Introduction

Antituberculosis agent; semisynthetic cyclopentylpiperazinyl derivative of rifamycin SV.

Uses for Rifapentine

Tuberculosis

Treatment of active (clinical) tuberculosis (TB) in conjunction with other antituberculosis agents.

For treatment of pulmonary TB, manufacturer states rifapentine can be used in both initial and continuation phases; ATC, CDC, and IDSA suggest the drug not be used in the initial phase, but consider the drug a first-line antituberculosis agent for the continuation phase of intermittent regimens used for treatment of pulmonary TB.

ATS, CDC, and IDSA state that rifapentine can be used in conjunction with isoniazid in the continuation phase in HIV-seronegative patients with noncavity pulmonary TB caused by susceptible Mycobacterium tuberculosis; rifapentine is an alternative to rifampin for use in conjunction with isoniazid in the continuation phase.

Experience in HIV-infected patients is limited; higher rate of TB relapse reported in HIV-infected patients receiving once-weekly regimens of rifapentine and isoniazid. ATS, CDC, IDSA, and other experts state that once-weekly regimens of rifapentine and isoniazid should not be used in HIV-infected patients.

Because of limited experience, ATS, CDC, and IDSA state that rifapentine should not be used for treatment of extrapulmonary TB.

For initial treatment of active TB caused by drug-susceptible M. tuberculosis, recommended multiple-drug regimens consist of an initial intensive phase (2 months) and a continuation phase (4 or 7 months). Although the usual duration of treatment for drug-susceptible pulmonary and extrapulmonary TB (except disseminated infections and TB meningitis) is 6–9 months, ATS, CDC, and IDSA state that completion of treatment is determined more accurately by the total number of doses and should not be based solely on the duration of therapy. A longer duration of treatment (e.g., 12–24 months) usually is necessary for infections caused by drug-resistant M. tuberculosis.

Patients with treatment failure or drug-resistant M. tuberculosis, including multidrug-resistant (MDR) TB (resistant to both isoniazid and rifampin) or extensively drug-resistant (XDR) TB (resistant to both isoniazid and rifampin and also resistant to a fluoroquinolone and at least one parenteral second-line antimycobacterial such as capreomycin, kanamycin, or amikacin), should be referred to or managed in consultation with experts in the treatment of TB as identified by local or state health departments or CDC.

Rifapentine Dosage and Administration

Administration

Oral Administration

Administer orally.

Administration with food may decrease nausea, vomiting, or GI upset in susceptible individuals.

Manufacturer recommends concomitant administration of pyridoxine (vitamin B₆) in those who are malnourished or predisposed to neuropathy (e.g., alcoholics, diabetics), and in adolescents.

Dosage

Must be used in conjunction with other antituberculosis agents for the treatment of active (clinical) TB.

Used in intermittent (once or twice weekly) multiple-drug TB regimens; manufacturer recommends an interval of ≥3 days (≥72 hours) between doses.

Pediatric Patients

Tuberculosis

Treatment of Active (Clinical) Tuberculosis

Children 12–15 years of age: 600 mg twice weekly in the initial intensive treatment phase (2 months), then 600 mg once weekly in the continuation treatment phase (4 months) recommended by manufacturer.

Adolescents ≥15 years of age: 10 mg/kg (up to 600 mg) once weekly recommended by ATS, CDC, and IDSA for the continuation phase; these experts do not recommend use in the intensive phase. Duration of the continuation phase is 4 months in those with negative sputum smears at completion of the initial phase or 7 months in those with positive sputum smears at completion of the initial phase.

Adults

Tuberculosis

Treatment of Active (Clinical) Tuberculosis

600 mg twice weekly in the initial intensive treatment phase (2 months), then 600 mg once weekly in the continuation treatment phase (4 months) recommended by manufacturer.

10 mg/kg (up to 600 mg) once weekly recommended by ATS, CDC, and IDSA for the continuation phase; these experts do not recommend use in the intensive phase. Duration of the continuation phase is 4 months in those with negative sputum smears at completion of the initial phase or 7 months in those with positive sputum smears at completion of the initial phase.

Prescribing Limits

Pediatric Patients

Tuberculosis

Treatment of Active (Clinical) Tuberculosis

Maximum 600 mg per dose in once- or twice-weekly regimens.

Adults

Tuberculosis

Treatment of Active (Clinical) Tuberculosis

Maximum 600 mg per dose in once- or twice-weekly regimens.

Special Populations

Hepatic Impairment

No specific dosage recommendations provided by manufacturer; dosage adjustments probably not necessary.

Renal Impairment

No specific dosage recommendations provided by manufacturer.

Geriatric Patients

Select dosage with caution. (See Geriatric Use under Cautions.)

Contraindications

• Known hypersensitivity to rifapentine, other rifamycins (rifabutin, rifampin), or any ingredient in the formulation.

Warnings/Precautions

Warnings

Hepatic Effects

Serious hepatic events reported with rifamycins.

Use rifapentine in patients with abnormal liver function tests and/or liver disease only when such use is considered necessary and only with caution and close medical supervision. (See Hepatic Impairment under Cautions.) Discontinue the drug if signs of liver disease develop or worsen. Consider hepatotoxicity profile of other antituberculosis agents (e.g., isoniazid, pyrazinamide) if these drugs are used with rifapentine.

Hyperbilirubinemia (resulting from competition between rifapentine and bilirubin for excretory pathways in the liver) possible; such competition has been reported between rifampin and bilirubin. An isolated report of moderate increase in bilirubin and/or transaminase concentrations is not an indication to interrupt rifapentine therapy; the decision to discontinue therapy should be made after repeating the tests, noting trends in the concentrations, and considering the patient’s clinical condition.

Clostridium difficile-associated Diarrhea and Colitis

Treatment with anti-infectives, including rifamycins, may permit overgrowth of clostridia. Consider C. difficile-associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis) if diarrhea develops and manage accordingly.

Some mild cases of CDAD may respond to discontinuance alone. Manage moderate to severe cases with fluid, electrolyte, and protein supplements; appropriate anti-infective therapy (e.g., oral metronidazole or vancomycin) recommended if colitis is severe. Agents inhibiting peristalsis contraindicated in these patients.

Interactions

Concomitant use with HIV protease inhibitors (PIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), or certain HIV entry inhibitors not recommended. (See Specific Drugs and Laboratory Tests under Interactions.)

General Precautions

Precautions Related to Treatment of Tuberculosis

Should not be used alone for treatment of active TB; must be used in conjunction with other antituberculosis agents.

Clinical specimens for microscopic examination and mycobacterial cultures and in vitro susceptibility testing should be obtained prior to initiation of antituberculosis therapy and periodically during treatment to monitor therapeutic response. The antituberculosis regimen should be modified as needed. Patients with positive cultures after 4 months of treatment should be considered to have failed treatment (usually as the result of noncompliance or drug-resistant TB).

Compliance with the full course of antituberculosis therapy and all drugs included in the multiple-drug regimen is critical. Missed doses increase the risk of treatment failure and increase the risk that M. tuberculosis will develop resistance to the antituberculosis regimen.

To ensure compliance, ATS, CDC, and IDSA recommend that directly observed (supervised) therapy (DOT) be used for treatment of active (clinical) TB whenever possible, especially when intermittent regimens are used, when the patient is immunocompromised or infected with HIV, or when drug-resistant M. tuberculosis is involved.

Patients with Porphyria

Should not be used in patients with porphyria.

There have been isolated reports of exacerbation of porphyria in patients receiving rifampin (rifampin has enzyme-inducing properties, including induction of delta amino levulinic acid synthetase); similar effects may occur with rifapentine.

Discoloration of Body Tissues or Fluids

Urine, sweat, sputum, tears, and breast milk may have a red-orange coloration during rifapentine therapy. Soft contact lenses and dentures may become permanently stained.

Patient Monitoring

Obtain baseline measurements of liver function (hepatic enzymes, bilirubin) and hematologic status (CBC, platelet count). Routine laboratory monitoring for drug-induced toxicity generally not necessary in patients with normal baseline test results.

Evaluate patient at least once monthly during therapy; question patient about symptoms associated with adverse effects. All patients with abnormalities should be followed up, including laboratory monitoring if indicated.

Specific Populations

Pregnancy

Category C.

Rifampin administration during the last few weeks of pregnancy can cause postnatal hemorrhages in the mother and infant that require treatment with vitamin K. Similar effects may occur with rifapentine; appropriate clotting parameters should be evaluated if use of rifapentine is considered necessary during the last few weeks of pregnancy.

ATS, CDC, and IDSA state data are insufficient to recommend use of rifapentine in pregnant women.

Lactation

Not known whether rifapentine is distributed into milk; discontinue nursing or the drug.

Breast milk may have a red-orange coloration during rifapentine therapy. (See Discoloration of Body Tissues or Fluids under Cautions.)

Pediatric Use

Safety and efficacy not established in children <12 years of age. Limited pharmacokinetic data available in children 12–15 years of age.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.

Select dosage with caution, starting at the low end of the dosage range, because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.

Hepatic Impairment

Use in patients with impaired liver function only when clearly necessary and only under strict medical supervision. Monitor liver function (especially serum transaminase concentrations) before initiating therapy and every 2–4 weeks during therapy. Discontinue if signs of liver disease worsen.

Common Adverse Effects

Neutropenia, increased AST/ALT, pyuria.

Administration

Oral Administration

Administer orally.

Administration with food may decrease nausea, vomiting, or GI upset in susceptible individuals.

Manufacturer recommends concomitant administration of pyridoxine (vitamin B₆) in those who are malnourished or predisposed to neuropathy (e.g., alcoholics, diabetics), and in adolescents.

Dosage

Must be used in conjunction with other antituberculosis agents for the treatment of active (clinical) TB.

Used in intermittent (once or twice weekly) multiple-drug TB regimens; manufacturer recommends an interval of ≥3 days (≥72 hours) between doses.

Pediatric Patients

Tuberculosis

Treatment of Active (Clinical) Tuberculosis

Children 12–15 years of age: 600 mg twice weekly in the initial intensive treatment phase (2 months), then 600 mg once weekly in the continuation treatment phase (4 months) recommended by manufacturer.

Adolescents ≥15 years of age: 10 mg/kg (up to 600 mg) once weekly recommended by ATS, CDC, and IDSA for the continuation phase; these experts do not recommend use in the intensive phase. Duration of the continuation phase is 4 months in those with negative sputum smears at completion of the initial phase or 7 months in those with positive sputum smears at completion of the initial phase.

Adults

Tuberculosis

Treatment of Active (Clinical) Tuberculosis

600 mg twice weekly in the initial intensive treatment phase (2 months), then 600 mg once weekly in the continuation treatment phase (4 months) recommended by manufacturer.

10 mg/kg (up to 600 mg) once weekly recommended by ATS, CDC, and IDSA for the continuation phase; these experts do not recommend use in the intensive phase. Duration of the continuation phase is 4 months in those with negative sputum smears at completion of the initial phase or 7 months in those with positive sputum smears at completion of the initial phase.

Prescribing Limits

Pediatric Patients

Tuberculosis

Treatment of Active (Clinical) Tuberculosis

Maximum 600 mg per dose in once- or twice-weekly regimens.

Adults

Tuberculosis

Treatment of Active (Clinical) Tuberculosis

Maximum 600 mg per dose in once- or twice-weekly regimens.

Special Populations

Hepatic Impairment

No specific dosage recommendations provided by manufacturer; dosage adjustments probably not necessary.

Renal Impairment

No specific dosage recommendations provided by manufacturer.

Geriatric Patients

Select dosage with caution. (See Geriatric Use under Cautions.)

Induces CYP3A4 and CYP2C8/9.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interactions likely with drugs metabolized by CYP3A4 or CYP2C8/9; increased metabolism of these drugs.

Induces hepatic enzymes to a lesser extent than rifampin and to a greater extent than rifabutin.

Specific Drugs and Laboratory Tests