Rifapentine

1 INDICATIONS AND USAGE PRIFTIN is a rifamycin antimycobacterial drug indicated in patients 12 years of age and older for the treatment of active pulmonary tuberculosis (TB) caused by Mycobacterium tuberculosis in combination with one or more antituberculosis (anti-TB) drugs to which the isolate is susceptible. ( 1.1 ) PRIFTIN is indicated for the treatment of latent tuberculosis infection (LTBI) caused by M. tuberculosis in combination with isoniazid in patients 2 years of age and older at high risk of progression to TB disease. ( 1.2 ) See Full Prescribing Information for Limitations of Use. ( 1.1 , 1.2 ) 1.1 Active Pulmonary Tuberculosis PRIFTIN ® (rifapentine) is indicated in adults and pediatric patients 12 years and older for the treatment of active pulmonary tuberculosis (TB) caused by Mycobacterium tuberculosis . PRIFTIN must always be used in combination with one or more antituberculosis (anti-TB) drugs to which the isolate is susceptible [see Dosage and Administration (2.1) and Clinical Studies (14.1) ] . Limitations of Use Do not use PRIFTIN monotherapy in either the initial or the continuation phases of active antituberculous treatment. PRIFTIN should not be used once weekly in the continuation phase regimen in combination with isoniazid (INH) in HIV-infected patients with active pulmonary tuberculosis because of a higher rate of failure and/or relapse with rifampin (RIF)-resistant organisms [see Warnings and Precautions (5.4) and Clinical Studies (14.1) ] . PRIFTIN has not been studied as part of the initial phase treatment regimen in HIV-infected patients with active pulmonary tuberculosis. 1.2 Latent Tuberculosis Infection PRIFTIN is indicated in adults and pediatric patients 2 years and older for the treatment of latent tuberculosis infection caused by Mycobacterium tuberculosis in patients at high risk of progression to tuberculosis disease (including those in close contact with active tuberculosis patients, recent conversion to a positive tuberculin skin test, HIV-infected patients, or those with pulmonary fibrosis on radiograph) [see Clinical Studies (14.2) ] . Limitations of Use Active tuberculosis disease should be ruled out before initiating treatment for latent tuberculosis infection. PRIFTIN must always be used in combination with isoniazid as a 12-week once-weekly regimen for the treatment of latent tuberculosis infection [see Dosage and Administration (2.2) and Clinical Studies (14.2) ] . PRIFTIN in combination with isoniazid is not recommended for individuals presumed to be exposed to rifamycin-resistant or isoniazid-resistant M. tuberculosis .

2 DOSAGE AND ADMINISTRATION Active pulmonary tuberculosis: PRIFTIN should be used in regimens consisting of an initial 2 month phase followed by a 4 month continuation phase. ( 2.1 ) Initial phase (2 Months): 600 mg twice weekly for two months as directly observed therapy (DOT), with no less than 72 hours between doses, in combination with other antituberculosis drugs. ( 2.1 ) Continuation phase (4 Months): 600 mg once weekly for 4 months as directly observed therapy with isoniazid or another appropriate antituberculosis agent. ( 2.1 ) Latent tuberculosis infection: PRIFTIN should be administered in combination with isoniazid once weekly for 12 weeks as directly observed therapy. ( 2.2 ) Adults and pediatric patients ≥12 years: PRIFTIN (based on weight, see table below) and isoniazid 15 mg/kg (900 mg maximum). ( 2.2 ) Pediatric patients 2 to 11 years: PRIFTIN (based on weight, see table below) and isoniazid 25 mg/kg (900 mg maximum). ( 2.2 ) Weight range PRIFTIN dose Number of PRIFTIN tablets 10–14 kg 300 mg 2 14.1–25 kg 450 mg 3 25.1–32 kg 600 mg 4 32.1–50 kg 750 mg 5 >50 kg 900 mg 6 For Latent Tuberculosis Infection, the maximum recommended dose of PRIFTIN is 900 mg once weekly for 12 weeks. ( 2.2 ) Take with food. Tablets may be crushed and added to semi-solid food. ( 2.3 ) 2.1 Dosage in Active Pulmonary Tuberculosis PRIFTIN is only recommended for the treatment of active pulmonary tuberculosis caused by drug-susceptible organisms as part of regimens consisting of a 2-month initial phase followed by a 4-month continuation phase. PRIFTIN should not be used in the treatment of active pulmonary tuberculosis caused by rifampin-resistant strains. Initial phase (2 Months): PRIFTIN should be administered at a dose of 600 mg twice weekly for two months as directly observed therapy (DOT), with an interval of no less than 3 consecutive days (72 hours) between doses, in combination with other antituberculosis drugs as part of an appropriate regimen which includes daily companion drugs such as isoniazid (INH), ethambutol (EMB) and pyrazinamide (PZA). Continuation phase (4 Months): Following the initial phase (2 months), continuation phase (4 months) treatment consists of PRIFTIN 600 mg once weekly for 4 months in combination with isoniazid or another appropriate antituberculosis agent for susceptible organisms administered as directly observed therapy. 2.2 Dosage in Latent Tuberculosis Infection PRIFTIN should be administered once weekly in combination with isoniazid for 12 weeks as directly observed therapy. Adults and pediatric patients 12 years and older: The recommended dose of PRIFTIN should be determined based on weight of the patient up to a maximum of 900 mg once weekly (see Table 1 ). The recommended dose of isoniazid is 15 mg/kg (rounded to the nearest 50 mg or 100 mg) up to a maximum of 900 mg once weekly for 12 weeks. Pediatric Patients 2 to 11 years: The recommended dose of PRIFTIN should be determined based on weight of the patient up to a maximum of 900 mg once weekly (see Table 1 ). The recommended dose of isoniazid is 25 mg/kg (rounded to the nearest 50 mg or 100 mg) up to a maximum of 900 mg once weekly for 12 weeks. Table 1: Weight Based Dose of PRIFTIN in the Treatment of Latent Tuberculosis Infection Weight range PRIFTIN dose Number of PRIFTIN tablets 10–14 kg 300 mg 2 14.1–25 kg 450 mg 3 25.1–32 kg 600 mg 4 32.1–50 kg 750 mg 5 >50 kg 900 mg 6 2.3 Administration Take PRIFTIN with meals. Administration of PRIFTIN with a meal increases oral bioavailability and may reduce the incidence of gastrointestinal upset, nausea, and/or vomiting [see Clinical Pharmacology (12.3) ] . For patients who cannot swallow tablets, the tablets may be crushed and added to a small amount of semi-solid food, all of which should be consumed immediately [see Clinical Pharmacology (12.3) ] .

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 sanofi-aventis U.S. LLC at 1-800-633-1610 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 PRIFTIN was 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 PRIFTIN 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 PRIFTIN group continued to receive PRIFTIN 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 PRIFTIN was 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 PRIFTIN combination therapy group. 18/361 (5%) rifampin combination therapy patients discontinued the study due to an adverse reaction compared to 11/361 (3%) PRIFTIN combination therapy patients. Three patients (two rifampin combination therapy patients and one PRIFTIN 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 PRIFTIN 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 Initial Phase Initial phase consisted of therapy with either PRIFTIN twice weekly or rifampin daily combined with daily isoniazid, pyrazinamide, and ethambutol for 60 days. Continuation Phase Continuation phase consisted of therapy with either PRIFTIN once weekly or rifampin twice weekly combined with daily isoniazid for 120 days. System Organ Class Adverse Reaction PRIFTIN Combination (N=361) N (%) Rifampin Combination (N=361) N (%) PRIFTIN 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) The following selected treatment-emergent adverse reactions were reported in less than 1% of the PRIFTIN 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 PRIFTIN 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 PRIFTIN 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 PRIFTIN combination regimen compared to 6.7% for the rifampin combination regimen. Latent Tuberculosis Infection Main study PRIFTIN 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. PRIFTIN was 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 Includes events reported through 60 days after last dose of study drug. 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) 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.

12.3 Pharmacokinetics When oral doses of PRIFTIN were administered once daily or once every 72 hours to healthy volunteers for 10 days, single dose AUC (0–∞) of rifapentine was similar to its steady-state AUC ss (0–24h) or AUC ss (0–72h) values, suggesting no significant auto-induction effect on steady-state pharmacokinetics of rifapentine. Steady-state conditions were achieved by day 10 following daily administration of PRIFTIN 600 mg. No plasma accumulation of rifapentine and 25-desacetyl rifapentine (active metabolite) is expected after once weekly administration of PRIFTIN. The pharmacokinetic parameters of rifapentine and 25-desacetyl rifapentine on day 10 following oral administration of 600 mg PRIFTIN every 72 hours to healthy volunteers are described in Table 5. Table 5: Pharmacokinetics and Rifapentine and 25-Desacetyl Rifapentine in Healthy Volunteers Parameter Rifapentine 25-desacetyl Rifapentine Mean ± SD (n=12) C max (µg/mL) 15.05 ± 4.62 6.26 ± 2.06 AUC (0–72h) ( µg∙h/mL) 319.54 ± 91.52 215.88 ± 85.96 T 1/2 (h) 13.19 ± 1.38 13.35 ± 2.67 T max (h) 4.83 ± 1.80 11.25 ± 2.73 Cl/F (L/h) 2.03 ± 0.60 -- The pharmacokinetic parameters of rifapentine and 25-desacetyl rifapentine following single-dose oral administration of 900 mg PRIFTIN in combination with 900 mg isoniazid in fed conditions are described in Table 6. Table 6: Mean ± SD Pharmacokinetic Parameters of Rifapentine and 25-Desacetyl Rifapentine in Healthy Volunteers When PRIFTIN is Coadministered with Isoniazid Under Fed Conditions (N=16) Parameter Rifapentine 25-desacetyl Rifapentine C max (µg/mL) 25.8 ± 5.83 13.3 ± 4.83 AUC (µg∙h/mL) 817 ± 128 601 ± 187 T 1/2 (h) 16.6 ± 5.02 17.5 ± 7.42 T max (h) Median (Min–Max). 8 (3–10) 24 (10–36) Cl/F (L/h) 1.13 ± 0.174 NA Not Applicable. Absorption The absolute bioavailability of PRIFTIN has not been determined. The relative bioavailability (with an oral solution as a reference) of PRIFTIN after a single 600 mg dose to healthy adult volunteers was 70%. The maximum concentrations were achieved from 5 hours to 6 hours after administration of the 600 mg PRIFTIN dose. The administration of PRIFTIN with a high fat meal increased rifapentine C max and AUC by 40% to 50% over that observed when PRIFTIN was administered under fasting conditions. The administration of PRIFTIN (900 mg single dose) and isoniazid (900 mg single dose) with a low fat, high carbohydrate breakfast, led to a 47% and 51% increase in rifapentine C max and AUC, respectively. In contrast, the ingestion of the same meal decreased isoniazid C max and AUC by 46% and of 23%, respectively. Distribution In a population pharmacokinetic analysis in 351 tuberculosis patients who received 600 mg PRIFTIN in combination with isoniazid, pyrazinamide and ethambutol, the estimated apparent volume of distribution was 70.2 ± 9.1 L. In healthy volunteers, rifapentine and 25-desacetyl rifapentine were 97.7% and 93.2% bound to plasma proteins, respectively. Rifapentine was mainly bound to albumin. Similar extent of protein binding was observed in healthy volunteers, asymptomatic HIV-infected subjects and hepatically impaired subjects. Metabolism/Excretion Following a single 600 mg oral dose of radiolabeled rifapentine to healthy volunteers (n=4), 87% of the total 14 C-rifapentine was recovered in the urine (17%) and feces (70%). Greater than 80% of the total 14 C-rifapentine dose was excreted from the body within 7 days. Rifapentine was hydrolyzed by an esterase enzyme to form a microbiologically active 25-desacetyl rifapentine. Rifapentine and 25-desacetyl rifapentine accounted for 99% of the total radioactivity in plasma. Plasma AUC (0–∞) and C max values of the 25-desacetyl rifapentine metabolite were one-half and one-third those of the rifapentine, respectively. Based upon relative in vitro activities and AUC (0– ∞) values, rifapentine and 25-desacetyl rifapentine potentially contributes 62% and 38% to the clinical activities against M. tuberculosis , respectively. Specific Populations Gender: In a population pharmacokinetics analysis of sparse blood samples obtained from 351 tuberculosis patients who received 600 mg PRIFTIN in combination with isoniazid, pyrazinamide and ethambutol, the estimated apparent oral clearance of PRIFTIN for males and females was 2.51 ± 0.14 L/h and 1.69 ± 0.41 L/h, respectively. The clinical significance of the difference in the estimated apparent oral clearance is not known. Elderly: Following oral administration of a single 600 mg dose of PRIFTIN to elderly (65 years and older) male healthy volunteers (n=14), the pharmacokinetics of rifapentine and 25-desacetyl metabolite were similar to that observed for young (18 to 45 years) healthy male volunteers (n=20). Pediatric: In a pharmacokinetic study in pediatric patients (age 2 to 12 years), a single oral dose of 150 mg PRIFTIN was administered to those weighing less than 30 kg (n=11) and a single oral dose of 300 mg was administered to those weighing greater than 30 kg (n=12). The mean estimates of AUC and C max were approximately 30% to 50% lower in these pediatric patients than those observed in healthy adults administered single oral doses of 600 mg and 900 mg. A study compared the pharmacokinetics of rifapentine in pediatric patients (age 2 years to 11 years) with latent tuberculosis infection (n=80) receiving PRIFTIN once weekly based on weight (15 mg/kg to 30 mg/kg, up to a maximum of 900 mg, see Table 1 ) to that of adults (n=77) receiving PRIFTIN 900 mg once weekly. Pediatric patients who could not swallow whole tablets were administered crushed tablets mixed in soft food. Overall, the geometric mean AUC of rifapentine in this age group was 31% higher compared to adult patients receiving 900 mg PRIFTIN once weekly (720 versus 551 mcg∙h/mL). The geometric mean AUC of rifapentine was 60% higher in pediatric patients administered whole tablets (884 versus 551 mcg∙h/mL) and 19% higher in pediatric patients administered crushed tablets (656 versus 551 mcg∙h/mL), as compared to exposures in adults. Pediatric patients administered crushed PRIFTIN tablets had 26% lower rifapentine exposures compared to those pediatric patients who were given whole tablets. Population pharmacokinetic analysis showed that rifapentine clearance adjusted to body weight decreased with increasing age of pediatric patients (2 to 18 years). In another pharmacokinetics study of PRIFTIN in healthy adolescents (age 12 to 15 years), 600 mg PRIFTIN was administered to those weighing ≥45 kg (n=10) and 450 mg was administered to those weighing less than 45 kg (n=2). The pharmacokinetics of rifapentine was similar to those observed in healthy adults. Renal Impaired Patients: The pharmacokinetics of rifapentine has not been evaluated in renal impaired patients. Although only about 17% of an administered dose is excreted via the kidneys, the clinical significance of impaired renal function on the disposition of rifapentine and its 25-desacetyl metabolite is not known. Hepatic Impaired Patients: Following oral administration of a single 600 mg dose of PRIFTIN to mild to severe hepatic impaired patients (n=15), the pharmacokinetics of rifapentine and 25-desacetyl metabolite were similar in patients with various degrees of hepatic impairment and to that observed in another study for healthy volunteers (n=12). Asymptomatic HIV-Infected Volunteers: Following oral administration of a single 600 mg dose of PRIFTIN to asymptomatic HIV-infected volunteers (n=15) under fasting conditions, mean C max and AUC (0–∞) of rifapentine were lower (20%–32%) than that observed in other studies in healthy volunteers (n=55). In a cross-study comparison, mean C max and AUC values of the 25-desacetyl rifapentine, when compared to healthy volunteers were higher (6%–21%) in one study (n=20), but lower (15%–16%) in a different study (n=40). The clinical significance of this observation is not known. Food (850 total calories: 33 g protein, 55 g fat, and 58 g carbohydrate) increases the mean AUC and C max of rifapentine observed under fasting conditions in asymptomatic HIV-infected volunteers by about 51% and 53%, respectively. Drug-Drug Interactions Isoniazid: Coadministration of PRIFTIN (900 mg single dose) and isoniazid (900 mg single dose), in fasted condition, did not result in any significant change in the exposure of rifapentine and isoniazid compared to when administered alone in fasted condition. Rifapentine is an inducer of cytochrome P450 3A4 and 2C8/9. Therefore, it may increase the metabolism and decrease the activity of other coadministered drugs that are metabolized by these enzymes. Dosage adjustments of the coadministered drugs may be necessary if they are given concurrently with PRIFTIN [see Drug Interactions (7.4) ] . Indinavir: In a study in which 600 mg PRIFTIN was administered twice weekly for 14 days followed by PRIFTIN twice weekly plus 800 mg indinavir 3 times a day for an additional 14 days, indinavir C max decreased by 55% while AUC reduced by 70%. Clearance of indinavir increased by 3-fold in the presence of PRIFTIN while half-life did not change. But when indinavir was administered for 14 days followed by coadministration with PRIFTIN for an additional 14 days, indinavir did not affect the pharmacokinetics of rifapentine [see Warnings and Precautions (5.6) and Drug Interactions (7.1) ] . Fixed-dose combination of efavirenz, emtricitabine and tenofovir: Once-weekly coadministration of 900 mg PRIFTIN with the antiretroviral fixed-dose combination of efavirenz 600 mg, emtricitabine 200 mg and tenofovir disoproxil fumarate 300 mg in HIV-infected patients did not result in any substantial change in steady state exposures of efavirenz, emtricitabine, and tenofovir (Table 7). A 15% decrease in efavirenz C min and AUC and a 13% decrease in tenofovir C min were observed with repeated weekly doses of PRIFTIN (Table 7). No clinically significant change in CD4 cell counts or viral loads were noted. Table 7: Treatment Ratio Estimates (with versus without repeated once-weekly PRIFTIN 900 mg) with 90% Confidence Intervals for Efavirenz, Emtricitabine and Tenofovir Pharmacokinetic Parameters Efavirenz Point Estimates (90% CI) Emtricitabine Point Estimates (90% CI) Tenofovir Point Estimates (90% CI) C max 0.92 (0.82–1.03) 0.95 (0.81–1.10) 1.00 (0.82–1.22) C min 0.85 (0.79–0.93) 0.97 (0.90–1.05) 0.87(0.73–1.05) AUC 0–24 0.86 (0.79–0.93) 0.93 (0.89–0.98) 0.91(0.85–0.98)