Rifapentine adverse reactions

# Adverse Reactions

## 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:
- Hypersensitivity 
- Hepatotoxicity 
- Hyperbilirubinemia 
- Discoloration of Body Fluids 
- Porphyria 
- Clostridium difficile-Associated Diarrhea 
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.

## 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 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.

## 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).