastroenteritis
Musculoskeletal and
Connective Tissue Disorders:
myalgia
Respiratory, Thoracic and
Mediastinal Disorders:
epistaxis

BIAXIN (clarithromycin for oral suspension USP)

The safety profile of BIAXIN (clarithromycin for oral suspension USP) is similar to that of the 250 mg tablet in adult patients.

As with other macrolides, hepatic dysfunction, including increased liver enzymes, and hepatocellular and/or cholestatic hepatitis, with or without jaundice, has been infrequently reported with BIAXIN. This hepatic dysfunction may be severe and is usually reversible. In very rare instances, hepatic failure with fatal outcome has been reported and generally has been associated with serious underlying diseases and/or concomitant medications.

Allergic reactions ranging from urticaria and mild skin eruptions to anaphylaxis and Stevens-Johnson Syndrome/toxic epidermal necrolysis have occurred with orally administered clarithromycin.

There have been rare reports of pancreatitis and convulsions.

Of the 1829 patients who received clarithromycin for oral suspension, 571 (31%) reported at least one adverse event. The adverse events reported are summarized in Table 10.

Table 10 Adverse Events Reported in Pediatric Clinical Trials
System Organ Class Number (%) of Patients N=1829
Infections and infestations 172 (9%)
Neoplasms benign, malignant and unspecified
(including cysts and polyps)
1 (< 1%)
Blood and the lymphatic system disorders 14 (< 1%)
Metabolism and nutrition disorders 9 (< 1%)
Psychiatric disorders 12 (0.7%)
Nervous system disorders 41 (2%)
Eye disorders 22 (1%)
Ear and labyrinth disorders 25 (1%)
Vascular disorders 2 (< 1%)
Respiratory, thoracic and mediastinal disorders 61 (3%)
Gastrointestinal disorders 355 (19%)
Skin and subcutaneous disorders 66 (4%)
Musculoskeletal and connective tissue disorders 2 (< 1%)
Renal and urinary disorders 5 (< 1%)
Reproductive system and breast disorders 2 (< 1%)
General disorders and administration site conditions 56 (3%)
Investigations 29 (2%)
Injury, poisoning and procedural complications 19 (1%)
TOTAL* 571 (31%)

* Patients with more than one event within a system organ class are only counted once in the total for that system organ class. Patients with events in more than one system organ class are counted only once in the overall total.

The majority of the patients reported adverse event in the Gastrointestinal disorders SOC (19%), and the Infections and infestations SOC (9%).

The events occurring most frequently in the Gastrointestinal disorder SOC were diarrhea (7%), vomiting (7%), abdominal pain (3%), dyspepsia (3%) and nausea (1%).

Other adverse events included infection (3%), rhinitis (2.2%), rash (2.2%), increased cough (2.1%), fever (2.2%), headache (1.6%), conjunctivitis (1.1%), dysgeusia (3%) and transient elevation of AST (0.9%).

The majority of adverse events were considered by the investigators to have either mild or moderate severity. Three hundred and seventy-five of 1829 patients (21%) had mild adverse events, 175/1829 patients (10%) had moderate adverse events and 20/1829 patients (1%) had severe adverse events.

In the 2 U.S. acute otitis media studies of clarithromycin versus antimicrobial/beta-lactamase inhibitor, the incidence of adverse events in all patients treated, primarily diarrhea (15% vs. 38%) and diaper rash (3% vs. 11%) in young children, was clinically or statistically lower in the clarithromycin arm versus the control arm.

In another U.S. otitis media study of clarithromycin versus cephalosporin, the incidence of adverse events in all patients treated, primarily diarrhea and vomiting, did not differ clinically or statistically for the 2 agents.

Less Common Clinical Trial Adverse Drug Reactions (<1%) for BIAXIN pediatric

The following adverse drug reactions are applicable to all indications approved for this formulation.

Blood and Lymphatic System
Disorders:
thrombocythemia
General Disorders and
Administration Site Conditions:
pyrexia
Infections and Infestations: infection
Musculoskeletal and
Connective Tissue Disorders:
muscle spasms
Psychiatric Disorders: nervousness
Skin and Subcutaneous Tissue
Disorders:
rash maculo-papular

Other adverse reactions have been observed in different patient populations and during post-marketing surveillance. See ADVERSE REACTIONS, Clinical Trial Adverse Drug Reactions, Table 1.

Post-Market Adverse Drug Reactions

The following list of adverse events is a compilation of adverse reactions from Post-marketing Surveillance and Post-marketing Clinical Studies for all clarithromycin formulations.

Table 11 Post-Market Adverse Drug Reactions
System Organ Class Adverse Event
Blood and lymphatic system disorders Agranulocytosis, leukopenia, thrombocytopenia
Cardiac disorders1 Atrial fibrillation, cardiac arrest, electrocardiogram QT prolonged, extrasystoles, palpitations, Torsades de pointes, ventricular tachycardia
Ear and labyrinth disorders Deafness, hearing impaired, hearing loss2, tinnitus, vertigo
Gastrointestinal disorders Abdominal pain, constipation, dry mouth, dyspepsia, eructation, esophagitis, flatulence, gastritis, glossitis, pancreatitis, stomatitis, tongue discolouration, tooth discolouration, vomiting
General disorders and administration site
conditions
Asthenia
Hepatobiliary disorders Hepatic failure3, hepatitis, hepatitis cholestatic, jaundice (cholestatic and hepatocellular)
Immune system disorders Angioedema, anaphylactic reaction, anaphylactoid reaction, anaphylaxis, hypersensitivity, myasthenia gravis
Infections and infestations Candidiasis, cellulitis, pseudomembranous colitis, vaginal infection
Investigations Albumin globulin ratio abnormal, alanine aminotransferase increased, aspartate aminotransferase increased, blood creatinine increased, blood urea increased, international normalized ratio (INR) increased4, liver enzymes increased, liver function test abnormal, prothrombin time prolonged4, urine color abnormal5
Metabolism and nutrition disorders Anorexia, decreased appetite
Musculoskeletal and connective tissue disorders Musculoskeletal stiffness, myalgia, myopathy, rhabdomyolysis6
Nervous system disorders Ageusia, alteration of sense of smell, anosmia, convulsions, dizziness, dysgeusia, dyskinesia, headache, loss of consciousness, paraesthesia, parosmia, tremor, somnolence
Psychiatric disorders Abnormal dreams, anxiety, confusion, depersonalization, depression, disorientation, hallucination, insomnia, mania, psychosis
Renal and urinary disorders Interstitial nephritis, renal failure
Respiratory, thoracic and mediastinal
disorder
Asthma, pulmonary embolism
Skin and subcutaneous tissue disorders Acne, dermatitis bullous, drug rash with eosinophilia and systemic symptoms (DRESS), Henoch-Schonlein purpura, hyperhidrosis, pruritus, rash, Stevens Johnson syndrome, toxic epidermal necrolysis, urticaria
Vascular disorders Hemorrhage4, vasodilation

1 As with other macrolides, QT prolongation, ventricular tachycardia, and torsades de pointes have been reported with clarithromycin.

2 There have been reports of hearing loss with clarithromycin which is usually reversible upon withdrawal of therapy.

3 Hepatic dysfunction may be severe and is usually reversible. Hepatic failure with fatal outcome has been reported and generally has been associated with serious underlying diseases and/or concomitant medications.

4 When clarithromycin is co-administered with warfarin.

5 Symptom of hepatic failure.

6 In some of the reports of rhabdomyolysis, clarithromycin was administered concomitantly with other drugs known to be associated with rhabdomyolosis (such as statins, fibrates, colchicine or allopurinol).

Colchicine

There have been post-marketing reports of colchicine toxicity with concomitant use of clarithromycin and colchicine, especially in the elderly, some of which occurred in patients with renal insufficiency. Deaths have been reported in some patients. See CONTRAINDICATIONS.

Drug Interactions

Serious Drug Interactions

  • Concomitant administration of clarithromycin with astemizole, cisapride, colchicine, pimozide, terfenadine, lovastatin, simvastatin, ergot alkaloids (e.g., ergotamine, dihydroergotamine) is contraindicated. See CONTRAINDICATIONS and DRUG INTERACTIONS, Drug-Drug Interactions.
  • Clarithromycin is an inhibitor of the cytochrome P450 3A isoform subfamily (CYP3A) and the P-glycoprotein transporter (P-gp). The concomitant administration of clarithromycin and drugs metabolized by CYP3A and/or transported by P-gp may lead to an increase in the plasma concentrations of the co-administered drug which could result in clinically significant safety concerns.

Overview

Many categories of drugs are metabolized by CYP3A and/or transported by P-gp located in the liver and in the intestine. Some drugs may inhibit or induce the activities of CYP3A and/or P-gp. Administration of such inhibitors or inducers may impact upon the metabolism. In some cases serum concentrations may be increased and in others decreased. Care must therefore be exercised when co-administering such drugs.

Effects of Clarithromycin on Other Drugs

Clarithromycin is an inhibitor of CYP3A and P-gp. This inhibition may lead to increased or prolonged serum levels of those drugs also metabolized by CYP3A or transported by P-gp when co-administered with clarithromycin. For such drugs the monitoring of their serum concentrations may be necessary.

Clarithromycin should be used with caution in patients receiving treatment with other drugs known to be CYP3A and/or P-gp substrates, especially if the CYP3A/P-gp substrate has a narrow safety margin (e.g., carbamazepine) and/or the substrate is extensively metabolized by CYP3A or transported by P-gp. Dosage adjustments may be considered, and when possible, serum concentrations of these drugs should be monitored closely in patients concurrently receiving clarithromycin.

With certain drugs, co-administration of clarithromycin is contraindicated or should be avoided (see Table 12).

Effects of Other Drugs on Clarithromycin

Clarithromycin is a substrate of CYP3A. Co-administration of strong inducers of the cytochrome P450 metabolism system may accelerate the metabolism of clarithromycin and thus lower exposure to clarithromycin while increasing exposure to its metabolite 14-OH-clarithromycin which could impair the intended therapeutic effect. Furthermore, it might be necessary to monitor the plasma levels of the CYP3A inducer, which could be increased owing to the inhibition of CYP3A by clarithromycin (see also the relevant product information for the CYP3A4 inhibitor administered). Co-administration of potent CYP3A inhibitors may lead to increased exposure to clarithromycin and decreased exposure to its metabolite 14-OH-clarithromycin. Clarithromycin dosage adjustment or consideration of alternative treatments may be required.

Bi-Directional Drug Interactions

Bi-directional drug interactions are complex and may occur if both of the interacting drugs are substrates and inhibitors/inducers of CYP3A.

Additional Mechanisms

Interactions with clarithromycin have been reported with drugs metabolized by cytochrome P450 isoforms other than CYP3A system. Additional mechanisms, such as effects upon absorption, may also be responsible for interaction between drugs, including zidovudine and clarithromycin.

Drug-Drug Interactions

Some of the drug-drug interactions which have been reported between clarithromycin-macrolides and other drugs or drug categories are listed in Table 12. The drugs listed in this table are based on drug interactions case reports, clinical trials, or potential interactions due to the expected mechanism of the interaction.

Table 12 Established or Potential Drug-Drug Interactions with Clarithromycin
Concomitant
Medication
Ref Effect Clinical Comments
Astemizole* /
Terfenadine
CTterfenadine-acid metabolite concentrations increaseMacrolides have been reported to alter the metabolism of terfenadine resulting in increased serum levels of terfenadine which has occasionally been associated with cardiac arrhythmias such as QT prolongation, ventricular tachycardia, ventricular fibrillation and torsades de pointes. See CONTRAINDICATIONS.
In a study involving 14 healthy volunteers, the concomitant administration of BIAXIN BID tablets and terfenadine resulted in a 2- to 3-fold increase in the serum levels of the acid metabolite of terfenadine, MDL 16, 455, and in prolongation of the QT interval. Similar effects have been observed with concomitant administration of astemizole and other macrolides.
↑ QT interval
AtazanavirCT↑ clarithromycin levels
↑ atazanavir AUC
Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction. Co-administration of clarithromycin (500 mg twice daily) with atazanavir (400 mg once daily) resulted in a 2-fold increase in exposure to clarithromycin and a 70% decrease in exposure to 14-OH-clarithromycin, with a 28% increase in the AUC of atazanavir.
Because of the large therapeutic window for clarithromycin, no dosage reduction should be necessary in patients with normal renal function. For patients with moderate renal function (creatinine clearance 30 to 60 mL/min), the dose of clarithromycin should be decreased by 50%. For patients with creatinine clearance < 30 mL/min, the dose of clarithromycin should be decreased by 75% using an appropriate clarithromycin formulation. Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.
Calcium Channe
Blockers

(e.g., verapamil,
amlodipine,
diltiazem)
CPotential ↑ in verapamil
concentrations
Caution is advised regarding the concomitant administration of clarithromycin and calcium channel blockers metabolized by CYP3A4 (e.g., verapamil, amlodipine, diltiazem) due to the risk of hypotension. Plasma concentrations of clarithromycin as well as calcium channel blockers may increase due to the interaction. Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent verapamil, belonging to the calcium channel blockers drug class.
CarbamazepineC↑ levels of
carbamazepine
Clarithromycin administration in patients receiving carbamazepine has been reported to cause increased levels of carbamazepine. Blood level monitoring of carbamazepine should be considered.
Cisapride* /
Pimozide
C↑ levels of cisapride
↑ levels of pimozide
Elevated cisapride levels have been reported in patients receiving clarithromycin and cisapride concomitantly. This may result in QT prolongation and cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation and torsade de pointes. Similar effects have been observed in patients taking clarithromycin and pimozide concomitantly. See CONTRAINDICATIONS.
ColchicineCPotential colchicine
toxicity
Colchicine is a substrate for both CYP3A and the efflux transporter, P-gp. Clarithromycin and other macrolides are known to inhibit CYP3A and P-gp. When clarithromycin and colchicine are administered together, inhibition of P-gp and/or CYP3A by clarithromycin may lead to increased exposure to colchicine. This risk may be further increased with concomitant medications metabolized by P-glycoprotein or strong CYP3A inhibitors. Concomitant use of clarithromycin and colchicine is contraindicated. See CONTRAINDICATIONS.
CyclosporineC↑ levels of cyclosporineThere have been reports of elevated cyclosporine serum concentrations when clarithromycin and cyclosporine are used concurrently. Cyclosporine levels should be monitored and the dosage should be adjusted as necessary. Patients should also be monitored for increased cyclosporine toxicity.
DidanosineCTNo change in
didanosine
pharmacokinetics in
HIV-infected patients
(n=12)
Simultaneous administration of BIAXIN BID tablets and didanosine to 12 HIV-infected adult patients resulted in no statistically significant change in didanosine pharmacokinetics.
DigoxinC↑ levels of digoxinDigoxin is thought to be a substrate for the efflux transporter, P-gp. Clarithromycin is known to inhibit P-gp. When clarithromycin and digoxin are administered together, inhibition of P-gp by clarithromycin may lead to increased exposure to digoxin.
Elevated digoxin serum concentrations have been reported in patients receiving BIAXIN BID tablets and digoxin concomitantly.
In post-marketing surveillance some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Serum digoxin levels should be carefully monitored while patients are receiving digoxin and clarithromycin simultaneously.
Disopyramide /
Quinidine
C↑ levels of
disopyramide,
resulting in
ventricular fibrillation
& QT prolongation
(rarely reported)
Torsades de pointes
Increased disopyramide plasma levels, resulting in ventricular fibrillation and QT prolongation, coincident with the co-administration of disopyramide and clarithromycin have rarely been reported.
There have been post-marketed reports of torsades de pointes occurring with concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QTc prolongation during co-administration of clarithromycin with these drugs. Serum levels of these medications should be monitored during clarithromycin therapy.
There have been post marketing 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.
Ergot alkaloids
Ergotamine /
Dihydroergotamine
CPotential ischemic
reactions

Potential ergot toxicity
Post-marketing reports indicate that co-administration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by severe peripheral vasospasm, dysesthesia, and ischemia of the extremities and other tissues including the central nervous system. Concomitant administration of clarithromycin and ergot alkaloids is contraindicated. See CONTRAINDICATIONS.
EtravirineCT↓ clarithromycin
↑14-OH-clarithromycin
Clarithromycin exposure was decreased by etravirine; however, concentrations of the active metabolite, 14-OH-clarithromycin, were increased. Because 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall acitivity against this pathogen may be altered; therefore alternatives to clarithromycin should be considered for the treatment of MAC.
FluconazoleCT↑ clarithromycin Cmin & AUCConcomitant administration of fluconazole 200 mg daily and clarithromycin 500 mg twice daily to 21 healthy volunteers led to increases in the mean steady-state clarithromycin Cmin and AUC of 33% and 18%, respectively.
Steady-state concentrations of 14-OH-clarithromycin were not significantly affected by concomitant administration of fluconazole. No clarithromycin dose adjustment is necessary.
HMG-CoA
Reductase Inhibitors

Lovastatin /
Simvastatin
CRhabdomyolysis
(rarely reported)
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. Reports of rhabdomyolysis have been received for 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. See WARNINGS AND PRECAUTIONS, HMG-CoA Reductase Inhibitors. Rare reports of rhabdomyolysis have also been reported in patients taking atorvastatin or rosuvastatin concomitantly with clarithromycin. Concurrent use of atorvastatin and clarithromycin may result in increased atorvastatin exposure.
Caution should be exercised when prescribing clarithromycin with statins. In situations where the concomitant use of clarithromycin with statins cannot be avoided, it is recommended to prescribe the lowest registered dose of the statin. Use of a statin that is not dependent on CYP3A metabolism (e.g., fluvastatin) can be considered. Patients should be monitored for signs and symptoms of myopathy.
Atorvastatin
Rosuvastatin
C
ItraconazoleCT,
P
↑ levels of
clarithromycin
↑ levels of itraconazole
Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, leading to a bi-directional drug interaction. Clarithromycin may increase the plasma levels of itraconazole, while itraconazole may increase the plasma levels of clarithromycin. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged pharmacologic effect.
Lansoprazole /
Omeprazole
CTMild change of
lansoprazole and
14-OH-clarithromycin
concentrations
One study demonstrated that concomitant administration of clarithromycin and lansoprazole resulted in mild changes of serum concentrations of lansoprazole and 14-OH-clarithromycin. However, no dosage adjustment is considered necessary based on these data.
Clarithromycin 500 mg three times daily was given in combination with omeprazole 40 mg once daily to healthy subjects. The steady-state plasma concentrations of omeprazole were increased (i.e., Cmax, AUC0-24, and t1/2 increased by 30%, 89%, and 34%, respectively), by concomitant administration of clarithromycin. The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when co-administered with clarithromycin.
To a lesser extent, omeprazole administration increases the serum concentrations of clarithromycin. Omeprazole administration also increases tissue and mucus concentrations of clarithromycin.
↑ omeprazole Cmax &
AUC0-24
↑ levels of
clarithromycin
Oral Anticoagulants
Warfarin /
Acenocoumarol
C↑ anticoagulant effectThere have been reports of increased anticoagulant effect when clarithromycin and oral anticoagulants are used concurrently. Anticoagulant parameters should be closely monitored. Adjustment of the anticoagulant dose may be necessary.
Clarithromycin has also been reported to increase the anticoagulant effect of acenocoumarol.
There is a risk of serious hemorrhage and significant elevations in International Normalized Ratio (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. See WARNINGS AND PRECAUTIONS, Use with Other Drugs, Oral Anticoagulants.
Oral Hypoglycemic
Agents

(e.g., Insulin)
C


P
HypoglycemiaThe concomitant use of clarithromycin and oral hypoglycaemic agents (such as sulphonylurias) and/or insulin can result in significant hypoglycaemia. With certain hypoglycaemic drugs such as nateglinide, pioglitazone, repaglinide and rosiglitazone, inhibition of CYP3A enzyme by clarithromycin may be involved and could cause hypoglycaemia when used concomitantly. Careful monitoring of glucose is recommended.
Phosphodiesterase
inhibitors

(e.g., sildenafil,
tadalafil , vardenafil)
P↑ phosphodiesterase
inhibitor exposure
Sildenafil, tadalafil, and vardenafil are metabolized, at least in part, by CYP3A, and CYP3A may be inhibited by concomitantly administered clarithromycin. Co-administration of clarithromycin with sildenafil, tadalafil or vardenafil would likely result in increased phosphodiesterase inhibitor exposure. Reduction of sildenafil, tadalafil and vardenafil dosages should be considered when these drugs are co-administered with clarithromycin.
RifabutinC↓ clarithromycin
↑ rifabutin
Clarithromycin has been reported to increase serum and tissue concentration of rifabutin and thus may increase the risk of toxicity. Clarithromycin levels decrease when co-administered with rifabutin.
Concomitant administration of clarithromycin and rifabutin in the treatment of Mycobacterial Avium complex infections resulted in rifabutin-associated uveitis.
A case control study in AIDS patients showed that concomitant administration of rifabutin and clarithromycin resulted in an approximately 50% reduction in serum clarithromycin concentration, approximately 77% increase in the area under the plasma concentration-time curve of rifabutin, and a 236% increase in the area under the plasma concentration-time curve of rifabutin’s active metabolite. The increase in rifabutin and/or its metabolite contributed to the development of uveitis (the incidence of uveitis was 14% in patients weighing >65 kg, 45%in patients between 55 and 65 kg, and 64% in patients <55 kg).
Ritonavir / IndinavirCT↑ clarithromycin Cmax,
Cmin, & AUC
A pharmacokinetic study demonstrated that the concomitant administration of ritonavir 200 mg every 8 hours and clarithromycin 500 mg every 12 hours resulted in a marked inhibition of the metabolism of clarithromycin. The clarithromycin Cmax increased by 31%, Cmin increased 182% and AUC increased by 77% with concomitant administration of ritonavir. An essentially complete inhibition of the formation of 14-[R]-hydroxy-clarithromycin was noted. Because of the large therapeutic window for clarithromycin, no dosage reduction should be necessary in patients with normal renal function. However, for patients with renal impairment, the following dosage adjustments should be considered: For patients with creatinine clearance 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients with creatinine clearance < 30 mL/min the dose of clarithromycin should be decreased by 75%. Doses of clarithromycin greater than 1g/day should not be co-administered with ritonavir.
Similar dose adjustments should be considered in patients with reduced renal function when ritonavir is used as a pharmacokinetic enhancer with other HIV protease inhibitors including atazanavir and saquinavir.
One study demonstrated that the concomitant administration of clarithromycin and indinavir resulted in a metabolic interaction; the clarithromycin AUC increased by 53% and the indinavir AUC was increased by 20%, but the individual variation was large. No dose adjustment is necessary with normal renal function.
↑ indinavir AUC
↑ clarithromycin AUC
SaquinavirCT↑ saquinavir AUC and
Cmax

↑ clarithromycin AUC
Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction.
Concomitant administration of clarithromycin (500 mg twice daily) and saquinavir (soft gelatin capsules, 1200 mg three times daily) to 12 healthy volunteers resulted in steady-state AUC and Cmax values of saquinavir which were 177% and 187% higher than those seen with saquinavir alone. Clarithromycin AUC and Cmax values were approximately 40% higher than those seen with clarithromycin alone.
No dose adjustment is required when the 2 drugs are co-administered for a limited time at the doses/ formulations studied.
Observations from drug interaction studies using the soft gelatin capsule formulation may not be representative of the effects seen using the saquinavir hard gelatin capsule. Observations from drug interaction studies performed with saquinavir alone may not be representative of the effects seen with saquinavir/ritonavir therapy. When saquinavir is co-administered with ritonavir, consideration should be given to the potential effects of ritonavir on clarithromycin.
TacrolimusPPotential ↑ in
tacrolimus
concentrations
Concomitant administration of tacrolimus and clarithromycin may result in increased plasma levels of tacrolimus and increased risk of toxicity.
TheophyllinePPotential ↑ in
theophylline
concentrations
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.
TolterodineP↑ serum tolterodine
concentrations
The primary route of metabolism for tolterodine is via the 2D6 isoform of cytochrome P450 (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. A reduction of tolterodine dosage may be necessary in the presence of CYP3A inhibitors, such as clarithromycin in the CYP2D6 poor metabolizer population.
Triazolobenzo-diazepines
(e.g., triazolam,
alprazolam)


Other related
benzodiazepines
(e.g., midazolam)
CT,
C, P
↑ midazolam AUCWhen midazolam was co-administered with clarithromycin tablets (500 mg twice daily), midazolam AUC was increased 2.7-fold after intravenous administration of midazolam and 7-fold after oral administration. Concomitant administration of oral midazolam and clarithromycin is contraindicated. See CONTRAINDICATIONS.If intravenous midazolam is co-administered with clarithromycin, the patient must be closely monitored to allow dose adjustment of midazolam.
The same precautions should also apply to other benzodiazepines that are metabolized by CYP3A, including triazolam and alprazolam. For benzodiazepines which are not dependent on CYP3A for their elimination (temazepam, nitrazepam, lorazepam), a clinically important interaction with clarithromycin is unlikely.
There have been post-marketing reports of drug interactions and central nervous system (CNS) effects (e.g., somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested.
ZidovudineCPotential ↓ in
zidovudine
concentrations
Simultaneous oral administration of BIAXIN BID tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations. Clarithromycin appears to interfere with the absorption of simultaneously administered oral zidovudine, and therefore, this interaction can be largely avoided by staggering the doses of clarithromycin and zidovudine. This interaction does not appear to occur in pediatric HIV-infected patients taking clarithromycin suspension with zidovudine or dideoxyinosine. Similar interaction studies have not been conducted with clarithromycin extended-release (ER) and zidovudine.
Other drugs
metabolized by
CYP3A

(e.g., alfentanil,
bromocriptine,
cilostazol,
methylprednisolone,
vinblastine)
C,PPotential increase in
serum concentration
Interactions with erythromycin and/or clarithromycin have been reported with a number of other drugs metabolized by CYP3A, such as alfentanil, bromocriptine, cilostazol, methylprednisolone, or vinblastine.
Serum concentrations of drugs metabolized by CYP3A should be monitored closely in patients concurrently receiving erythromycin or clarithromycin.
Other drugs
metabolized by
cytochrome P450
isoforms other than
CYP3A

(e.g., hexobarbital,
phenytoin, and
valproate)
C,PPotential change in
serum concentration
Interactions with erythromycin and/or clarithromycin have been reported with drugs metabolized by other cytochrome P450 isoforms (i.e., not CYP3A), such as hexobarbital, phenytoin, and valproate.
Serum concentrations of these drugs should be monitored closely in patients concurrently receiving erythromycin or clarithromycin.
Other drug inducers
of the cytochrome
P450 system

(e.g, efavirenz,
nevirapine, rifampin,
rifabutin, rifampicin,
phenobarbital,
rifapentine)
CT,
P
↓ levels of
clarithromycin
Strong inducers of the cytochrome P450 metabolism system such as efavirenz, nevirapine, rifampin, rifabutin, rifampicin, phenobarbital and rifapentine* may accelerate the metabolism of clarithromycin and thus lower the plasma levels of clarithromycin, while increasing those of 14-OH-clarithromycin, a metabolite that is also microbiologically active.
Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers.

Legend: C = Case Study; CT = Clinical Trial; P = Potential.

Interactions with other drugs have not been established.

* not marketed in Canada.

Combination Therapy with Omeprazole and/or Amoxicillin

For more information on drug interactions for omeprazole and amoxicillin, refer to their respective Product Monographs, under DRUG INTERACTIONS.

Drug-Food Interactions

BIAXIN BID (clarithromycin tablets USP, film-coated) and BIAXIN (clarithromycin for oral suspension USP) may be given with or without meals. BIAXIN XL (clarithromycin extended-release tablets) must be taken with food.

Drug-Herb Interactions

St. John’s Wort (Hypericum perforatum) is an inducer of CYP3A and may induce the metabolism of clarithromycin. This may result in sub-therapeutic levels of clarithromycin leading to reduced efficacy.

Drug-Laboratory Interactions

Interactions with laboratory tests have not been established.

Drug-Lifestyle Interactions

Effects on Ability to Drive and Use Machines

There are no data on the effect of clarithromycin on the ability to drive or use machines. The potential for dizziness, vertigo, confusion and disorientation, which may occur with the medication, should be taken into account before patients drive or use machines.

Dosage and Administration

Dosing Considerations

BIAXIN BID (clarithromycin tablets USP, film-coated) and BIAXIN (clarithromycin for oral suspension USP) may be given with or without meals. BIAXIN XL (clarithromycin extended-release tablets) must be taken with food.

In patients with a combination of hepatic (mild to moderate) and renal impairments or in the presence of severe renal impairment, decreased dosage of clarithromycin or prolonged dosing intervals might be appropriate. See DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment.

Clarithromycin is contraindicated in patients with severe hepatic failure in combination with renal impairment. See CONTRAINDICATIONS.

In children with renal impairment and a creatinine clearance < 30 mL/min, the dosage of BIAXIN should be reduced by one-half, i.e., up to 250 mg once daily, or 250 mg twice daily in more severe infections. Dosage should not be continued beyond 14 days in these patients.

Recommended Dose and Dosage adjustment

BIAXIN BID (clarithromycin tablets USP, film-coated)

Adults with Respiratory Tract or Skin Infections

The adult dosage of BIAXIN BID is 250 mg to 500 mg every 12 hours (Table 13) for 7 to 14 days. For infections caused by less susceptible organisms, the upper dosage should be used.

Table 13 Adult Dosage Guidelines
Infection Dosage (b.i.d.) Duration
Upper Respiratory Tract 250-500 mg
Pharyngitis/tonsillitis 250 mg 10 days
Acute maxillary sinusitis 500 mg 7 to 14 days
Lower Respiratory Tract 250-500 mg
Acute exacerbation of chronic bronchitis and
pneumonia
250-500 mg 7 to 14 days
Uncomplicated Skin and Skin Structure
Infections
250 mg 7 to 14 days

Legend: b.i.d. = twice daily.

In the treatment of Group A streptococcus infections, therapy should be continued for 10 days. The usual drug of choice in the treatment of streptococcal infections and the prophylaxis of rheumatic fever is penicillin administered by either the intramuscular or the oral route.

Clarithromycin is generally effective in the eradication of S. pyogenes from the nasopharynx; however, data establishing the efficacy of clarithromycin in the subsequent prevention of rheumatic fever are not presently available.

Renal Impairment

In patients with renal impairment and a creatinine clearance < 30 mL/min., the dosage of BIAXIN BID should be reduced by one-half, i.e., 250 mg once daily, or 250 mg twice daily in more severe infections. Dosage should not be continued beyond 14 days in these patients. The safety and efficacy of 500 mg clarithromycin in patients with severe renal impairment has not been established.

Hepatic Impairment

In patients with a combination of hepatic (mild to moderate) and renal impairments, decreased dosage of clarithromycin or prolonged dosing intervals may be appropriate. Clarithromycin may be administered without dosage adjustment in the presence of hepatic impairment if there is normal renal function.

Clarithromycin is contraindicated in patients with severe hepatic failure in combination with renal impairment. See CONTRAINDICATIONS.

Eradication of Helicobacter Pylori
Triple Therapy: BIAXIN BID/omeprazole/amoxicillin

The recommended dose is clarithromycin 500 mg twice daily in conjunction with omeprazole 20 mg daily and amoxicillin 1000 mg twice daily for 10 days. See CLINICAL TRIALS, Eradication of Helicobacter pylori, Triple Therapy: BIAXIN BID/omeprazole/amoxicillin.

For more information on omeprazole or amoxicillin, refer to their respective Product Monographs, under DOSAGE AND ADMINISTRATION.

(For additional information on the use of BIAXIN BID in triple therapy for the treatment of H. pylori infection and active duodenal ulcer recurrence, refer to the Hp-PAC Product Monograph.)

Adults with Mycobacterial Infections
Prophylaxis

The recommended dose of BIAXIN BID for the prevention of disseminated M. avium disease is 500 mg twice daily.

Treatment

Clarithromycin is recommended as the primary agent for the treatment of disseminated infection due to MAC. Clarithromycin should be used in combination with other antimycobacterial drugs which have shown in vitro activity against MAC, including ethambutol and rifampin. Although no controlled clinical trial information is available for combination therapy with clarithromycin, the U.S. Public Health Service Task Force has provided recommendations for the treatment of MAC.

The recommended dose for mycobacterial infections in adults is 500 mg twice daily.

Treatment of disseminated MAC infections in AIDS patients should continue for life if clinical and mycobacterial improvement are observed.

BIAXIN XL (clarithromycin extended-release tablets)

Adults with Respiratory Tract Infection

The adult dosage is 2 x 500 mg tablets (1000 mg) every 24 hours for 5, 7 or 14 days. Clarithromycin extended-release tablets must be taken with food. Clarithromycin extended-release tablets should be swallowed whole and not chewed, broken or crushed. Table 14 provides dosage guidelines.

Table 14 Adult Dosage Guidelines
Infection Dosage
(Once daily)
Duration
(days)
Acute maxillary sinusitis 1000 mg 14
Acute bacterial exacerbation of
chronic bronchitis
1000 mg 5 or 7
Community-acquired pneumonia 1000 mg 7
Renal Impairment

Based on a study done with BIAXIN BID, patients with severe renal impairment (creatinine clearance < 30 mL/min) have greater clarithromycin exposure than patients with normal renal function (creatinine clearance > 80 mL/min). Clarithromycin Cmax was about 3.3 times higher and AUC was about 4.2 times higher in the patients with severe renal impairment. The maximum daily clarithromycin dose for patients with severe renal impairment is 500 mg. The safety and efficacy of 500 mg clarithromycin in patients with severe renal impairment has not been established.

In the same study, patients with moderate renal impairment (creatinine clearance 30 to 79 mL/min) had greater clarithromycin exposure than patients with normal renal function, but the elevations were much less than those observed in severe renal impairment. Compared to the subjects with normal renal function, the clarithromycin Cmax was about 52% higher and the AUC was about 74% higher in the patients with moderate renal impairment. No clarithromycin dose adjustment is required for patients with moderate renal impairment.

Hepatic Impairment

Based on studies done with BIAXIN BID, no adjustment of dosage is necessary for subjects with moderate or severe hepatic impairment but with normal renal function. In patients with a combination of hepatic (mild to moderate) and renal impairments, decreased dosage of clarithromycin or prolonged dosing intervals might be appropriate.

Clarithromycin is contraindicated in patients with severe hepatic failure in combination with renal impairment. See CONTRAINDICATIONS.

BIAXIN (clarithromycin for oral suspension USP)

The recommended daily dosage of BIAXIN (clarithromycin for oral suspension USP) is 15 mg/kg/day, in divided doses every 12 hours, not to exceed 1000 mg/day. The usual duration of treatment is for 5 to 10 days depending on the pathogen involved and the severity of the condition. Treatment for pharyngitis caused by Streptococcal species should be 10 days.

In children with renal impairment and a creatinine clearance < 30 mL/min, the dosage of BIAXIN should be reduced by one-half, i.e., up to 250 mg once daily, or 250 mg twice daily in more severe infections. Dosage should not be continued beyond 14 days in these patients.

Table 15 is a suggested guide for determining dosage.

Table 15 BIAXIN Oral Suspension Pediatric Dosage Guidelines Based on Body Weight in kg
125 mg/5 mL 250 mg/5 mL
Weight* Dosage (mL)
given twice daily
Dosage (mL)
given twice daily
8 to 11 kg (1 to 2 years)** 2.5 1.25
12 to 19 kg (2 to 4 years) 5 2.5
20 to 29 kg (4 to 8 years) 7.5 3.75
30 to 40 kg (8 to 12 years) 10 5

* Children < 8 kg should be dosed on a per kg basis (approximately 7.5 mg/kg twice daily).

** Approximate ages.

Children with Mycobacterial Infections

Clarithromycin is recommended as the primary agent for the treatment of disseminated infection due to MAC. Clarithromycin should be used in combination with other antimycobacterial drugs which have shown in vitro activity against MAC, including ethambutol and rifampin. Although no controlled clinical trial information is available for combination therapy with clarithromycin, the U.S. Public Health Service Task Force has provided recommendations for the treatment of MAC.

In children, the recommended dose is 7.5 mg/kg twice daily up to 500 mg twice daily clarithromycin per day in 2 divided doses. Dosing recommendations for children are shown in Table 15 above.

Treatment of disseminated MAC infections in AIDS patients should continue for life if clinical and mycobacterial improvement are observed.

Missed Dose

If a dose of clarithromycin is missed, the patient should take the dose as soon as possible and then return to their normal scheduled dose. However, if a dose is skipped, the patient should not double the next dose.

Administration

BIAXIN BID may be taken with or without food.

BIAXIN XL (clarithromycin extended-release tablets) must be taken with food. The tablets should be swallowed whole and not chewed, broken or crushed.

BIAXIN (clarithromycin for oral suspension USP) may be taken with or without food.

Directions for Reconstitution: 125 mg/5 mL

150 mL size 79 mL of water should be added to the granules in the bottle and shaken to yield 150 mL of reconstituted suspension.
105 mL size: 55 mL of water should be added to the granules in the bottle and shaken to yield 105 mL of reconstituted suspension.
55 mL size: 29 mL of water should be added to the granules in the bottle and shaken to yield 55 mL of reconstituted suspension.

Directions for Reconstitution: 250 mg/5 mL

150 mL size: 77 mL of water should be added to the granules in the bottle and shaken to yield 150 mL of reconstituted suspension.
105 mL size: 54 mL of water should be added to the granules in the bottle and shaken to yield 105 mL of reconstituted suspension.
55 mL size: 28 mL of water should be added to the granules in the bottle and shaken to yield 55 mL of reconstituted suspension.

Shake until all the particles are suspended. Avoid vigorous and/or lengthy shaking. Shake prior to each subsequent use to ensure resuspension. After reconstitution, store between (15 and 25ºC) and use within 14 days. Do not refrigerate. Any reconstituted unused medication should be discarded after 14 days. The graduated syringe included in the package should be rinsed between uses. Do not leave syringe in bottle. Do not store reconstituted suspension in syringe.

Overdosage

For management of a suspected drug overdose, contact your regional Poison Control Centre.

Reports indicate that the ingestion of large amounts of clarithromycin can be expected to produce gastrointestinal symptoms. Adverse reactions accompanying overdosage should be treated by the prompt elimination of unabsorbed drug and supportive measures.

Clarithromycin is protein bound (70%). No data are available on the elimination of clarithromycin by hemodialysis or peritoneal dialysis.

Action and Clinical Pharmacology

Mechanism of Action

General

Clarithromycin exerts its antibacterial action by binding to the 50S ribosomal subunit of susceptible bacteria and suppressing protein synthesis.

Pharmacodynamics

Eradication of Helicobacter pylori

H. pylori is now established as a major etiological factor in duodenal ulcer disease. The presence of H. pylori may damage the mucosal integrity due to the production of enzymes (catalase, lipases, phospholipases, proteases, and urease), adhesins and toxins; the generated inflammatory response contributes to mucosal damage.

The concomitant administration of an antimicrobial(s) such as clarithromycin and an antisecretory agent, improves the eradication of H. pylori as compared to individual drug administration. The higher pH resulting from antisecretory treatment optimizes the environment for the pharmacologic action of the antimicrobial agent(s) against H. pylori.

Pharmacokinetics

Clarithromycin Tablets USP, Film-Coated

A summary of clarithromycin pharmacokinetic parameters following the administration of clarithromycin film-coated tablets is provided in Table 16. See DETAILED PHARMACOLOGY, Pharmacokinetics.

Table 16 Clarithromycin Pharmacokinetic Parameters following the Administration of Clarithromycin Film-coated Tablets
Single dose* Cmax
(mg/L)
tmax
(hr)
t½
(hr)
AUC0-t
(mg•hr/L)
250 mg
Mean
1 1.5 2.7 5.47
500 mg
Mean
1.77 2.2 - 11.66
Multiple
Doses**
250 mg b.i.d.
Mean
1 - 3 to 4 6.34
500 mg b.i.d.
Mean
3.38 2.1 5 to 7 44.19

* Single doses

** Multiple doses

Legend: b.i.d. = twice daily

Clarithromycin Extended-Release Tablets

A summary of clarithromycin pharmacokinetic parameters following the administration of clarithromycin extended-release tablets is provided in Table 17. See DETAILED PHARMACOLOGY, Pharmacokinetics.

Table 17 Clarithromycin Pharmacokinetic Parameters following the Administration of Clarithromycin Extended-Release Tablets
Cmax
(mg/L)
tmax
(hr)
AUC0-t
(mg•hr/L)
2 x 500 mg once daily
Mean
(fasting conditions)
2.21 5.5 33.72
2 x 500 mg once daily
Mean
(fed conditions)
3.77 5.6 48.09

Clarithromycin for Oral Suspension USP

A summary of clarithromycin pharmacokinetic parameters in adult volunteers following the administration of clarithromycin for oral suspension is provided in Table 18. See DETAILED PHARMACOLOGY, Pharmacokinetics.

Table 18 Clarithromycin Pharmacokinetic Parameters in Adult Subjects following the Administration of Clarithromycin for Oral Suspension
250 mg/10 mL Cmax
(mg/L)
Tmax
(hr)
t½
(hr)
AUC0-∞
(mg•hr/L)
Mean
(fasting conditions)
1.24 3.3 3.7 7.2
Mean
(fed conditions)
0.95 5.3 3.7 6.5

A summary of clarithromycin pharmacokinetic parameters in pediatric patients following the administration of clarithromycin for oral suspension is provided in Table 19. See DETAILED PHARMACOLOGY, Pharmacokinetics.

Table 19 Clarithromycin Pharmacokinetic Parameters in Pediatric Patients following the Administration of Clarithromycin for Oral Suspension
Cmax
(mg/L)
tmax
(hr)
AUC0-t
(mg•hr/L)
Single Dose
(125 mg/5 mL)
Mean
(fasting conditions)
3.59 3.1 10
Mean
(fed conditions)
4.58 2.8 14.2
Multiple Dose
(7.5 mg/kg b.i.d.)
Mean
(fasting conditions)
4.6 2.8 15.7

Legend: b.i.d. = twice daily

Absorption

Clarithromycin Tablets USP, Film-Coated

The absolute bioavailability of 250 mg and 500 mg clarithromycin tablets is approximately 50%. Food slightly delays the onset of clarithromycin absorption but does not affect the extent of bioavailability. Therefore, BIAXIN BID tablets may be given without regard to meals.

In fasting healthy human subjects, peak serum concentrations are attained within 2 hours after oral dosing. Steady-state peak serum clarithromycin concentrations, which are attained within 2 to 3 days, are approximately 1 mg/L with a 250 mg dose twice daily and 2 to 3 mg/L with a 500 mg dose twice daily. The elimination half-life of clarithromycin is about 3 to 4 hours with 250 mg twice daily dosing but increases to about 5 to 7 hours with 500 mg administered twice daily.

Clarithromycin displays non-linear pharmacokinetics at clinically relevant doses, producing greater than proportional increases in AUC with increasing dose. The degree of non-linearity is reduced on chronic clarithromycin administration (i.e., at steady-state). The non-linearity of the pharmacokinetics of the principle metabolite, 14-OH-clarithromycin, is slight at the recommended doses of 250 mg and 500 mg administered twice daily. With 250 mg twice daily, 14-OH-clarithromycin attains a peak steady-state concentration of about 0.6 mg/L and has an elimination half-life of 5 to 6 hours. With a 500 mg twice daily dose, the peak steady-state of 14 OH-concentrations of clarithromycin are slightly higher (up to 1 mg/L) and its elimination half-life is about 7 hours. With either dose, the steady-state concentration of this metabolite is generally attained within 2 to 3 days.

Adult Patients with HIV

Steady-state concentrations of clarithromycin and 14-OH-clarithromycin observed following administration of 500 mg doses of clarithromycin twice a day to adult patients with HIV infection were similar to those observed in healthy volunteers. However, at the higher clarithromycin doses which may be required to treat mycobacterial infections, clarithromycin concentrations can be much higher than those observed at 500 mg clarithromycin doses. In adult HIV-infected patients taking 2000 mg/day in two divided doses, steady-state clarithromycin Cmax values ranged from 5 to10 mg/L. Cmax values as high as 27 mg/L have been observed in HIV-infected adult patients taking 4000 mg/day in two divided doses of clarithromycin tablets.

Elimination half-lives appeared to be lengthened at these higher doses as well. The higher clarithromycin concentrations and longer elimination half-lives observed at these doses are consistent with the known non-linearity in clarithromycin pharmacokinetics.

Clarithromycin and omeprazole

Clarithromycin 500 mg three times daily and omeprazole 40 mg once daily were studied in fasting healthy adult subjects.When clarithromycin was given alone as 500 mg every 8 hours, the mean steady-state Cmax value was approximately 3.8 mcg/mL and the mean Cmin value was approximately 1.8 mcg/mL. The mean AUC0-8 for clarithromycin was 22.9 mcg·hr/mL. The Tmax and half-life were 2.1 hours and 5.3 hours, respectively, when clarithromycin was dosed at 500 mg three times daily. When clarithromycin was administered with omeprazole, increases in omeprazole half-life and AUC0-24 were observed. For all subjects combined, the mean omeprazole AUC0-24 was 89% greater and the harmonic mean for omeprazole t½was 34% greater when omeprazole was administered with clarithromycin than when omeprazole was administered alone. When clarithromycin was administered with omeprazole, the steady-state Cmax, Cmin, and AUC0-8 of clarithromycin were increased by 10%, 27%, and 15%, respectively over values achieved when clarithromycin was administered with placebo.

A re-formulated 500 mg BIAXIN BID has been developed, an ovaloid smooth film-sealed tablet, which is slightly smaller than the original formulation. Overall bioavailability of both formulations is comparable.

Clarithromycin Extended-Release Tablets

Clarithromycin extended-release tablets provided extended absorption of clarithromycin from the gastrointestinal tract after oral administration. Relative to an equal dose of immediate-release clarithromycin film-coated tablets, clarithromycin extended-release tablets provide lower and later steady-state peak plasma concentrations, but equivalent 24-hour AUCs for both clarithromycin and its microbiologically-active metabolite, 14-OH-clarithromycin.

While the extent of formation of 14-OH-clarithromycin following administration of clarithromycin extended-release tablets (2 x 500 mg once daily) under steady-state conditions is not affected by food, administration under fasting conditions is associated with approximately 30% lower clarithromycin AUC relative to administration with food. Similarly, single-dose administration of clarithromycin extended-release (500 mg once daily) is associated with a 25% lower clarithromycin AUC relative to administration of clarithromycin immediate-release film-coated tablets (250 mg twice daily). Therefore, it is recommended that BIAXIN XL (clarithromycin extended-release tablets be given with food.

Figure 1 illustrates the steady-state clarithromycin plasma concentration-time profile for BIAXIN XL (2 x 500 mg once daily) relative to BIAXIN (500 mg twice daily).



Figure 1: Steady-State Clarithromycin Plasma Concentration-Time Profiles for BIAXIN XL (2 x 500 mg once daily) Relative to BIAXIN (500 mg twice daily)

In healthy human subjects, steady-state peak plasma clarithromycin concentrations of approximately 2 to 3 mg/L were achieved about 5 to 8 hours after oral administration of 2 x 500 mg clarithromycin extended-release tablets once daily; for 14-OH-clarithromycin, steady-state peak plasma concentrations of approximately 0.8 mg/L were attained 6 to 9 hours after dosing. Steady-state peak plasma concentrations of approximately 1 to 2 mg/L were achieved about 5 to 6 hours after oral administration of a single 500 mg clarithromycin extended-release tablet once daily; for 14-OH-clarithromycin, steady-state peak plasma concentrations of approximately 0.6 mg/L were attained about 6 hours after dosing.

Clarithromycin for Oral Suspension USP
Adult Volunteers

Single and multiple dose adult volunteer studies showed that the suspension formulation was not significantly different from the tablet formulation in terms of Cmax of clarithromycin and AUC, although the onset and/or rate of absorption of the suspension formulation was slower than that of the tablet. As with the tablet formulation, steady-state is achieved by the fifth dose of a 12 hour multiple-dose suspension regimen.

Children

In children taking 15 to 30 mg/kg/day in two divided doses, steady-state clarithromycin Cmax values generally ranged from 8 to 20 mcg/mL. Cmax values as high as 23 mcg/mL have been observed in HIV-infected pediatric patients taking 30 mg/kg/day in two divided doses. In children requiring antibiotic therapy, administration of 7.5 mg/kg q12h doses every 12 hours of clarithromycin as the suspension generally resulted in steady-state peak plasma concentrations of 3 to 7 mcg/mL for clarithromycin, and 1 to 2 mcg/mL for 14-OH-clarithromycin. In HIV-infected children taking 15 mg/kg every 12 hours, steady-state clarithromycin peak concentrations generally ranged from 6 to 15 mcg/mL. A single and multiple dose study conducted in pediatric patients showed that food leads to a slight delay in the onset of absorption, but does not affect the overall bioavailability of clarithromycin.

Clarithromycin and its 14-OH metabolite penetrate into middle ear effusion (MEE) of patients with secretory otitis media.

For adult patients, the bioavailability of 10 mL of the 125 mg/5mL suspension is similar to a 250 mg tablet.

Single dose adult volunteer studies show that the reformulated (125 mg/5 mL and 250 mg/5 mL) and the current (125 mg/5 mL) clarithromycin for oral suspension have comparable bioavailability under fasting and non-fasting conditions.

Distribution

Clarithromycin distributes readily into body tissues and fluids, and provides tissue concentrations that are higher than serum concentrations. Examples from tissue and serum concentrations are presented in Table 20.

Table 20 Representative Clarithromycin Tissue and Serum Concentrations Following the Administration of 250 mg b.i.d of Clarithromycin Film-Coated Tablets
Tissue Type Concentrations
Tissue (mcg/g) Serum (mg/L)
Tonsil 1.6 0.8
Lung 8.8 1.7
Leukocytes* 9.2 1.0

* in vitro data.

Legend: b.i.d. = twice daily.

Metabolism

Clarithromycin is principally excreted by the liver and kidney. The major metabolite found in urine is 14-OH-clarithromycin.

Excretion

At 250 mg twice daily, approximately 20% of an orally administered dose of clarithromycin film-coated tablet is excreted in the urine as the unchanged parent drug. The urinary excretion of unchanged clarithromycin is somewhat greater (approximately 30%) with 500 mg twice daily dosing. The renal clearance of clarithromycin is, however, relatively independent of the dose size and approximates the normal glomerular filtration rate. The major metabolite found in urine is 14-OH-clarithromycin which accounts for an additional 10 to 15% of the dose with twice daily dosing at either 250 mg or 500 mg. Most of the remainder of the dose is eliminated in the feces, primarily via the bile. About 5 to 10% of the parent drug is recovered from the feces. Fecal metabolites are largely products of N-demethylation, 14-hydroxylation or both.

Special Populations and Conditions

Pediatrics

Refer to the Absorption section above.

Geriatrics

Dosage adjustment should be considered in elderly with severe renal impairment. In a steady-state study in which healthy elderly subjects (age 65 to 81 years old) were given 500 mg of clarithromycin every 12 hours, the maximum concentrations of clarithromycin and 14-OH-clarithromycin were increased. The AUC was also increased. These changes in pharmacokinetics parallel known age-related decreases in renal function. In clinical trials, elderly patients did not have an increased incidence of adverse events when compared to younger patients.

Hepatic Insufficiency

The steady-state concentrations of clarithromycin in subjects with impaired hepatic function did not differ from those in normal subjects; however, the 14-OH-clarithromycin concentrations were lower in the hepatically impaired subjects. The decreased formation of 14-OH-clarithromycin was at least partially offset by an increase in renal clearance of clarithromycin in subjects with impaired hepatic function when compared to healthy subjects. See WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic and DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment.

Renal Insufficiency

The elimination of clarithromycin was impaired in patients with impaired renal function. The daily dose of clarithromycin should be limited to 500 mg in patients with severe renal impairment (creatinine clearance < 30 mL/min). See WARNINGS AND PRECAUTIONS, Renal and DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment.

Storage and Stability

BIAXIN BID (clarithromycin tablets USP, film-coated)

Store film-coated tablets between 15 and 25°C in a tightly closed container. Protect from light.

BIAXIN XL (clarithromycin extended-release tablets)

Store extended-release tablets between 15 and 25°C in a tightly closed container. Protect from light.

BIAXIN (clarithromycin for oral suspension USP)

Store granules for suspension between 15 and 25°C in a tightly closed bottle. Protect from light. After reconstitution, store between (15 and 25ºC) and use within 14 days. Do not refrigerate. Any reconstituted unused medication should be discarded after 14 days. The graduated syringe included in the package should be rinsed between uses. Do not leave syringe in bottle. Do not store reconstituted suspension in syringe.

Dosage Forms, Composition and Packaging

BIAXIN BID (clarithromycin tablets USP, film-coated)

BIAXIN BID tablets are available in two strengths: 250 mg and 500 mg clarithromycin for oral administration.

BIAXIN BID 250 mg tablets are supplied as yellow, film-coated, oval tablets printed with Abbott logo on one side and are available in HDPE bottles of 100 tablets.

BIAXIN BID 500 mg tablets are supplied as pale yellow, film-coated, oval tablets printed with Abbott logo on one side and are available in HDPE bottles of 100 tablets.

Listing of Non-Medicinal Ingredients

Each BIAXIN BID 250 mg tablet contains 250 mg of clarithromycin with the following non-medicinal ingredients: cellulosic polymers, croscarmellose sodium, D&C Yellow No. 10, magnesium stearate, povidone, pregelatinized starch, propylene glycol, silicon dioxide, sorbic acid, sorbitan monooleate, stearic acid, talc, titanium dioxide and vanillin. BIAXIN BID does not contain tartrazine.

Each BIAXIN BID 500 mg tablet contains 500 mg of clarithromycin with the following non-medicinal ingredients: cellulosic polymers, croscarmellose sodium, D&C Yellow No. 10, magnesium stearate, povidone, propylene glycol, silicon dioxide, sorbic acid, sorbitan monooleate, stearic acid, talc, titanium dioxide and vanillin. BIAXIN BID does not contain tartrazine.

BIAXIN BID (clarithromycin tablets USP, film-coated: new formulation)

BIAXIN BID 500 mg tablets (new formulation) are supplied as yellow, film-coated, oval, debossed tablets.

Listing of Non-Medicinal Ingredients

Each BIAXIN BID 500 mg tablet (new formulation) contains 500 mg of clarithromycin with the following non-medicinal ingredients: cellulosic polymers, colloidal silicon dioxide, croscarmellose sodium, D&C Yellow No. 10, magnesium stearate, povidone, propylene glycol, sorbic acid, sorbitan monooleate, titanium dioxide and vanillin. BIAXIN BID (new formulation) does not contain tartrazine.

BIAXIN XL (clarithromycin extended-release tablets)

BIAXIN XL 500 mg tablets are supplied as yellow, film-coated, oval, tablets debossed with Abbott logo and “LC” on one side and are available in HDPE bottles of 60 tablets.

Listing of Non-Medicinal Ingredients

Each BIAXIN XL tablet contains 500 mg clarithromycin with the following non-medicinal ingredients: cellulosic polymers, lactose monohydrate, magnesium stearate, propylene glycol, Quinoline Yellow Lake E104, sorbitan monooleate, talc, titanium dioxide and vanillin.

Each BIAXIN XL tablet contains less than 300 mg of lactose.

BIAXIN (clarithromycin for oral suspension USP)

BIAXIN 125 mg/5 mL oral suspension is supplied as a white to off-white granular preparation and is available in 55 mL, 105 mL and 150 mL in HDPE bottles.

BIAXIN 250 mg/5 mL oral suspension is supplied as a white to off-white granular preparation and is available in 105 mL in HDPE bottles.

Reconstituted product is a white to off-white opaque suspension. The bottles allow capacity for shaking and are packaged with a graduated syringe.

Listing of Non-Medicinal Ingredients

BIAXIN 125 mg/5 mL and 250 mg/5 mL oral suspensions contain a granular preparation of clarithromycin with carbopol and povidone (K90), coated with HP-55 polymer (hydroxypropyl methylcellulose phthalate). The coated granules are mixed with the following inactive ingredients: artificial and natural fruit flavour, castor oil, citric acid, maltodextrin, potassium sorbate, silicon dioxide, sucrose or sugar, titanium dioxide and xanthan gum. Water is added to reconstitute the suspension prior to use.

BIAXIN 125 mg/5 mL and 250 mg/5 mL oral suspensions contain less than 550 mg/mL of sucrose.