Chemical formula: C₄₇H₆₄N₄O₁₂ Molecular mass: 877.031 g/mol PubChem compound: 6323497
Based on animal data, rifapentine may cause fetal harm when administered to a pregnant woman. Available data from clinical trials, case reports, epidemiology studies and postmarketing experience with rifapentine 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, rifapentine 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.
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.
When administered during the last few weeks of pregnancy, rifapentine 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 rifapentine during the last few weeks of pregnancy. Treatment with Vitamin K may be indicated.
Fourteen patients with active tuberculosis treated with multiple antituberculosis drugs including rifapentine 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 rifapentine in combination with isoniazid to isoniazid alone for the treatment of latent tuberculosis infection, a total of 45 (2.5%) women in the rifapentine/isoniazid arm and 71 (4.1%) women in the isoniazid arm became pregnant. Among the 46 total pregnancies in the rifapentine/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 rifapentine/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 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.
There are no data on the presence of rifapentine or its metabolite in human or animal milk, the effects on the breastfed infant, or the effects on milk production. Monitor infants exposed to rifapentine through breast milk for signs of hepatotoxicity (see Clinical Considerations). The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for rifapentine and any potential adverse effects on the breastfed infant from rifapentine or from the underlying maternal condition.
Monitor infants exposed to rifapentine through breast milk for signs of hepatotoxicity to include irritability, prolonged unexplained crying, yellowing of the eyes, loss of appetite, vomiting, and changes in color of the urine (darkening) or stool (lightening, pale or light brown).
Hepatocellular carcinomas were increased in male NMRI mice (Harlan Winklemann) which were treated orally with rifapentine for two years at or above doses of 5 mg/kg/day (0.04 times the recommended human dose based on body surface area conversions). In a two year rat study, there was an increase in nasal cavity adenomas in Wistar rats treated orally with rifapentine at 40 mg/kg/day (0.6 times human dose based on body surface area conversions).
Rifapentine was negative in the following genotoxicity tests: in vitro gene mutation assay in bacteria (Ames test); in vitro point mutation test in Aspergillus nidulans; in vitro gene conversion assay in Saccharomyces cerevisiae; host-mediated (mouse) gene conversion assay with Saccharomyces cerevisiae; in vitro Chinese hamster ovary cell/hypoxanthine-guanine phosphoribosyltransferase (CHO/HGPRT) forward mutation assay; in vitro chromosomal aberration assay utilizing rat lymphocytes; and in vivo mouse bone marrow micronucleus assay.
The 25-desacetyl metabolite of rifapentine was positive in the in vitro mammalian chromosome aberration test in V79 Chinese hamster cells, but was negative in the in vitro gene mutation assay in bacteria (Ames test), the in vitro Chinese hamster ovary cell/hypoxanthine-guanine phosphoribosyltransferase (CHO/HGPRT) forward mutation assay, and the in vivo mouse bone marrow micronucleus assay. Fertility and reproductive performance were not affected by oral administration of rifapentine to male and female rats at doses of up to 20 mg/kg/day (one-third of the human dose based on body surface area conversions).
The following serious and otherwise important adverse drug reactions are discussed in greater detail in other sections of labeling:
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.
Rifapentine 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 rifapentine 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 group continued to receive rifapentine 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 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 rifapentine combination therapy group. 18/361 (5%) rifampin combination therapy patients discontinued the study due to an adverse reaction compared to 11/361 (3%) rifapentine combination therapy patients. Three patients (two rifampin combination therapy patients and one rifapentine 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 overdose. These reactions included hematuria, neutropenia, hyperglycemia, ALT increased, hyperuricemia, pruritus, and arthritis.
Table 1 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 1. Selected Treatment Emergent Adverse Reactions during Treatment of Active Pulmonary Tuberculosis and through Three Months Follow-up:
| Initial Phase* | Continuation Phase† | |||
|---|---|---|---|---|
| System Organ Class Adverse Reaction | Rifapentine Combination (N=361) N (%) | Rifampin Combination (N=361) N (%) | Rifapentine 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) |
* Initial phase consisted of therapy with either rifapentine twice weekly or rifampin daily combined with daily isoniazid, pyrazinamide, and ethambutol for 60 days.
† Continuation phase consisted of therapy with either rifapentine 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 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 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 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 combination regimen compared to 6.7% for the rifampin combination regimen.
Rifapentine 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 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 children 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 children 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 2 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 2. 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) |
Six hundred and ninety children 2 to 17 years of age received at least one dose of study drugs in the main study. An additional 342 children 2 to 17 years of age received at least one dose in the pediatric extension study (total 1032 children; 539 received 3RPT/INH and 493 received 9INH).
No children in either treatment arm developed hepatotoxicity. Using the same definition for rifamycin hypersensitivity reaction as in the main study, 7 (1.3%) of children in the 3RPT/INH group experienced a rifamycin hypersensitivity reaction. Adverse reactions in children 2 to 11 years of age and 12 to 17 years of age were similar.
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.
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.
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
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