No

Antitubercular Agent

Treatment of pulmonary tuberculosis (indication is based on the 6-month follow-up treatment outcome observed in controlled clinical trial). Rifapentine must always be used in conjunction with at least one other antituberculosis drug to which the isolate is susceptible; it may also be necessary to add a third agent (either streptomycin or ethambutol) until susceptibility is known.

C

Has been shown to be teratogenic in rats and rabbits. Rat offspring showed cleft palates, right aortic arch, and delayed ossification and increased number of ribs. Rabbits displayed ovarian agenesis, pes varus, arhinia, microphthalmia, and irregularities of the ossified facial tissues. Rat studies also show decreased fetal weight, increased number of stillborns, and decreased gestational survival. No adequate well-controlled studies in pregnant women are available. Rifapentine should be used during pregnancy only if the potential benefits justifies the potential risk to the fetus.

Patients with a history of hypersensitivity to rifapentine, rifampin, rifabutin, and any rifamycin analog

Compliance with dosing regimen is absolutely necessary for successful drug therapy. patients with abnormal liver tests and/or liver disease should only be given rifapentine when absolutely necessary and under strict medical supervision. Monitoring of liver function tests should be carried out prior to therapy and then every 2-4 weeks during therapy if signs of liver disease occur or worsen, rifapentine should be discontinued. Pseudomembranous colitis has been reported to occur with various antibiotics including other rifamycins. If this is suspected, rifapentine should be stopped and the patient treated with specific and supportive treatment. Experience in treating TB in HIV-infected patients is limited.

>10%: Endocrine & metabolic: Hyperuricemia (most likely due to pyrazinamide from initiation phase combination therapy)

1% to 10%:

Cardiovascular: Hypertension

Central nervous system: Headache, dizziness

Dermatologic: Rash, pruritus, acne

Gastrointestinal: Anorexia, nausea, vomiting, dyspepsia, diarrhea

Hematologic: Neutropenia, lymphopenia, anemia, leukopenia, thrombocytosis

Hepatic: Increased ALT/AST

Neuromuscular & skeletal: Arthralgia, pain

Renal: Pyuria, proteinuria, hematuria, urinary casts

Respiratory: Hemoptysis

<1%: Peripheral edema, aggressive reaction, fatigue, urticaria, skin discoloration, hyperkalemia, hypovolemia, increased alkaline phosphatase, increased LDH, constipation, esophagitis, gastritis, pancreatitis, thrombocytopenia, neutrophilia, leukocytosis, purpura, hematoma, bilirubinemia, hepatitis, gout, arthrosis

There is no experience with treatment of acute overdose with rifapentine; experience with other rifamycins suggests that gastric lavage followed by activated charcoal may help adsorb any remaining drug from the GI tract. Hemodialysis or forced diuresis is not expected to enhance elimination of unchanged rifapentine in an overdose.

CYP3A4 and 2C8/9 inducer. Rifapentine may increase the metabolism of coadministered drugs that are metabolized by these enzymes. Enzymes are induced within 4 days after the first dose and returned to baseline 14 days after discontinuation of rifapentine. The magnitude of enzyme induction is dose and frequency dependent. Rifampin has been shown to accelerate the metabolism and may reduce activity of the following drugs (therefore, rifapentine may also do the same): Phenytoin, disopyramide, mexiletine, quinidine, tocainide, chloramphenicol, clarithromycin, dapsone, doxycycline, fluoroquinolones, warfarin, fluconazole, itraconazole, ketoconazole, barbiturates, benzodiazepines, beta-blockers, diltiazem, nifedipine, verapamil, corticosteroids, cardiac glycoside preparations, clofibrate, oral or other systemic hormonal contraceptives, haloperidol, HIV protease inhibitors, sulfonylureas, cyclosporine, tacrolimus, levothyroxine, methadone, progestins, quinine, delavirdine, zidovudine, sildenafil, theophylline, amitriptyline, and nortriptyline.

Patients using oral or other systemic hormonal contraceptives should be advised to change to nonhormonal methods of birth control when receiving concomitant rifapentine.

Rifapentine metabolism is mediated by esterase activity, therefore, there is minimal potential for rifapentine metabolism to be affected by other drug therapy.

Store at room temperature (15°C to 30°C; 59°F to 86°F); protect from excessive heat and humidity

Inhibits DNA-dependent RNA polymerase in susceptible strains of Mycobacterium tuberculosis (but not in mammalian cells). Rifapentine is bactericidal against both intracellular and extracellular MTB organisms. MTB resistant to other rifamycins including rifampin are likely to be resistant to rifapentine. Cross-resistance does not appear between rifapentine and other nonrifamycin antimycobacterial agents.

Absorption: Food increases AUC and C_max by 43% and 44% respectively.

Distribution: V_d: ~70.2 L

Metabolism: Hydrolyzed by an esterase and esterase enzyme to form the active metabolite 25-desacetyl rifapentine

Protein binding: Rifapentine and 25-desacetyl metabolite were 97.7% and 93.2% protein bound (mainly to albumin). Rifapentine and metabolite accumulate in human monocyte-derived macrophages with intracellular/extracellular ratios of 24:1 and 7:1 respectively

Half-life: Rifapentine: 14-17 hours; 25-desacetyl rifapentine: 13 hours

Bioavailability: ~70%

Time to peak serum concentration: 5-6 hours

Elimination: Extent of renal excretion is unknown; excreted as parent drug and metabolite; 17% of administered dose is excreted via the kidneys

Children: No dosing information available

Adults: Rifapentine should not be used alone; initial phase should include a 3- to 4-drug regimen

Intensive phase of short-term therapy: 600 mg (four 150 mg tablets) given weekly (every 72 hours); following the intensive phase, treatment should continue with rifapentine 600 mg once weekly for 4 months in combination with INH or appropriate agent for susceptible organisms

Dosing adjustment in renal or hepatic impairment: Unknown

Food increases AUC and maximum serum concentration by 43% and 44% respectively as compared to fasting conditions

Patients with pre-existing hepatic problems should have liver function tests monitored every 2-4 weeks during therapy

Rifampin has been shown to inhibit standard microbiological assays for serum folate and vitamin B₁₂; this should be considered for rifapentine; therefore, alternative assay methods should be considered.

May cause dizziness or drowsiness; has rarely been associated with aggression

May cause neutropenia; use caution with clozapine and carbamazepine; rifapentine is an inducer of CYP3A4; monitor of altered clinical effects with barbiturates, benzodiazepines, phenytoin, beta-blockers, haloperidol and TCAs.

No information available to require special precautions

No effects or complications reported

Best to take on empty stomach (1 hour before or 2 hours after meals); however, may be taken with food if GI upset occurs. Follow recommended dosing schedule exactly; do not increase dose or skip doses. You will need to be monitored on a regular basis while taking this medication. This medication will stain urine, stool, saliva, tears, sweat, and other body fluids a red-brown color. Stains on clothing or contact lenses are permanent. Report vomiting; fever, chills or flu-like symptoms; muscle weakness or unusual fatigue; dark urine, pale stools, or unusual bleeding or bruising; yellowing skin or eyes; skin rash; swelling of extremities; chest pain or palpitations; or persistent gastrointestinal upset. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to be pregnant - nonhormonal contraceptive use may be recommended. Do not breast-feed.

Tablet, film-coated: 150 mg

Grosser J, Lounis N, Truffot-Pernot C, et al, "Once Weekly Rifapentine-Containing Regimens for Treatment of Tuberculosis in Mice," Am J Respir Crit Care Med, 1998, 157:1436-40.

Jarvis B and Lamb HM, "Rifapentine," Drugs, 1998, 56(4):607-16.

Keung AC, Eller MG, and Weir SJ, "Pharmacokinetics of Rifapentine in Patients With Varying Degrees of Hepatic Dysfunction," J Clin Pharmacol, 1998, 38:517-24.

Moghazeh Sl, Pan X, Arain T, et al, "Comparative Antimycobacterial Activities of Rifampin, Rifapentine, and KRM-1648 Against a Collection of Rifampin-Resistant Mycobacterium Tuberculosis Isolates With Known rpob Mutations," Antimicrob Agents Chemother, 1996, 40:265-7.

Tam CM, Chan SL, Lam CW, et al, "Rifapentine and Isoniazid in the Continuation Phase of Treating Pulmonary Tuberculosis, Initial Report," Am J Respir Crit Care Med, 1998, 157:1726-33.