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Rifapentine is an antimycobacterial drug that is FDA approved for the treatment of active pulmonary tuberculosis and latent tuberculosis. Common adverse reactions include anemia, lymphopenia, neutropenia, increased ALT, arthralgia, conjunctivitis, headache, vomiting, nausea, diarrhea, rash, pruritus, anorexia and lymphadenopathy.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Active Pulmonary Tuberculosis
- PRIFTIN® (rifapentine) is indicated in adults and children 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.
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.
- PRIFTIN has not been studied as part of the initial phase treatment regimen in HIV- infected patients with active pulmonary tuberculosis.
Latent Tuberculosis Infection
- PRIFTIN is indicated in adults and children 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).
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.
- PRIFTIN in combination with isoniazid is not recommended for Individuals presumed to be exposed to rifamycin- or - isoniazid resistant M. tuberculosis.
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 anti- tuberculosis 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 anti- tuberculosis agent for susceptible organisms administered as directly observed therapy.
Dosage in Latent Tuberculosis Infection
- PRIFTIN should be administered once-weekly in combination with isoniazid for 12 weeks as directly observed therapy.
- Adults and children 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 100mg) up to a maximum of 900 mg once-weekly for 12 weeks.
- Children 2–11 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 100mg) up to a maximum of 900 mg once-weekly for 12 weeks.
DOSAGE FORMS AND STRENGTHS
- PRIFTIN is supplied as 150 mg round normal convex dark-pink film-coated tablets debossed "Priftin" on top and "150" on the bottom.
Off-Label Use and Dosage (Adult)
- There is limited information regarding Off-Label Guideline-Supported Use of Rifapentine in adult patients.
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Rifapentine in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
- There is limited information regarding FDA-Labeled Use of Rifapentine in pediatric patients.
Off-Label Use and Dosage (Pediatric)
- There is limited information regarding Off-Label Guideline-Supported Use of Rifapentine in pediatric patients.
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Rifapentine in pediatric patients.
- PRIFTIN is contraindicated in patients with a history of hypersensitivity to rifamycins.
- Elevations of liver transaminases may occur in patients receiving PRIFTIN. Patients on PRIFTIN 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 PRIFTIN in cases of necessity and under strict medical supervision. In such patients, obtain serum transaminase levels prior to therapy and every 2–4 weeks while on therapy. Discontinue PRIFTIN if evidence of liver injury occurs.
Hypersensitivity and Related Reactions
- Hypersensitivity reactions may occur in patients receiving PRIFTIN. 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.
- Monitor patients receiving PRIFTIN therapy for signs and/or symptoms of hypersensitivity reactions. If these symptoms occur, administer supportive measures and discontinue PRIFTIN.
Relapse in the Treatment of Active Pulmonary Tuberculosis
- PRIFTIN has not been evaluated as part of the initial phase treatment regimen in HIV-infected patients with active pulmonary TB.
- Do not use PRIFTIN 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.
- 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.
- Poor adherence to therapy is associated with high relapse rate. Emphasize the importance of compliance with therapy.
- 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.
Discoloration of Body Fluids
- PRIFTIN 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.
Clostridium difficile-Associated Diarrhea
- Clostridium difficile-associated diarrhea (CDAD) has been reported with the use of nearly all systemic antibacterial agents, including PRIFTIN, 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.
- Porphyria has been reported in patients receiving rifampin, attributed to induction of delta amino levulinic acid synthetase. Because PRIFTIN may have similar enzyme induction properties, avoid the use of PRIFTIN in patients with porphyria.
Clinical Trials Experience
- The following serious and otherwise important adverse drug reactions are discussed in greater detail in other sections of labeling:
- Discoloration of Body Fluids
- Clostridium difficile-Associated Diarrhea
- 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 of 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.
- 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.
- Metabolic & Nutritional: BUN increased, alkaline phosphatase increased.
- Infectious Disease: infection fungal.
- Pregnancy, Puerperium and Perinatal conditions: abortion
- 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. 502 HIV non-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
- 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 children 2–17 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 years–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. 161 (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. 113 (3%) 9INH subjects and 24 (0.6%) 3RPT/INH subjects developed hepatotoxicity.
- 196 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%.
- Six-hundred and ninety children 2 years–17 years of age received at least one dose of study drugs in the main study. An additional 342 children 2 years–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 years–11 years of age and 12 years–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 0.5% of the 3RPT/INH combination-therapy group in the main study are presented below by body system.
- Eye Disorders: conjunctivitis.
- Renal and Urinary Disorders: azotemia.
- Reproductive System and Breast Disorders: vulvovaginal pruritus.
- There is limited information regarding Postmarketing Experience of Rifapentine in the drug label.
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 co-administration of 900 mg PRIFTIN with the antiretroviral fixed dose combination of efavirenz 600 mg, emtricitabine 200 mg and tenofovir disoproxyl fumarate 300mg 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.
- PRIFTIN may reduce the effectiveness of hormonal contraceptives. Therefore, patients using oral, transdermal patch, or other systemic hormonal contraceptives should be advised to change to non-hormonal methods of birth control.
Cytochrome P450 3A4 and 2C8/9
- Rifapentine is an inducer of cytochromes P4503A4 and P4502C8/9. 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 P4503A4 or P4502C8/9 may be necessary if they are given concurrently with PRIFTIN.
- 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 B12. Similar drug-laboratory interactions should be considered for PRIFTIN; thus, alternative assay methods should be considered.
Use in Specific Populations
Pregnancy Category (FDA): Pregnancy Category C:
- There are no adequate and well controlled trials of PRIFTIN in pregnant women; however, there are limited pregnancy outcome data reported from women enrolled in clinical trials of various PRIFTIN treatment regimens for active tuberculosis and latent tuberculosis infection. The reported rate of spontaneous abortion following PRIFTIN exposure did not represent an increase over the background rate of spontaneous abortion reported in the general population. Further interpretation of these data is limited by the quality of clinical trial adverse event reporting. In animal reproduction and developmental toxicity studies, rifapentine produced fetal harm and was teratogenic at doses less than and similar to the recommended human dose. Because animal studies are not always predictive of human response, PRIFTIN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Rifapentine in women who are pregnant.
Labor and Delivery
- When administered during the last few weeks of pregnancy, rifampin, another rifamycin product, 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.
- It is not known whether PRIFTIN is present in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Since PRIFTIN may produce a red-orange discoloration of body fluids, there is a potential for discoloration of breast milk.
- A slight increase in rat pup mortality was observed during lactation when dams were dosed late in gestation through lactation.
- 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 (2–17 years of age) for the treatment of latent tuberculosis infection. In clinical studies, the safety profile in children was similar to that observed in adult patients.
- In a pharmacokinetic study conducted in 2 year to 11 year-old pediatric patients with latent tuberculosis infection, PRIFTIN was administered once-weekly based on weight (15mg/kg to 30 mg/Kg, up to a maximum of 900 mg). Exposures (AUC) in children 2 years–11 years with latent tuberculosis infection were higher (average 31%) than those observed in adults receiving PRIFTIN 900mg once-weekly
- Clinical studies with PRIFTIN did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. In a pharmacokinetic study with PRIFTIN, no substantial differences in the pharmacokinetics of rifapentine and 25-desacetyl metabolite were observed in the elderly compared to younger adults.
There is no FDA guidance on the use of Rifapentine with respect to specific gender populations.
There is no FDA guidance on the use of Rifapentine with respect to specific racial populations.
There is no FDA guidance on the use of Rifapentine in patients with renal impairment.
There is no FDA guidance on the use of Rifapentine in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Rifapentine in women of reproductive potentials and males.
There is no FDA guidance one the use of Rifapentine in patients who are immunocompromised.
Administration and Monitoring
- There is limited information regarding Monitoring of Rifapentine in the drug label.
- There is limited information regarding IV Compatibility of Rifapentine in the drug label.
- 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.
Mechanism of Action
- Rifapentine, a cyclopentyl rifamycin, inhibits DNA-dependent RNA polymerase in susceptible strains of Mycobacterium tuberculosis but does not affect mammalian cells at concentrations that are active against these bacteria. At therapeutic levels, rifapentine inhibits RNA transcription by preventing the initiation of RNA chain formation. It forms a stable complex with bacterial DNA-dependent RNA polymerase, leading to repression of RNA synthesis and cell death. Rifapentine and its 25-desacetyl metabolite accumulate in human monocyte-derived macrophages and are bactericidal to both intracellular and extracellular M. tuberculosis bacilli.
- PRIFTIN (rifapentine) for oral administration contains 150 mg of the active ingredient rifapentine per tablet.
- The 150 mg tablets also contain, as inactive ingredients: calcium stearate, disodium EDTA, FD&C Blue No. 2 aluminum lake, hydroxypropyl cellulose, hypromellose USP, microcrystalline cellulose, polyethylene glycol, pregelatinized starch, propylene glycol, sodium ascorbate, sodium lauryl sulfate, sodium starch glycolate, synthetic red iron oxide, and titanium dioxide.
- Rifapentine is a rifamycin derivative antimicrobial and has a similar profile of microbiological activity to rifampicin. The molecular weight is 877.04.
- The molecular formula is C47H64N4O12.
- The chemical name for rifapentine is rifamycin, 3-[[(4-cyclopentyl-1-piperazinyl)imino]methyl]]-or 3-[N-(4-Cyclopentyl-1-piperazinyl)formimidoyl]rifamycin or 5,6,9,17,19,21-hexahydroxy-23-methoxy-2,4,12,16,18,20,22-heptamethyl-8-[N-(4-cyclopentyl-l-piperazinyl)-formimidoyl]-2,7-(epoxypentadeca[1,11,13]trienimino)naphtho[2,1-b]furan-1,11(2H)-dione 21-acetate. It has the following structure:
There is limited information regarding Pharmacodynamics of Rifapentin in the drug label.
- 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 AUCss (0–24h) or AUCss (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.
- 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.
- 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 Cmax 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 Cmax and AUC, respectively. In contrast, the ingestion of the same meal decreased isoniazid Cmax and AUC by 46% and of 23%, respectively.
- 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.
- Following a single 600 mg oral dose of radiolabeled rifapentine to healthy volunteers (n=4), 87% of the total 14C rifapentine was recovered in the urine (17%) and feces (70%). Greater than 80% of the total 14C 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 Cmax 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.
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 than30kg (n=12). The mean estimates of AUC and Cmax 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–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. Children 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 children administered whole tablets (884 versus 551 mcg*h/mL) and 19% higher in children 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 (2–18 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 were similar to those observed in healthy adults.
Renal Impaired Patients: The pharmacokinetics of rifapentine have 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 Cmax 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 Cmax 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 Cmax of rifapentine observed under fasting conditions in asymptomatic HIV-infected volunteers by about 51% and 53%, respectively.
Isoniazid: Co-administration 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 P4503A4 and 2C8/9. Therefore, it may increase the metabolism and decrease the activity of other co-administered drugs that are metabolized by these enzymes. Dosage adjustments of the co-administered 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 Cmax 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 co-administration with PRIFTIN for an additional 14 days, indinavir did not affect the pharmacokinetics of rifapentine.
Fixed dose combination of efavirenz, emtricitabine and tenofovir: Once-weekly co-administration of 900 mg PRIFTIN with the antiretroviral fixed dose combination of efavirenz 600 mg, emtricitabine 200 mg and tenofovir disoproxyl fumarate 300mg in HIV- infected patients did not result in any substantial change in steady state exposures of efavirenz, emtricitabine, and tenofovir (Table7). A 15% decrease in efavirenz Cmin and AUC and a 13% decrease in tenofovir Cmin were observed with repeated weekly doses of PRIFTIN (Table 7). No clinically significant change in CD4 cell counts or viral loads were noted.
Carcinogenesis, Mutagenesis, Impairment of Fertility
- 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/hypoxanthineguanine-phosphoribosyl transferase (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-phosphoribosyl transferase (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).
Active Pulmonary Tuberculosis
- PRIFTIN was studied in two randomized, open-label controlled clinical trials in the treatment of active pulmonary tuberculosis.
- The first trial was an open-label, prospective, parallel group, active controlled trial in HIV-negative patients with active pulmonary tuberculosis. The population mostly comprised Black (approximately 60%) or multiracial (approximately 31%) patients. Treatment groups were comparable for age and sex and 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 rifampin600 mg in combination with isoniazid, pyrazinamide and ethambutol all administered daily. The doses of the companion drugs were the same in both treatment groups during the initial phase: isoniazid 300 mg, pyrazinamide 2000 mg, and ethambutol 1200 mg. For patients weighing less than 50 kg, the doses of rifampin (450 mg), pyrazinamide (1500 mg) and ethambutol (800 mg) were reduced. Ethambutol was discontinued when isoniazid and rifampin susceptibility testing results were confirmed. During the 4 month continuation phase, 317 patients in the PRIFTIN group continued to receive PRIFTIN 600 mg dosed once-weekly with isoniazid 300 mg and 304 patients in the rifampin group received twice weekly rifampin and isoniazid 900 mg. For patients weighing less than 50 kg, the doses of rifampin (450 mg) and isoniazid (600 mg) were reduced. Both treatment groups received pyridoxine (Vitamin B6) over the 6 month treatment period. Treatment was directly observed. 65/361 (18%) of patients in the PRIFTIN group and 34/361 (9%) in the rifampin group received overdoses of one or more of the administered study medications during the initial or continuation phase of treatment. Seven of these patients had adverse reactions reported with the overdose (5 in the PRIFTIN group and 2 in the rifampin group).
- Table 8 below contains assessments of sputum conversion at end of treatment (6 months) and relapse rates at the end of follow-up (24 months).
- Risk of relapse was greater in the group treated with the PRIFTIN combination. Higher relapse rates were associated with a lower rate of compliance as well as a failure to convert sputum cultures at the end of the initial 2 month treatment phase. Relapse rates were also higher for males in both regimens. Relapse in the PRIFTIN group was not associated with development of mono-resistance to rifampin.
- The second trial was randomized, open-label performed in 1075 HIV-negative and positive patients with active pulmonary tuberculosis. Patients with culture-positive, drug-susceptible pulmonary tuberculosis who had completed the initial 2-month phase of treatment with 4 drugs (rifampin, isoniazid, pyrazinamide, and either ethambutol or streptomycin) under direct observation were randomly assigned to receive either PRIFTIN 600 mg and isoniazid 15 mg/kg (max 900 mg) once-weekly or rifampin 10 mg/kg (max 600 mg) and isoniazid 15 mg/kg (max 900 mg) twice weekly for the 4 month continuation phase. Study drugs were given under direct observation therapy in both groups.
- In the PRIFTIN group, 502 HIV-negative and 36 HIV-positive patients were randomized and in the rifampin group 502 HIV-negative and 35 HIV-positive patients were randomized to treatment. Enrollment of HIV-infected patients was stopped when 4 of 36 patients in the PRIFTIN combination group relapsed with isolates that were rifampin resistant.
- Table 9 below contains assessments of sputum conversion at the end of treatment (6 months total: 2 months of initial and 4 months of randomized continuation treatment) and relapse rates at the end of follow-up (24 months) in all HIV-negative patients randomized to treatment. Positive culture was based on either one sputum sample with >10 colonies on solid media OR at least 2 positive sputum samples on liquid or solid media. However, only one sputum sample was collected at each visit in a majority of patients.
- In HIV-negative patients, higher relapse rates were seen in patients with a positive sputum culture at 2 months (i.e., at the time of study randomization), cavitation on chest x-ray, and bilateral pulmonary involvement.
- Sixty-one HIV-positive patients were assessed for relapse. The rates of relapse were 16.7% (5/30) in the PRIFTIN group and 9.7% (3/31) in the rifampin group. In HIV-positive patients, 4 of the 5 relapses in the PRIFTIN combination group involved M. tuberculosis strains with rifampin monoresistance. No relapse strain in the twice weekly rifampin / isoniazid group acquired drug resistance.
- The death rate among all study participants did not differ between the two treatment groups.
Latent Tuberculosis Infection
- A multi-center, prospective, open-label, randomized, active-controlled trial compared the effectiveness of 12 weekly doses of PRIFTIN in combination with isoniazid (3RPT/INH arm) administered by directly observed therapy to 9 months of self-administered daily isoniazid (9INH arm). The trial enrolled patients two years of age or older with positive tuberculin skin test and at high risk for progression to tuberculosis disease. Enrolled patients included those having close contact with a patient with active tuberculosis disease, recent (within two years) conversion to a positive tuberculin skin test, HIV-infection, or fibrosis on chest radiograph. PRIFTIN was dosed by weight, for a maximum of 900 mg weekly. Isoniazid mg/kg dose was determined by age, for a maximum of 900 mg weekly in the 3RPT/INH arm and 300 mg daily in the 9INH arm.
- The outcome measure was the development of active tuberculosis disease, defined as culture confirmed tuberculosis in adults and culture-confirmed or clinical tuberculosis in children less than 18 years of age, at 33 months after trial enrollment. Patients who were found after enrollment to be ineligible because they had active tuberculosis disease, were contacts of a source case with culture-negative or drug-resistant tuberculosis disease cases or no information regarding susceptibility of M. tuberculosis, and young children lacking a positive TST on initial and repeat testing were excluded from the analysis.
- Active tuberculosis disease developed in 5 of 3074 randomized patients in the 3RPT/INH group (0.16%) versus 10 of 3074 patients in 9INH group (0.32%), for a difference in cumulative rates of 0.17%, 95% CI (-0.43, 0.09) (Table 10).
- The proportion of patients completing treatment was 81.2% in the 3RPT/INH group and 68.3% in the 9INH group for a difference (3RPT/INH-9INH) of 12.8% 95% CI (10.7, 15.0).
- In the 9INH treatment group, two of the thirteen culture-confirmed cases were found to be isoniazid -monoresistant. In the 3RPT/INH treatment group, one of the seven cases was rifampin -resistant, isoniazid -susceptible M. bovis infection.
- Enrollment of children was extended after the overall target number of patients was attained in the main study. Data from both the main study and the extension were pooled resulting in an eligible population for analysis of 375 children in the 3RPT/INH arm and 367 in the 9INH arm.
- One child in the 9INH group developed tuberculosis (1/367, cumulative rate 0.32%) versus zero tuberculosis cases in the 3RPT/INH group (0/375) at 33 months post-enrollment. The proportion of patients completing treatment in the 3RPT/INH and the 9INH groups was 87.5% and 79.6% respectively for a difference of 7.9%, 95% CI (2.5, 13.2).
- Enrollment of HIV-positive patients was extended after the overall target number of patients was attained in the main study. Data from both the main study and the extension were pooled resulting in an eligible population for analysis of 206 patients in the 3RPT/INH group and 193 in the 9INH group. Tuberculosis disease developed in 2/206 patients in the 3RPT/INH group (cumulative rate, 1.01%) and in 6/193 patients in the 9INH group (cumulative rate, 3.45%). The proportion of patients completing treatment in the 3RPT/INH and 9INH groups was 88.8% and 63.7%, respectively for a difference of 25.1%, 95% CI (16.8, 32.9).
- PRIFTIN is supplied as 150 mg round normal convex dark-pink film-coated tablets debossed "Priftin" on top and "150" on the bottom, packaged in aluminum formable foil blister strips inserted into an aluminum foil laminated pouch.
- Carton of 32 tablets (4 strips of 8 tablets) NDC 0088-2100-32
- Carton of 24 tablets (3 strips of 8 tablets) NDC 0088-2100-24
- Store at 25°C (77°F); excursions permitted 15–30°C (59–86°F) (see USP Controlled Room Temperature). Protect from excessive heat and humidity.
Package and Label Display Panel
Patient Counseling Information
- Emphasize the importance of compliance with the full course of therapy, and the importance of not missing any doses of PRIFTIN or companion medications in the treatment of active pulmonary tuberculosis or the treatment of latent tuberculosis infection.
- Inform patients that PRIFTIN may cause hypersensitivity reactions. Signs and symptoms of this reaction may include a flu-like illness, hypotension, urticaria, angioedema, bronchospasm, conjunctivitis, thrombocytopenia or neutropenia. Anaphylaxis may also occur.
- Inform patients of signs and symptoms of hypersensitivity reactions and advise them to stop the medication and contact their healthcare provider if they experience any of these symptoms.
- Instruct patients to stop the medication and notify their physician promptly if they experience any of the following: fever, loss of appetite, malaise, nausea and vomiting, darkened urine, yellowish discoloration of the skin and eyes, and pain or swelling of the joints [see WARNINGS AND PRECAUTIONS (5.1)].
- Rifapentine may increase the metabolism and decrease the activity of other drugs that are metabolized by the P4503A4 and 2C8/9 pathways. Dosage adjustments of the co-administered drugs may be necessary. Advise patients to discuss with their physician any other medications they are taking before starting treatment with PRIFTIN.
- Concomitant use of PRIFTIN with protease inhibitors or reverse transcriptase inhibitors may cause a significant decrease in plasma concentrations and loss of therapeutic effect of the protease inhibitor or reverse transcriptase inhibitor.
- Rifapentine may reduce the effectiveness of hormonal contraceptives. Advise patients using oral, transdermal patch, or other systemic hormonal contraceptives to change to non-hormonal methods of birth control. [see DRUG INTERACTIONS (7.3)]
Discoloration of Body Fluids
- Inform the patient that PRIFTIN produces a reddish coloration of the urine, sweat, sputum, tears, and breast milk. Contact lenses or dentures may be permanently stained.
Administration with Food
- Advise patients to take PRIFTIN with food.
- Advise nursing mothers that breastfeeding is not recommended with PRIFTIN use
Precautions with Alcohol
Alcohol-Rifapentin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
- PRIFTIN ®
Look-Alike Drug Names
There is limited information regarding Rifapentine Look-Alike Drug Names in the drug label.
The contents of this FDA label are provided by the National Library of Medicine.