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Priftin (Rifapentine) - Warnings and Precautions

 
 



WARNINGS

Poor compliance with the dosage regimen, particularly the daily administered non-rifamycin drugs in the Intensive Phase, was associated with late sputum conversion and a high relapse rate in the rifapentine arm of Clinical Study 008. Therefore, compliance with the full course of therapy must be emphasized, and the importance of not missing any doses must be stressed. (See PRECAUTIONS and DOSAGE AND ADMINISTRATION.)

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 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.

Pseudomembranous colitis has been reported to occur with various antibiotics, including other rifamycins. Diarrhea, particularly if severe and/or persistent, occurring during treatment or in the initial weeks following treatment may be symptomatic of Clostridium difficile -associated disease, the most severe form of which is pseudomembranous colitis. If pseudomembranous colitis is suspected, rifapentine should be stopped immediately and the patient should be treated with supportive and specific treatment without delay (eg, oral vancomycin). Products inhibiting peristalsis are contraindicated in this clinical situation.

Experience in HIV-infected patients is limited. In an ongoing CDC TB trial, five out of 30 HIV‑infected patients randomized to once weekly rifapentine (plus INH) in the Continuation Phase who completed treatment, relapsed. Four of these patients developed rifampin mono-resistant (RMR) TB. Each RMR patient had late-stage HIV infection, low CD4 counts and extrapulmonary disease, and documented co-administration of antifungal azoles (See Reference 1). These findings are consistent with the literature in which an emergence of RMR TB in HIV-infected TB patients has been reported in recent years. Further study in this sub-population is warranted. As with other antituberculous treatments, when rifapentine is used in HIV‑infected patients, a more aggressive regimen should be employed (eg, more frequent dosing). Based on results to date of the CDC trial (see above), once weekly dosing during the Continuation Phase of treatment is not recommended at this time.

Because rifapentine has been shown to increase indinavir metabolism (see DRUG INTERACTIONS), it should be used with extreme caution, if at all, in patients who are also taking protease inhibitors.

PRECAUTIONS

General

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.

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.

Information for Patients

The patient should be told that PRIFTIN may produce a reddish coloration of the urine, sweat, sputum, tears, and breast milk and the patient should be forewarned that contact lenses or dentures may be permanently stained. The patient should be advised that the reliability of oral or other systemic hormonal contraceptives may be affected; consideration should be given to using alternative contraceptive measures. For those patients with a propensity to nausea, vomiting, or gastrointestinal upset, administration of PRIFTIN with food may be useful. Patients should be instructed to 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.

Compliance with the full course of therapy must be emphasized, and the importance of not missing any doses of the daily administered companion medications in the Intensive Phase must be stressed. (See DOSAGE AND ADMINISTRATION and WARNINGS).

Laboratory Tests

Adults treated for tuberculosis with rifapentine should have baseline measurements of hepatic enzymes, bilirubin, a complete blood count, and a platelet count (or estimate).

Patients should be seen at least monthly during therapy and should be specifically questioned concerning symptoms associated with adverse reactions. All patients with abnormalities should have follow-up, including laboratory testing, if necessary. Routine laboratory monitoring for toxicity in people with normal baseline measurements is generally not necessary.

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 rifapentine; thus, alternative assay methods should be considered.

Drug Interaction

Rifapentine-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 administered 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.)

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 enzyme 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 600 mg 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: eg, phenytoin

Antiarrhythmics: eg, disopyramide, mexiletine, quinidine, tocainide

Antibiotics: eg, chloramphenicol, clarithromycin, dapsone, doxycycline, fluoroquinolones (such as ciprofloxacin)

Oral anticoagulants: eg, warfarin

Antifungals: eg, fluconazole, itraconazole, ketoconazole

Barbiturates

Benzodiazepines: eg, diazepam

Beta-blockers, calcium channel blockers: eg, diltiazem, nifedipine, verapamil

Corticosteroids

Cardiac glycoside preparations

Clofibrate

Oral or other systemic hormonal contraceptives

Haloperidol

HIV protease inhibitors: eg, indinavir, ritonavir, nelfinavir, saquinavir (see Rifapentine-Indinavir Interaction above)

Oral hypoglycemic agents: eg, sulfonylureas

Immunosuppressants: eg, cyclosporine, tacrolimus

Levothyroxine

Narcotic analgesics: eg, methadone

Progestins

Quinine

Reverse transcriptase inhibitors: eg, delavirdine, zidovudine

Sildenafil

Theophylline

Tricyclic antidepressants: eg, amitriptyline, 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 ingestion of antacids.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies with rifapentine have not been completed. 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-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 also 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. This metabolite did induce chromosomal aberrations in an in vitro chromosomal aberration 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).

Pregnancy Category C

Teratogenic Effects

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 of organogenesis, pups showed cleft palates, right aortic arch and increased incidence of 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).

Nonteratogenic Effects

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.

Pregnancy–Human Experience

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 clotting parameters evaluated.

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

Nursing Mothers

It is not known whether rifapentine is excreted 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 rifapentine may produce a red-orange discoloration of body fluids, there is a potential for discoloration of breast milk.

Pediatric Use

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 ACTIONS/CLINICAL PHARMACOLOGY Special Populations for pharmacokinetic information).

Geriatric Use

Clinical studies of PRIFTIN 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 ACTIONS/CLINICAL PHARMACOLOGY, Pharmacokinetics, Special Populations-Elderly).

Page last updated: 2007-08-21

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