Priftin Drug Information

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 41 5 10 Lymphopenia 38 37 10 9 Neutropenia 22 21 27 24 Leukocytosis 6 13 5 2 Thrombocytosis 20 13 1 0 Thrombocytopenia 6 6 4 6 Lymphadenopathy 4 2 0 2 Eye Conjunctivitis 8 2 1 1 Gastrointestinal Dyspepsia 6 11 4 6 Vomiting 6 14 3 3 Nausea 7 3 2 1 Diarrhea 5 2 2 0 General Back Pain 15 11 11 4 Abdominal Pain 3 3 4 4 Fever 5 7 1 1 Anorexia 14 18 8 6 Hepatic and biliary ALT Increased 18 23 7 10 AST Increased 15 18 7 8 Investigations Blood urea increased 4 3 10 15 Musculoskeletal Arthralgia 13 13 3 5 Neurologic Headache 11 13 3 7 Dizziness 5 5 1 1 Respiratory Hemoptysis 27 20 6 6 Coughing 21 8 9 11 Skin Rash 15 26 8 8 Sweating Increased 19 18 5 4 Pruritus 10 16 3 0 Rash Maculopapular 6 3 0 1 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 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 18 Hepatobiliary disorders Hepatitis 24 113 Nervous system disorders Headache 26 17 Skin and subcutaneous tissue disorders Skin reaction 31 21 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.

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.

Protease Inhibitors and Reverse Transcriptase Inhibitors Rifapentine is an inducer of

CYP450 enzymes. Concomitant use of PRIFTIN with other drugs metabolized by these enzymes, such as protease inhibitors and certain reverse transcriptase inhibitors, may cause a significant decrease in plasma concentrations and loss of therapeutic effect of the protease inhibitor or reverse transcriptase inhibitor .

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. No clinically significant change in CD4 cell counts or viral loads were noted .

Hormonal Contraceptives

PRIFTIN may reduce the effectiveness of hormonal contraceptives. Patients using hormonal contraception should be advised to use an alternative non-hormonal contraceptive method or add a barrier method of contraception during treatment with PRIFTIN .

Cytochrome P450 3A4 and 2C8/9 Rifapentine is an inducer of cytochromes P450

3A4 and P450 2C8/9. Therefore, PRIFTIN may increase the metabolism of other coadministered drugs that are metabolized by these enzymes. Induction of enzyme activities by PRIFTIN occurred within 4 days after the first dose. Enzyme activities returned to baseline levels 14 days after discontinuing PRIFTIN. Rifampin has been reported to accelerate the metabolism and may reduce the activity of the following drugs; hence, PRIFTIN may also increase the metabolism and decrease the activity of these drugs.

Dosage adjustments of the drugs in Table 4 or of other drugs metabolized by cytochrome P450 3A4 or P450 2C8/9 may be necessary if they are given concurrently with PRIFTIN. Table 4: Drug Interactions with PRIFTIN: Dosage Adjustment May be Necessary Drug Class Examples of Drugs Within Class Antiarrhythmics Disopyramide, mexiletine, quinidine, tocainide Antibiotics Chloramphenicol, clarithromycin, dapsone, doxycycline; Fluoroquinolones (such as ciprofloxacin) Oral Anticoagulants Warfarin Anticonvulsants Phenytoin Antimalarials Quinine Azole Antifungals Fluconazole, itraconazole, ketoconazole Antipsychotics Haloperidol Barbiturates Phenobarbital Benzodiazepines Diazepam Beta-Blockers Propranolol Calcium Channel Blockers Diltiazem, nifedipine, verapamil Cardiac Glycoside Preparations Digoxin Corticosteroids Prednisone Fibrates Clofibrate Oral Hypoglycemics Sulfonylureas (e.g., glyburide, glipizide) Hormonal Contraceptives/Progestins Ethinyl estradiol, levonorgestrel Immunosuppressants Cyclosporine, tacrolimus Methylxanthines Theophylline Narcotic analgesics Methadone Phosphodiesterase-5 (PDE-5) Inhibitors Sildenafil Thyroid preparations Levothyroxine Tricyclic antidepressants Amitriptyline, nortriptyline

Other Interactions

The conversion of PRIFTIN to 25-desacetyl rifapentine is mediated by an esterase enzyme. There is minimal potential for PRIFTIN metabolism to be inhibited or induced by another drug, based upon the characteristics of the esterase enzymes. Since PRIFTIN is highly bound to albumin, drug displacement interactions may also occur .

Interactions with Laboratory Tests Therapeutic concentrations of rifampin have been shown to

inhibit standard microbiological assays for serum folate and Vitamin B 12. Similar drug-laboratory interactions should be considered for PRIFTIN; thus, alternative assay methods should be considered.

Pregnancy Risk Summary Based on animal data, PRIFTIN may cause fetal harm when administered to a pregnant woman. Available data from clinical trials, case reports, epidemiology studies and postmarketing experience with PRIFTIN use in pregnant women are insufficient to establish a drug-associated risk of major birth defects, adverse maternal or fetal outcomes. In two clinical trials, a total of 59 patients who were treated with rifapentine in combination with other anti-tuberculosis drugs became pregnant.

Overall, the reported rate of miscarriage following rifapentine exposure in these two clinical trials did not represent an increase over the background rate of miscarriage reported in the general population (see Data ). There are risks associated with active tuberculosis during pregnancy. When administered during the last few weeks of pregnancy, PRIFTIN may be associated with maternal postpartum hemorrhage and bleeding in the exposed neonates (see Clinical Considerations ). In animal reproduction and developmental toxicity studies, adverse developmental outcomes (including cleft palate or mal-positioned aortic arches) were observed following administration of rifapentine to pregnant rats and rabbits at doses approximately 0.6 and 0.3 to 1.3 times, respectively, of the recommended human dose based on body surface area comparisons (see Data ). Based on animal data, advise pregnant women of the risk for fetal harm. As rifapentine is always used in combination with other antituberculosis drugs such as isoniazid, ethambutol, and pyrazinamide, refer to the prescribing information of the other drug(s) for more information on their associated risks of use during pregnancy.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%–4% and 15%–20%, respectively.

Clinical Considerations Disease-associated maternal and/or embryo-fetal risk Active tuberculosis in pregnancy is associated with adverse maternal and neonatal outcomes including maternal anemia, cesarean delivery, preterm birth, low birth weight, birth asphyxia, and perinatal infant death. Labor or delivery When administered during the last few weeks of pregnancy, PRIFTIN may increase the risk for maternal postpartum hemorrhage and bleeding in the exposed neonate. Monitor prothrombin time of pregnant women and neonates who are exposed to PRIFTIN during the last few weeks of pregnancy.

Treatment with Vitamin K may be indicated. Data Human data Fourteen patients with active tuberculosis treated with multiple antituberculosis drugs including PRIFTIN became pregnant during clinical studies. Six delivered normal infants, four had first trimester spontaneous abortions (of these, one patient abused ethanol and another patient was HIV-infected), one had an elective abortion, and outcome was unknown in three patients.

These data are, however, limited by the quality of reporting and confounded by comorbid medical conditions and multiple antituberculosis drug exposures. In the trial that compared the safety and effectiveness of PRIFTIN in combination with isoniazid to isoniazid alone for the treatment of latent tuberculosis infection, a total of 45 (2.5%) women in the PRIFTIN/isoniazid arm and 71 (4.1%) women in the isoniazid arm became pregnant. Among the 46 total pregnancies in the PRIFTIN/isoniazid arm, there were 31 live births, 6 elective abortions, 7 spontaneous abortions, and 2 unknown outcomes.

Of the 31 live infants, 21 were reported healthy while in the other ten cases no further details were available. The rate of spontaneous abortion in the PRIFTIN/isoniazid arm (15%) and the rate of spontaneous abortion in the isoniazid arm (19%) did not represent an increase over the background rate of 15 to 20 percent reported in the general population. Further interpretation of these results is limited by the quality of adverse event reporting.

Animal data Animal studies in rats and rabbits revealed malformations and other adverse developmental outcomes in both species. Pregnant rats given oral rifapentine during organogenesis (gestational days 5 through 15) at 40 mg/kg/day (0.6 times the human dose of 600 mg based on body surface area comparisons) produced pups with cleft palates and mal-positioned aortic arches, delayed ossification, increased number of ribs, a decrease in litter size and mean litter weight, an increase in number of stillbirths, and an increase in mortality during lactation. When rifapentine was administered orally to mated female rats late in gestation, at 20 mg/kg/day (0.3 times the human dose based on body surface area), pup weights and gestational survival (live pups born/pups born) were reduced compared to controls.

Increased resorptions and postimplantation loss, decreased mean fetal weights, increased numbers of stillborn pups, and slightly increased pup mortality during lactation were also noted. When pregnant rabbits received oral rifapentine at 10 mg/kg to 40 mg/kg (0.3 times to 1.3 times the human dose based on body surface area) during organogenesis (GD6 to GD18), major fetal malformations occurred including: ovarian agenesis, pes varus, arhinia, microphthalmia, and irregularities of the ossified facial tissues. At 40 mg/kg/day, there were increases in postimplantation loss and the incidence of stillborn pups.

Pediatric Use The safety and effectiveness of PRIFTIN in the treatment of active pulmonary tuberculosis have not been established in pediatric patients under the age of 12. The safety and effectiveness of PRIFTIN in combination with isoniazid once-weekly regimen has been evaluated in pediatric patients (2 to 17 years of age) for the treatment of latent tuberculosis infection. In clinical studies, the safety profile in pediatric patients was similar to that observed in adult patients . In a pharmacokinetic study conducted in 2 to 11-year-old pediatric patients with latent tuberculosis infection, PRIFTIN was administered once weekly based on weight (15 mg/kg to 30 mg/kg, up to a maximum of 900 mg). Exposures (AUC) in pediatric patients 2 to 11 years old with latent tuberculosis infection were higher (average 31%) than those observed in adults receiving PRIFTIN 900 mg once weekly .

Hypersensitivity

PRIFTIN is contraindicated in patients with a history of hypersensitivity to rifamycins.

While there is no experience with the treatment of acute overdose with PRIFTIN, clinical experience with rifamycins suggests that gastric lavage to evacuate gastric contents (within a few hours of overdose), followed by instillation of an activated charcoal slurry into the stomach, may help adsorb any remaining drug from the gastrointestinal tract. Rifapentine and 25-desacetyl rifapentine are 97.7% and 93.2% plasma protein bound, respectively. Rifapentine and related compounds excreted in urine account for only 17% of the administered dose, therefore, neither hemodialysis nor forced diuresis is expected to enhance the systemic elimination of unchanged rifapentine from the body of a patient with PRIFTIN overdose.