Priftin (Page 3 of 7)
6.2 Postmarketing Experience
The following adverse reactions have been identified from postmarketing surveillance of rifapentine. Because these reactions are reported from a population of unknown size, it is not always possible to estimate their frequency or establish a causal relationship to drug exposure.
Skin and subcutaneous tissue disorders: Severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome (SJS) and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome [see Warnings and Precautions (5.3)].
7 DRUG INTERACTIONS
7.1 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 [see Warnings and Precautions (5.5) and Clinical Pharmacology (12.3)].
7.2 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. No clinically significant change in CD4 cell counts or viral loads were noted [see Clinical Pharmacology (12.3)].
7.3 Hormonal Contraceptives
PRIFTIN may reduce the effectiveness of hormonal contraceptives. Patients using hormonal contraception should be advised to use an alternative non-hormonal contraceptive method or add a barrier method of contraception during treatment with PRIFTIN [see Use in Specific Populations (8.3) and Clinical Pharmacology (12.3)].
7.4 Cytochrome P450 3A4 and 2C8/9
Rifapentine is an inducer of cytochromes P450 3A4 and P450 2C8/9. 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 P450 3A4 or P450 2C8/9 may be necessary if they are given concurrently with PRIFTIN.
| Drug Class | Examples of Drugs Within Class |
|---|---|
| Antiarrhythmics | Disopyramide, mexiletine, quinidine, tocainide |
| Antibiotics | Chloramphenicol, clarithromycin, dapsone, doxycycline; Fluoroquinolones (such as ciprofloxacin) |
| Oral Anticoagulants | Warfarin |
| Anticonvulsants | Phenytoin |
| Antimalarials | Quinine |
| Azole Antifungals | Fluconazole, itraconazole, ketoconazole |
| Antipsychotics | Haloperidol |
| Barbiturates | Phenobarbital |
| Benzodiazepines | Diazepam |
| Beta-Blockers | Propranolol |
| Calcium Channel Blockers | Diltiazem, nifedipine, verapamil |
| Cardiac Glycoside Preparations | Digoxin |
| Corticosteroids | Prednisone |
| Fibrates | Clofibrate |
| Oral Hypoglycemics | Sulfonylureas (e.g., glyburide, glipizide) |
| Hormonal Contraceptives/Progestins | Ethinyl estradiol, levonorgestrel |
| Immunosuppressants | Cyclosporine, tacrolimus |
| Methylxanthines | Theophylline |
| Narcotic analgesics | Methadone |
| Phosphodiesterase-5 (PDE-5) Inhibitors | Sildenafil |
| Thyroid preparations | Levothyroxine |
| Tricyclic antidepressants | Amitriptyline, nortriptyline |
7.5 Other Interactions
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 [see Clinical Pharmacology (12.3)].
7.6 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.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
Based on animal data, PRIFTIN may cause fetal harm when administered to a pregnant woman. Available data from clinical trials, case reports, epidemiology studies and postmarketing experience with PRIFTIN use in pregnant women are insufficient to establish a drug-associated risk of major birth defects, adverse maternal or fetal outcomes. In two clinical trials, a total of 59 patients who were treated with rifapentine in combination with other anti-tuberculosis drugs became pregnant. Overall, the reported rate of miscarriage following rifapentine exposure in these two clinical trials did not represent an increase over the background rate of miscarriage reported in the general population (see Data). There are risks associated with active tuberculosis during pregnancy. When administered during the last few weeks of pregnancy, PRIFTIN may be associated with maternal postpartum hemorrhage and bleeding in the exposed neonates (see Clinical Considerations). In animal reproduction and developmental toxicity studies, adverse developmental outcomes (including cleft palate or mal-positioned aortic arches) were observed following administration of rifapentine to pregnant rats and rabbits at doses approximately 0.6 and 0.3 to 1.3 times, respectively, of the recommended human dose based on body surface area comparisons (see Data). Based on animal data, advise pregnant women of the risk for fetal harm. As rifapentine is always used in combination with other antituberculosis drugs such as isoniazid, ethambutol, and pyrazinamide, refer to the prescribing information of the other drug(s) for more information on their associated risks of use during pregnancy.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%–4% and 15%–20%, respectively.
Clinical Considerations
Disease-associated maternal and/or embryo-fetal risk
Active tuberculosis in pregnancy is associated with adverse maternal and neonatal outcomes including maternal anemia, cesarean delivery, preterm birth, low birth weight, birth asphyxia, and perinatal infant death.
Labor or delivery
When administered during the last few weeks of pregnancy, PRIFTIN 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.
Data
Human data
Fourteen patients with active tuberculosis treated with multiple antituberculosis drugs including PRIFTIN became pregnant during clinical studies. Six delivered normal infants, four had first trimester spontaneous abortions (of these, one patient abused ethanol and another patient was HIV-infected), one had an elective abortion, and outcome was unknown in three patients. These data are, however, limited by the quality of reporting and confounded by comorbid medical conditions and multiple antituberculosis drug exposures.
In the trial that compared the safety and effectiveness of PRIFTIN in combination with isoniazid to isoniazid alone for the treatment of latent tuberculosis infection, a total of 45 (2.5%) women in the PRIFTIN/isoniazid arm and 71 (4.1%) women in the isoniazid arm became pregnant. Among the 46 total pregnancies in the PRIFTIN/isoniazid arm, there were 31 live births, 6 elective abortions, 7 spontaneous abortions, and 2 unknown outcomes. Of the 31 live infants, 21 were reported healthy while in the other ten cases no further details were available. The rate of spontaneous abortion in the PRIFTIN/isoniazid arm (15%) and the rate of spontaneous abortion in the isoniazid arm (19%) did not represent an increase over the background rate of 15 to 20 percent reported in the general population. Further interpretation of these results is limited by the quality of adverse event reporting.
Animal data
Animal studies in rats and rabbits revealed malformations and other adverse developmental outcomes in both species. Pregnant rats given oral rifapentine during organogenesis (gestational days 5 through 15) at 40 mg/kg/day (0.6 times the human dose of 600 mg based on body surface area comparisons) produced pups with cleft palates and mal-positioned aortic arches, delayed ossification, increased number of ribs, a decrease in litter size and mean litter weight, an increase in number of stillbirths, and an increase in mortality during lactation.
When rifapentine was administered orally to mated female rats late in gestation, at 20 mg/kg/day (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 postimplantation loss, decreased mean fetal weights, increased numbers of stillborn pups, and slightly increased pup mortality during lactation were also noted. When pregnant rabbits received oral rifapentine at 10 mg/kg to 40 mg/kg (0.3 times to 1.3 times the human dose based on body surface area) during organogenesis (GD6 to GD18), major fetal malformations occurred including: ovarian agenesis, pes varus, arhinia, microphthalmia, and irregularities of the ossified facial tissues. At 40 mg/kg/day, there were increases in postimplantation loss and the incidence of stillborn pups.
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