FDA label 2cd59db1-e2b2-4d31-ad4c-5ee1813f045d

5 WARNINGS AND PRECAUTIONS Severe Acute Hypersensitivity Reactions : Discontinue clarithromycin if occurs (5.1) QT Prolongation : Avoid clarithromycin in patients with known QT prolongation or receiving drugs known to prolong the QT interval, ventricular arrhythmia ( torsades de pointes ), hypokalemia/hypomagnesemia, significant bradycardia, or taking Class IA or III antiarrhythmics (5.2) Hepatotoxicity : Discontinue if signs and symptoms of hepatitis occur (5.3) Serious adverse reactions can occur due to drug interactions of clarithromycin with colchicine, some lipid-lowering agents, some calcium channel blockers, and other drugs (5.4) Risk of all-cause mortality one year or more after the end of treatment in patients with coronary artery disease. Balance this potential risk with the treatment benefits when prescribing clarithromycin in these patients. (5.5) Clostridium difficile associated diarrhea (CDAD) : Evaluate if diarrhea occurs (5.6) Embryo-Fetal Toxicity : Based on animal findings, clarithromycin is not recommended for use in pregnant women except in clinical circumstances where no alternative therapy is appropriate (5.7) Exacerbation of myasthenia gravis has been reported in patients receiving clarithromycin therapy. (5.8) 5.1 Severe Acute Hypersensitivity Reactions In the event of severe acute hypersensitivity reactions, such as anaphylaxis, Stevens-Johnson Syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS), Henoch-Schonlein purpura, and acute generalized exanthematous pustulosis, discontinue clarithromycin therapy immediately and institute appropriate treatment. 5.2 QT Prolongation • Clarithromycin has been associated with prolongation of the QT interval and infrequent cases of arrhythmia. Cases of torsades de pointes have been spontaneously reported during postmarketing surveillance in patients receiving clarithromycin. Fatalities have been reported. Avoid clarithromycin in the following patients: Patients with known prolongation of the QT interval, ventricular cardiac arrhythmia, including torsades de pointes Patients receiving drugs known to prolong the QT interval [see also Contraindications (4.2)] Patients with ongoing proarrhythmic conditions such as uncorrected hypokalemia or hypomagnesemia, clinically significant bradycardia and in patients receiving Class IA (e.g., quinidine, procainamide, disopyramide) or Class III (e.g., dofetilide, amiodarone, sotalol) antiarrhythmic agents. Elderly patients may be more susceptible to drug-associated effects on the QT interval [see Use in Specific Populations (8.5)]. 5.3 Hepatotoxicity 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 outcome has been reported and generally has been associated with serious underlying diseases and/or concomitant medications. Symptoms of hepatitis can include anorexia, jaundice, dark urine, pruritus, or tender abdomen. Discontinue clarithromycin immediately if signs and symptoms of hepatitis occur. 5.4 Serious Adverse Reactions Due to Concomitant Use with Other Drugs Drugs metabolized by CYP3A4: Serious adverse reactions have been reported in patients taking clarithromycin concomitantly with CYP3A4 substrates. These include colchicine toxicity with colchicine; markedly increased transaminases with lomitapide; rhabdomyolysis with simvastatin, lovastatin, and atorvastatin; hypoglycemia and cardiac arrhythmias (e.g., torsades de pointes ) with disopyramide; and hypotension and acute kidney injury with calcium channel blockers metabolized by CYP3A4 (e.g., verapamil, amlodipine, diltiazem, nifedipine). Most reports of acute kidney injury with calcium channel blockers metabolized by CYP3A4 involved elderly patients 65 years of age or older. Use clarithromycin with caution when administered concurrently with medications that induce the cytochrome CYP3A4 enzyme. The use of clarithromycin with simvastatin, lovastatin, ergotamine, or dihydroergotamine is contraindicated [see Contraindications (4.5, 4.6) and Drug Interactions (7)]. Colchicine: Life-threatening and fatal drug interactions have been reported in patients treated with clarithromycin and colchicine. Clarithromycin is a strong CYP3A4 inhibitor and this interaction may occur while using both drugs at their recommended doses. If co-administration of clarithromycin and colchicine is necessary in patients with normal renal and hepatic function, reduce the dose of colchicine. Monitor patients for clinical symptoms of colchicine toxicity. Concomitant administration of clarithromycin and colchicine is contraindicated in patients with renal or hepatic impairment [see Contraindications (4.4) and Drug Interactions (7)]. Lomitapide: Concomitant use of Clarithromycin with lomitapide is contraindicated [see Contraindications (4.5)] . Lomitapide is metabolized by CYP3A4, and concomitant treatment with Clarithromycin increases the plasma concentration of lomitapide, which increases the risk of elevation in transaminases [see Drug Interactions (7)] . If treatment with Clarithromycin cannot be avoided, therapy with lomitapide must be suspended during the course of treatment. HMG-CoA Reductase Inhibitors (statin s ): Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated [see Contraindications (4.5)] as these statins are extensively metabolized by CYP3A4, and concomitant treatment with clarithromycin increases their plasma concentration, which increases the risk of myopathy, including rhabdomyolysis. Cases of rhabdomyolysis have been reported in patients taking clarithromycin concomitantly with these statins. If treatment with clarithromycin cannot be avoided, therapy with lovastatin or simvastatin must be suspended during the course of treatment. Exercise caution when prescribing clarithromycin with atorvastatin or pravastatin. In situations where the concomitant use of clarithromycin with atorvastatin or pravastatin cannot be avoided, atorvastatin dose should not exceed 20 mg daily and pravastatin dose should not exceed 40 mg daily. Use of a statin that is not dependent on CYP3A metabolism (e.g. fluvastatin) can be considered. It is recommended to prescribe the lowest registered dose if concomitant use cannot be avoided. Oral Hypoglycemic Agents/Insulin: The concomitant use of clarithromycin and oral hypoglycemic agents and/or insulin can result in significant hypoglycemia. With certain hypoglycemic drugs such as nateglinide, pioglitazone, repaglinide and rosiglitazone, inhibition of CYP3A enzyme by clarithromycin may be involved and could cause hypoglycemia when used concomitantly. Careful monitoring of glucose is recommended [see Drug Interactions (7)] . Quetiapine: Use quetiapine and clarithromycin concomitantly with caution. Co-administration could result in increased quetiapine exposure and quetiapine related toxicities such as somnolence, orthostatic hypotension, altered state of consciousness, neuroleptic malignant syndrome, and QT prolongation. Refer to quetiapine prescribing information for recommendations on dose reduction if co-administered with CYP3A4 inhibitors such as clarithromycin [see Drug Interactions (7)]. Oral Anticoagulants: There is a risk of serious hemorrhage and significant elevations in INR and prothrombin time when clarithromycin is co-administered with warfarin. Monitor INR and prothrombin times frequently while patients are receiving clarithromycin and oral anticoagulants concurrently [see Drug Interactions (7)]. Benzodiazepines: Increased sedation and prolongation of sedation have been reported with concomitant administration of clarithromycin and triazolobenzodiazepines, such as triazolam and midazolam [see Drug Interactions (7)]. 5.5 All-Cause Mortality in Patients With Coronary Artery Disease 1 to 10 Years After Clarithromycin Exposure In one clinical trial evaluating treatment with clarithromycin on outcomes in patients with coronary artery disease, an increase in risk of all-cause mortality one year or more after the end of treatment was observed in patients randomized to receive clarithromycin. 1 Clarithromycin for treatment of coronary artery disease is not an approved indication. The cause of the increased risk has not been established. Other epidemiologic studies evaluating this risk have shown variable results [see Adverse Reactions (6.1)] . Consider balancing this potential risk with the treatment benefits when prescribing Clarithromycin in patients who have suspected or confirmed coronary artery disease. 5.6 Clostridium difficile Associated Diarrhea Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including clarithromycin, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile . C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile , and surgical evaluation should be instituted as clinically indicated. 5.7 Embryo-Fetal Toxicity Based on findings from animal studies, Clarithromycin is not recommended for use in pregnant women except in clinical circumstances where no alternative therapy is appropriate. If clarithromycin is used during pregnancy, or if pregnancy occurs while the patient is taking this drug, the patient should be apprised of the potential hazard to the fetus. Clarithromycin demonstrated adverse effects on pregnancy outcome and/or embryo fetal development, including fetal malformations, in pregnant animals administered oral clarithromycin [ see Use in Specific Populations (8.1) ]. 5.8 Exacerbation of Myasthenia Gravis Exacerbation of symptoms of myasthenia gravis and new onset of symptoms of myasthenic syndrome has been reported in patients receiving clarithromycin therapy. 5.9 Development of Drug Resistant Bacteria Prescribing clarithromycin in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling: Acute Hypersensitivity Reactions [see Warnings and Precautions (5.1)] QT Prolongation [see Warnings and Precautions (5.2)] Hepatotoxicity [see Warnings and Precautions (5.3)] Serious Adverse Reactions Due to Concomitant Use with Other Drugs [see Warnings and Precautions (5.4)] Clostridium difficile Associated Diarrhea [see Warnings and Precautions (5.6)] Exacerbation of Myasthenia Gravis [see Warnings and Precautions (5.8)] Most frequent adverse reactions for both adult and pediatric populations in clinical trials: abdominal pain, diarrhea, nausea, vomiting, dysgeusia (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Strides Pharma Inc. at 1-877-244-9825 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Based on pooled data across all indications, the most frequent adverse reactions for both adult and pediatric populations observed in clinical trials are abdominal pain, diarrhea, nausea, vomiting and dysgeusia. Also reported were dyspepsia, liver function test abnormal, anaphylactic reaction, candidiasis, headache, insomnia, and rash. The subsequent subsections list the most common adverse reactions for prophylaxis and treatment of mycobacterial infections and duodenal ulcer associated with H. pylori infection. In general, these profiles are consistent with the pooled data described above. Prophylaxis of Mycobacterial Infections In AIDS patients treated with clarithromycin over long periods of time for prophylaxis against M. avium , it was often difficult to distinguish adverse reactions possibly associated with clarithromycin administration from underlying HIV disease or intercurrent illness. Median duration of treatment was 10.6 months for the clarithromycin group and 8.2 months for the placebo group. Table 4. Incidence Rates (%) of Selected Adverse Reactions a in Immunocompromised Adult Patients Receiving Prophylaxis Against M. avium Complex Body System b Adverse Reaction Clarithromycin (n=339) % Placebo (n=339) % Body as a Whole Abdominal pain 5% 4% Headache 3% 1% Digestive Diarrhea 8% 4% Dyspepsia 4% 3% Flatulence 2% 1% Nausea 11% 7% Vomiting 6% 3% Skin & Appendages Rash 3% 4% Special Senses Taste Perversion 8% c 0.3% a Includes those events possibly or probably related to study drug and excludes concurrent conditions. b 2% or greater Adverse Reaction Incidence Rates for either treatment group. c Significant higher incidence compared to the placebo-treated group. Discontinuation due to adverse reactions occurred in 18% of patients receiving clarithromycin compared to 17% of patients receiving placebo in this trial. Primary reasons for discontinuation in clarithromycin treated patients include headache, nausea, vomiting, depression, and taste perversion. Changes in Laboratory Values Selected laboratory adverse experiences that were reported during therapy in greater than 2 % of adult patients treated with clarithromycin in a randomized double-blind clinical trial involving 682 patients are presented in Table 5. In immunocompromised patients receiving prophylaxis against M. avium , evaluations of laboratory values were made by analyzing those values outside the seriously abnormal value (i.e., the extreme high or low limit) for the specified test. Table 5. Percentage of Patients a Exceeding Extreme Laboratory Values in Patients Receiving Prophylaxis Against M. avium Complex Clarithromycin 500 mg twice a day Placebo WBC Count <1 x 10 9 /L 2/103 (4%) 0/95 SGOT >5 x ULN b 7/196 (4%) 5/208 (2%) SGPT >5 x ULN b 6/217 (3%) 4/232 (2%) a Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within normal range or borderline low (chemistry variables). b ULN= Upper Limit of Normal Treatment of Mycobacterial Infections The adverse reaction profiles for both the 500 mg and 1000 mg twice a day dose regimens were similar. In AIDS patients and other immunocompromised patients treated with the higher doses of clarithromycin over long periods of time for mycobacterial infections, it was often difficult to distinguish adverse reactions possibly associated with clarithromycin administration from underlying signs of HIV disease or intercurrent illness. The following analysis summarizes experience during the first 12 weeks of therapy with clarithromycin. Data are reported separately for trial 1 (randomized, double-blind) and trial 2 (open-labeled, compassionate use) and also combined. Adverse reactions were reported less frequently in trial 2, which may be due in part to differences in monitoring between the two studies. In adult patients receiving clarithromycin 500 mg twice a day, the most frequently reported adverse reactions, considered possibly or possibly related to study drug, with an incidence of 5% or greater, are listed below (Table 6). Approximately 8% of the patients who received 500 mg twice a day and 12% of the patients who received 1000 mg twice a day discontinued therapy due to drug related adverse reactions during the first 12 weeks of therapy; adverse reactions leading to discontinuation in at least 2 patients included nausea, vomiting, abdominal pain, diarrhea, rash, and asthenia. Table 6. Selected Treatment-Related a Adverse Reaction Incidence Rates (%) in Immunocompromised Adult Patients During the First 12 Weeks of Therapy with 500 mg Twice a Day Clarithromycin Dose Adverse Reaction Trial 1 (n=53) Trial 2 (n=255) Combined (n=308) Abdominal Pain 8 2 3 Diarrhea 9 2 3 Flatulence 8 0 1 Headache 8 0 2 Nausea 28 9 12 Rash 9 2 3 Taste Perversion 19 0 4 Vomiting 25 4 8 a Includes those events possibly or probably related to study drug and excludes concurrent conditions A limited number of pediatric AIDS patients have been treated with clarithromycin suspension for mycobacterial infections. The most frequently reported adverse reactions excluding those due to the patient's concurrent conditions were consistent with those observed in adult patients. Changes in Laboratory Values In the first 12 weeks of starting on clarithromycin 500 mg twice a day, 3% of patients has SGOT increases and 2% of patients has SGPT increases > 5 times the upper limit of normal in trial 2 (469 enrolled adult patients) while trial 1 (154 enrolled patients) had no elevation of transaminases. This includes only patients with baseline values within the normal range or borderline low. Duodenal ulcer associated with H. pylori Infection In clinical trials using combination therapy with clarithromycin plus omeprazole and amoxicillin, no adverse reactions specific to the combination of these drugs have been observed. Adverse reactions that have occurred have been limited to those that have been previously reported with clarithromycin, omeprazole or amoxicillin. The adverse reaction profiles are shown below (Table 7) for four randomized double-blind clinical trials in which patients received the combination of clarithromycin 500 mg three times a day, and omeprazole 40 mg daily for 14 days, followed by omeprazole 20 mg once a day, (three studies) or 40 mg once a day (one study) for an additional 14 days. Of the 346 patients who received the combination, 3.5% of patients discontinued drug due to adverse reactions. Table 7. Adverse Reactions with an Incidence of 3% or Greater Adverse Reaction Clarithromycin + Omeprazole (n=346) % of Patients Omeprazole (n=355) % of Patients Clarithromycin (n=166) % of Patients a Taste Perversion 15 1 16 Nausea 5 1 3 Headache 5 6 9 Diarrhea 4 3 7 Vomiting 4 <1 1 Abdominal Pain 3 2 1 Infection 3 4 2 a Only two of four studies. Changes in Laboratory Values Changes in laboratory values with possible clinical significance in patients taking clarithromycin and omeprazole in four randomized double-blind trials in 945 patients are as follows: Hepatic: elevated direct bilirubin <1%; GGT <1%; SGOT (AST) <1%; SGPT (ALT) <1%, Renal: elevated serum creatinine <1%. Less Frequent Adverse Reactions Observed During Clinical Trials of Clarithromycin Based on pooled data across all indications, the following adverse reactions were observed in clinical trials with clarithromycin at a rate less than 1%: Blood and Lymphatic System Disorders: Leukopenia, neutropenia, thrombocythemia, eosinophilia Cardiac Disorders : Electrocardiogram QT prolonged, cardiac arrest, atrial fibrillation, extrasystoles, palpitations Ear and Labyrinth Disorders: Vertigo, tinnitus, hearing impaired Gastrointestinal Disorders: Stomatitis, glossitis, esophagitis, gastrooesophageal reflux disease, gastritis, proctalgia, abdominal distension, constipation, dry mouth, eructation, flatulence General Disorders and Administration Site Conditions: Malaise, pyrexia, asthenia, chest pain, chills, fatigue Hepatobiliary Disorders: Cholestasis, hepatitis Immune System Disorders: Hypersensitivity Infections and Infestations: Cellulitis, gastroenteritis, infection, vaginal infection Investigations: Blood bilirubin increased, blood alkaline phosphatase increased, blood lactate dehydrogenase increased, albumin globulin ratio abnormal Metabolism and Nutrition Disorders: Anorexia, decreased appetite Musculoskeletal and Connective Tissue Disorders: Myalgia, muscle spasms, nuchal rigidity Nervous System Disorders: Dizziness, tremor, loss of consciousness, dyskinesia, somnolence Psychiatric Disorders: Anxiety, nervousness Renal and Urinary Disorders: Blood creatinine increased, blood urea increased Respiratory, Thoracic and Mediastinal Disorders: Asthma, epistaxis, pulmonary embolism Skin and Subcutaneous Tissue Disorders: Urticaria, dermatitis bullous, pruritus, hyperhidrosis, rash maculo-papular Gastrointestinal Adverse Reactions In the acute exacerbation of chronic bronchitis and acute maxillary sinusitis studies overall gastrointestinal adverse reactions were reported by a similar proportion of patients taking either clarithromycin tablets or clarithromycin extended-release tablets; however, patients taking clarithromycin extended-release tablets reported significantly less severe gastrointestinal symptoms compared to patients taking clarithromycin tablets. In addition, patients taking clarithromycin extended-release tablets had significantly fewer premature discontinuations for drug-related gastrointestinal or abnormal taste adverse reactions compared to clarithromycin tablets. All-Cause Mortality in Patients with Coronary Artery Disease 1 to 10 Years Following Clarithromycin Exposure In one clinical trial evaluating treatment with clarithromycin on outcomes in patients with coronary artery disease, an increase in risk of all-cause mortality was observed in patients randomized to clarithromycin. Clarithromycin for treatment of coronary artery disease is not an approved indication. Patients were treated with clarithromycin or placebo for 14 days and observed for primary outcome events (e.g., all-cause mortality or non-fatal cardiac events) for several years. 1 A numerically higher number of primary outcome events in patients randomized to receive clarithromycin was observed with a hazard ratio of 1.06 (95% confidence interval 0.98 to 1.14). However, at follow-up 10 years post-treatment, there were 866 (40%) deaths in the clarithromycin group and 815 (37%) deaths in the placebo group that represented a hazard ratio for all-cause mortality of 1.10 (95% confidence interval 1.00 to 1.21). The difference in the number of deaths emerged after one year or more after the end of treatment. The cause of the difference in all-cause mortality has not been established. Other epidemiologic studies evaluating this risk have shown variable results [see Warnings and Precautions (5.5)]. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of clarithromycin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System : Thrombocytopenia, agranulocytosis Cardiac : Ventricular arrhythmia, ventricular tachycardia, torsades de pointes Ear and Labyrinth : Deafness was reported chiefly in elderly women and was usually reversible. Gastrointestina l: Pancreatitis acute, tongue discoloration, tooth discoloration was reported and was usually reversible with professional cleaning upon discontinuation of the drug. There have been reports of clarithromycin extended-release tablets in the stool, many of which have occurred in patients with anatomic (including ileostomy or colostomy) or functional gastrointestinal disorders with shortened GI transit times. In several reports, tablet residues have occurred in the context of diarrhea. It is recommended that patients who experience tablet residue in the stool and no improvement in their condition should be switched to a different clarithromycin formulation (e.g. suspension) or another antibacterial drug. Hepatobiliary : Hepatic failure, jaundice hepatocellular. Adverse reactions related to hepatic dysfunction have been reported with clarithromycin [see Warnings and Precautions (5.2)]. Infections and Infestations : Pseudomembranous colitis [see Warnings and Precautions (5.6)] Immune System : Anaphylactic reactions, angioedema Investigations : Prothrombin time prolonged, white blood cell count decreased, international normalized ratio increased. Abnormal urine color has been reported, associated with hepatic failure. Metabolism and Nutrition : Hypoglycemia has been reported in patients taking oral hypoglycemic agents or insulin. Musculoskeletal and Connective Tissue : Myopathy rhabdomyolysis was reported and in some of the reports, clarithromycin was administered concomitantly with statins, fibrates, colchicine or allopurinol [see Contraindications (4.5) and Warnings and Precautions (5.4)]. Nervous System : Parosmia, anosmia, ageusia, paresthesia and convulsions Psychiatric : Abnormal behavior, confusional state, depersonalization, disorientation, hallucination, depression, manic behavior, abnormal dream, psychotic disorder. These disorders usually resolve upon discontinuation of the drug. Renal and Urinary : Nephritis interstitial, renal failure Skin and Subcutaneous Tissue : Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS), Henoch-Schonlein purpura, acne, acute generalized exanthematous pustulosis Vascular : Hemorrhage

<table ID="ID102" width="45%" styleCode="Noautorules"><caption> Table 4. Incidence Rates (%) of Selected Adverse Reactions^a in Immunocompromised Adult Patients Receiving Prophylaxis Against M. avium Complex </caption><col width="43%"/><col width="31%"/><col width="25%"/><tbody><tr><td valign="top" styleCode="Lrule Toprule Botrule Rrule" align="left"><content styleCode="bold"> Body System^b</content> <content styleCode="bold"> Adverse Reaction</content> </td><td valign="top" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Clarithromycin (n=339) %</content> </td><td valign="top" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Placebo (n=339) %</content> </td></tr><tr><td colspan="3" valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Body as a Whole</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Abdominal pain </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 5% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 4% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Headache </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1% </td></tr><tr><td colspan="3" valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Digestive</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Diarrhea </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 8% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 4% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Dyspepsia </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 4% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Flatulence </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Nausea </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 11% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 7% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Vomiting </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 6% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3% </td></tr><tr><td colspan="3" valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Skin &amp; Appendages</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Rash </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 4% </td></tr><tr><td colspan="3" valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Special Senses</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Taste Perversion </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 8%^c </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0.3% </td></tr><tr><td colspan="3" valign="top" styleCode="Lrule Botrule Rrule" align="left">^a Includes those events possibly or probably related to study drug and excludes concurrent conditions. ^b 2% or greater Adverse Reaction Incidence Rates for either treatment group. ^c Significant higher incidence compared to the placebo-treated group. </td></tr></tbody></table>

<table ID="ID104" width="100%" styleCode="Noautorules"><caption> Table 5. Percentage of Patients^a Exceeding Extreme Laboratory Values in Patients Receiving Prophylaxis Against M. avium Complex </caption><col width="25%"/><col width="25%"/><col width="25%"/><col width="25%"/><tbody><tr><td valign="top" styleCode="Lrule Toprule Botrule Rrule"/><td valign="top" styleCode=" Toprule Botrule Rrule"/><td valign="top" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Clarithromycin 500 mg </content> <content styleCode="bold"> twice a day</content> </td><td styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Placebo</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="center"> WBC Count </td><td valign="top" styleCode=" Botrule Rrule" align="center"> &lt;1 x 10⁹/L </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2/103 (4%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0/95 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="center"> SGOT </td><td valign="top" styleCode=" Botrule Rrule" align="center"> &gt;5 x ULN^b </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 7/196 (4%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 5/208 (2%) </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="center"> SGPT </td><td valign="top" styleCode=" Botrule Rrule" align="center"> &gt;5 x ULN^b </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 6/217 (3%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 4/232 (2%) </td></tr><tr><td colspan="4" valign="top" styleCode="Lrule Botrule Rrule" align="left">^a Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within normal range or borderline low (chemistry variables). ^b ULN= Upper Limit of Normal </td></tr></tbody></table>

<table ID="ID106" width="100%" styleCode="Noautorules"><caption> Table 6. Selected Treatment-Related^aAdverse Reaction Incidence Rates (%) in Immunocompromised Adult Patients During the First 12 Weeks of Therapy with 500 mg Twice a Day Clarithromycin Dose </caption><col width="25%"/><col width="25%"/><col width="25%"/><col width="25%"/><tbody><tr><td styleCode="Lrule Toprule Botrule Rrule" align="center"><content styleCode="bold"> Adverse Reaction</content> </td><td valign="top" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Trial 1 (n=53)</content> </td><td valign="top" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Trial 2 (n=255)</content> </td><td valign="top" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Combined (n=308)</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="center"> Abdominal Pain </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 8 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="center"> Diarrhea </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 9 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="center"> Flatulence </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 8 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="center"> Headache </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 8 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="center"> Nausea </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 28 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 9 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 12 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="center"> Rash </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 9 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="center"> Taste Perversion </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 19 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 4 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="center"> Vomiting </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 25 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 4 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 8 </td></tr><tr><td colspan="4" valign="top" styleCode="Lrule Botrule Rrule" align="left">^a Includes those events possibly or probably related to study drug and excludes concurrent conditions </td></tr></tbody></table>