Teva-Clarithromycin XL Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

TEVA-CLARITHROMYCIN 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. See WARNINGS AND PRECAUTIONS, Susceptibility/Resistance.

The efficacy and safety of TEVA-CLARITHROMYCIN XL in treating other infections for which other dosage forms of clarithromycin are approved have not been established.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of TEVA-CLARITHROMYCIN XL and other antibacterial drugs, TEVA-CLARITHROMYCIN XL should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

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 3.

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

TEVA-CLARITHROMYCIN XL (clarithromycin extended-release tablets) is 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 (congenital or documented acquired 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, domperidone, 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 2.

• Concomitant therapy with saquinavir due to potentially life-threatening cardiac arrhythmia.
• 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 2.
• concomitant therapy with ergot alkaloids (e.g., ergotamine or dihydroergotamine) as this may result in ergot toxicity. See DRUG INTERACTIONS, Drug-Drug Interactions, Table 2.
• concomitant administration with oral midazolam. See DRUG INTERACTIONS, Drug-Drug Interactions, Table 2.
• concomitant therapy with colchicine due to the risk of life threatening and fatal colchicine toxicity. This risk may be further increased with concomitant medications metabolized by P-glycoprotein or strong CYP3A inhibitors. See DRUG INTERACTIONS, Drug-Drug Interactions, Table 2.

• concomitant therapy with ticagrelor or ranolazine*.

  * Not marketed in Canada.

WARNINGS AND PRECAUTIONS

General

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.

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.

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.

Atypical Antipsychotics (quetiapine)

Due to inhibition of CYP3A by clarithromycin, co-administration of clarithromycin with quetiapine results in increased quetiapine concentrations. Serious and life-threatening quetiapine-related adverse reactions, including malignant neuroleptic syndrome, have been reported. Clarithromycin should not be used in combination with quetiapine unless clinically necessary. See DRUG INTERACTIONS. Monitoring and dose reductions may be required.

Oral Hypoglycemic Agents/Insulin

The concomitant use of clarithromycin and oral hypoglycaemic agents (such as sulphonylureas) and/or insulin can result in significant hypoglycaemia. Careful monitoring of glucose is recommended. See DRUG INTERACTIONS, Drug-Drug Interactions, Table 2.

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 2.

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 2.

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 2.

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 2.

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 2.

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

Cardiovascular Events

Prolonged cardiac repolarisation and QT interval, imparting a risk of developing cardiac arrhythmia and torsades de pointes, have been seen in treatment with macrolides, including clarithromycin. See ADVERSE REACTIONS. Fatalities have been reported. Elderly patients may be more susceptible to drug-associated effects on the QT interval.

As the following situations may lead to an increased risk for ventricular arrhythmias (including torsades de pointes), clarithromycin should be used with caution in patients with coronary artery disease, cardiac insufficiency, conduction disturbances, electrolyte disturbances such as hypomagnesemia, clinically significant bradycardia (e.g., < 50 bpm), or when concomitantly taking with other medicinal products associated with QT prolongation, due to the risk for QT prolongation and torsades de pointes. See 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. Concomitant administration of clarithromycin with astemizole, cisapride, domperidone, pimozide, terfenadine and saquinavir is also contraindicated. See CONTRAINDICATIONS.

Epidemiological studies investigating the risk of adverse cardiovascular outcomes with macrolides have shown variable results. Studies have identified risks of arrhythmia, myocardial infarction and cardiovascular mortality associated with macrolides including clarithromycin.

Consideration of these findings should be balanced with treatment benefits when prescribing clarithromycin.

Endocrine and Metabolism

TEVA-CLARITHROMYCIN XL (clarithromycin extended-release tablets) 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.

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

In the event of severe acute hypersensitivity reactions, such as anaphylaxis, severe cutaneous adverse reactions (SCAR) (e.g., acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug rash with eosinophilia and systemic symptoms (DRESS)), clarithromycin therapy should be discontinued immediately and appropriate treatment should be urgently initiated.

Renal

Caution should be exercised when administering clarithromycin to patients with moderate to severe renal impairment.

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.

Susceptibility/Resistance

In view of the emerging resistance of Streptococcus pneumoniae, Staphylococcus aureus and Streptococcus pyogenes to macrolides, it is important that susceptibility 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.

Development of Drug-Resistant Bacteria

Prescribing TEVA-CLARITHROMYCIN XL in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and risks the development of drug-resistant bacteria.

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 clarithromycin extended-release tablets in children under 12 years of age has not been studied.

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 most frequently reported events in adults taking clarithromycin extended-release tablets were diarrhea, abnormal taste and nausea.

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.

Fewer than 2% of adult patients taking 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%)

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

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.

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

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

Serious Drug Interactions

• Concomitant administration of clarithromycin with astemizole, cisapride, domperidone, 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.

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 (Table 2).

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 inducer 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 2. 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.

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

Interactions with other drugs have not been established.

* not marketed in Canada.

Drug-Food Interactions

TEVA-CLARITHROMYCIN 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

TEVA-CLARITHROMYCIN 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.

Recommended Dose and Dosage Adjustment

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 3 provides dosage guidelines.

Renal Impairment

Based on a study done with clarithromycin tablets, 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 C_max 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 C_max 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 clarithromycin tablets, 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.

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

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

OVERDOSAGE

Activated charcoal may be administered to aid in the removal of unabsorbed drug. General supportive measures are recommended.

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.

Pharmacokinetics

A summary of clarithromycin pharmacokinetic parameters following the administration of clarithromycin extended-release tablets is provided in Table 4. See DETAILED PHARMACOLOGY, Pharmacokinetics.

Absorption

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 TEVA- CLARITHROMYCIN XL (clarithromycin extended-release tablets) be given with food.

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

Figure 1: Steady-State Clarithromycin Plasma Concentration-Time Profiles for Clarithromycin Extended-Release Tablets (2 x 500 mg once daily) Relative to Clarithromycin Tablets (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.

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 5.

* 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

Store TEVA-CLARITHROMYCIN XL between 15°C and 30°C in a tightly closed container. Protect from light.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Dosage Forms

TEVA-CLARITHROMYCIN XL 500 mg tablets are supplied as yellow, film-coated, oval shaped tablets debossed with “ ” and “777” on one side.

Composition

Each TEVA-CLARITHROMYCIN XL tablet contains 500 mg of clarithromycin with the following non-medicinal ingredients: compressible sugar, glyceryl monostearate, and sodium phosphate monobasic (anhydrous). The film coating contains: D&C Yellow #10 Aluminum Lake, polyethylene glycol, polyvinyl alcohol, talc and titanium dioxide.

Packaging

TEVA-CLARITHROMYCIN XL 500 mg tablets are available in HDPE bottles of 60 tablets.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Clarithromycin

Chemical name: (3R, 4S, 5S, 6R, 7R, 9R, 11R, 12R, 13S, 14R)-4-[(2,6-Dideoxy-3-C-methyl-3-O-methyl-α-L-ribo-hexopyranosyl)oxy]-14-ethyl-12,13-dihydroxy-7-methoxy-3,5,7,9,11,13-hexamethyl-6-{[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy} oxacyclotetradecane-2,10-dione.

Molecular formula: C₃₈H₆₉NO₁₃

Molecular mass: 747.95 g/mol

Structural formula:

Physicochemical properties: Clarithromycin is a white to off-white crystalline powder. It is soluble in acetone; slightly soluble in ethanol, methanol, and in acetonitrile; and practically insoluble in water.

CLINICAL TRIALS

Comparative Bioavailability Studies

A randomized, double-blinded, two treatment, two period, two sequence, single oral dose, two-way crossover bioequivalence study of TEVA-CLARITHROMYCIN XL (Clarithromycin Extended-Release Tablets), 500 mg against Biaxin^® XL (Clarithromycin Extended-Release Tablets), 500 mg manufactured by Abbott Laboratories, Limited (Canada) was performed on 46 healthy human, adult subjects under fasting conditions.

In addition, a randomized, double-blinded, two treatment, two period, two sequence, single oral dose, two-way crossover bioequivalence study of TEVA-CLARITHROMYCIN XL (Clarithromycin Extended-Release Tablets), 500 mg against Biaxin^® XL (Clarithromycin Extended-Release Tablets), 500 mg manufactured by Abbott Laboratories, Limited (Canada) was performed on 49 healthy human, adult subjects under fed conditions.

Comparative Bioavailability Data for TEVA-CLARITHROMYCIN XL (Clarithromycin Extended-Release Tablets), 500 mg vs. Biaxin^® XL 500 mg in Fasted Conditions

^* TEVA-CLARITHROMYCIN XL Extended-Release Tablets, 500 mg, Teva Canada Limited

^† BIAXIN^® XL, 500 mg, (Clarithromycin Extended –Release Tablets) manufactured by Abbott Laboratories, Limited, Canada, purchased in Canada.

^§ Expressed as the median (range) only

^€Expressed as the arithmetic mean (CV %) only

^‡ N = 30

^¥ N = 39

Comparative Bioavailability Data for TEVA-CLARITHROMYCIN XL (Clarithromycin Extended-Release Tablets), 500 mg vs. Biaxin^® XL 500 mg in Fed Conditions

^* TEVA-CLARITHROMYCIN XL Extended-Release Tablets, 500 mg, Teva Canada Limited

^† BIAXIN^® XL, 500 mg, (Clarithromycin Extended –Release Tablets) manufactured by Abbott Laboratories, Limited, Canada, purchased in Canada.

^§ Expressed as the median (range) only

^€ Expressed as the arithmetic mean (CV %) only

^‡ N = 47

^¥ N = 49

Safety and Efficacy Trials

Pneumonia

The clinical and the bacteriological cure rates for all Clinically and Bacteriologically Evaluable

Subjects treated with clarithromycin extended-release (ER) in the Community-Acquired

Pneumonia (CAP) pivotal study were 87% and 86%, respectively.

Clinical and bacteriological cure rates with the corresponding confidence intervals for Clinically and Bacteriologically Evaluable Subjects in 2 Studies are presented in Table 7.

A summary of the study demographics and trial design is presented below.

* Legend: ER = extended-release; q.d. = once daily

^a Exact binomial confidence interval..

^b Assessment was made after 7 days posttreatment in pivotal study and between 7-28 days posttreatment in non-pivotal study unless the subject was a prior clinical failure.

^c P-value is from Fisher's exact test comparing treatment groups.

^d Binomial confidence interval based on normal approximation.

^e comparator is levofloxacin

^f comparator is trovafloxacin mesylate

* Clinically and Bacteriologically Evaluable Subjects in the CAP Studies

Legend: ER = extended-release

Acute Bacterial Exacerbation of Chronic Bronchitis

5-Day Treatment Regimen

One double-blind, controlled study was conducted to evaluate efficacy and safety of clarithromycin extended-release 1000 mg once daily for 5 days treatment of ABECB, as presented in Table 8.

Legend: b.i.d = twice daily; q.d. = once daily; ER = extended-release; IR = immediate-release

The bacteriological cure rate for all Clinically and Bacteriologically Evaluable Subjects treated with clarithromycin extended-release in the Acute Bacterial Exacerbation of Chronic Bronchitis (ABECB) pivotal study was 87%.

Bacteriological cure rates with the corresponding confidence intervals for Clinically and Bacteriologically Evaluable Subjects are presented in Table 9.

^a Exact binomial confidence interval.

^b Bacteriological assessment was made at Evaluation 4 (between Study Days 14 and 40), unless the subject was a bacteriological failure.

^c P-value is from Fisher's exact test comparing treatment groups.

^d Binomial confidence interval based on normal distribution approximation with a continuity correction.

* Clinically and Bacteriologically Evaluable Subjects in the ABECB Study

Legend: ER = extended-release; IR = immediate-release

The clinical cure rates for all Clinically and Bacteriologically Evaluable Subjects treated with clarithromycin extended-release in the Acute Bacterial Exacerbation of Chronic Bronchitis (ABECB) pivotal study are presented in Table 10.

^a p-value from Fisher’s exact test comparing treatment groups.

Legend: ER = extended-release; IR = immediate-release

Long-term (3 months) recurrence rates of ABECB after 5-day treatment with clarithromycin extended-release has not been investigated in the pivotal trial.

7-Day Treatment Regimen

One double-blind controlled clinical trial was conducted to evaluate the efficacy and safety of clarithromycin 500 mg two tablets once daily for 7 days treatment of ABECB, as presented in Table 11.

Legend: b.i.d = twice daily; q.d. = once daily; ER = extended-release; IR = immediate-release

The primary efficacy parameters evaluated in Study 756 were the bacteriological cure rates, target pathogen eradication and clinical cure rates. Bacteriological and clinical cure rates with the corresponding confidence intervals for Clinically and Bacteriologically Evaluable Subjects are presented in Table 12.

* One subject with indeterminate bacteriological response was not included in calculating the rate.

^a P-value is from Fisher's exact test comparing treatment groups

^b Exact binomial confidence interval.

^c Binomial confidence interval based on normal approximation.

^d Assessment was made at Evaluation 3 (7 to 23 days post-treatment) unless the subject was a bacteriological failure before Evaluation 3.

Legend: ER = extended-release; IR = immediate-release

Overall eradication rates and corresponding confidence intervals, as well as target pathogen eradication rates, for clinically and bacteriologically evaluabale subjects are presented in Table 13.

* One subject with indeterminate bacteriological response was not included in calculating the rate.

^a P-value is from Fisher's exact test comparing treatment groups

^b Exact binomial confidence interval.

^c Binomial confidence interval based on normal approximation.

^d Assessment was made at Evaluation 3 (7 to 23 days post-treatment) unless the subject was a bacteriological failure before Evaluation 3.

DETAILED PHARMACOLOGY

Pharmacokinetics

Pharmacokinetics for clarithromycin and 14-OH-clarithromycin metabolite following the oral administration of a single dose or multiple doses of clarithromycin are outlined below.

Clarithromycin Immediate-Release Tablets

Pharmacokinetics for clarithromycin and 14-OH-clarithromycin metabolite was first studied following the oral administration of a single dose of 250 mg or 500 mg or multiple doses of clarithromycin 250 mg tablet.

Single Dose

Plasma levels were determined in 20 subjects following oral administration of a single-dose of 250 mg or 500 mg of clarithromycin under fasting conditions. C_max occurred at 1.00 and 1.77 (mg/L) and T_max were 1.5 and 2.2 hours, respectively for the 250 mg and 500 mg (Table 14, Figure 2 and Figure 3).

¹ C_max/100 mg = C_max x ; AUC/100 mg = AUC x

2 AUC0-12 hr

3 AUC0-14 hr

100 mg

dose

100 mg

dose

Figure 2: Plasma Clarithromycin Concentration (mg/mL) vs. Time Following Oral Administration of a Single Dose of Clarithromycin 250 mg

Figure 3: Plasma Clarithromycin Concentration (mg/L) vs. Time Following Oral Administration of a Single Dose of Clarithromycin 500 mg

Multiple Dose

Representative estimated pharmacokinetic parameters for clarithromycin and 14-OH-clarithromycin metabolite after a single oral 250 mg dose and after the 5^th dose of clarithromycin administered orally at 250 mg twice daily are listed in Table 15.

Legend: 14-OH = 14-OH-clarithromycin; b.i.d = twice daily

The pharmacokinetics of clarithromycin and its 14-OH metabolite indicate that the steady-state concentration is achieved by the 5th dose using 250 mg of clarithromycin twice daily.

The mean plasma concentration-time along the predicted curves for clarithromycin and 14-OH-clarithromycin metabolite are shown in Figure 4.

Figure 4: Mean Plasma Concentrations of Clarithromycin and 14-OH-Clarithromycin vs. Time Following Seven 250 mg b.i.d Oral Doses of Clarithromycin

At 250 mg twice daily, approximately 20% of an orally administered dose 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.

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 the subjects with impaired hepatic function when compared to healthy subjects.

The pharmacokinetics of clarithromycin were also altered in subjects with impaired renal function. See WARNINGS AND PRECAUTIONS, Renal and DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment.

MICROBIOLOGY

Clarithromycin exerts its antimicrobial action by binding to the 50S ribosomal subunit of susceptible microorganisms resulting in inhibition of protein synthesis.

Clarithromycin is active in vitro against various aerobic and anaerobic gram-positive and gram-negative organisms. The in vitro activity of clarithromycin is presented in Table 16.

Additionally, the 14-OH-clarithromycin metabolite also has significant antimicrobial activity which may be additive to the activity of the parent compound. Against Haemophilus influenzae, 14-OH clarithromycin is twice as active as the parent compound in vitro.

The ranges of MICs of clarithromycin, 14-OH-clarithromycin metabolite and the MICs required to inhibit 50% (MIC₅₀) and 90% (MIC₉₀) of bacteria are presented in Table 17 and Table 18. Beta-lactamase production should not have any effect on clarithromycin activity.

Cross-resistance to azithromycin has been documented. Attention should be paid to the possibility of cross resistance between clarithromycin and other macrolide drugs, as well as lincomycin and clindamycin.

The in vitro data indicate enterobacteriaceae, pseudomonas species and other non-lactose fermenting gram negative bacilli are not sensitive to clarithromycin.

Clarithromycin has been shown to be active against most strains of the following micro- organisms both in vitro and in clinical infections as described in the INDICATIONS AND

CLINICAL USE section:

The following in vitro data are available, but their clinical significance is unknown. Clarithromycin exhibits in vitro activity against most strains of the following microorganisms; however, the safety and effectiveness of clarithromycin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials (See MICROBIOLOGY, Tables 16-18 below):

* MICs do not take into account the antimicrobial activity of the 14-OH –clarithromycin metabolite.

^†Hardy DJ, Hanson CW, Hensey DM, Beyer JM, Fernandes PB. Susceptibility of Campylobacter pylori to macrolides and fluoroquinolones. J Antimicrob Chemother 1988;22:631-636.

Susceptibility Testing excluding Mycobacteria and Helicobacter

Dilution Techniques

Quantitative methods are used to determine antimicrobial minimal inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method43 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of clarithromycin powder.

The standard single disc susceptibility test (using the 15 mcg clarithromycin disc) and the dilution susceptibility test should be interpreted according to the criteria in Table 19.

* Indicates that the test results are equivocal; therefore, dilution tests may be indicated.

N.B. These criteria and the definition are in agreement with NCCLS. Documents M2-A6¹⁹ and M100-S8²⁰.

The standard single disc susceptibility test (using the 15 mcg clarithromycin disc) for H. Influenzae should be interpreted according to the criteria in Table 20.

* Indicates that the test results are equivocal; therefore, dilution tests may be indicated.

N.B. According to the revised NCCLS 1997 and 1998 Guidelines, the zone diameter and MIC values reflect both the activities of the parent compound and 14-OH metabolite.

A report of "Susceptible" indicates that the pathogen is likely to respond to monotherapy with clarithromycin.

A report of "Intermediate" indicates that the result be considered equivocal, and if the microorganism is not fully susceptible to alternative clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where clarithromycin is physiologically concentrated or in situations where high clarithromycin dosages can be used. This category provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretations.

A report of "Resistant" indicates that achievable drug concentrations are unlikely to be inhibitory, and other therapy should be selected.

Diffusion Techniques

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure¹⁹ requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 15-mcg clarithromycin to test the susceptibility of microorganisms to clarithromycin.

Reports from the laboratory providing results of the standard single-disk susceptibility test with a 15-mcg clarithromycin disk should be interpreted according to the criteria in Table 19.

Standardized Dilution Techniques

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard clarithromycin powder should provide the following MIC values for S. aureus and H. influenzae (Table 21).

Standardized Diffusion Techniques

As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 15-mcg clarithromycin disk should provide the following zone diameters for S. aureus and H. influenzae (Table 22).

TOXICOLOGY

Acute Toxicity

Clarithromycin Immediate-Release Tablets

The acute toxicity of clarithromycin administered by a variety of routes, was studied in mice and rats. The median lethal dose by the oral route ranged from 2.7 to > 5.0 g/kg. Acute toxicity did not differ markedly between sexes (Table 23).

Legend: i.p. = intraperitoneal; i.v. = intravenous; p.o. = oral; s.c. = subcutaneous

The primary signs of toxicity included reduction in activities, behaviours, weight gains, respiration rates and sedation. The emetic activity of clarithromycin prevented the determination of the lethal dose in dog.

The acute oral toxicity of clarithromycin in very young mice and rats was determined. The median lethal dose (1.2 g/kg) was about 2-fold that seen in the older rodents.

Subchronic Toxicity

Clarithromycin Immediate-Release Tablets

Studies were conducted in rats, dogs and monkeys with clarithromycin administered orally. The duration of administration ranged from 14 days to 42 days.

Rats

One study in rats (with oral doses up to 800 mg/kg/day) failed to show adverse effects in rats exposed to 50 mg/kg/day for 4 weeks. The clinical signs observed at toxic doses were reduced motility, piloerection, hypothermia and perineal urine staining. Changes occurred in biochemical parameters at 200 and 800 mg/kg/day indicative of hepatotoxicity which was confirmed by histopathologic findings of hepatocyte necrosis.

Other pathologic findings at the top 2 dose levels included swelling of the renal cortical tubular epithelia and atrophic changes to the lymphatic and genital systems. The same toxicity profile was observed in immature rats following the daily administration of oral doses up to 150 mg/kg/day of clarithromycin for 6 weeks. At 150 mg/kg/day, there was an increase in relative weights of liver and kidneys.

Dogs

Dogs were dosed orally with 0, 6.25, 25, 100 or 400 mg/kg/day of clarithromycin daily for 28 days. Emesis occurred sporadically in the treated dogs. No other adverse effects were seen in dogs exposed to 6.25 mg/kg/day. The clinical signs at higher dosages included loose stools, lacrimation and conjunctivitis.

Slight anorexia was noted in dogs receiving 100 mg/kg/day or more. Dogs at 400 mg/kg/day exhibited reduced red blood cell count, hematocrit, hemoglobin concentration, serum albumin, and mean urine pH and specific gravity. Increases were seen in serum transaminase, alkaline phosphatase, and total bilirubin concentrations.

Bilirubin was detected in the urine. Other pathologic changes at 400 mg/kg/day included Biliary hyperplasia, gastric glandular atrophy, renal tubule epithelial atrophy, edema of the iris, ciliary body and choroid, capillary proliferation in the cornea, suppression of spermatogenesis, and adrenal medullary degeneration.

Monkeys

Monkeys were treated daily for 1 month with oral doses of 0, 25, 100 or 400 mg/kg/day. Two animals out of 10 receiving 400 mg/kg/day died. Salivation was recorded at all dosage levels. No other adverse effects were seen in animals treated daily with 25 mg/kg/day.

The clinical signs observed at higher doses and most frequently at 400 mg/kg/day were vomiting, emesis, sunken eyes, dehydration, emaciation, low rectal temperature, body weight loss, reduced food consumption, cloudiness of the cornea and reduction in intra-ocular pressure. Yellow discoloured feces were passed on a few isolated occasions by some animals given a dose of 400 mg/kg/day. As with the other species, the liver was the primary target at toxic doses as shown by early elevation of serum concentration of glucose, BUN, creatinine, ALT, AST, LDH, amylase and/or triglyceride; an electrolyte imbalance and low levels of protein, cholesterol, phospholipid; elevated leucine aminopeptidase (LAP).

Principal histopathologic changes were seen mainly in high dose monkeys, but some mid-dose monkeys exhibited similar alterations. Changes included necrosis and vacuolation of hepatocytes, vacuolation of renal cortical tubules, no spermatogenesis, thymic regression and single cell necrosis of the stomach. In man the recommended dose is 500 to 1000 mg/day or 7.1 to 14.3 mg/kg/day (70 kg person).

Chronic Toxicity

Clarithromycin Immediate-Release Tablets

Rats (20/sex/group) were treated daily with oral doses of 0, 15, 37.5, 75 or 150 mg/kg/day for 3 months. There were 8 incidental deaths, but none of them were considered treatment related. Clinical signs included increased salivation, dehydration, hyperactivity and were observed in a dose-related manner. The only toxic effect noted, was some variation in body weight gain. No toxicologically significant changes occurred in hematology, biochemistry or urinalysis results.

Post mortem, there was an increase in mean relative liver and kidney weights at the top dose level. No microscopic changes were detected in the kidneys, but in the liver, there was a sex/dose-related increase in multinucleated hepatocytes. Effects were only seen in females at 150 mg/kg/day but in males occurred as low as 37.5 mg/kg/day.

A 6-month oral study was performed in rats (20 to 27/sex/group) at dosages of 0, 1 to 6, 8, 40 or 200 mg/kg/ day. Seven male and female rats from the control group and the 40 and 200 mg/kg/day groups were allowed a 63-day non-dosed recovery period. No mortalities occurred. Body weight and food intake were reduced at high doses during the dosing phase but normalized during recovery.

Water intake and urine volume increased in males and females of the 40 and 200 mg/ kg/day groups. Dose-related hematological changes included reduced erythrocytes and HCT with increased MCV, MCH and MCHC and relative eosinophil counts. Biochemical changes were mainly restricted to the high dose group and included increased ALP and decreased phospholipids; decreased total cholesterol and triglycerides, and increased AST and ALT in males only and decreased albumin in females only.

Organ weight increases were found to include cecum, adrenals, liver, and spleen. Histopathological examinations showed drug-related, recovery-reversible increases in multinucleated hepatocytes associated with minimal and focal necrosis in livers of both sexes at the top 2 dose levels. No relevant pathology was found in the cecum, adrenals or spleen to account for the increased weights. After recovery only the 200 mg/kg/day group had increased multinucleated hepatocytes.

Dogs (7/sex/group) were administered daily with oral doses of 0, 10, 30, or 100 mg/kg/day of clarithromycin for 3 months. Emesis occurred at levels of 30 mg/kg and above. One male high-dose dog was killed in extremis on day 69. Drug-related lesions were seen in the liver, gall bladder, thymus and stomach.

Hematological and biochemical changes at the high dose level included, decreased RBC and HCT, increased ALT, ALP, GGT, and decreased total protein and albumin. No significant organ weight changes were recorded, but treatment-related microscopic alterations in the liver and stomach of mild- and high-dose dogs were seen, as well as changes in gall bladder, spleen and thymus of high-dose animals.

A 6-month oral study was also performed in dogs (4 to 5/sex/group) at dosages of 0, 0.8, 4, 20 or 100 mg/kg/day. At the 0 and 100 mg/kg levels, 1 male and 1 female dog were allowed a 1-month, non-dosed, recovery period. One male-high dose dog died on day 174. This death was considered to be as a direct result of clarithromycin administration. Histopathologic examination revealed hepatic parenchymal damage, identifying the cause of clinical jaundice. Clinical signs during the dosing phase of the study were restricted to the top 2 dose levels and included emesis and ocular signs. Food consumption and water intake were reduced at 20 and 100 mg/kg/day.

Hematologic changes at 100 mg/kg were indicative of subclinical anemia. Biochemical alterations at the same level were associated with liver damage. Ocular changes were only apparent at the top dose level.

Increase in the weights of lung, liver, spleen, adrenals and kidneys were found at 100 mg/kg/day. Histopathologic examination of these organs showed degeneration of liver parenchyma, and toxic effects in adrenals. The thymus weight was reduced at 100 mg/kg/day. At the end of the recovery period all findings had regressed or reduced.

Monkeys (5 to 6/sex/group) were similarly administered clarithromycin at levels of 0, 25, 50 or 100 mg/kg/day for 6 months. At the 0 and 100 mg/kg levels, 1 male and 1 female monkey were allowed a one-month recovery period. One high-dose female died in week 25. Inhalation of vomit was considered to be the cause of death. Clinical signs were restricted to a dose-related incidence of emesis and salivation. No treatment-related effects were found in food consumption, ophthalmoscopy or hematology. Weight loss was restricted to 1 high-dose female. Minor serum chemistry changes were seen at the 100 mg/kg level, particularly in plasma proteins. Urinalysis revealed a dose-related lowering of pH and SG at 13 weeks only. Organ weight increases in liver, adrenal and kidneys were seen at high doses, but pathology was restricted to minimal liver changes consisting of cytoplasmic rarefaction of centrilobular hepatocytes. All changes were reversed during the recovery period.

Carcinogenicity

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

Mutagenicity

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.

Reproduction and Teratology

Fertility and reproduction studies have shown that daily doses of 150 to160 mg/kg/day to male and female rats caused no adverse effects on the estrous cycle, fertility, parturition, or number and viability of offspring. Plasma levels in rats after 150 mg/kg/day were 2 times the human serum levels.

In the 150 mg/kg/day monkey studies, plasma levels were 3 times the human serum levels. When given orally after 150 mg/kg/day, clarithromycin was shown to produce embryonic loss in monkeys. This effect has been attributed to marked maternal toxicity of the drug at this high dose.

In rabbits, in utero fetal loss occurred at an intravenous dose of 33 mg/m², which is 17 times less than the maximum proposed human oral daily dose of 618 mg/m².

Special Studies

Acute Renal Toxicity

There was no evidence of nephrotoxicity of clarithromycin in the rat at doses up to 500 mg/kg/day.

Hepatotoxicity

In the in vitro and in vivo hepatotoxicity studies comparing clarithromycin with erythromycin, it was found that clarithromycin caused no greater cytotoxicity than erythromycin stearate and much less toxicity than erythromycin estolate. Hepatic enzyme induction was not found in doses below 500 mg/kg/day. In cynomolgus monkeys, the closest metabolic model for humans, elevations of ALT and LDH were identified at 200 mg/kg/day.

In dogs, a rise of ALT has been seen at 100 mg/kg/day, and in Wistar rats, a similar elevation of enzymes was seen at 200 mg/kg/day. Morphologic lesions related to prolonged exposure to clarithromycin (up to 6 months) have been consistent with reportedly reversible changes in rat, dog and monkey studies. Such doses are many times beyond the therapeutic range in humans, which is within 8 to 10 mg/kg/day.

Ocular Toxicity

Ocular lesions appear confined to dogs and monkeys receiving lethal doses, which were large multiples of the human therapeutic dose. Radiolabelled clarithromycin studies indicate the eye is not selectively burdened by drug deposits and that clearance from this tissue follows that seen in other tissues. Opacities occur in the cornea following widespread extraocular tissue changes which are detectable via numerous diagnostic methods. Reduced intraocular pressure precedes corneal opacity in a relatively predictive manner. Some evidence for transient opacity and at least partial resolution was noted in animal studies, but most animals succumbed to other organ dysfunctions shortly after opacities were observed.

Animals given doses close to the therapeutic dose had no ocular changes. No ophthalmologic effects were noted in rabbits treated at doses of 40 and 160 mg/kg/day for 28 days.

Ototoxicity

No effects on pinna reflex were seen in guinea pigs at a dose of 400 mg/kg/day but inner and outer hair cells disappeared suggesting toxic damage. No evidence of damage was reported at 200 mg/kg/day.

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