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Priftin

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Priftin

Side Effects
Interactions

SIDE EFFECTS

The following serious and otherwise important adverse drug reactions are discussed in greater detail in other sections of labeling:

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.

Five patients had adverse reactions associated with PRIFTIN overdose. These reactions included hematuria, neutropenia, hyperglycemia, ALT increased, hyperuricemia, pruritus, and arthritis.

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 Follow-up

System Organ Class Preferred Term Initial Phase1 Continuation Phase2
PRIFTIN Combination
(N=361)
N (%)
Rifampin Combination
(N=361)
N (%)
PRIFTIN Combination
(N=317)
N (%)
Rifampin Combination
(N=304)
N (%)
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)
EYE
Conjunctivitis 8 (2.2) 2 (0.6) 1 (0.3) 1 (0.3)
GASTROINTESTINAL
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)
GENERAL
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)
MUSCULOSKELETAL
Arthralgia 13 (3.6) 13 (3.6) 3 (0.9) 5 (1.6)
NEUROLOGIC
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)
RESPIRATORY
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)
SKIN
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.

Blood and Lymphatics: lymphocytosis, hematoma, purpura, thrombosis.

Cardiovascular: syncope, tachycardia, palpitation, orthostatic hypotension, pericarditis.

Metabolic & Nutritional: BUN increased, alkaline phosphatase increased.

Gastrointestinal: gastritis, esophagitis, pancreatitis, salivary gland enlargement.

General: asthenia, facial edema.

Hepatobiliary: bilirubinemia, hepatomegaly, jaundice.

Infectious Disease: infection fungal.

Musculoskeletal: myalgia, myositis.

Neurologic: somnolence, dysphonia.

Pregnancy, Puerperium and Perinatal conditions: abortion

Psychiatric: anxiety, confusion

Reproductive Disorders: vaginitis, vaginal hemorrhage, leukorrhea.

Respiratory: dyspnea, pneumonitis, pulmonary fibrosis, asthma, bronchospasm, laryngeal edema, laryngitis.

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

Main Study

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
(N=4040)
N (%)
9INH
(N=3759)
N (%)
Immune system disorders
Hypersensitivity 161 (4) 18 (0.5)
Hepatobiliary disorders
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

Pediatric Substudy

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.

HIV Substudy

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.

Blood and Lymphatic System Disorders: leukopenia, anemia, lymphadenopathy, neutropenia.

Gastrointestinal Disorders: nausea, diarrhea, vomiting, abdominal pain constipation, dry mouth, dyspepsia, esophageal irritation, gastritis, pancreatitis.

General Disorders and Administration Site Conditions: fatigue, pyrexia, asthenia, chest pain, chills, feeling jittery.

Infections and Infestations: pharyngitis, viral infection, vulvovaginal candidiasis.

Metabolism and Nutrition Disorders: hyperglycemia, gout, hyperkalemia, decreased appetite, hyperlipidemia.

Musculoskeletal and Connective Tissue Disorders: arthralgia, myalgia, back pain, rhabdomyolysis.

Nervous system Disorders: dizziness, convulsion, paresthesia, headache, neuropathy peripheral, syncope.

Psychiatric Disorders: depression, anxiety, disorientation, suicidal ideation.

Renal and Urinary Disorders: azotemia.

Reproductive System and Breast Disorders: vulvovaginal pruritus.

Respiratory, Thoracic and Mediastinal Disorders: cough, dyspnea, oropharyngeal pain, asthma, bronchial hyperactivity, epistaxis.

Skin and Subcutaneous Tissue Disorders: rash, hyperhidrosis, pruritus, urticaria.

Read the Priftin (rifapentine) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

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].

Hormonal Contraceptives

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)
Oral Anticoagulants Warfarin
Anticonvulsants Phenytoin
Antimalarials Quinine
Azole Antifungals Fluconazole, itraconazole, ketoconazole
Antipsychotics Haloperidol
Barbiturates Phenobarbital
Benzodiazepines Diazepam
Beta-Blockers Propanolol
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
Phophodiesterase-5 (PDE-5) Inhibitors Sildenafil
Thyroid preparations Levothyroxine
Tricyclic antidepressants Amitriptyline, nortriptyline

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].

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
This monograph has been modified to include the generic and brand name in many instances.

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