Ratio-Clarithromycin Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

ratio-CLARITHROMYCIN (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

ratio-CLARITHROMYCIN (clarithromycin tablets, USP, film-coated) is indicated for the prevention of disseminated Mycobacterium avium complex (MAC) disease in patients with advanced HIV infection (see CLINICAL TRIALS, Mycobacterial Infections), and for the treatment of

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disseminated mycobacterial infections due to Mycobacterium avium (M. avium) and Mycobacterium intracellulare (M. intracellulare).

Eradication of Helicobacter pylori

ratio-CLARITHROMYCIN (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 H. pylori – Triple Therapy and Eradication of H. pylori

• Dual Therapy).

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

CONTRAINDICATIONS

ratio-CLARITHROMYCIN (clarithromycin tablets, USP, film-coated) is contraindicated in patients with a known hypersensitivity to clarithromycin, erythromycin, other macrolide antibacterial agents or to any ingredient in the formulation or component of the container. (see DOSAGE FORMS, COMPOSITION AND PACKAGING).

Clarithromycin is contraindicated as concurrent therapy with astemizole, terfenadine, cisapride, pimozide, ergotamine or dihydroergotamine. There have been post-marketing reports of drug interactions when clarithromycin and/or erythromycin are co-administered with cisapride, astemizole, 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).

WARNINGS AND PRECAUTIONS

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_^.
• The concomitant administration of clarithromycin and drugs metabolized by CYP3A and/or transported by P-gp may result in significant safety concerns (see DRUG INTERACTIONS).

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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.

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.

There have been postmarketing reports of colchicine toxicity with concurrent use of clarithromycin and colchicine. In patients with impaired renal function and/or who are elderly, colchicine and clarithromycin should not be used concurrently due to the risk of colchicine toxicity. Deaths have been reported in some such patients (see DRUG INTERACTIONS, Drug-Drug Interactions, Colchicine and ADVERSE REACTIONS, Post-Market Adverse Drug Reactions).

Several studies of 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.

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 may lead to drug-drug interactions. For 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.

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.

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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 two 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

Clarithromycin is principally excreted by the liver and kidney. In patients with both hepatic 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).

Renal

Clarithromycin is principally excreted by the liver and kidney. In patients with both hepatic 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).

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 one study) has been seen in HIV positive patients receiving clarithromycin for prophylaxis and treatment of MAC infection.

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.

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Antibiotic Resistance in Relation to H. pylori Eradication

Triple and Dual 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. Twenty-six patients 26/104 (25%) with pretreatment isolates susceptible to clarithromycin developed resistance after treatment with omeprazole and clarithromycin. 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 (three with oral doses and one with intravenous doses up to 160 mg/kg/day administered during the period of major organogenesis) and two 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

1. 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.

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Pediatrics (6 months - 12 years of age)

Use of clarithromycin tablets in children under 12 years of age has not been studied.

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 clarithromycin 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 clarithromycin were nausea, diarrhea, abdominal pain, dyspepsia, headache, taste perversion and vomiting.

Clinical Trial Adverse Drug Reactions

General Statement

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.

Patients with Respiratory Tract or Skin Infections

Adverse Reactions

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.

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Treatment of Patients with Mycobacterial Infections

Adverse Reactions

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.

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Patients with H. Pylori Infection - Triple Therapy

(clarithromycin/omeprazole/amoxicillin)

Adverse Reactions

A summary of drug-related adverse event incidence rates is presented in Table 7.

(Other adverse reactions have been observed in different patient populations and during post-marketing surveillance. Please also refer to ADVERSE REACTIONS, Clinical Trial Adverse Drug Reactions, Patients with Respiratory Tract or Skin Infections).

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Patients with H. Pylori Infection - Dual Therapy

(clarithromycin/omeprazole)

Adverse Reactions

Of 346 patients, 156 (45%) reported at least one adverse event. Adverse events associated with the Gastrointestinal disorders, Nervous system disorders, and Infections and infestations system organ class (SOC) were the most commonly reported adverse events among clarithromycin/omeprazole-treated patients. One hundred and two patients (29%) reported gastrointestinal disorder events. The most common adverse events reported in the Gastroinstestinal disorder SOC were nausea (5%) diarrhea (4%), vomiting (3%), and abdominal pain (3%). Eighty-three patients (24%) reported adverse events in the Nervous system disorders SOC. Dysgeusia (15%), headache (5%), and dizziness (2%) were the most frequently reported events in the Nervous system disorders SOC. Twenty-nine patients (8%) reported adverse events in the Infections and infestations SOC. Infection (3%) was the most frequently reported adverse event in the Infections and infestations SOC. Adverse events by system organ class for all patients treated with clarithromycin and omeprazole are presented in Table 8.

(Other adverse reactions have been observed in different patient populations and during post-marketing surveillance. Please also refer to ADVERSE REACTIONS, Clinical Trial Adverse Drug Reactions, Patients with Respiratory Tract or Skin Infections).

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The most commonly reported adverse events for the 346 patients who received clarithromycin and omeprazole were: taste perversion (15%), nausea (5%), headache (5%), diarrhea (4%), vomiting (3%), abdominal pain (3%), and infection (3%).

Table 9 presents adverse events reported by 1% or more of clarithromycin/omeprazole-treated patients.

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Twelve (4%) of the clarithromycin/omeprazole-treated patients prematurely discontinued from study drug therapy due to adverse events. The most frequently reported adverse events leading to withdrawal included taste perversion, nausea, and headache. Three patients treated with clarithromycin and omeprazole died during follow-up periods; none of the deaths were considered by the investigator to be related to study drug administration.

Few laboratory abnormalities were observed among clarithromycin/ omeprazole-treated patients. The incidence of possibly clinically significant hematology and serum chemistry variables was < 1% for any variable evaluated.

Post-Market Adverse Drug Reactions

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

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

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

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

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 such patients (see WARNINGS AND PRECAUTIONS, General and DRUG INTERACTIONS, Drug-Drug Interactions).

Formatted: English (Canada), Condensed by 0.55 pt

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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

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 should be avoided, e.g. oral midazolam (see Table 11).

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

Serious Drug Interactions

• Concomitant administration of clarithromycin with astemizole, cisapride, pimozide, terfenadine, egotamine, or 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.

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exposure to clarithromycin while increasing exposure to its metabolite 14-OH-clarithromycin which could impair the intended therapeutic effect. Co-administration of potent CYP3A inhibitors may lead to increased exposure to clarithromycin and decreased exposure to its metabolite 14-OHclarithromycin. 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 11. 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.

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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

ratio-CLARITHROMYCIN (clarithromycin tablets, USP, film-coated) may be given with or without meals.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

Interactions with laboratory tests have not been established.

DOSAGE AND ADMINISTRATION

Dosing Considerations

ratio-CLARITHROMYCIN (clarithromycin tablets, USP, film-coated) may be given with or without meals.

In patients with both hepatic 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).

In children with renal impairment and a creatinine clearance less than 30 mL/min, the dosage of clarithromycin 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

Adults with Respiratory Tract or Skin Infections

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

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Eradication of Helicobacter Pylori

Triple Therapy: ratio-CLARITHROMYCIN/omeprazole/amoxicillin

The recommended dose is clarithromycin 500 mg twice daily in conjunction with amoxicillin 1 g twice daily and omeprazole 20 mg daily for 10 days (see CLINICAL TRIALS, Eradication of H. pylori – Triple Therapy).

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

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

Dual Therapy: ratio-CLARITHROMYCIN/omeprazole

In patients who are sensitive to penicillin-based therapy (e.g. amoxicillin), dual therapy with clarithromycin and omeprazole may provide a feasible alternative.

The recommended dose is clarithromycin 500 mg three times daily plus omeprazole 40 mg once daily for 14 days, followed by 20 mg omeprazole once daily for 14 days (see CLINICAL TRIALS, Eradication of H. pylori – Dual Therapy).

Optimal therapeutic regimens consisting of a shorter treatment duration for the eradication of H. pylori are yet to be determined.

Adults with Mycobacterial Infections

Prophylaxis

The recommended dose of ratio-CLARITHROMYCIN 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.

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

ratio-CLARITHROMYCIN may be taken with or without food.

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OVERDOSAGE

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

A summary of clarithromycin pharmacokinetic parameters following the administration of clarithromycin film-coated tablets is provided in Table 13. For details see DETAILED PHARMACOLOGY, Pharmacokinetics in PART II of the Product Monograph.

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

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Absorption

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, ratio-CLARITHROMYCIN 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.

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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 C_max values ranged from 5 to10 mg/L. C_max 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 C_max value was approximately 3.8 mcg/mL and the mean C_min value was approximately 1.8 mcg/mL. The mean AUC_0-8 for clarithromycin was 22.9 mcg⋅hr/mL. The T_max 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 AUC_0-24 were observed. For all subjects combined, the mean omeprazole AUC_0-24 was 89% greater and the harmonic mean for omeprazole t½ was 34% greater when omeprazole was administered with clarithromycin than when omeprazole was administered alone. When clarithromycin was administered with omeprazole, the steady state C_max, C_min, and AUC_0-8 of clarithromycin were increased by 10%, 27%, and 15%, respectively over values achieved when clarithromycin was administered with placebo.

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 14.

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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 5-10% 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

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impairment (CRCL < 30 mL/min). (see WARNINGS AND PRECAUTIONS, Renal and DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment).

STORAGE AND STABILITY

Store between 15° - 30°C (59° and 77°F) in a tightly closed container. Protect from light.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Composition:

ratio-CLARITHROMYCIN 250 mg (clarithromycin film-coated tablets, USP) contains: 250 mg of clarithromycin for oral administration.

Non-medicinal ingredients: croscarmellose sodium, magnesium stearate, povidone, pregelatinized starch, silicon dioxide, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose/hypromellose, polyethylene glycol, maltodextrin, microcrystalline cellulose and vanillin.

ratio-CLARITHROMYCIN 500 mg (clarithromycin film-coated tablets, USP) contains: 500 mg of clarithromycin for oral administration.

Non-medicinal ingredients: croscarmellose sodium, magnesium stearate, povidone, pregelatinized starch, silicon dioxide, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose/hypromellose, polyethylene glycol, maltodextrin, microcrystalline cellulose and vanillin.

Dosage Forms:

ratio-CLARITHROMYCIN (clarithromycin film-coated tablets) 250 mg

Each oval, biconvex, yellow, film-coated tablet with an odour of vanilla, marked with "rph" on one side and with "C112" on the other side, contains: clarithromycin 250 mg. Supplied in HDPE bottles of 100 and 500 tablets.

ratio-CLARITHROMYCIN (clarithromycin film-coated tablets) 500 mg

Each oval, biconvex, yellow, film-coated tablet with an odour of vanilla marked with "rph" on one side and with "C111" on the other side, contains: clarithromycin 500 mg. Supplied in HDPE bottles of 100 and 500 tablets.

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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-3-0-methyl-alpha-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)-beta-D-xylo-hexopyranosyl]oxy] oxacyclotetradecane-2-10-dione.

Molecular formula: C₃₈H₆₉NO₁₃,

Molecular mass: 747.96

Structural formula:

Physicochemical properties: Clarithromycin is a white to off-white crystalline powder. It is slightly soluble in methanol, ethanol and acetonitrile, and practically insoluble in water. The pKa of clarithromycin is 8.48; the pH of a 0.2% (Methanol:Water, 5:95) slurry is 8.8.

The partition coefficient of clarithromycin is influenced by the pH of the water phase and polarity of the organic phase. For octanol (dipole moment = 0.25): water, the partition co-efficient varies from 5.63 to 46.0 for pH water increases from 2 to 8. The melting point of clarithromycin is approximately 225°C.

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CLINICAL TRIALS

BIOAVAILABILITY

Comparative Bioequivalence Study (500 mg strength) - Fasting

A comparative bioavailability study using 38 healthy adult male volunteers under fasting conditions was performed between ratio-CLARITHROMYCIN 500 mg tablets, manufactured by ratiopharm inc., and Biaxin^® BID 500 mg tablet manufactured by Abbott Laboratories Limited, the Canadian Reference Product (CRP). Results are tabulated below.

Based on these results, ratio-CLARITHROMYCIN and Biaxin^® BID 500 mg tablets are bioequivalent under fasting conditions.

Comparative Bioequivalence Study (500 mg strength) - Fed

A comparative bioavailability study using 57 healthy adult male volunteers under fed conditions was performed between ratio-CLARITHROMYCIN 500 mg tablets, manufactured by ratiopharm inc., and Biaxin^® BID 500 mg tablet manufactured by Abbott Laboratories Limited, the CRP. Results are tabulated below.

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Based on these results, ratio-CLARITHROMYCIN and Biaxin^® BID 500 mg tablets are bioequivalent under fed conditions.

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On an intent-to-treat basis, the one-year cumulative incidence of MAC bacteremia was 5.0% for patients randomized to clarithromycin and 19.4% for patients randomized to placebo (see Table 19). While only 19 of the 341 patients randomized to clarithromycin developed MAC, 11 of these cases were resistant to clarithromycin. The patients with resistant MAC bacteremia had a median baseline CD₄ count of 10 cells/mm³ (range 2 to 25 cells/mm³). Information regarding the clinical course and response to treatment of the patients with resistant MAC bacteremia is limited. The 8 patients who received clarithromycin and developed susceptible MAC bacteremia had a median baseline CD₄ count of 25 cells/mm³ (range 10 to 80 cells/mm³). Comparatively, 53 of the 341 placebo patients developed MAC; none of these isolates were resistant to clarithromycin. The median baseline CD₄ count was 15 cells/mm³ for placebo patients that developed MAC.

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Figure 1: Survival of All Randomized Immunocompromized Adult Patients Receiving

Clarithromycin in Prophylaxis Against M. avium Complex or Placebo

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The median duration of response, defined as improvement of resolution of clinical signs and symptoms, was 2 to 6 weeks.

Since the study was not designed to determine the benefit of monotherapy beyond 12 weeks, the duration of response may be underestimated for the 25 to 33% of patients who continued to show clinical response after 12 weeks.

Survival. Median survival time from study entry (Study 500) was 249 days at the 500 mg twice daily dose compared to 215 days with the 1000 mg twice daily dose. However, during the first 12 weeks of therapy, there were 2 deaths in 53 patients in the 500 mg twice daily group versus 13 deaths in 51 patients in the 1000 mg twice daily group. The reason for this apparent mortality difference is not known. Survival in the two groups was similar beyond 12 weeks. The median survival times for these dosages were similar to recent historical controls with MAC when treated with combination therapies.

Median survival time from study entry in Study 577 was 199 days for the 500 mg twice daily dose and 179 days for the 1000 mg twice daily dose. During the first four weeks of therapy, while patients were maintained on their originally assigned dose, there were 11 deaths in 255 patients taking 500 mg twice daily and 18 deaths in 214 patients taking 1000 mg twice daily.

Eradication of Helicobacter pylori - Triple Therapy

Clarithromycin/omeprazole/amoxicillin

In a well controlled double-blind study, Helicobacter pylori (H. pylori) infected duodenal ulcer patients received triple therapy with clarithromycin 500 mg twice daily, amoxicillin 1000 mg twice daily and omeprazole 20 mg daily for 10 days or dual therapy with clarithromycin 500 mg three times daily and omeprazole 40 mg daily for 14 days. H. pylori was eradicated in 90% of the patients receiving clarithromycin triple therapy and in 60% of the patients receiving dual therapy.

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The ulcer healing rates and corresponding 95% confidence intervals are presented in Table 24.

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Results of Study A are displayed in Table 27.

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Overall summary

In study A, H. pylori was eradicated in over 80% of patients who received clarithromycin and omeprazole and in only 1% of patients receiving omeprazole alone. In studies B, C, and D, the combined eradication rate was over 70% in patients receiving clarithromycin and omeprazole and less than 1% in patients receiving omeprazole alone. In each study, the rate of ulcer recurrence at 6 months was statistically lower in the clarithromycin and omeprazole treated patients when compared to patients receiving omeprazole alone.

DETAILED PHARMACOLOGY

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Although the activity of the hydroxy metabolite is about half of the parent drug and its concentrations are lower, it may still contribute antibacterial activity.

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Figure 2: Plasma Clarithromycin Concentration (mg/mL) vs Time Following Oral Administration of a Single Dose of Clarithromyicn 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 5th dose of clarithromycin administered orally at 250 mg twice daily are listed in Table 35.

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The pharmacokinetics of clarithromycin and its 14-OH metabolite indicate that the steady-state concentration is achieved by the 5^th 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.

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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).

Clarithromycin and Omeprazole

A pharmacokinetic study was conducted with clarithromycin 500 mg three times daily and omeprazole 40 mg once daily. When clarithromycin was given alone at 500 mg every 8 hours, the mean steady-state C_max value was approximately 31% higher and the mean C_min value was approximately 119% higher than when clarithromycin is compared with a previous study at 500 mg every 12 hours. The mean AUC_0-24 for clarithromycin was 65% greater when 500 mg clarithromycin was given every 8 hours rather than every 12 hours. Neither T_max nor half-life values appeared substantially different between the every 8 hours and every 12 hours regimens.

When clarithromycin was administered with omeprazole, increases in omeprazole half-life and AUC_0-

₂₄ were observed. For all subjects combined, the mean omeprazole AUC_0-24 was 89% greater and the harmonic mean for omeprazole t½ was 34% greater when omeprazole was administered with clarithromycin than when omeprazole was administered alone. When clarithromycin was administered with omeprazole, the steady state C_max, C_min, and AUC_0-8 of clarithromycin were increased by 10%, 27%, and 15%, respectively over values achieved when clarithromycin was administered with placebo.

At steady-state, clarithromycin gastric mucus concentrations six hours post dosing were approximately 25-fold higher in the clarithromycin/omeprazole group compared with the clarithromycin alone group. Six hours post-dosing, mean clarithromycin gastric tissue concentrations were approximately 2-fold higher when clarithromycin was given with omeprazole than when clarithromycin was given with placebo.

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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 36.

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 as well as most MAC microorganisms. The in vitro activity of clarithromycin is presented in Table 37.

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. However, for MAC isolates, the 14-OH metabolite was 4 to 7 times less active than clarithromycin. The clinical significance of this activity against MAC is unknown.

Clarithromycin is bactericidal to H. pylori; this activity is greater at neutral pH than at acid pH.

The ranges of MICs of clarithromycin, 14-OH-clarithromycin metabolite and the MICs required to inhibit 50% (MIC₅₀) and 90% (MIC₉₀) of bacterial are presented in Tables 38 and 40. Beta-lactamase production should not have any effect on clarithromycin activity.

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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.

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

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Clarithromycin Kill Kinetics Against Helicobacter pylori

Figure 5 illustrates the kill kinetics of clarithromycin and 14-OH clarithromycin against H. pylori at 8 × MIC and at pH 8.0; and Figure 6 illustrates the kill kinetics of clarithromycin and amoxicillin against H. pylori at pH 6.5.

Figure 5: Kill kinetics of clarithromycin and 14-OH clarithromycin against H. pylori strain 2597 at

8 × MIC and at pH 8.0. A flask was inoculated to produce a starting inoculum of approximately 10⁶ cfu/mL. The flask was then incubated in an anaerobe jar with CampyPak® and shaken gently at 37 ⁰C. Counts were done at 0, 2, 4, 8, 24, and 48 h in physiological saline after 72 h incubation. ● , No antimicrobial; ○ , clarithromycin (0.12 mg/L); x, 14-OH clarithromycin (0.24 mg/L).

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Figure 6: Kill kinetics of clarithromycin and amoxicillin against H. pylori strain 2597 at pH 6.5. Counts were done at 0, 2, 4, 8, 24, and 48 h in physiological saline after 72 h incubation. ● , No antimicrobial; ○, clarithromycin (3 mg/L); ■ , amoxicillin (3 mg/L)

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 40.

The standard single disc susceptibility test (using the 15 mcg clarithromycin disc) for H. Influenzae should be interpreted according to the criteria in Table 41.

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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 procedure⁴⁴ 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 40.

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 (see Table 42).

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Clarithromycin activity against 80 MAC isolates from AIDS patients and 211 MAC isolates from non-AIDS patients was evaluated using a microdilution method with Middlebrook 7H9 broth. Results showed MIC values of ≤4.0 mcg/mL in 81% and 89% of the AIDS and non-AIDS MAC isolates, respectively. Twelve percent of the non-AIDS isolates had an MIC value ≤0.5 mcg/mL. Clarithromycin activity was evaluated against phagocytized MAC in mouse and human macrophage cell cultures as well as in the beige mouse infection model.

Clarithromycin activity was evaluated against Mycobacterium tuberculosis microorganisms. In one study utilizing the agar dilution method with Middlebrook 7H10 media, 3 of 30 clinical isolates had an MIC of 2.5 mcg/mL. Clarithromycin inhibited all isolates at >10.0 mcg/mL.

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Susceptibility Testing for Mycobacterium avium Complex

The disk diffusion and dilution techniques for susceptibility testing against gram-positive and gram-negative bacteria should not be used for determining clarithromycin MIC values against mycobacteria. In vitro susceptibility testing methods and diagnostic products currently available for determining MIC values against MAC organisms have not been standardized nor validated. Clarithromycin MIC values will vary depending on the susceptibility testing method employed, composition and pH of the media, and the utilization of nutritional supplements. Breakpoints to determine whether clinical isolates of M. avium or M. intracellulare are susceptible or resistant to clarithromycin have not been established.

In vitro Activity of Clarithromycin against Helicobacter pylori

Clarithromycin has demonstrated in vitro activity against H. pylori isolated from patients with duodenal ulcers. In vitro susceptibility testing methods (broth microdilution, agardilution, E-test , and disk diffusion) and diagnostic products currently available for determining MICs and zone sizes have not been standardized, validated, or approved for testing H. pylori. The clarithromycin MIC values and zone sizes will vary depending on the susceptibility testing methodology employed, media, growth additives, pH, inoculum concentration tested, growth phase, incubation atmosphere, and time.

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Susceptibility Test for Helicobacter pylori

In vitro susceptibility testing methods and diagnostic products currently available for determining MICs and zone sizes have not been standardized, validated, or approved for testing H. pylori microorganisms. MIC values for H. pylori isolates collected during two U. S. clinical trials evaluating clarithromycin plus omeprazole, were determined by broth microdilution MIC methodology (Hachem CY et al, 1996). Results obtained during the clarithromycin plus omeprazole clinical trials fell into a distinct bimodal distribution of susceptible and resistant clarithromycin MICs.

If the broth microdilution MIC methodology published in Hachem CY et al, 1996 is used and the following tentative breakpoints are employed, there should be reasonable correlation between MIC results and clinical and microbiological outcomes for patients treated with clarithromycin plus omeprazole (see Table 44).

These breakpoints should not be used to interpret results obtained using alternative methods.

TOXICOLOGY

Acute Toxicity

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 (see Table 45).

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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

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 two 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.

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Monkeys were treated daily for one month with oral doses of 0, 25, 100 or 400 mg/kg/day. Two animals out of ten 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

Rats (20/sex/group) were treated daily with oral doses of 0, 15, 37.5, 75 or 150 mg/kg/day for three months. There were eight 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 six-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.

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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/ sq m, which is 17 times less than the maximum proposed human oral daily dose of 618 mg/sq m.

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

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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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REFERENCES

1. 1) Barry AL, Thornsberry C, Jones RN. In vitro activity of a new macrolide, A-56268, compared with that of Roxithromycin, Erythromycin, and Clindamycin. Antimicrob Agents Chemother 1987;31:343-345.
2. 2) Bazzoli F, Zagari RM, Fossi S et al. Efficacy and tolerability of a short-term, low-dose triple therapy for eradication of Helicobacter pylori. Eur J Gastroenterol & Hepatol. 1994;6:773-777.
3. 3)

   Benson C, Segreti J, Kessler H, Hines D, Goodman L, Kaplan R, Trenholme.

   Comparative in vitro activity of A-56268, (TE-031) against gram-positive and gram-negative bacteria and Chlamydia trachomatis. Eur J Clin Microbiol 1987;173-178.

4. 4)

   Benson CA, Segreti J, Beaudette FE, Hines DW, Goodman LJ, Kaplan RL, Trenholme

   GM. In vitro activity of A-56268 (TE-031) a new macrolide compared with that of erythromycin and clindamycin against selected gram-positive and gram-negative organisms. Antimicrob Agents Chemother 1987;31:328-330.

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11. 58) Product Monograph Hp-PAC^® (lansoprazole delayed-release capsules - 30mg, clarithromycin tablets – 500 mg, amoxicillin capsules – 500 mg), Takeda Pharmaceuticals America, Inc, Date of preparation: Saptember 25, 2008.
12. 59) Product Monograph, Biaxin^® BID, (clarithromycin tablets, USP, film-coated) 250 mg and 500 mg, BIAXIN^® XL (clarithromycin extended-release tablets, Abbott Standard) 500 mg and BIAXIN^® (clarithromycin for oral suspension, USP) 125 mg/5 mL and 250 mg/5 mL, Abbott Laboratories Limited, Date of Revision: August 31, 2009.