Rifapentine

5 WARNINGS AND PRECAUTIONS •Hepatotoxicity: Monitor for symptoms of liver injury and discontinue rifapentine tablets if signs or symptoms or liver injury occur. ( 5.1 ) •Hypersensitivity: Discontinue rifapentine tablets if signs or symptoms of hypersensitivity reaction occur. ( 5.2 ) •Severe cutaneous adverse reactions: Discontinue rifapentine tablets at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity. ( 5.3 ) •Relapse in the treatment of active pulmonary tuberculosis: Do not use as a once-weekly continuation phase regimen with isoniazid in HIV-infected patients. Monitor for signs or symptoms of relapse in patients with cavitary lesions or bilateral disease. ( 5.4 , 14.1 ) • Paradoxical Drug Reactions: If worsening of symptoms or signs occur during antimycobacterial treatment, consider paradoxical drug reaction in the differential diagnosis, and monitor or treat accordingly. ( 5.5 ) •Drug Interactions: May interact with drugs metabolized by CYP450. ( 5.6 , 7.1 , 7.4 ) •Discoloration of body fluids: May permanently stain contact lenses or dentures red-orange. ( 5.7 ) • Clostridioides difficile– associated diarrhea: Evaluate if diarrhea occurs. ( 5.8 ) •Porphyria: Avoid use in patients with porphyria. ( 5.9 ) 5.1 Hepatotoxicity Elevations of liver transaminases may occur in patients receiving rifapentine tablets [see Adverse Reactions ( 6.1 )]. Patients on rifapentine tablets should be monitored for symptoms of liver injury. Patients with abnormal liver tests and/or liver disease or patients initiating treatment for active pulmonary tuberculosis should only be given rifapentine tablets in cases of necessity and under strict medical supervision. In such patients, obtain serum transaminase levels prior to therapy and every 2 to 4 weeks while on therapy. Discontinue rifapentine tablets if evidence of liver injury occurs. 5.2 Hypersensitivity and Related Reactions Hypersensitivity reactions may occur in patients receiving rifapentine tablets. Signs and symptoms of these reactions may include hypotension, urticaria, angioedema, acute bronchospasm, conjunctivitis, thrombocytopenia, neutropenia or flu-like syndrome (weakness, fatigue, muscle pain, nausea, vomiting, headache, fever, chills, aches, rash, itching, sweats, dizziness, shortness of breath, chest pain, cough, syncope, palpitations). There have been reports of anaphylaxis [see Patient Counseling Information ( 17 )]. Monitor patients receiving rifapentine tablets therapy for signs and/or symptoms of hypersensitivity reactions. If these symptoms occur, administer supportive measures and discontinue rifapentine tablets. 5.3 Severe Cutaneous Adverse Reactions Severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome (SJS) and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome have been reported in association with the use of rifapentine tablets treatment regimens in patients with active and latent tuberculosis. Discontinue rifapentine tablets at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity [see Patient Counseling Information ( 17 )]. 5.4 Relapse in the Treatment of Active Pulmonary Tuberculosis Rifapentine tablets have not been evaluated as part of the initial phase treatment regimen in HIV-infected patients with active pulmonary TB. Do not use rifapentine tablets as a once-weekly continuation phase regimen in HIV-infected patients with active pulmonary tuberculosis because of a higher rate of failure and/or relapse with rifampin-resistant organisms [see Clinical Studies ( 14.1 )]. Higher relapse rates may occur in patients with cavitary pulmonary lesions and/or positive sputum cultures after the initial phase of active tuberculosis treatment and in patients with evidence of bilateral pulmonary disease. Monitor for signs and symptoms of TB relapse in these patients [see Clinical Studies ( 14.1 )]. Poor adherence to therapy is associated with high relapse rate. Emphasize the importance of compliance with therapy [see Patient Counseling Information ( 17 )]. 5.5 Paradoxical Drug Reactions Paradoxical drug reactions are characterized by the recurrence or appearance of new symptoms or physical and radiological signs in a patient who had previously shown improvement with appropriate antimycobacterial treatment, in the absence of disease relapse, poor treatment compliance, drug resistance, side effects of treatment, or secondary infection/diagnosis. Paradoxical drug reactions have been reported with antimycobacterial therapy, including rifapentine tablets, within the first few weeks or months of initiation of tuberculosis therapy [see Adverse Reactions ( 6.2 )]. Paradoxical drug reactions are often transient and should not be misinterpreted as failure to respond to treatment. If worsening of symptoms or signs occurs during antimycobacterial treatment, consider paradoxical drug reaction in the differential diagnosis, and monitor or treat accordingly. Advise patients to seek medical advice immediately if their symptoms of tuberculosis worsen or reappear. 5.6 Drug Interactions Rifapentine is an inducer of CYP450 enzymes. Concomitant use of rifapentine with other drugs metabolized by these enzymes, such as protease inhibitors, certain reverse transcriptase inhibitors, and hormonal contraception may cause a significant decrease in plasma concentrations and loss of therapeutic effect [see Drug Interactions ( 7.1 , 7.2 , 7.3 , 7.4 ) and Clinical Pharmacology ( 12.3 )]. 5.7 Discoloration of Body Fluids Rifapentine tablets may produce a red-orange discoloration of body tissues and/or fluids (e.g., skin, teeth, tongue, urine, feces, saliva, sputum, tears, sweat, and cerebrospinal fluid). Contact lenses or dentures may become permanently stained. 5.8 Clostridioides Difficile–Associated Diarrhea Clostridioides difficile –associated diarrhea (CDAD) has been reported with the use of nearly all systemic antibacterial agents, including rifapentine tablets, with severity ranging from mild diarrhea to fatal colitis. Treatment with antibacterial agents can alter the normal flora of the colon and may permit 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 because CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, discontinue antibacterial use not directed against C. difficile if possible. Institute appropriate measures such as fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile , and surgical evaluation as clinically indicated. 5.9 Porphyria Porphyria has been reported in patients receiving rifampin, attributed to induction of delta amino levulinic acid synthetase. Because rifapentine tablets may have similar enzyme induction properties, avoid the use of rifapentine tablets in patients with porphyria.

6 ADVERSE REACTIONS The following serious and otherwise important adverse drug reactions are discussed in greater detail in other sections of labeling: •Hepatotoxicity [see Warnings and Precautions ( 5.1 )] •Hypersensitivity [see Contraindications ( 4.1 ) and Warnings and Precautions ( 5.2 )] •Severe Cutaneous Adverse Reactions [see Warnings and Precautions ( 5.3 )] •Paradoxical Drug Reactions [see Warnings and Precautions ( 5.5 )] •Discoloration of Body Fluids [see Warnings and Precautions ( 5.7 )] • Clostridioides Difficile –Associated Diarrhea [see Warnings and Precautions ( 5.8 )] •Porphyria [see Warnings and Precautions ( 5.9 )] The most common adverse reactions with regimen for active pulmonary tuberculosis (3% and greater) are anemia, lymphopenia, hemoptysis, neutropenia, cough, thrombocytosis, increased sweating, increased ALT, increased AST, back pain, rash, anorexia, arthralgia, increased blood urea, and headache. The most common adverse reaction (3% and greater) with the regimen for latent tuberculosis infection is hypersensitivity reaction. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Macleods Pharma USA, Inc. at 1-888-943-3210 or 1-855-926-3384 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Active Pulmonary Tuberculosis Rifapentine tablets were studied in a randomized, open label, active-controlled trial of HIV-negative patients with active pulmonary tuberculosis. The population consisted primarily of male subjects with a mean age of 37 ± 11 years. In the initial 2-month phase of treatment, 361 patients received rifapentine tablets 600 mg twice a week in combination with daily isoniazid, pyrazinamide, and ethambutol and 361 subjects received rifampin in combination with isoniazid, pyrazinamide and ethambutol all administered daily. Ethambutol was discontinued when drug susceptibly testing was known. During the 4-month continuation phase, 317 patients in the rifapentine tablets group continued to receive rifapentine tablets 600 mg dosed once weekly with isoniazid and 304 patients in the rifampin group received twice weekly rifampin and isoniazid. Both treatment groups received pyridoxine (Vitamin B6) over the 6-month treatment period. Because rifapentine tablets were administered as part of a combination regimen, the adverse reaction profile reflects the entire regimen. Twenty-two deaths occurred in the study, eleven in the rifampin combination therapy group and eleven in the rifapentine tablets combination therapy group. 18/361 (5%) rifampin combination therapy patients discontinued the study due to an adverse reaction compared to 11/361 (3%) rifapentine tablets combination therapy patients. Three patients (two rifampin combination therapy patients and one rifapentine tablets combination therapy patient) were discontinued in the initial phase due to hepatotoxicity. Concomitant medications for all three patients included isoniazid, pyrazinamide, ethambutol, and pyridoxine. All three recovered without sequelae. Five patients had adverse reactions associated with rifapentine tablets overdose. These reactions included hematuria, neutropenia, hyperglycemia, ALT increased, hyperuricemia, pruritus, and arthritis. Table 2 presents selected treatment-emergent adverse reactions associated with the treatment regimens which occurred in at least 1% of patients during treatment and post treatment through the first three months of follow-up. Table 2: Selected Treatment Emergent Adverse Reactions during Treatment of Active Pulmonary Tuberculosis and through Three Months Follow-up System Organ Class Adverse Reaction Initial Phase 1 Continuation Phase 2 Rifapentine Tablets Combination (N=361) N (%) Rifampin Combination (N=361) N (%) Rifapentine Tablets Combination (N=317) N (%) Rifampin Combination (N=304) N (%) Blood and lymphatics Anemia 41 (11.4) 41 (11.4) 5 (1.6) 10 (3.3) Lymphopenia 38 (10.5) 37 (10.2) 10 (3.2) 9 (3.0) Neutropenia 22 (6.1) 21 (5.8) 27 (8.5) 24 (7.9) Leukocytosis 6 (1.7) 13 (3.6) 5 (1.6) 2 (0.7) Thrombocytosis 20 (5.5) 13 (3.6) 1 (0.3) 0 (0.0) Thrombocytopenia 6 (1.7) 6 (1.7) 4 (1.3) 6 (2) Lymphadenopathy 4 (1.1) 2 (0.6) 0 (0.0) 2 (0.7) Eye Conjunctivitis 8 (2.2) 2 (0.6) 1 (0.3) 1 (0.3) Gastrointestinal Dyspepsia 6 (1.7) 11 (3) 4 (1.3) 6 (2) Vomiting 6 (1.7) 14 (3.9) 3 (0.9) 3 (1) Nausea 7 (1.9) 3 (0.8) 2 (0.6) 1 (0.3) Diarrhea 5 (1.4) 2 (0.6) 2 (0.6) 0 (0.0) General Back Pain 15 (4.2) 11 (3) 11 (3.5) 4 (1.3) Abdominal Pain 3 (0.8) 3 (0.8) 4 (1.3) 4 (1.3) Fever 5 (1.4) 7 (1.9) 1 (0.3) 1 (0.3) Anorexia 14 (3.9) 18 (5) 8 (2.5) 6 (2) Hepatic and biliary ALT Increased 18 (5) 23 (6.4) 7 (2.2) 10 (3.3) AST Increased 15 (4.2) 18 (5) 7 (2.2) 8 (2.6) Investigations Blood urea increased 4 (1.1) 3 (0.8) 10 (3.2) 15 (4.9) Musculoskeletal Arthralgia 13 (3.6) 13 (3.6) 3 (0.9) 5 (1.6) Neurologic Headache 11 (3) 13 (3.6) 3 (0.9) 7 (2.3) Dizziness 5 (1.4) 5 (1.4) 1 (0.3) 1 (0.3) Respiratory Hemoptysis 27 (7.5) 20 (5.5) 6 (1.9) 6 (2) Coughing 21 (5.8) 8 (2.2) 9 (2.8) 11 (3.6) Skin Rash 15 (4.2) 26 (7.2) 8 (2.5) 8 (2.6) Sweating Increased 19 (5.3) 18 (5) 5 (1.6) 4 (1.3) Pruritus 10 (2.8) 16 (4.4) 3 (0.9) 0 (0.0) Rash Maculopapular 6 (1.7) 3 (0.8) 0 (0.0) 1 (0.3) 1 Initial phase consisted of therapy with either rifapentine tablets twice weekly or rifampin daily combined with daily isoniazid, pyrazinamide, and ethambutol for 60 days. 2 Continuation phase consisted of therapy with either rifapentine tablets once weekly or rifampin twice weekly combined with daily isoniazid for 120 days. The following selected treatment-emergent adverse reactions were reported in less than 1% of the rifapentine tablets combination therapy patients during treatment and post treatment through the first three months of follow-up. Blood and Lymphatics: lymphocytosis, hematoma, purpura, thrombosis. Cardiovascular: syncope, tachycardia, palpitation, orthostatic hypotension, pericarditis. Metabolic & Nutritional: alkaline phosphatase increased. Gastrointestinal: gastritis, esophagitis, pancreatitis, salivary gland enlargement. General: asthenia, facial edema. Hepatobiliary: bilirubinemia, hepatomegaly, jaundice. Infectious Disease: infection fungal. Musculoskeletal: myalgia, myositis. Neurologic: somnolence, dysphonia. Pregnancy, Puerperium and Perinatal Conditions: abortion. Psychiatric: anxiety, confusion. Reproductive Disorders: vaginitis, vaginal hemorrhage, leukorrhea. Respiratory: dyspnea, pneumonitis, pulmonary fibrosis, asthma, bronchospasm, laryngeal edema, laryngitis. Skin: urticaria, skin discoloration. In another randomized, open-label trial, 1075 HIV non-infected and infected patients with active pulmonary tuberculosis who had completed an initial 2-month phase of treatment with 4 drugs were randomly assigned to receive either rifapentine tablets 600 mg and isoniazid once weekly or rifampin and isoniazid twice weekly for the 4-month continuation phase. Five hundred and two non–HIV-infected and 36 HIV-infected patients were randomized to receive the rifapentine tablets regimen and 502 HIV-noninfected and 35 HIV-infected patients were randomized to receive the rifampin regimen. The death rate was 6.5% for the rifapentine tablets combination regimen compared to 6.7% for the rifampin combination regimen. Latent Tuberculosis Infection Main study Rifapentine tablets in combination with isoniazid given once weekly for 3 months (3RPT/INH) was compared to isoniazid given once daily for 9 months (9INH) in an open-label, randomized trial in patients with a positive tuberculin skin test, and at high risk for progression from latent tuberculosis infection to active tuberculosis disease. Rifapentine tablets were dosed by weight, and isoniazid mg/kg dose was determined according to age [see Dosage and Administration ( 2.2 )] to a maximum of 900 mg each. A total of 4040 patients received at least one dose of the 3RPT/INH regimen, including 348 pediatric patients 2 to 17 years of age and 105 HIV-infected individuals. A total of 3759 received at least one dose of the 9INH regimen, including 342 pediatric patients 2 to 17 years of age and 95 HIV-infected individuals. Patients were followed for 33 months from the time of enrollment. Treatment-emergent adverse reactions were defined as those occurring during treatment and 60 days after the last dose of treatment. One hundred and sixty-one (4%) 3RPT/INH subjects had a rifamycin hypersensitivity reaction, defined as either: a) one of the following: hypotension, urticaria, angioedema, acute bronchospasm, or conjunctivitis occurring in relation to study drug or b) at least four of the following symptoms occurring in relation to the study drug, with at least one symptom being CTCAE Grade 2 or higher: weakness, fatigue, nausea, vomiting, headache, fever, aches, sweats, dizziness, shortness of breath, flushing or chills. No specific definition was used for isoniazid hypersensitivity; 18 (0.5%) 9INH subjects were classified as having a hypersensitivity reaction. Hepatotoxicity was defined as AST ≥3 × upper limit of normal in the presence of specific signs and symptoms of hepatitis, or AST >5 × upper limit of normal regardless of signs or symptoms. One hundred and thirteen (3%) 9INH subjects and 24 (0.6%) 3RPT/INH subjects developed hepatotoxicity. One hundred and ninety-six subjects (4.9%) in the 3RPT/INH arm discontinued treatment due to a treatment related adverse reaction patients and 142 (3.8%) in the 9INH arm discontinued treatment due to a treatment related adverse reaction. In the 3RPT/INH group, the most frequent treatment related adverse reaction resulting in treatment discontinuation was hypersensitivity reaction, occurring in 120 (3%) patients. In the 9INH group, the most frequent treatment related adverse reaction resulting in treatment discontinuation was hepatotoxicity, occurring in 76 (2%) patients. Seventy-one deaths occurred, 31/4040, 0.77% in the 3RPT/INH group and 40/3759 (1.06%) in the 9INH group) during the 33-month study period. During the treatment emergent period, 11 deaths occurred, 4 in the 3RPT/INH group and 7 in the 9INH group. None of the reported deaths were considered related to treatment with study drugs or were attributed to tuberculosis disease. Table 3 presents select adverse reactions that occurred during the treatment emergent period in the main study in LTBI patients treated with 3RPT/INH or 9INH at a frequency greater than 0.5%. Table 3: Select Adverse Reactions Occurring in 0.5% or Greater of Patients* in the Latent Tuberculosis Infection Main Study System Organ Class Adverse Reaction 3RPT/INH (N=4040) N (%) 9INH (N=3759) N (%) Immune system disorders Hypersensitivity 161 (4) 18 (0.5) Hepatobiliary disorders Hepatitis 24 (0.6) 113 (3) Nervous system disorders Headache 26 (0.6) 17 (0.5) Skin and subcutaneous tissue disorders Skin reaction 31 (0.8) 21 (0.6) * Includes events reported through 60 days after last dose of study drug. Pediatric substudy Six hundred and ninety pediatric patients 2 to 17 years of age received at least one dose of study drugs in the main study. An additional 342 pediatric patients 2 to 17 years of age received at least one dose in the pediatric extension study (total 1032 pediatric patients; 539 received 3RPT/INH and 493 received 9INH). No pediatric patients in either treatment arm developed hepatotoxicity. Using the same definition for rifamycin hypersensitivity reaction as in the main study, 7 (1.3%) of pediatric patients in the 3RPT/INH group experienced a rifamycin hypersensitivity reaction. Adverse reactions in pediatric patients 2 to 11 years of age and 12 to 17 years of age were similar. HIV substudy Two hundred HIV-infected patients with latent tuberculosis infection received at least one dose of study drugs in the main study and an additional 193 patients received at least one dose in the extension study (total of 393; 207 received 3RPT/INH and 186 received 9INH). Compared to the HIV-negative patients enrolled in the main study, a higher proportion of HIV-infected patients in each treatment arm experienced a treatment emergent adverse reaction, including a higher incidence of hepatotoxicity. Hepatotoxicity occurred in 3/207 (1.5%) patients in the 3RPT/INH arm and in 14/186 (7.5%) in the 9INH arm. Rifamycin hypersensitivity occurred in only one HIV-infected patient. Eleven deaths occurred during the 33-month follow up period (6/207 in the 3RPT/INH group and 5/186 in the 9INH group) including one death in the 9INH arm during the treatment emergent period. None of the reported deaths were considered related to treatment with study drugs or tuberculosis disease. Selected treatment-emergent adverse reactions reported during treatment and 60 days post treatment in less than 0.5% of the 3RPT/INH combination-therapy group in the main study are presented below by body system. Eye Disorders: conjunctivitis. Blood and Lymphatic System Disorders: leukopenia, anemia, lymphadenopathy, neutropenia. Gastrointestinal Disorders: nausea, diarrhea, vomiting, abdominal pain, constipation, dry mouth, dyspepsia, esophageal irritation, gastritis, pancreatitis. General Disorders and Administration Site Conditions: fatigue, pyrexia, asthenia, chest pain, chills, feeling jittery. Infections and Infestations: pharyngitis, viral infection, vulvovaginal candidiasis. Metabolism and Nutrition Disorders: hyperglycemia, gout, hyperkalemia, decreased appetite, hyperlipidemia. Musculoskeletal and Connective Tissue Disorders: arthralgia, myalgia, back pain, rhabdomyolysis. Nervous System Disorders: dizziness, convulsion, paresthesia, headache, neuropathy peripheral, syncope. Psychiatric Disorders: depression, anxiety, disorientation, suicidal ideation. Renal and Urinary Disorders: azotemia. Reproductive System and Breast Disorders: vulvovaginal pruritus. Respiratory, Thoracic and Mediastinal Disorders: cough, dyspnea, oropharyngeal pain, asthma, bronchial hyperactivity, epistaxis. Skin and Subcutaneous Tissue Disorders: rash, hyperhidrosis, pruritus, urticaria. 6.2 Postmarketing Experience The following adverse reactions have been identified from postmarketing surveillance of rifapentine. Because these reactions are reported from a population of unknown size, it is not always possible to estimate their frequency or establish a causal relationship to drug exposure. General and administration site conditions: Paradoxical drug reactions. Skin and subcutaneous tissue disorders: Severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome (SJS) and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome.

<table cellspacing="0" cellpadding="0" border="0" width="100%"><colgroup><col width="24.8890161821567%"/><col width="17.5855649434341%"/><col width="19.1751396248031%"/><col width="19.1751396248031%"/><col width="19.1751396248031%"/></colgroup><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" rowspan="2" valign="middle"> <content styleCode="bold">System Organ Class </content> <content styleCode="bold"> </content>Adverse Reaction </td><td styleCode="Rrule" colspan="2" align="center" valign="middle"> <content styleCode="bold">Initial Phase¹</content> </td><td styleCode="Rrule" colspan="2" align="center" valign="middle"> <content styleCode="bold">Continuation Phase²</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="center" valign="middle"> <content styleCode="bold">Rifapentine Tablets Combination </content> <content styleCode="bold">(N=361) </content> <content styleCode="bold">N (%)</content> </td><td styleCode="Rrule" align="center" valign="middle"> <content styleCode="bold">Rifampin Combination </content> <content styleCode="bold">(N=361) </content> <content styleCode="bold">N (%)</content> </td><td styleCode="Rrule" align="center" valign="middle"> <content styleCode="bold">Rifapentine Tablets Combination </content> <content styleCode="bold">(N=317) </content> <content styleCode="bold">N (%)</content> </td><td styleCode="Rrule" align="center" valign="middle"> <content styleCode="bold">Rifampin Combination </content> <content styleCode="bold">(N=304) </content> <content styleCode="bold">N (%)</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5" valign="top"> <content styleCode="bold">Blood and lymphatics</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Anemia </td><td styleCode="Rrule" align="center" valign="middle"> 41 (11.4) </td><td styleCode="Rrule" align="center" valign="middle"> 41 (11.4) </td><td styleCode="Rrule" align="center" valign="middle"> 5 (1.6) </td><td styleCode="Rrule" align="center" valign="middle"> 10 (3.3) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Lymphopenia </td><td styleCode="Rrule" align="center" valign="middle"> 38 (10.5) </td><td styleCode="Rrule" align="center" valign="middle"> 37 (10.2) </td><td styleCode="Rrule" align="center" valign="middle"> 10 (3.2) </td><td styleCode="Rrule" align="center" valign="middle"> 9 (3.0) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Neutropenia </td><td styleCode="Rrule" align="center" valign="middle"> 22 (6.1) </td><td styleCode="Rrule" align="center" valign="middle"> 21 (5.8) </td><td styleCode="Rrule" align="center" valign="middle"> 27 (8.5) </td><td styleCode="Rrule" align="center" valign="middle"> 24 (7.9) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Leukocytosis </td><td styleCode="Rrule" align="center" valign="top"> 6 (1.7) </td><td styleCode="Rrule" align="center" valign="top"> 13 (3.6) </td><td styleCode="Rrule" align="center" valign="top"> 5 (1.6) </td><td styleCode="Rrule" align="center" valign="top"> 2 (0.7) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Thrombocytosis </td><td styleCode="Rrule" align="center" valign="top"> 20 (5.5) </td><td styleCode="Rrule" align="center" valign="top"> 13 (3.6) </td><td styleCode="Rrule" align="center" valign="top"> 1 (0.3) </td><td styleCode="Rrule" align="center" valign="top"> 0 (0.0) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Thrombocytopenia </td><td styleCode="Rrule" align="center" valign="top"> 6 (1.7) </td><td styleCode="Rrule" align="center" valign="top"> 6 (1.7) </td><td styleCode="Rrule" align="center" valign="top"> 4 (1.3) </td><td styleCode="Rrule" align="center" valign="top"> 6 (2) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Lymphadenopathy </td><td styleCode="Rrule" align="center" valign="top"> 4 (1.1) </td><td styleCode="Rrule" align="center" valign="top"> 2 (0.6) </td><td styleCode="Rrule" align="center" valign="top"> 0 (0.0) </td><td styleCode="Rrule" align="center" valign="top"> 2 (0.7) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5" valign="top"> <content styleCode="bold">Eye</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Conjunctivitis </td><td styleCode="Rrule" align="center" valign="top"> 8 (2.2) </td><td styleCode="Rrule" align="center" valign="top"> 2 (0.6) </td><td styleCode="Rrule" align="center" valign="top"> 1 (0.3) </td><td styleCode="Rrule" align="center" valign="top"> 1 (0.3) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5" valign="top"> <content styleCode="bold">Gastrointestinal</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Dyspepsia </td><td styleCode="Rrule" align="center" valign="top"> 6 (1.7) </td><td styleCode="Rrule" align="center" valign="top"> 11 (3) </td><td styleCode="Rrule" align="center" valign="top"> 4 (1.3) </td><td styleCode="Rrule" align="center" valign="top"> 6 (2) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Vomiting </td><td styleCode="Rrule" align="center" valign="middle"> 6 (1.7) </td><td styleCode="Rrule" align="center" valign="middle"> 14 (3.9) </td><td styleCode="Rrule" align="center" valign="middle"> 3 (0.9) </td><td styleCode="Rrule" align="center" valign="middle"> 3 (1) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Nausea </td><td styleCode="Rrule" align="center" valign="middle"> 7 (1.9) </td><td styleCode="Rrule" align="center" valign="middle"> 3 (0.8) </td><td styleCode="Rrule" align="center" valign="middle"> 2 (0.6) </td><td styleCode="Rrule" align="center" valign="middle"> 1 (0.3) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Diarrhea </td><td styleCode="Rrule" align="center" valign="middle"> 5 (1.4) </td><td styleCode="Rrule" align="center" valign="middle"> 2 (0.6) </td><td styleCode="Rrule" align="center" valign="middle"> 2 (0.6) </td><td styleCode="Rrule" align="center" valign="middle"> 0 (0.0) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5" valign="top"> <content styleCode="bold">General</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Back Pain </td><td styleCode="Rrule" align="center" valign="middle"> 15 (4.2) </td><td styleCode="Rrule" align="center" valign="middle"> 11 (3) </td><td styleCode="Rrule" align="center" valign="middle"> 11 (3.5) </td><td styleCode="Rrule" align="center" valign="middle"> 4 (1.3) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Abdominal Pain </td><td styleCode="Rrule" align="center" valign="middle"> 3 (0.8) </td><td styleCode="Rrule" align="center" valign="middle"> 3 (0.8) </td><td styleCode="Rrule" align="center" valign="middle"> 4 (1.3) </td><td styleCode="Rrule" align="center" valign="middle"> 4 (1.3) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Fever </td><td styleCode="Rrule" align="center" valign="middle"> 5 (1.4) </td><td styleCode="Rrule" align="center" valign="middle"> 7 (1.9) </td><td styleCode="Rrule" align="center" valign="middle"> 1 (0.3) </td><td styleCode="Rrule" align="center" valign="middle"> 1 (0.3) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Anorexia </td><td styleCode="Rrule" align="center" valign="middle"> 14 (3.9) </td><td styleCode="Rrule" align="center" valign="middle"> 18 (5) </td><td styleCode="Rrule" align="center" valign="middle"> 8 (2.5) </td><td styleCode="Rrule" align="center" valign="middle"> 6 (2) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5" valign="top"> <content styleCode="bold">Hepatic and biliary</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> ALT Increased </td><td styleCode="Rrule" align="center" valign="middle"> 18 (5) </td><td styleCode="Rrule" align="center" valign="middle"> 23 (6.4) </td><td styleCode="Rrule" align="center" valign="middle"> 7 (2.2) </td><td styleCode="Rrule" align="center" valign="middle"> 10 (3.3) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> AST Increased </td><td styleCode="Rrule" align="center" valign="middle"> 15 (4.2) </td><td styleCode="Rrule" align="center" valign="middle"> 18 (5) </td><td styleCode="Rrule" align="center" valign="middle"> 7 (2.2) </td><td styleCode="Rrule" align="center" valign="middle"> 8 (2.6) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5" valign="top"> <content styleCode="bold">Investigations</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Blood urea increased </td><td styleCode="Rrule" align="center" valign="middle"> 4 (1.1) </td><td styleCode="Rrule" align="center" valign="middle"> 3 (0.8) </td><td styleCode="Rrule" align="center" valign="middle"> 10 (3.2) </td><td styleCode="Rrule" align="center" valign="middle"> 15 (4.9) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5" valign="top"> <content styleCode="bold">Musculoskeletal</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Arthralgia </td><td styleCode="Rrule" align="center" valign="middle"> 13 (3.6) </td><td styleCode="Rrule" align="center" valign="middle"> 13 (3.6) </td><td styleCode="Rrule" align="center" valign="middle"> 3 (0.9) </td><td styleCode="Rrule" align="center" valign="middle"> 5 (1.6) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5" valign="top"> <content styleCode="bold">Neurologic</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Headache </td><td styleCode="Rrule" align="center" valign="middle"> 11 (3) </td><td styleCode="Rrule" align="center" valign="middle"> 13 (3.6) </td><td styleCode="Rrule" align="center" valign="middle"> 3 (0.9) </td><td styleCode="Rrule" align="center" valign="middle"> 7 (2.3) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Dizziness </td><td styleCode="Rrule" align="center" valign="middle"> 5 (1.4) </td><td styleCode="Rrule" align="center" valign="middle"> 5 (1.4) </td><td styleCode="Rrule" align="center" valign="middle"> 1 (0.3) </td><td styleCode="Rrule" align="center" valign="middle"> 1 (0.3) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5" valign="top"> <content styleCode="bold">Respiratory</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Hemoptysis </td><td styleCode="Rrule" align="center" valign="middle"> 27 (7.5) </td><td styleCode="Rrule" align="center" valign="middle"> 20 (5.5) </td><td styleCode="Rrule" align="center" valign="middle"> 6 (1.9) </td><td styleCode="Rrule" align="center" valign="middle"> 6 (2) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Coughing </td><td styleCode="Rrule" align="center" valign="middle"> 21 (5.8) </td><td styleCode="Rrule" align="center" valign="middle"> 8 (2.2) </td><td styleCode="Rrule" align="center" valign="middle"> 9 (2.8) </td><td styleCode="Rrule" align="center" valign="middle"> 11 (3.6) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="5" valign="top"> <content styleCode="bold">Skin</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Rash </td><td styleCode="Rrule" align="center" valign="middle"> 15 (4.2) </td><td styleCode="Rrule" align="center" valign="middle"> 26 (7.2) </td><td styleCode="Rrule" align="center" valign="middle"> 8 (2.5) </td><td styleCode="Rrule" align="center" valign="middle"> 8 (2.6) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Sweating Increased </td><td styleCode="Rrule" align="center" valign="middle"> 19 (5.3) </td><td styleCode="Rrule" align="center" valign="middle"> 18 (5) </td><td styleCode="Rrule" align="center" valign="middle"> 5 (1.6) </td><td styleCode="Rrule" align="center" valign="middle"> 4 (1.3) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Pruritus </td><td styleCode="Rrule" align="center" valign="middle"> 10 (2.8) </td><td styleCode="Rrule" align="center" valign="middle"> 16 (4.4) </td><td styleCode="Rrule" align="center" valign="middle"> 3 (0.9) </td><td styleCode="Rrule" align="center" valign="middle"> 0 (0.0) </td></tr><tr><td styleCode="Lrule Rrule" valign="top"> Rash Maculopapular </td><td styleCode="Rrule" align="center" valign="middle"> 6 (1.7) </td><td styleCode="Rrule" align="center" valign="middle"> 3 (0.8) </td><td styleCode="Rrule" align="center" valign="middle"> 0 (0.0) </td><td styleCode="Rrule" align="center" valign="middle"> 1 (0.3) </td></tr></tbody></table>

<table cellspacing="0" cellpadding="0" border="0" width="100%"><colgroup><col width="40.5560332473488%"/><col width="30.481513327601%"/><col width="28.9624534250502%"/></colgroup><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="bottom"> <content styleCode="bold">System Organ Class</content> Adverse Reaction </td><td styleCode="Rrule" align="center" valign="top"> <content styleCode="bold">3RPT/INH</content> <content styleCode="bold">(N=4040)</content> <content styleCode="bold">N (%)</content> </td><td styleCode="Rrule" align="center" valign="top"> <content styleCode="bold">9INH</content> <content styleCode="bold">(N=3759)</content> <content styleCode="bold">N (%)</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top"> <content styleCode="bold">Immune system disorders</content> </td><td styleCode="Rrule" align="justify" valign="top"> </td><td styleCode="Rrule" align="justify" valign="top"> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top"> Hypersensitivity </td><td styleCode="Rrule" align="center" valign="top"> 161 (4) </td><td styleCode="Rrule" align="center" valign="top"> 18 (0.5) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top"> <content styleCode="bold">Hepatobiliary disorders</content> </td><td styleCode="Rrule" align="justify" valign="top"> </td><td styleCode="Rrule" align="justify" valign="top"> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top"> Hepatitis </td><td styleCode="Rrule" align="center" valign="top"> 24 (0.6) </td><td styleCode="Rrule" align="center" valign="top"> 113 (3) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top"> <content styleCode="bold">Nervous system disorders</content> </td><td styleCode="Rrule" align="justify" valign="top"> </td><td styleCode="Rrule" align="justify" valign="top"> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top"> Headache </td><td styleCode="Rrule" align="center" valign="top"> 26 (0.6) </td><td styleCode="Rrule" align="center" valign="top"> 17 (0.5) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top"> <content styleCode="bold">Skin and subcutaneous tissue disorders</content> </td><td styleCode="Rrule" align="justify" valign="top"> </td><td styleCode="Rrule" align="justify" valign="top"> </td></tr><tr><td styleCode="Lrule Rrule" align="justify" valign="top"> Skin reaction </td><td styleCode="Rrule" align="center" valign="top"> 31 (0.8) </td><td styleCode="Rrule" align="center" valign="top"> 21 (0.6) </td></tr></tbody></table>