PRIFTIN Film-coated tablet Ref.[11132] Active ingredients: Rifapentine

When oral doses of PRIFTIN were administered once daily or once every 72 hours to healthy volunteers for 10 days, single dose AUC_(0–∞) of rifapentine was similar to its steady-state AUC_ss(0–24h) or AUC_ss(0–72h) values, suggesting no significant auto-induction effect on steady-state pharmacokinetics of rifapentine. Steady-state conditions were achieved by day 10 following daily administration of PRIFTIN 600 mg. No plasma accumulation of rifapentine and 25-desacetyl rifapentine (active metabolite) is expected after once weekly administration of PRIFTIN.

The pharmacokinetic parameters of rifapentine and 25-desacetyl rifapentine on day 10 following oral administration of 600 mg PRIFTIN every 72 hours to healthy volunteers are described in Table 5.

Table 5. Pharmacokinetics and Rifapentine and 25-Desacetyl Rifapentine in Healthy Volunteers:

The pharmacokinetic parameters of rifapentine and 25-desacetyl rifapentine following single-dose oral administration of 900 mg PRIFTIN in combination with 900 mg isoniazid in fed conditions are described in Table 6.

Table 6. Mean ± SD Pharmacokinetic Parameters of Rifapentine and 25-Desacetyl Rifapentine in Healthy Volunteers When PRIFTIN is Coadministered with Isoniazid Under Fed Conditions (N=16):

^* Median (Min–Max).
^† Not Applicable.

Absorption

The absolute bioavailability of PRIFTIN has not been determined. The relative bioavailability (with an oral solution as a reference) of PRIFTIN after a single 600 mg dose to healthy adult volunteers was 70%. The maximum concentrations were achieved from 5 hours to 6 hours after administration of the 600 mg PRIFTIN dose.

The administration of PRIFTIN with a high fat meal increased rifapentine C_max and AUC by 40% to 50% over that observed when PRIFTIN was administered under fasting conditions.

The administration of PRIFTIN (900 mg single dose) and isoniazid (900 mg single dose) with a low fat, high carbohydrate breakfast, led to a 47% and 51% increase in rifapentine C_max and AUC, respectively. In contrast, the ingestion of the same meal decreased isoniazid C_max and AUC by 46% and of 23%, respectively.

Distribution

In a population pharmacokinetic analysis in 351 tuberculosis patients who received 600 mg PRIFTIN in combination with isoniazid, pyrazinamide and ethambutol, the estimated apparent volume of distribution was 70.2 ± 9.1 L. In healthy volunteers, rifapentine and 25-desacetyl rifapentine were 97.7% and 93.2% bound to plasma proteins, respectively. Rifapentine was mainly bound to albumin. Similar extent of protein binding was observed in healthy volunteers, asymptomatic HIV-infected subjects and hepatically impaired subjects.

Metabolism/Excretion

Following a single 600 mg oral dose of radiolabeled rifapentine to healthy volunteers (n=4), 87% of the total 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 C_max values of the 25-desacetyl rifapentine metabolite were one-half and one-third those of the rifapentine, respectively. Based upon relative in vitro activities and AUC_(0–∞) values, rifapentine and 25-desacetyl rifapentine potentially contributes 62% and 38% to the clinical activities against M. tuberculosis, respectively.

Specific Populations

Gender

In a population pharmacokinetics analysis of sparse blood samples obtained from 351 tuberculosis patients who received 600 mg PRIFTIN in combination with isoniazid, pyrazinamide and ethambutol, the estimated apparent oral clearance of PRIFTIN for males and females was 2.51 ± 0.14 L/h and 1.69 ± 0.41 L/h, respectively. The clinical significance of the difference in the estimated apparent oral clearance is not known.

Elderly

Following oral administration of a single 600 mg dose of PRIFTIN to elderly (65 years and older) male healthy volunteers (n=14), the pharmacokinetics of rifapentine and 25-desacetyl metabolite were similar to that observed for young (18 to 45 years) healthy male volunteers (n=20).

Pediatric

In a pharmacokinetic study in pediatric patients (age 2 to 12 years), a single oral dose of 150 mg PRIFTIN was administered to those weighing less than 30 kg (n=11) and a single oral dose of 300 mg was administered to those weighing greater than 30 kg (n=12). The mean estimates of AUC and C_max were approximately 30% to 50% lower in these pediatric patients than those observed in healthy adults administered single oral doses of 600 mg and 900 mg.

A study compared the pharmacokinetics of rifapentine in pediatric patients (age 2 years to 11 years) with latent tuberculosis infection (n=80) receiving PRIFTIN once weekly based on weight (15 mg/kg to 30 mg/kg, up to a maximum of 900 mg, see Table 1) to that of adults (n=77) receiving PRIFTIN 900 mg once weekly. 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 to 18 years).

In another pharmacokinetics study of PRIFTIN in healthy adolescents (age 12 to 15 years), 600 mg PRIFTIN was administered to those weighing ≥45 kg (n=10) and 450 mg was administered to those weighing less than 45 kg (n=2). The pharmacokinetics of rifapentine was similar to those observed in healthy adults.

Renal Impaired Patients

The pharmacokinetics of rifapentine has not been evaluated in renal impaired patients. Although only about 17% of an administered dose is excreted via the kidneys, the clinical significance of impaired renal function on the disposition of rifapentine and its 25-desacetyl metabolite is not known.

Hepatic Impaired Patients

Following oral administration of a single 600 mg dose of PRIFTIN to mild to severe hepatic impaired patients (n=15), the pharmacokinetics of rifapentine and 25-desacetyl metabolite were similar in patients with various degrees of hepatic impairment and to that observed in another study for healthy volunteers (n=12).

Asymptomatic HIV-Infected Volunteers

Following oral administration of a single 600 mg dose of PRIFTIN to asymptomatic HIV-infected volunteers (n=15) under fasting conditions, mean C_max and AUC_(0–∞) of rifapentine were lower (20%–32%) than that observed in other studies in healthy volunteers (n=55). In a cross-study comparison, mean C_max and AUC values of the 25-desacetyl rifapentine, when compared to healthy volunteers were higher (6%–21%) in one study (n=20), but lower (15%–16%) in a different study (n=40). The clinical significance of this observation is not known. Food (850 total calories: 33 g protein, 55 g fat, and 58 g carbohydrate) increases the mean AUC and C_max of rifapentine observed under fasting conditions in asymptomatic HIV-infected volunteers by about 51% and 53%, respectively.

Drug-Drug Interactions

Isoniazid

Coadministration of PRIFTIN (900 mg single dose) and isoniazid (900 mg single dose), in fasted condition, did not result in any significant change in the exposure of rifapentine and isoniazid compared to when administered alone in fasted condition.

Rifapentine is an inducer of cytochrome P450 3A4 and 2C8/9. Therefore, it may increase the metabolism and decrease the activity of other coadministered drugs that are metabolized by these enzymes. Dosage adjustments of the coadministered drugs may be necessary if they are given concurrently with PRIFTIN [see Drug Interactions (7.4)].

Indinavir

In a study in which 600 mg PRIFTIN was administered twice weekly for 14 days followed by PRIFTIN twice weekly plus 800 mg indinavir 3 times a day for an additional 14 days, indinavir C_max decreased by 55% while AUC reduced by 70%. Clearance of indinavir increased by 3-fold in the presence of PRIFTIN while half-life did not change. But when indinavir was administered for 14 days followed by coadministration with PRIFTIN for an additional 14 days, indinavir did not affect the pharmacokinetics of rifapentine [see Warnings and Precautions (5.5) and Drug Interactions (7.1)].

Fixed-dose combination of efavirenz, emtricitabine and tenofovir

Once-weekly coadministration of 900 mg PRIFTIN with the antiretroviral fixed-dose combination of efavirenz 600 mg, emtricitabine 200 mg and tenofovir disoproxil fumarate 300 mg in HIV-infected patients did not result in any substantial change in steady state exposures of efavirenz, emtricitabine, and tenofovir (Table 7). A 15% decrease in efavirenz C_min and AUC and a 13% decrease in tenofovir C_min were observed with repeated weekly doses of PRIFTIN (Table 7). No clinically significant change in CD4 cell counts or viral loads were noted.

Table 7. Treatment Ratio Estimates (with versus without repeated once-weekly PRIFTIN 900 mg) with 90% Confidence Intervals for Efavirenz, Emtricitabine and Tenofovir Pharmacokinetic Parameters:

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.

Mechanism of Resistance

The mechanism of resistance to rifapentine appears to be similar to that of rifampin. Bacterial resistance to rifapentine is caused by an alteration in the target site, the beta subunit of the DNA-dependent RNA polymerase, caused by a one-step mutation in the rpoβ gene. The incidence of rifapentine resistant mutants in an otherwise susceptible population of M. tuberculosis strains is approximately one in 10⁷ to 10⁸ bacilli. Rifapentine resistance appears to be associated with monotherapy. Therefore, rifapentine should always be used in combination with other antituberculosis drugs.

Cross Resistance

M. tuberculosis organisms resistant to other rifamycins are likely to be resistant to rifapentine. A high level of cross-resistance between rifamycin and rifapentine has been demonstrated with M. tuberculosis strains. Cross-resistance between rifapentine and non-rifamycin antimycobacterial agents has not been identified in clinical isolates.

Susceptibility Testing

For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

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).

14.1 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 rifampin 600 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).

Table 8. Clinical Outcome in HIV Negative Patients with Active Pulmonary Tuberculosis (Trial 1):

^* All data for patients with confirmed susceptible M. tuberculosis (PRIFTIN combination treatment, N=286; rifampin combination treatment, N=283).
^† Twenty-two (22) deaths occurred during the study; 11 in each treatment group.

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 monoresistance to rifampin.

The second trial was randomized, open-label performed in 1075 HIV-negative and HIV-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.

Table 9. Clinical Outcome in HIV Negative Patients with Active Pulmonary Tuberculosis (Trial 2):

^* Treatment response was defined as subjects who had two negative sputum cultures after 16 doses of rifampin and isoniazid or after 8 doses of PRIFTIN and isoniazid, and remained sputum negative through the end of continuation phase therapy.
^† Due to drug toxic effects, non-adherence, withdrawal of consent, receipt of non-study regimen, other.

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.

14.2 Latent Tuberculosis Infection

A multicenter, 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 [see Dosage and Administration (2.2)].

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).

Table 10. Outcomes in Randomized Patients at 33 Months Post Enrollment*:

^* Similar results were observed when all enrolled patients were included in the analysis.
^† Rate in the 3RPT/INH group minus the rate in the 9INH group.

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.

Pediatric substudy

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).

HIV substudy

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).