The investigators in the tuberculosis treatment clinical trial (Study 008) assessed the causality of adverse events as definitely, probably, possibly, unlikely or not related to one of the two drug regimens tested. The following table Table 2-3) presents treatment- related adverse events deemed by the investigators to be at least possibly related to any of the four drugs in the regimens (rifapentine/rifampin, isoniazid, pyrasinamide, or ethambutol) which occurred in >1 % of patients. Hyperuricemia was the most frequently reported event that was assessed as treatment related and was most likely related to the pyrazinamide since no cases were reported in the Continuation Pphase when this drug was no longer included in the treatment regimen.

Treatment-related adverse evens of moderate or severe intensity in <1% of the rifapentine combination therapy patients in Study 008 are presented below by body system.

Hepatic & Biliary: bilirubmemia, hepatitis

Dermatologic: urticaria, skin discoloration

Hematologic: thrombocytopenia, neutrophilia, leukocytosis, purpura, hematoma

Metabolic & Nutritional: hyperkalemia, hypovolemia, alkaline phosphatase increased LDH increased

Body as a Whole General: peripheral edema, fatigue

Gastrointestinal: constipation, esophagitis, gastitis, pancreatitis

Musculoskeletal: gout, arthrosis

Psychiatric: aggressive reaction

Three patients (two rifampin combination therapy patients and on erifapentine combination therapy patient) were discontinued in the Intensive Phase as a result of hepatitis with increased liver function tests (ALT, AST, LDH, and bilirubin). Concomitant medications for all three patients included isoniazid, pyrazinamide, ethambutol, and pyridoxine. The two rifampin patients and one rifapentine patient recovered without sequelae.

Eighteen deaths occurred in Study 008 (nine in the rifampin combination therapy group and nine in the rifapentine combination therapy group). None of the deaths were attributed to study medication. In the study, 18/361 (5.0%) rifampin combination therapy patients discontinued the study due to an adverse event compared to 9/361 (2.5%) rifapentine combination therapy patients.

The overall occurrence rate of treatment-related adverse events was higher in males with the rifapentine combination regimen (50%) versus the rifampin combination regimen (43%), while in females the overall rate was greater in the rifampin combination group (68%) compared to the rifapentine combination group (59%) However, there were higher frequencies of treatment-related hematuria and ALT increases for female patients in both treatment groups compared to those for male patients.

Adverse events associated with rifampin may occur with rifapentine: effects of enzyme induction to increase metabolism resulting in decreased concentration of endogenous substrates, including adrenal hormones, thyroid hormones, and vitamin D.

Rigapentine-Indinavir Interaction: In a study in which 600 mg rifapentine was administered twice weekly for 14 days followed by rifapentine 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 rifapentine while half-life did not change. But when indinavir was administrated for 14 days followed by coadministration with rifapentine for an additional 14 days, indinavir did not affect the pharmacokinetics of rifapentine. Rifapentine should be used with extreme caution, if at all, in patients who are also taking protease inhibitors. (See WARNINGS and DOSAGE AND ADMINISTRATION) (See Reference 1)

Rifapentine is an inducer of cytochromes P4503A4 and P4502C8/9. Therefore,rifapentine may increase the metabolism of other coadministered drugs that are metabolized by these enzymes. Induction of enzymes activities by rifapentine occurred within 4 days after the first dose. Enzyme activities returned to baseline levels 14 days after discontinuing rifapentine. In addition, the magnitude of enzyme induction by rifapentine was dose and dosing frequency dependent; less enzyme induction occurred when 600mg oral doses of rifapentine were given once every 72 hours versus daily. In vitro and in vivo enzyme induction studies have suggested rifapentine induction potential may be less than rifampin but more potent than rifabutin. Rifampin has been reported to accelerate the metabolism and may reduce the activity of the following drugs; hence, rifapentine may also increase the metabolism and decrease the activity of these drugs. Dosage adjustments of the following drugs or of drugs metabolized by cytochrome P4503A4 or P4502C8/9 may be necessary if they are given concurrently with rifapentine. Patients using oral or other systemic hormonal contraceptives should be advised to change to nonhormonal methods of birth control.

Anticonvulsants: e.g., phenytoin

Antiarrhythmics: e.g., disopyramide, mexiletine. Quinidine, tocainide

Antibiotics: e.g., : chloramphenicol, clarithromycin, dapsone. Doxycycline, fluoroquinolones (such as ciprofloxacin)

Oral anticoagulants: e.g., warfarin

Antifungals:e.g., fluconazole, Itraconazole, ketoconazole

Barbiturates

Beta-blockers, calcium channel blockers: e.g., diltiazem, nifedipine, verapamil

Corticosteroids:

Cardiac glycoside preparations

Clofibrate:

Oral or other systemic hormonal contraceptives

Haloperidol

HIV protease inhibitors: e.g., indinavir, ritonavir, sequinavir (See Rifapentine-Indinavir Interaction above)

Oral hypoglycemic agents: e.g., sulfonylureas

Immunosuppressants: e.g., cyclosporine, tacrolimus

Levothyroxine

Narcotic analgesics: e.g., methadone

Progestins

Quinine

Reverse transcriptase inhibitors:e.g., delavirdine, zidovudine

Sildenafil

Theophylline

Tricyclic antidepressants: e.g., amtoptyline, nortriptyline.

The conversion of rifapentine to 25-desacetyl rifapentine is mediated by an esterase enzyme. There is minimal potential for rifapentine metabolism to be inhibited or induced by another drug, or for rifapentine to inhibit the metabolism of another drug based upon the characteristics of the esterase enzymes. Rifapentine does not induce its own metabolism. Since rifapentine is highly bound to albumin, drug displacement interactions may also occur.

In Clinical Study 008 patients were advised to take rifapentine at least 1 hour before or 2 hours after the ingestion of antacids.

Carcinogenicity, studies with rifapentine have not been completed. Rifapentine was negative in the following genotoxicity tests: in vitro gene routation 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-phosphoribosyl transferase (CHO/HGPRT), forward mutation assay: in vitro chromosomal aberration assay utilizing rat lymphocytes; and in vivo mouse bone marrow mocronucleus assay. Fertility and reproductive performance were not affected by oral administration of rifapentine to male and female rats at doses of up to one-third of the human dose (based on body surface area conversions).

Rifapentine has been shown to be teratogenic in rats and rabbits. In rats, when given in doses 0.6 times the human dose (based on body surface area comparisons )during the period if organogenesis, pups showed cleft palates, right aortic arch and increased incidence if delayed ossification and increased number of ribs. Rabbits treated with drug at doses between 0.3 and 1.3 times the human dose (based on body surface area comparison) displayed major malformations including ovarian agenesis, pes varus, arhinia, microphthalmia and irregularities of the ossified facial tissues (4 of 321 examined fetuses).

In rats, rifapentine administration was associated with increased resorption rate and post implantation loss, decreased mean fetus weight, increased number of stillborn pups and slightly increased mortality during lactation. Rabbits given 1.3 times the human dose (based on body surface area comparisons) showed higher post-implantation losses and an increased incidence of stillborn pups.

When rifapentine was administered at 0.3 times the human dose (based on body surface area comparisons) to mated female rats late in gestation (from day 15 of gestation to day 21 postpartum), pup weights and gestational survival (live pups born/pups born) were reduced compared to controls.

There are no adequate and well-controlled studies in pregnant women. In Clinical Study 008, six patients randomized to rifapentine became pregnant; two had normal deliveries, two had first trimester spontaneous abortions one had an elective abortion and one patient was lost to follow-up Of the two patients who spontaneously aborted, co-morbid conditions of ethanol abuse in one and HIV infection in the other were noted.

When administered during the last few weeks of pregnancy, rifampin can cause postnatal hemorrhages in the mother and infant for which treatment with Vitamin K may be indicated, Thus, patients and infants who receive rifapentine during the last few weeks of pregnancy should have appropriate clothing parameters evaluated.

Rifapentine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

It is not known whether rifapentine is excreated 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.

The safety and effectiveness of rifapentine in pediatric patients under the age of 12 have not been established. A pharmacokinetic study was conducted in 12 to 15 year old healthy volunteers. (See CLINICAL PHARMACOLOGY Special Populations for pharmacokinetic information).

Bookmark this page: