Teva-Clarithromycin Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

TEVA-CLARITHROMYCIN (clarithromycin tablets, 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). See WARNINGS AND PRECAUTIONS, Susceptibility/Resistance.

Uncomplicated Skin and Skin Structure Infections

Uncomplicated Skin and Skin Structure Infections caused by Streptococcus pyogenes (S. pyogenes), Staphylococcus aureus (S. aureus). See WARNINGS AND PRECAUTIONS, Susceptibility/Resistance.

Mycobacterial Infections

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

Eradication of Helicobacter pylori

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

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

To reduce the development of drug-resistant bacteria and maintain the effectiveness of TEVA-CLARITHROMYCIN and other antibacterial drugs, TEVA-CLARITHROMYCIN 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):

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. See WARNINGS AND PRECAUTIONS, Special Populations, Geriatrics.

CONTRAINDICATIONS

TEVA-CLARITHROMYCIN (clarithromycin tablets, film-coated) 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, 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 9.

• 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 9.
• concomitant therapy with ergot alkaloids (e.g., ergotamine or dihydroergotamine) as this may result in ergot toxicity. See DRUG INTERACTIONS, Drug-Drug Interactions, Table 9.

• concomitant administration with oral midazolam. See DRUG INTERACTIONS, Drug-

  Drug Interactions, Table 9.

• 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 9.

• concomitant therapy with ticagrelor or ranolazine*.

  * Not marketed in Canada.

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, Pregnant Women.
• The concomitant administration of clarithromycin and drugs metabolized by CYP3A and/or transported by P-gp may result in significant safety concerns. See WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS, Overview.

General

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

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

Patients Infected with Human Immunodeficiency Virus

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

Myasthenia Gravis

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

Use of Clarithromycin with Other Drugs

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

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 sulphonylurias) and/or insulin can result in significant hypoglycaemia. Careful monitoring of glucose is recommended. See DRUG INTERACTIONS, Drug-Drug Interactions, Table 9.

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 9.

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 9.

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 9.

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 9.

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 9.

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

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, pimozide, terfenadine and saquinavir is also contraindicated. See CONTRAINDICATIONS.

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.

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.

Susceptibility/Resistance

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

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

Antibiotic Resistance in Relation to Helicobacter pylori Eradication

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

Triple Therapy with Omeprazole

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

Special Populations

Pregnant Women

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

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

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

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

Nursing Women

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

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

Pediatrics (6 months to 12 years of age)

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

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

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

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

Geriatrics (> 65 years of age)

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

ADVERSE REACTIONS

Adverse Drug Reaction Overview

The majority of side effects observed in clinical trials involving 3563 patients treated with clarithromycin film-coated tablets 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 film-coated tablets were nausea, diarrhea, abdominal pain, dyspepsia, headache, dysgeusia (taste perversion) and vomiting.

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.

Patients with Respiratory Tract or Skin Infections

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

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

Abnormal Laboratory Values

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

Patients with Mycobacterial Infections

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

Prophylaxis

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

Abnormal Laboratory Values

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

Treatment of Patients with Mycobacterial Infections

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

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

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

Abnormal Laboratory Values

In immunocompromised patients treated with clarithromycin for mycobacterial infections, evaluations of laboratory values were made by analysing those values outside the seriously abnormal level (i.e., the extreme high or low limit) for the specified test (Table 6).

Patients with Helicobacter pylori Infection

Triple Therapy: (clarithromycin/omeprazole/amoxicillin)

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

Less Common Clinical Trial Adverse Drug Reactions (<1%) for Clarithromycin Film-Coated Tablets

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

Blood and Lymphatic

System Disorders:

eosinophilia and neutropenia

Gastrointestinal Disorders: abdominal distension

General Disorders and

Administration Site

Conditions:

chest pain, chills, fatigue, influenza and malaise

Hepatobiliary Disorders:

Investigations:

cholestasis, gamma-glutamyltransferase increased and hepatitis

blood alkaline phosphatase increased and blood lactate dehydrogenase increased

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.

Colchicine

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

DRUG INTERACTIONS

Serious Drug Interactions

• Concomitant administration of clarithromycin with astemizole, cisapride, colchicine, pimozide, terfenadine, lovastatin, simvastatin, ergot alkaloids (e.g., ergotamine, dihydroergotamine) is contraindicated. See

  CONTRAINDICATIONS and DRUG INTERACTIONS, Drug-Drug Interactions.

• Clarithromycin is an inhibitor of the cytochrome P450 3A isoform subfamily

  (CYP3A) and the P-glycoprotein transporter (P-gp). The concomitant administration of clarithromycin and drugs metabolized by CYP3A and/or transported by P-gp may lead to an increase in the plasma concentrations of the co-administered drug which could result in clinically significant safety concerns.

Overview

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

Effects of Clarithromycin on Other Drugs

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

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

With certain drugs, co-administration of clarithromycin is contraindicated or should be avoided (Table 9).

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 9. 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.

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

TEVA-CLARITHROMYCIN may be given with or without meals.

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 may be given with or without meals.

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 or Skin Infections

The adult dosage of TEVA-CLARITHROMYCIN is 250 mg to 500 mg every 12 hours (Table

1. 10) for 7 to 14 days. For infections caused by less susceptible organisms, the upper dosage should be used.

In the treatment of Group A streptococcus infections, therapy should be continued for 10 days. The usual drug of choice in the treatment of streptococcal infections and the prophylaxis of rheumatic fever is penicillin administered by either the intramuscular or the oral route. Clarithromycin is generally effective in the eradication of S. pyogenes from the nasopharynx; however, data establishing the efficacy of clarithromycin in the subsequent prevention of rheumatic fever are not presently available.

Renal Impairment

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

Hepatic Impairment

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

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

Eradication of Helicobacter Pylori

Triple Therapy: clarithromycin /omeprazole/amoxicillin

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

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

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

Adults with Mycobacterial Infections

Prophylaxis

The recommended dose of TEVA-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

TEVA-CLARITHROMYCIN (clarithromycin tablets, film-coated) may be taken with or without food.

OVERDOSAGE

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

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

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

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

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

General

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

Pharmacodynamics

Eradication of Helicobacter pylori

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

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

Pharmacokinetics

A summary of clarithromycin pharmacokinetic parameters following the administration of clarithromycin film-coated tablets is provided in Table 11. See DETAILED PHARMACOLOGY, Pharmacokinetics.

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, TEVA-CLARITHROMYCIN may be given without regard to meals.

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

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

Adult Patients with HIV

Steady-state concentrations of clarithromycin and 14-OH-clarithromycin observed following administration of 500 mg doses of clarithromycin twice a day to adult patients with HIV infection were similar to those observed in healthy volunteers. However, at the higher clarithromycin doses which may be required to treat mycobacterial infections, clarithromycin concentrations can be much higher than those observed at 500 mg clarithromycin doses. In adult HIV-infected patients taking 2000 mg/day in two divided doses, steady-state clarithromycin 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 12.

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

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 film-coated tablets between 15° and 30°C in a tightly closed container. Protect from light.

DOSAGE FORMS, COMPOSITION AND PACKAGING

TEVA-CLARITHROMYCIN film-coated tablets contains 250 mg or 500 mg clarithromycin and are supplied as follows:

• 250 mg: Yellow, film coated oval shaped tablet, debossed with “93”

  on one side and “7157” on the other. They are supplied in HDPE bottles of 60 and 100 tablets.

• 500 mg: Light yellow, film coated oval shaped tablet, debossed with “93” on one side and “7158” on the other. They are supplied in HDPE bottles of 60 and 100 tablets.

Non-Medicinal Ingredients: Each TEVA-CLARITHROMYCIN tablet also contains the following non-medicinal ingredients: colloidal anhydrous silica, croscarmellose sodium, hypromellose, magnesium hydroxide, magnesium stearate, microcrystalline cellulose, povidone, polyethylene glycol, sodium starch glycolate, stearic acid, titanium dioxide, FD&C blue #2/indigo carmine aluminum lake, yellow iron oxide and artificial vanilla flavor.

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 g/mol

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. pKa: 8.48; pH of a 0.2% (Methanol:Water, 5:95) slurry: 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. Melting point: approximately 225°C.

CLINICAL TRIALS

Comparative Bioavailability Studies

Study #2010-2302: A comparative, single-dose, randomized, two-period, two-treatment, two-sequence, replicate crossover bioavailability study was performed on two Clarithromycin tablet products, TEVA-CLARITHROMYCIN 500 mg tablets and Biaxin BID^® 500 mg (clarithromycin tablets, USP, film-coated) (Abbott Laboratories Limited, Canada), in 26 healthy subjects under fasting conditions.

2010-2302 SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

^* Clarithromycin 500 mg Tablets (Teva Pharmaceutical Industries Ltd.) ^† Biaxin BID^® 500 mg (clarithromycin tablets, USP, film-coated) (Abbott Laboratories Limited, Canada) ^# Expressed as the median (range) only

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

Mycobacterial Infections

Prophylaxis

More patients in the placebo arm than the clarithromycin arm discontinued prematurely from the study (75.6% and 67.4%, respectively). However, if premature discontinuations due to Mycobacterium avium complex (MAC) or death are excluded, approximately equal percentages of patients on each arm (54.8% on clarithromycin and 52.5% on placebo) discontinued study drug early for other reasons.

On an intent-to-treat basis, the 1-year cumulative incidence of MAC bacteremia was 5.0% for patients randomized to clarithromycin and 19.4% for patients randomized to placebo (Table 15). 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.

Figure 1: Survival of All Randomized Immunocompromized Adult Patients Receiving

Clarithromycin in Prophylaxis Against M. avium Complex or Placebo

Since the analysis at 18 months includes patients no longer receiving prophylaxis the survival benefit of clarithromycin may be underestimated.

Treatment of Mycobacterial Infections

Three studies summarized in Table 16 were designed to evaluate the following end points:

• Change in MAC bacteremia or blood cultures negative for M. avium.
• Change in clinical signs and symptoms of MAC infection including one or more of the following: fever, night sweats, weight loss, diarrhea, splenomegaly, and hepatomegaly.

521 Pediatric Study

3.75 mg/kg b.i.d.

7.5 mg/kg b.i.d.

15 mg/kg b.i.d.

CDC-defined AIDS and

CD4 counts < 100 cells/μL

(n=25)

1-20 mo * compassionate use.

Legend: b.i.d. = twice daily

The results of the Study 500 are described below. The Study 577 results were similar to the results of the Study 500.

MAC Bacteremia

Decreases in MAC bacteremia or negative blood cultures were seen in the majority of patients in all dose groups. Mean reductions in colony forming units (CFU) are shown below. Included in the table are results from a separate study with a 4-drug regimen (ciprofloxacin, ethambutol, rifampicin, and clofazimine). Since patient populations and study procedures may vary between these 2 studies, comparisons between the clarithromycin results and the combination therapy results should be interpreted cautiously (Table 17).

Although the 1000 mg and 2000 mg twice daily doses showed significantly better control of bacteremia during the first 4 weeks during therapy, no significant differences were seen beyond that point. The percent of patients whose blood was sterilized as shown by 1 or more negative cultures at any time during acute therapy was 61% (30/49) for the 500 mg twice daily group and 59% (29/49) and 52% (25/28) for the 1000 and 2000 mg twice daily groups, respectively. The percent of patients who had 2 or more negative cultures during acute therapy that were sustained through study Day 84 was 25% (12/49) in both the 500 and 1000 mg twice daily groups and 8% (4/48) for the 2000 mg twice daily group. By Day 84, 23% (11/49), 37% (18/49), and 56% (27/48) of patients had died or discontinued from the study, and 14% (7/49), 12% (6/49), and 13% (6/48) of patients had relapsed in the 500, 1000, and 2000 mg twice daily dose groups, respectively. All of the isolates had a minimum inhibitory concentration (MIC) < 8 mcg/mL at pretreatment. Relapse was almost always accompanied by an increase in MIC. The median time to first negative culture was 54, 41, and 29 days for the 500, 1000, and 2000 mg twice daily groups, respectively.

Clinically Significant Disseminated MAC Disease

Among patients experiencing night sweats prior to therapy, 84% showed resolution or improvement at some point during the 12 weeks of clarithromycin at 500 to 2000 mg twice daily doses. Similarly, 77% of patients reported resolution or improvement in fevers at some point. Response rates for clinical signs of MAC are given in Table 18.

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 2 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 4 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, omeprazole 20 mg daily and amoxicillin 1000 mg twice 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.

A summary of the Trial Design is presented in Table 19.

The ulcer healing rates and corresponding 95% confidence intervals are presented in Table 20.

ulcer pretreatment, but included as failures patients who did not return for a particular visit or did not have a particular procedure performed (e.g., endoscopy).

The H. pylori eradication rates and corresponding 95% confidence intervals are summarized in Table 21.

For all patient subsets, triple therapy with clarithromycin, omeprazole, and amoxicillin achieved a statistically higher eradication rate than dual therapy (p < 0.001). These differences were also observed when the eradication rates were adjusted for potentially influential factors such as ulcer characteristics, age, and smoking. In addition, the eradication rates within each treatment group were similar for smokers and non-smokers.

International, Randomized, Double-Blind, Placebo-Controlled Study

In an international, randomized, double-blind, placebo-controlled study involving more than 100 patients in each of 6 treatment groups, patients with proven duodenal ulcer disease were randomized to treatment twice daily for 1 week with omeprazole, 20 mg (O), plus either placebo (P) or combinations of 2 of the following antimicrobials: amoxicillin, 1g (A), clarithromycin, 250 mg or 500 mg (C250, C500), or metronidazole, 400 mg (M). H. pylori eradication rates for the “all-patients-treated” analysis were 96% (OAC500), 95% (OMC250), 90% (OMC500), 84% (OAC250), 79% (OAM), and 1% (OP).

Independent, Open and Non-Randomized Study

In an independent, open, and non-randomized study, H. pylori infected patients received eradication therapy with clarithromycin 500 mg twice daily in conjunction with amoxicillin 1000 mg twice daily and omeprazole 20 mg once daily (Group A) or omeprazole 20 mg twice daily (Group B) for 7 days. In those patients not previously treated with anti-H. pylori therapy, H. pylori was eradicated in 86% (95% CI=69-95) of patients in Group A and 75% (95% CI=62-85) of patients in Group B, the difference was not statistically significant.

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

DETAILED PHARMACOLOGY

General

Helicobacter pylori

The presence of H. pylori may damage the mucosal integrity and defenses so that exposure to acid/pepsin, even in normal concentrations, produces ulceration.

H. pylori displays potent urease activity which may produce an alkaline environment around the organism. Excess ammonia produced by urea hydrolysis is toxic to mucosal cells and may lead to parietal cell failure and/or to a disturbance of the normal negative feedback of acid to the antral G-cells which secrete gastrin. In addition, H. pylori produces catalases, lipases, phospholipases, proteases, adhesins and toxins. These enzymes may further degrade the mucous layer and damage the epithelial cell membrane. Also, the presence of H. pylori stimulates an active inflammatory response which contributes to mucosal damage.

Gustavson et al. (1995) showed that concentrations of 39.3, 23.1 and 25.2 mcg/g clarithromycin were achieved in the gastric mucosa 2, 4, and 6 hours respectively after administering 500 mg clarithromycin three times daily and that corresponding concentrations of the 14-OH metabolite were 3.2, 1.1, and 4.1 mcg/g respectively. Similar results were obtained whether or not clarithromycin was given alone or together with 40 mg omeprazole once daily (Logan et al., 1995). Although the activity of the 14-OH metabolite is about half of the parent drug and its concentrations are lower, it may still contribute antibacterial activity.

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.

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 22, and Figures 2 and 3).

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 23.

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.

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-hour and every-12-hour 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 6 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.

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 24.

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 25.

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 bacteria are presented in Tables 26 and 27. 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 25-27 below):

Table 25 In Vitro Susceptibility® of Strains of Gram-Positive and Gram-Negative Bacteria to Clarithromycin

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

Table 26

In vitro Susceptibility of Different Bacteria to Clarithromycin

Microorganisms Number

of strains

MIC (mg/L)

Range 50% 90%

Mycoplasma pneumoniae 30 ≤0.004-0.125 ≤0.004 ≤0.031 Bordetella pertussis 18 ≤0.008-0.06 ≤0.008 0.03 Legionella pneumophila 14 0.12-0.25 0.12 0.25 Haemophilus influenzae 22 2-8 4 8 Moraxella catarrhalis 17 0.03-0.25 0.06 0.25 Chlamydia trachomatis 11 0.002-0.008 0.004 0.008 Neisseria gonorrhoea 26 0.0625-4 0.125 0.5 Mycobacterium avium 30 4-32 8 16 Mycobacterium avium- 124 < 0.25-4 1 2 intracellulare Mycobacterium chelonae 137 -- -- 0.25 Mycobacterium fortuitum 86 -- 2.0 >8.0 Mycobacterium kansassi 24 ≤0.125-0.25 ≤0.125 0.25 Pasteurella multocida 10 1.0-4 1.0 2.0 Bacteriodes melaninogenicus 12 ≤0.125-0.2 ≤0.125 ≤0.125 Clostridium perfringens 10 0.25-0.5 0.5 0.5 Staphylococcus aureus 20 0.06-0.25 0.17 0.24 (methicillin sensitive) Streptococcus pyogenes 10 ≤0.06 ≤0.06 ≤0.06 Chlamydia pneumoniae 49 0.004-0.025 0.016 0.031 Helicobacter pylori † 13 0.03-0.06 0.03 0.03

† 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.

Table 27

In vitro Susceptibility of Different Bacteria to 14-OH-Clarithromycin

Microorganisms Number

of strains

MIC (mg/L)

Range 50% 90%

Streptococcus pyogenes 15 0.015-0.03 0.015 0.03 Streptococcus pneumoniae 13 ≤0.004-0.015 0.008 0.015 Streptococcus agalactiae 15 0.03-0.06 0.06 0.06 Listeria monocytogenes 14 0.25-0.5 0.5 0.5 Moraxella catarrhalis 17 0.03-0.12 0.06 0.12 Neisseria gonorrhoeae 15 0.06-1 0.25 0.5 Campylobacter jejuni 12 0.25-2 0.5 2 Legionella pneumophila 14 0.12-0.5 0.25 0.5 Haemophilus influenzae 22 1-4 2 4 Bordetella pertussis 18 ≤0.008-0.06 0.015 0.06 Bacteroides fragilis 10 0.5->128 1 1 Clostridium perfringens 10 0.5-0.5 0.5 0.5 Propionibacterium acnes 12 0.03->128 0.03 0.06

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).

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 28.

The standard single disc susceptibility test (using the 15 mcg clarithromycin disc) for H. Influenzae should be interpreted according to the criteria in Table 29.

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 28.

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 30).

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 31).

In vitro Activity of Clarithromycin against Mycobacteria

Clarithromycin has demonstrated in vitro activity against MAC microorganisms isolated from both AIDS and non-AIDS patients. While gene probe techniques may be used to distinguish M. avium species from M. intracellulare, many studies only reported results on MAC isolates. Various in vitro methodologies employing broth or solid media at different pH's, with and without oleic acid-albumin-dextrose-catalase (OADC), have been used to determine clarithromycin MIC values for mycobacterial species. In general, MIC values decrease more than 16-fold as the pH of Middlebrook 7H12 broth increases from 5.0 to 7.4. At pH 7.4, MIC values determined with Mueller-Hinton agar were 4- to 8-fold higher than those observed with Middlebrook 7H12 media. Utilization of OADC in these assays has been shown to further alter MIC values.

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 1 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.

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, agar dilution, 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.

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 2 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 (Table 32).

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 (Table 33).

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 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

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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