PRIFTIN SIDE EFFECTS
- Generic Name: rifapentine
- Brand Name: Priftin
- Drug Class: Antitubercular Agents
SIDE EFFECTS
The following serious and otherwise important adverse drug reactions are discussed in greater detail in other sections of labeling:
- Hepatotoxicity
- Hypersensitivity
- Discoloration of Body Fluids
- Clostridium difficile-Associated Diarrhea
- Porphyria
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 1 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 1: 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 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 2 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 2 : 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.
SRC: NLM .