" Citing a lack of cardiovascular benefit, the FDA is taking the unusual step of withdrawing approvals it had previously given for use of niacin and fenofibric acid with statins to treat high cholesterol.
The decision affects niac"...
The following serious and otherwise important adverse drug reactions are discussed in greater detail in other sections of labeling:
- Hepatotoxicity [see WARNINGS AND PRECAUTIONS]
- Hypersensitivity [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS]
- Discoloration of Body Fluids [see WARNINGS AND PRECAUTIONS]
- Clostridium difficile-Associated Diarrhea [see WARNINGS AND PRECAUTIONS]
- Porphyria [see WARNINGS AND PRECAUTIONS]
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Active Pulmonary Tuberculosis
PRIFTIN was studied in a randomized, open label, active-controlled trial of HIV-negative patients with active pulmonary tuberculosis. The population consisted of 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 in combination with isoniazid, pyrazinamide and ethambutol all administered daily. Ethambutol was discontinued when drug susceptibly testing was known. During the 4 month continuation phase, 317 patients in the PRIFTIN group continued to receive PRIFTIN 600 mg dosed once-weekly with isoniazid and 304 patients in the rifampin group received twice weekly rifampin and isoniazid. Both treatment groups received pyridoxine (Vitamin B6) over the 6 month treatment period.
Because PRIFTIN was administered as part of a combination regimen, the adverse reaction profile reflects the entire regimen.
Twenty-two deaths occurred in the study, eleven in the rifampin combination therapy group and eleven in the PRIFTIN combination therapy group. 18/361 (5%) rifampin combination therapy patients discontinued the study due to an adverse reaction compared to 11/361 (3%) PRIFTIN combination therapy patients. Three patients (two rifampin combination therapy patients and one PRIFTIN combination therapy patient) were discontinued in the initial phase due to hepatotoxicity. Concomitant medications for all three patients included isoniazid, pyrazinamide, ethambutol, and pyridoxine. All three recovered without sequelae.
Table 2 presents selected treatment-emergent adverse reactions associated with the treatment regimens which occurred in at least 1% of patients during treatment and post-treatment through the first three months of follow-up.
Table 2: Selected Treatment Emergent Adverse Reactions
During Treatment of Active Pulmonary Tuberculosis and Through Three Months
|System Organ Class Preferred Term||Initial Phase1||Continuation Phase2|
|BLOOD AND LYMPHATICS|
|Anemia||41 (11.4)||41 (11.4)||5 (1.6)||10 (3.3)|
|Lymphopenia||38 (10.5)||37 (10.2)||10 (3.2)||9 (3.)|
|Neutropenia||22 (6.1)||21 (5.8)||27 (8.5)||24 (7.9)|
|Leukocytosis||6 (1.7)||13 (3.6)||5 (1.6)||2 (0.7)|
|Thrombocytosis||20 (5.5)||13 (3.6)||1 (0.3)||0 (0.0)|
|Thrombocytopenia||6 (1.7)||6 (1.7)||4 (1.3)||6 (2)|
|Lymphadenopathy||4 (1.1)||2 (0.6)||0 (0.0)||2 (0.7)|
|Nonprotein Nitrogen Increased||4 (1.1)||3 (0.8)||10 (3.2)||15 (4.9)|
|Conjunctivitis||8 (2.2)||2 (0.6)||1 (0.3)||1 (0.3)|
|Dyspepsia||6 (1.7)||11 (3)||4 (1.3)||6 (2)|
|Vomiting||6 (1.7)||14 (3.9)||3 (0.9)||3 (1)|
|Nausea||7 (1.9)||3 (0.8)||2 (0.6)||1 (0.3)|
|Diarrhea||5 (1.4)||2 (0.6)||2 (0.6)||0 (0.0)|
|Back Pain||15 (4.2)||11 (3)||11 (3.5)||4 (1.3)|
|Abdominal Pain||3 (0.8)||3 (0.8)||4 (1.3)||4 (1.3)|
|Fever||5 (1.4)||7 (1.9)||1 (0.3)||1 (0.3)|
|Anorexia||14 (3.9)||18 (5)||8 (2.5)||6 (2)|
|HEPATIC & BILIARY|
|ALT Increased||18 (5)||23 (6.4)||7 (2.2)||10 (3.3)|
|AST Increased||15 (4.2)||18 (5)||7 (2.2)||8 (2.6)|
|Arthralgia||13 (3.6)||13 (3.6)||3 (0.9)||5 (1.6)|
|Headache||11 (3)||13 (3.6)||3 (0.9)||7 (2.3)|
|Dizziness||5 (1.4)||5 (1.4)||1 (0.3)||1 (0.3)|
|Hemoptysis||27 (7.5)||20 (5.5)||6 (1.9)||6 (2)|
|Coughing||21 (5.8)||8 (2.2)||9 (2.8)||11 (3.6)|
|Rash||15 (4.2)||26 (7.2)||8 (2.5)||8 (2.6)|
|Sweating Increased||19 (5.3)||18 (5)||5 (1.6)||4 (1.3)|
|Pruritus||10 (2.8)||16 (4.4)||3 (0.9)||0 (0.0)|
|Rash Maculopapular||6 (1.7)||3 (0.8)||0 (0.0)||1 (0.3)|
|1Initial phase consisted of therapy with either PRIFTIN
twice weekly or rifampin daily combined with daily isoniazid, pyrazinamide, and
ethambutol for 60 days.
2Continuation phase consisted of therapy with either PRIFTIN once weekly or rifampin twice weekly combined with daily isoniazid for 120 days.
The following selected treatment-emergent adverse reactions were reported in less than 1% of the PRIFTIN combination therapy patients during treatment and post-treatment through the first three months of follow-up.
Metabolic & Nutritional: BUN increased, alkaline phosphatase increased.
General: asthenia, facial edema.
Infectious Disease: infection fungal.
Pregnancy, Puerperium and Perinatal conditions: abortion
Psychiatric: anxiety, confusion
Skin: urticaria, skin discoloration,
In another randomized, open-label trial, 1075 HIV non-infected and infected patients with active pulmonary tuberculosis who had completed an initial 2 month phase of treatment with 4 drugs were randomly assigned to receive either PRIFTIN 600 mg and isoniazid once weekly or rifampin and isoniazid twice weekly for the 4 month continuation phase. 502 HIV non-infected and 36 HIV-infected patients were randomized to receive the PRIFTIN regimen and 502 HIVnoninfected and 35 HIV-infected patients were randomized to receive the rifampin regimen. The death rate was 6.5% for the PRIFTIN combination regimen compared to 6.7% for the rifampin combination regimen.
Latent Tuberculosis Infection
PRIFTIN in combination with isoniazid given once-weekly for 3 months (3RPT/INH) was compared to isoniazid given once daily for 9 months (9INH) in an open-label, randomized trial in patients with a positive tuberculin skin test, and at high risk for progression from latent tuberculosis infection to active tuberculosis disease. PRIFTIN was dosed by weight, and isoniazid mg/kg dose was determined according to age [see DOSING AND ADMINISTRATION] to a maximum of 900 mg each.
A total of 4040 patients received at least one dose of the 3RPT/INH regimen, including 348 children 2-17 years of age and 105 HIV-infected individuals. A total of 3759 received at least one dose of the 9INH regimen, including 342 children 2 years-17 years of age and 95 HIV-infected individuals.
Patients were followed for 33 months from the time of enrollment. Treatment-emergent adverse reactions were defined as those occurring during treatment and 60 days after the last dose of treatment. 161 (4%) 3RPT/INH subjects had a rifamycin hypersensitivity reaction, defined as either: a) one of the following: hypotension, urticaria, angioedema, acute bronchospasm, or conjunctivitis occurring in relation to study drug or b) at least four of the following symptoms occurring in relation to the study drug, with at least one symptom being CTCAE Grade 2 or higher: weakness, fatigue, nausea, vomiting, headache, fever, aches, sweats, dizziness, shortness of breath, flushing or chills. No specific definition was used for isoniazid hypersensitivity; 18 (0.5%) 9INH subjects were classified as having a hypersensitivity reaction. Hepatotoxicity was defined as AST ≥ 3x upper limit of normal in the presence of specific signs and symptoms of hepatitis, or AST > 5x upper limit of normal regardless of signs or symptoms. 113 (3%) 9INH subjects and 24 (0.6%) 3RPT/INH subjects developed hepatotoxicity.
196 subjects (4.9%) in the 3RPT/INH arm discontinued treatment due to a treatment related adverse reaction patients and 142 (3.8%) in the 9INH arm discontinued treatment due to a treatment related adverse reaction. In the 3RPT/INH group, the most frequent treatment related adverse reaction resulting in treatment discontinuation was hypersensitivity reaction, occurring in 120 (3%) patients. In the 9INH group, the most frequent treatment related adverse reaction resulting in treatment discontinuation was hepatotoxicity, occurring in 76 (2%) patients.
Seventy one deaths occurred, 31/4040, 0.77% in the 3RPT/INH group and 40/3759 (1.06%) in the 9INH group) during the 33 month study period. During the treatment emergent period, 11 deaths occurred, 4 in the 3RPT/INH group and 7 in the 9INH group. None of the reported deaths were considered related to treatment with study drugs or were attributed to tuberculosis disease.
Table 3 presents select adverse reactions that occurred during the treatment emergent period in the main study in LTBI patients treated with 3RPT/INH or 9INH at a frequency greater than 0.5%.
Table 3 : Select Adverse Reactions occurring in 0.5%
or greater of patients* in the Latent Tuberculosis Infection Main Study
|System Organ Class Preferred Term||3RPT/INH
|Immune system disorders|
|Hypersensitivity||161 (4)||18 (0.5)|
|Hepatitis||24 (0.6)||113 (3)|
|Nervous system disorders|
|Headache||26 (0.6)||17 (0.5)|
|Skin and subcutaneous tissue disorders|
|Skin reaction||31 (0.8)||21 (0.6)|
|*Includes events reported through 60 days after last dose of study drug|
Six-hundred and ninety children 2 years-17 years of age received at least one dose of study drugs in the main study. An additional 342 children 2 years-17 years of age received at least one dose in the pediatric extension study (total 1032 children; 539 received 3RPT/INH and 493 received 9INH).
No children in either treatment arm developed hepatotoxicity. Using the same definition for rifamycin hypersensitivity reaction as in the main study, 7 (1.3%) of children in the 3RPT/INH group experienced a rifamycin hypersensitivity reaction. Adverse reactions in children 2 years11 years of age and 12 years-17 years of age were similar.
Two-hundred HIV-infected patients with latent tuberculosis infection received at least one dose of study drugs in the main study and an additional 193 patients received at least one dose in the extension study (total of 393; 207 received 3RPT/INH and 186 received 9INH). Compared to the HIV-negative patients enrolled in the main study, a higher proportion of HIV-infected patients in each treatment arm experienced a treatment emergent adverse reaction, including a higher incidence of hepatotoxicity. Hepatotoxicity occurred in 3/207 (1.5%) patients in the 3RPT/INH arm and in 14/186 (7.5%) in the 9INH arm. Rifamycin hypersensitivity occurred in only one HIV-infected patient.
Eleven deaths occurred during the 33 month follow up period (6/207 in the 3RPT/INH group and 5/186 in the 9INH group) including one death in the 9INH arm during the treatment emergent period. None of the reported deaths were considered related to treatment with study drugs or tuberculosis disease.
Selected treatment-emergent adverse reactions reported during treatment and 60 days posttreatment in less 0.5% of the 3RPT/INH combination-therapy group in the main study are presented below by body system.
Eye Disorders: conjunctivitis.
General Disorders and Administration Site Conditions: fatigue, pyrexia, asthenia, chest pain, chills, feeling jittery.
Psychiatric Disorders: depression, anxiety, disorientation, suicidal ideation.
Renal and Urinary Disorders: azotemia.
Reproductive System and Breast Disorders: vulvovaginal pruritus.
Skin and Subcutaneous Tissue Disorders: rash, hyperhidrosis, pruritus, urticaria.
Read the Priftin (rifapentine) Side Effects Center for a complete guide to possible side effects
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 and CLINICAL PHARMACOLOGY].
Fixed Dose Combination Of Efavirenz, Emtricitabine And Tenofovir
Once-weekly co-administration of 900 mg PRIFTIN with the antiretroviral fixed dose combination of efavirenz 600 mg, emtricitabine 200 mg and tenofovir disoproxyl fumarate 300mg 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].
PRIFTIN may reduce the effectiveness of hormonal contraceptives. Therefore, patients using oral, transdermal patch, or other systemic hormonal contraceptives should be advised to change to non-hormonal methods of birth control.
Cytochrome P450 3A4 And 2C8/9
Rifapentine is an inducer of cytochromes P4503A4 and P4502C8/9. 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 P4503A4 or P4502C8/9 may be necessary if they are given concurrently with PRIFTIN.
Table 4: Drug Interactions with PRIFTIN: Dosage
Adjustment may be Necessary
|Drug Class||Examples of Drugs Within Class|
|Antiarrhythmics||Disopyramide, mexiletine, quinidine, tocainide|
|Antibiotics||Chloramphenicol, clarithromycin, dapsone, doxycycline; Fluoroquinolones (such as ciprofloxacin)|
|Azole Antifungals||Fluconazole, itraconazole, ketoconazole|
|Calcium Channel Blockers||Diltiazem, nifedipine, verapamil|
|Cardiac Glycoside Preparations||Digoxin|
|Oral Hypoglycemics||Sulfonylureas (e.g., glyburide, glipizide)|
|Hormonal Contraceptives/ Progestins||Ethinyl estradiol, levonorgestrel|
|Phophodiesterase-5 (PDE-5) Inhibitors||Sildenafil|
|Tricyclic antidepressants||Amitriptyline, nortriptyline|
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.
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.
Read the Priftin Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 12/16/2014
Additional Priftin Information
Report Problems to the Food and Drug Administration
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
Find out what women really need.