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Priftin

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Priftin

Priftin

SIDE EFFECTS

Serious and Otherwise Important Adverse Reactions

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.

The data described below reflect exposure to PRIFTIN (rifapentine) in a randomized, open label, active-controlled trial of patients with pulmonary tuberculosis, excluding those with HIV-infection. The population consisted of primarily of male subjects with a mean age of 37 11 years. In the initial 2 month phase of treatment (60 days), 361 patients received rifapentine 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 completed. During the 4 month continuation phase, 321 patients in the rifapentine group continued to receive rifapentine 600 mg dosed once weekly with isoniazid and 307 patients in the rifampin arm received twice weekly rifampin and isoniazid. Both treatment groups received pyridoxine (Vitamin B6) over the 6 month treatment period.

Twenty-two deaths occurred in the study (eleven in the rifampin combination therapy group and eleven in the rifapentine combination therapy group).

In the study, 18/361 (5.0%) rifampin combination therapy patients discontinued the study due to an adverse reaction compared to 11/361 (3.0%) rifapentine combination therapy patients. Three patients (two rifampin combination therapy patients and one rifapentine combination therapy patient) were discontinued in the Initial Phase as a result of hepatitis with increased liver function tests (ALT, AST, LDH, and bilirubin). Concomitant medications for all three patients included isoniazid, pyrazinamide, ethambutol, and pyridoxine. The two rifampin patients and one rifapentine patient recovered without sequelae.

As shown in Table 1, hyperuricemia was the most frequently reported reaction and was most likely related to the pyrazinamide since only two cases were reported in the Continuation Phase when this drug was no longer included in the treatment regimen.

Seven patients had adverse reactions associated with an overdose. In the rifampin combination group these reactions included hematuria, anorexia, back pain, arthralgia, and myalgia. In the rifapentine combination group these reactions included hematuria, neutropenia, hyperglycemia, ALT increased, hyperuricemia, pruritus, and arthritis.

The following table (Table 1) presents treatment-emergent adverse reactions associated with the use of any of the four drugs in the regimens (rifapentine/rifampin, isoniazid, pyrazinamide, or ethambutol) which occurred in ≥ 1% of patients during treatment and post-treatment through the first three months of follow-up.

Table 1. Treatment-Emergent Adverse Reactions Occurring in ≥ 1% of Patients

System Organ Class Preferred Term Initial Phase1 Continuation Phase2 Total3
Rifapentine Combination (N=361) N(%) Rifampin Combination (N=361) N(%) Rifapentine Combination (N=304) N(%) Rifampin Combination (N=317) N(%) Rifapentine Combination (N=361) N(%) Rifampin Combination (N=361) N(%)
RENAL & URINARY
Pyuria 39 (10.8) 56 (15.5) 47 (14.8) 36 (11.8) 78 (21.6) 83 (23.0)
Proteinuria 36 (10.0) 53 (14.7) 14 (4.4) 27 (8.9) 47 (13.0) 71 (19.7)
Hematuria 39 (10.8) 38 (10.5) 32 (10.1) 27 (8.9) 64 (17.7) 61 (16.9)
Urinary Tract Infection 32 (8.9) 24 (6.6) 23 (7.3) 10 (3.3) 48 (13.3) 32 (8.9)
Urinary Casts 20 (5.5) 22 (6.1) 11 (3.5) 7 (2.3) 29 (8.0) 28 (7.8)
Cystitis 5(1.4) 6 (1.7) 1 (0.3) 1 (0.3) 6 (1.7) 7(1.9)
METABOLIC & NUTRITIONAL
Hyperuricemia 115 (31.9) 83 (23.0) 0 (0.0) 2 (0.7) 115 (31.9) 83 (23.0)
Hyperkalemia 14 (3.9) 22 (6.1) 20 (6.3) 21 (6.9) 33 (9.1) 41 (11.4)
Hypoglycemia 22 (6.1) 27 (7.5) 15 (4.7) 11 (3.6) 36 (10.0) 35 (9.7)
Nonprotein Nitrogen Increased 4(1.1) 3 (0.8) 10 (3.2) 15 (4.9) 14 (3.9) 17 (4.7)
Hyperglycemia 10 (2.8) 8 (2.2) 4(1.3) 2 (0.7) 13 (3.6) 9 (2.5)
LDH Increased 5 (1.4) 7(1.9) 0 (0.0) 2 (0.7) 5 (1.4) 9 (2.5)
Hyperphosphatemia 2 (0.6) 1 (0.3) 3 (0.9) 5 (1.6) 5 (1.4) 6 (1.7)
HEMATOLOGIC
Anemia 41 (11.4) 41 (11.4) 5 (1.6) 10 (3.3) 44 (12.2) 51 (14.1)
Lymphopenia 38 (10.5) 37 (10.2) 10 (3.2) 9 (3.0) 46 (12.7) 45 (12.5)
Neutropenia 22 (6.1) 21 (5.8) 27 (8.5) 24 (7.9) 45 (12.5) 41 (11.4)
Leukopenia 16 (4.4) 11 (3.0) 11 (3.5) 9 (3.0) 24 (6.6) 17 (4.7)
Leukocytosis 6 (1.7) 13 (3.6) 5 (1.6) 2 (0.7) 11 (3.0) 15 (4.2)
Neutrophilia 5 (1.4) 11 (3.0) 4 (1.3) 2 (0.7) 9 (2.5) 13 (3.6)
Thrombocytosis 20 (5.5) 13 (3.6) 1 (0.3) 0 (0.0) 20 (5.5) 13 (3.6)
Thrombocytopenia 6 (1.7) 6 (1.7) 4 (1.3) 6 (2.0) 9 (2.5) 11 (3.0)
Polycythemia 3 (0.8) 2 (0.6) 5 (1.6) 3 (1.0) 8 (2.2) 5 (1.4)
Lymphadenopathy 4(1.1) 2 (0.6) 0 (0.0) 2 (0.7) 4(1.1) 4(1.1)
BODY AS A WHOLE -GENERAL
Back Pain 15 (4.2) 11 (3.0) 11 (3.5) 4 (1.3) 25 (6.9) 15 (4.2)
Pain 14 (3.9) 17 (4.7) 8 (2.5) 5 (1.6) 22 (6.1) 22 (6.1)
Chest Pain 10 (2.8) 11 (3.0) 10 (3.2) 5 (1.6) 20 (5.5) 16 (4.4)
Injury Accident 5 (1.4) 5 (1.4) 12 (3.8) 14 (4.6) 17 (4.7) 17 (4.7)
Abdominal Pain 3 (0.8) 3 (0.8) 4 (1.3) 4 (1.3) 7(1.9) 7(1.9)
Fever 5 (1.4) 7(1.9) 1 (0.3) 1 (0.3) 5 (1.4) 7(1.9)
Fatigue 3 (0.8) 1 (0.3) 1 (0.3) 3 (1.0) 4(1.1) 4(1.1)
Edema Dependent 4(1.1) 1 (0.3) 0 (0.0) 1 (0.3) 4(1.1) 2 (0.6)
DERMATOLOGIC
Rash 15 (4.2) 26 (7.2) 8 (2.5) 8 (2.6) 22 (6.1) 33 (9.1)
Sweating Increased 19 (5.3) 18 (5.0) 5 (1.6) 4 (1.3) 23 (6.4) 22 (6.1)
Pruritus 10 (2.8) 16 (4.4) 3 (0.9) 0 (0.0) 13 (3.6) 16 (4.4)
Acne 9 (2.5) 5 (1.4) 0 (0.0) 3 (1.0) 9 (2.5) 8 (2.2)
Skin Disorder 2 (0.6) 3 (0.8) 3 (0.9) 5 (1.6) 5 (1.4) 8 (2.2)
Rash Maculopapular 6 (1.7) 3 (0.8) 0 (0.0) 1 (0.3) 6 (1.7) 4(1.1)
Eczema 2 (0.6) 2 (0.6) 3 (0.9) 2 (0.7) 4(1.1) 3 (0.8)
RESPIRATORY
Hemoptysis 27 (7.5) 20 (5.5) 6 (1.9) 6 (2.0) 30 (8.3) 25 (6.9)
Coughing 21 (5.8) 8 (2.2) 9 (2.8) 11 (3.6) 29 (8.0) 17 (4.7)
Upper Respiratory Tract Infection 5 (1.4) 9 (2.5) 12 (3.8) 15 (4.9) 17 (4.7) 22 (6.1)
Bronchitis 1 (0.3) 1 (0.3) 8 (2.5) 1 (0.3) 9 (2.5) 2 (0.6)
Pharyngitis 5 (1.4) 0 (0.0) 2 (0.6) 5(1.6) 7(1.9) 5 (1.4)
Epistaxis 2 (0.6) 2 (0.6) 3 (0.9) 1 (0.3) 5 (1.4) 3 (0.8)
Pleuritis 4 (1.1) 1 (0.3) 0 (0.0) 1 (0.3) 4(1.1) 2 (0.6)
GASTROINTESTINAL
Dyspepsia 6 (1.7) 11 (3.0) 4(1.3) 6 (2.0) 10 (2.8) 17 (4.7)
Vomiting 6 (1.7) 14 (3.9) 3 (0.9) 3 (1.0) 9 (2.5) 17 (4.7)
Nausea 7 (1.9) 3 (0.8) 2 (0.6) 1 (0.3) 9 (2.5) 4(1.1)
Constipation 6 (1.7) 1 (0.3) 2 (0.6) 1 (0.3) 7(1.9) 2 (0.6)
Diarrhea 5 (1.4) 2 (0.6) 2 (0.6) 0 (0.0) 7(1.9) 2 (0.6)
Hemorrhoids 4 (1.1) 0 (0.0) 1 (0.3) 0 (0.0) 5 (1.4) 0 (0.0)
INFECTIOUS DISEASE
Influenza 9 (2.5) 8 (2.2) 22 (6.9) 12 (3.9) 28 (7.8) 20 (5.5)
Infection Tuberculosis 0 (0.0) 5 (1.4) 9 (2.8) 4 (1.3) 9 (2.5) 9 (2.5)
Infection 1 (0.3) 2 (0.6) 4(1.3) 4(1.3) 5 (1.4) 6 (1.7)
Herpes Zoster 2 (0.6) 0 (0.0) 2 (0.6) 3 (1.0) 4(1.1) 3 (0.8)
HEPATIC & BILIARY
ALT Increased 18 (5.0) 23 (6.4) 7(2.2) 10 (3.3) 25 (6.9) 32 (8.9)
AST Increased 15 (4.2) 18 (5.0) 7 (2.2) 8 (2.6) 21 (5.8) 26 (7.2)
NEUROLOGIC
Headache 11 (3.0) 13 (3.6) 3 (0.9) 7 (2.3) 14 (3.9) 20 (5.5)
Dizziness 5 (1.4) 5 (1.4) 1 (0.3) 1 (0.3) 6 (1.7) 6 (1.7)
Tremor 3 (0.8) 1 (0.3) 2 (0.6) 0 (0.0) 5 (1.4) 1 (0.3)
PSYCHIATRIC
Anorexia 14 (3.9) 18 (5.0) 8 (2.5) 6 (2.0) 21 (5.8) 22 (6.1)
Insomnia 2 (0.6) 2 (0.6) 2 (0.6) 2 (0.7) 4 (1.1) 4(1.1)
MUSCULOSKELETAL
Arthralgia 13 (3.6) 13 (3.6) 3 (0.9) 5 (1.6) 16 (4.4) 18 (5.0)
Arthritis 4 (1.1) 5 (1.4) 1 (0.3) 0 (0.0) 4(1.1) 5 (1.4)
Arthrosis 4 (1.1) 1 (0.3) 0 (0.0) 1 (0.3) 4(1.1) 2 (0.6)
Gout 3 (0.8) 1 (0.3) 1 (0.3) 0 (0.0) 4(1.1) 1 (0.3)
CARDIOVASCULAR
Hypertension 3 (0.8) 5 (1.4) 3 (0.9) 2 (0.7) 6 (1.7) 7(1.9)
OPHTHALMOLOGIC
Conjuctivitis 8 (2.2) 2 (0.6) 1 (0.3) 1 (0.3) 9 (2.5) 3 (0.8)
Note: ≥ 1% refers to rifapentine in the TOTAL column.
1 Initial Phase consisted of therapy with either rifapentine or rifampin combined with isoniazid, pyrazinamide, and ethambutol administered daily (rifapentine twice weekly) for 60 days.
2 Continuation Phase consisted of therapy with either rifapentine or rifampin combined with isoniazid for 120 days. Rifapentine patients were dosed once weekly; rifampin patients were dosed twice weekly.
3 A patient may have experienced the same adverse reaction more than once during the course of the study, therefore, patient counts across the columns may not equal the patient counts in the TOTAL column.

In addition to the adverse reactions reported in Table 1, adverse reactions were reported post-treatment during the 3 month through 24 month follow-up period. Although the protocol for this study specified collection of serious adverse reactions during this period, some non-serious adverse reactions were reported as well. For the rifapentine combination group these included the following: hematuria, infection tuberculosis, proteinuria, urinary casts, hyperkalemia, hypoglycemia, injury accident, skin disorder, respiratory disorder, stupor, prostatic disorder.

Treatment-emergent adverse reactions reported during treatment and post-treatment through the first three months of follow-up in <1% of the rifapentine combination therapy patients are presented below by body system in order of frequency.

Renal & Urinary: urethral disorder, dysuria, pyelonephritis, urinary incontinence, urination disorder.

Metabolic & Nutritional: weight decrease, BUN increased, diabetes mellitus, alkaline phosphatase increased, hypophosphatemia, hypercalcemia, hypovolemia, weight increase.

Hematologic: lymphocytosis, hematoma, purpura, anemia hypochromic, anemia normocytic, thrombosis.

Body as a Whole - General: laboratory test abnormal, edema legs, asthenia, edema face, abscess, edema peripheral, malaise.

Dermatologic: skin ulceraction, urticaria, dry skin, furunculosis, skin discoloration, dermatitis fungal, nail disorder, alopecia, rash erythematous.

Respiratory: abnormal breath sounds, pneumothorax, pneumonia, pleural effusion, rhinitis, dyspnea, pneumonitis, sinusitis, sputum increased, pulmonary fibrosis, upper respiratory congestion, asthma, chest x-ray abnormal, bronchospasm, laryngeal edema, laryngitis, respiratory disorder.

Gastrointestinal: tooth disorder, gastroenteritis, gastritis, esophagitis, cheilitis, dry mouth, pancreatitis, proctitis, salivary gland enlargement, tenesmus, gastrointestinal disorder not specified.

Infectious Disease: infection fungal, infection parasitic, infection protozoan.

Hepatic & Biliary: bilirubinemia, hepatomegaly, jaundice.

Neurologic: somnolence, seizure not specified, dysphonia, hypoesthesia, torticollis, hypertonia, hyporeflexia, meningitis, migraine headache, stupor.

Psychiatric: anxiety, confusion, drug abuse, aggressive reaction, agitation.

Musculoskeletal: myalgia, myositis, bone fracture, muscle weakness, muscle spasm.

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

Reproductive Disorders: penis disorder, vaginitis, vaginal hemorrhage, cervical smear test positive, leukorrhea, mastitis male, prostatic disorder.

Hearing & Vestibular: ear disorder not specified, otitis media, earache, otitis externa, tympanic membrane perforation.

Ophthalmologic: eye pain, eye abnormality.

Neoplasms: pulmonary carcinoma, neoplasm not specified, carcinoma, lipoma.

Vascular (Extracardiac): thrombophlebitis deep, vascular disorder, vasodilation.

Special Senses Other: taste loss.

Pregnancy, puerperium and perinatal conditions: abortion

In another randomized, open-label trial in 1075 HIV seronegative and seropositive patients with pulmonary tuberculosis the overall adverse event rate did not differ substantially from the previous trial. Patients who had completed an initial 2 month phase of treatment with 4 drugs were randomly assigned to receive either rifapentine 600 mg and isoniazid once weekly or rifampin and isoniazid twice weekly for the 4 month continuation phase.

In the rifapentine arm, 502 HIV seronegative and 36 HIV seropositive patients were randomized and in the rifampin arm 502 HIV seronegative and 35 HIV seropositive patients were randomized to treatment.

The death rate among all study participants was 71/1075 (6.6%) and did not differ between the two treatment groups (6.5% for the rifapentine combination regimen compared to 6.7% for the rifampin combination regimen; P = 0.87).

There were 526 treatment-emergent adverse events regardless of causality reported from 251 patients treated with the rifapentine combination regimen and 513 adverse events reported from 248 patients treated with the rifampin combination regimen. On both study arms the most frequently reported adverse events were hyperglycemia, pneumonia, liver toxicity, and death and were consistent with concurrent underlying conditions that included alcohol abuse, pancreatitis and HIV.

There was a greater percentage of patients in the rifampin combination arm who developed hepatic adverse events (35/513; 6.8 %) compared to 20/526 (3.8%) in the rifapentine combination arm. The types of other adverse events were similar between the treatment arms.

Hyperuricemia was not reported as an adverse reaction in this study of continuation phase therapy. In the previous study which evaluated initial therapy containing pyrazinamide, hyperuricemia was reported in 32% of rifapentine and 23% of rifampin combination treated patients (see Table 1).

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 (rifapentine) with other drugs metabolized by these enzymes, such as protease inhibitors and 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]

Hormonal Contraceptives

PRIFTIN (rifapentine) 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, 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 drugs in Table 2 or of other drugs metabolized by cytochrome P4503A4 or P4502C8/9 may be necessary if they are given concurrently with rifapentine.

Table 2. Drug Interactions with PRIFTIN (rifapentine) : 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-B lockers 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 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 [see CLINICAL PHARMACOLOGY].

Since rifapentine 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 rifapentine; thus, alternative assay methods should be considered.

Read the Priftin Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 8/27/2010
This monograph has been modified to include the generic and brand name in many instances.

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