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Priftin

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Priftin

Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

HIV Seropositive Patients

PRIFTIN (rifapentine) should not be used as a once weekly Continuation Phase regimen in combination with isoniazid in HIV seropositive patients with pulmonary tuberculosis because of a higher rate of failure and/or relapse documented with the presence of rifampin-resistant organisms [see Clinical Studies].

PRIFTIN (rifapentine) has not been studied as part of the Initial Phase treatment regimen in HIV seropositive patients with pulmonary tuberculosis.

Protease Inhibitors and Reverse Transcriptase Inhibitors

Rifapentine is an inducer of CYP450 enzymes. Concomitant use of PRIFTIN (rifapentine) with other drugs metabolized by these enzymes, such as protease inhibitors and reverse transcriptase inhibitors, may cause a significant decrease in plasma concentrations and loss of therapeutic effect of the

protease inhibitor or reverse transcriptase inhibitor. [see DRUG INTERACTIONS and CLINICAL PHARMACOLOGY]

Relapse of Tuberculosis

PRIFTIN (rifapentine) should be used cautiously in subjects with cavitary pulmonary lesions and/or positive sputum cultures after the initial phase of treatment or in those with evidence of bilateral pulmonary disease due to higher rates of relapse. [see Clinical Studies].

Poor compliance with the dosage regimen, particularly during the initial phase in the companion antituberculosis drugs administered with rifapentine, is associated with late sputum conversion and a high relapse rate. Therefore, compliance with the full course of therapy must be emphasized, and the importance of not missing any doses must be stressed [see PATIENT INFORMATION].

Higher relapse rates have also been seen in HIV positive patients receiving PRIFTIN (rifapentine) during the continuation phase. Risk factors for relapse included the presence of both pulmonary and extrapulmonary disease at baseline, low CD4 counts, use of azole antifungals and age (younger) [see Clinical Studies].

Hepatotoxicity

Since antituberculous multidrug treatments, including the rifamycin class, are associated with serious hepatic events, patients with abnormal liver tests and/or liver disease should only be given rifapentine in cases of necessity and then with caution and under strict medical supervision. In these patients, careful monitoring of liver tests (especially serum transaminases) should be carried out prior to therapy and then every 2 to 4 weeks during therapy. If signs of liver disease occur or worsen, rifapentine should be discontinued. Hepatotoxicity of other antituberculosis drugs (eg, isoniazid, pyrazinamide) used in combination with rifapentine should also be taken into account.

Hyperbilirubinemia

Hyperbilirubinemia resulting from competition for excretory pathways between rifapentine and bilirubin cannot be excluded since competition between the related drug rifampin and bilirubin can occur. An isolated report showing a moderate rise in bilirubin and/or transaminase level is not in itself an indication for interrupting treatment; rather, the decision should be made after repeating the tests, noting trends in the levels and considering them in conjunction with the patient's clinical condition.

Discoloration of Body Fluids

PRIFTIN (rifapentine) may produce a predominately red-orange discoloration of body tissues and/or fluids (eg, skin, teeth, tongue, urine, feces, saliva, sputum, tears, sweat, and cerebrospinal fluid). Contact lenses or dentures may become permanently stained.

Porphyria

PRIFTIN (rifapentine) should not be used in patients with porphyria. Rifampin has enzyme-inducing properties, including induction of delta amino levulinic acid synthetase. Isolated reports have associated porphyria exacerbation with rifampin administration. Based on these isolated reports with rifampin, it may be assumed that rifapentine has a similar effect.

Clostridium difficile-Associated Diarrhea

Clostridium difficile--associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including the rifamycins, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to 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 antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Nonclinical Toxicology

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 (equivalent to a human dose of 0.4 mg/kg/day or 1/5 th of the recommended human dose, in the intensive phase, 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 (equivalent to a human dose of 6.5 mg/kg/day or 3 times the recommended human dose in the intensive phase, 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 one-third of the human dose (based on body surface area conversions).

Use In Specific Populations

Pregnancy

Pregnancy Category C: There are no adequate and well controlled studies of rifapentine use during pregnancy. In animal reproduction and developmental toxicity studies, rifapentine

produced fetal harm and was teratogenic. However, because animal studies are not always predictive of human response, rifapentine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

When administered during the last few weeks of pregnancy, rifampin, another rifamycin, may increase the risk for maternal postpartum hemorrhage and bleeding in the exposed infant. Therefore, pregnant women and their infants, who are exposed to rifapentine during the last few weeks of pregnancy, should have appropriate monitoring of clotting parameters. Treatment with Vitamin K may be indicated.

Six patients randomized to rifapentine became pregnant during a study of initial treatment of tuberculosis. Two delivered normal infants; two had first trimester spontaneous abortions; one had an elective abortion; and one patient was lost to follow-up. The two patients who spontaneously aborted had co-morbid conditions: One patient abused ethanol and the other patient was HIV positive.

Animal studies in rats and rabbits revealed embryofetal toxicity in both species. Pregnant rats given rifapentine during organogenesis at doses 0.6 times the human dose (based on body surface area), produced pups with cleft palates, right aortic arch, increased incidence of delayed ossification, and increased numbers of ribs. When rifapentine was administered to mated female rats late in gestation, at 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 post implantation loss, decreased mean fetal weights, increased numbers of stillborn pups, and slightly increased pup mortality during lactation were also noted. When pregnant rabbits received rifapentine at doses 0.3 to 1.3 times the human dose (based on body surface area), major fetal malformations occurred including: ovarian agenesis, pes varus, arhinia, microphthalmia and irregularities of the ossified facial tissues. At the higher dose, there were increases in post-implantation loss and the incidence of stillborn pups.

Nursing Mothers

It is not known whether rifapentine is excreted into 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 and the benefits of breastfeeding. Since rifapentine 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.

Pediatric Use

The safety and effectiveness of rifapentine in pediatric patients under the age of 12 have not been established. In a pharmacokinetic study conducted in 2 to 12 year-old pediatric patients, the exposure to rifapentine (i.e., AUC and Cmax) was lower compared with that observed in healthy adults [see CLINICAL PHARMACOLOGY]. Another pharmacokinetic study was conducted in 12 to 15 year-old healthy volunteers and the pharmacokinetics of rifapentine were similar to those observed in healthy adults [see CLINICAL PHARMACOLOGY].

Geriatric Use

The Clinical studies of PRIFTIN (rifapentine) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy [see CLINICAL PHARMACOLOGY].

Last reviewed on RxList: 8/27/2010
This monograph has been modified to include the generic and brand name in many instances.

Warnings
Precautions
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