Rifapentine - Dosage, Indication, Contraindications, and Administration

Overview

Rifapentine (cyclopentyl-rifamycin) is a novel antimycobacterial drug derived from oral Rifamycin. It is available in two forms: a tablet form ( DL473, MDL473) approved for treating pulmonary TB in the United States and a capsule formulation used by the People's Republic of China.

Rifapentine has a wide range of antimicrobial effects. Besides its antitubercular action, the medicine is more active than Rifampicin (Rifampin) and less active than Rifabutin against Mycobacterium avium complex strains. It also exhibits activity against Gram-positive and Gram-negative bacteria and Toxoplasma gondii.

Indication of Rifapentine:

• Rifapentine is a Rifamycin antimycobacterial used together with one or more antituberculosis medications for treating pulmonary tuberculosis caused by Mycobacterium tuberculosis.

Dosage:

• Dosage Form and Strength: This is available in tablet and capsule form.

• Dosage Strength: 150 mg.

• Recommended Dose:

Rifapentine has been assessed as part of regimens comprising an initial 2-month phase followed by a 4-month maintenance phase for treating TB caused by drug-susceptible organisms. Rifapentine should not be given alone during the initial or maintenance phases of antituberculous therapy.

During the Initial Phase (2 Months): 600 mg twice weekly for two months, with no less than three consecutive days (72 hours) between doses, in conjunction with other antituberculosis medications.

During the Continuation Phase (4 Months): 600 mg once weekly by direct observation treatment with Isoniazid or any suitable antituberculous drug for four months.

To prevent Isoniazid (INH) - associated peripheral neuropathy, pyridoxine (Vitamin B6) should be administered concurrently. Therefore, it should be taken along with the meal.

Contraindication: Rifapentine should not be given if the patient has a known hypersensitivity to Rifamycin or other components in the drug.

Warnings and Precautions:

• HIV Seropositive Patients: Due to a significant risk of failure or relapse observed due to the presence of Rifapentine-resistant organisms, Rifapentine should not be given as a once-weekly continuation phase regimen in HIV seropositive patients with pulmonary tuberculosis along with Isoniazid. Rifapentine has not been evaluated as part of the initial phase therapy regimen in HIV-positive pulmonary tuberculosis patients.

• Protease Inhibitors and Reverse Transcriptase Inhibitors: Rifapentine is a (cytochrome P450) CYP450 enzyme inducer. Concurrent use of Rifapentine with other medications metabolized by protease inhibitors and reverse transcriptase inhibitors may result in a considerable reduction in plasma concentrations and a decrease of the protease inhibitor's or reverse transcriptase inhibitor's therapeutic action.

• Relapse of Tuberculosis: Because of the increased risk of recurrence, Rifapentine should be administered with care in persons with cavitary lung lesions and positive sputum cultures after the initial phase of treatment or those with signs of relapse in both lungs due to infection.

• Poor compliance with the dosing regimen, especially during the initial phase of antituberculosis medications not necessarily reflecting Rifapentine, is linked with late sputum conversion and a high rate only during pregnancy. As a result, compliance with the complete course of therapy must be highlighted, as well as the need not to miss any doses prescribed.

• High recurrence rates have also been seen in HIV-positive individuals using Rifapentine during the continuation phase. Both pulmonary and extrapulmonary illness at baseline, low CD4 counts, use of azole antifungals, and age are the risk factors for relapse.

• Hepatotoxicity: Because antituberculous multidrug regimens, such as the Rifamycin class, have been linked to severe liver conditions, patients with abnormal liver tests or liver disease should only be given Rifapentine when necessary, and then only with extreme care and under strict medical supervision. In these individuals, liver tests (particularly serum transaminases) should be carefully monitored before medication every two to four weeks during treatment. If symptoms of liver disease develop or worsen, Rifapentine should be stopped immediately. The hepatotoxicity of other antituberculosis drugs (for example, Isoniazid, Pyrazinamide) used in conjunction with Rifapentine should also be considered.

• Hyperbilirubinemia: Hyperbilirubinemia due to Rifapentine and bilirubin competing over excretory systems cannot be ruled out. A single report of a moderate rise in bilirubin and transaminase levels is not enough to support discontinuation of the therapy; instead, the choice should be taken after conducting the tests repeatedly, observing patterns in the bilirubin and transaminase levels, and considering them in conjunction with the disease condition of the patient.

• Discoloration of Body Fluids: Rifapentine may cause red-orange staining of human tissues and fluids into red-orange color (For example-skin, teeth, tongue, urine, feces, saliva, sputum, tears, sweat, and cerebrospinal fluid). Contact lenses and dentures can discolor permanently.

• Porphyria: Rifapentine should not be given to patients with porphyria. Rifampin stimulates the activity of enzymes, including delta amino levulinic acid synthetase. Isolated studies suggest that Rifapentine may have a similar impact.

• Clostridium Difficile-Associated Diarrhea: Clostridium difficile-associated diarrhea (CDAD) has been shown due to the administration of almost all antibacterial drugs, such as Rifamycins, and symptoms can vary from mild diarrhea to fatal colitis. Antibacterial therapy changes the natural flora of the colon, resulting in C.difficile overgrowth.

• Toxins A and B produced by C.difficile contribute to the onset of CDAD. C.difficile hyper toxic-releasing strains produce more significant morbidity and death because these infections are resistant to antimicrobial treatment and may need colectomy. All individuals who appear to have diarrhea after antibiotic usage should be evaluated for CDAD. A thorough medical history is required since CDAD has been documented to occur more than two months following the intake of antimicrobial medicines.

• If CDAD is anticipated or diagnosed, antibiotics not targeted against C.difficile may need to be stopped. In addition, as clinically recommended, protein supplements do not necessarily reflect therapy for C.difficile, and surgical assessment should be implemented only during pregnancy and electrolyte management.

For Patients

What Is Active Tuberculosis?

• Active tuberculosis is a multisystem infection characterized by either a primary infection or the reactivation of latent tuberculosis. As a result, active tuberculosis might be either primary tuberculosis or tuberculosis due to reactivation.

• Primary tuberculosis develops when the immune system fails to protect against Mycobacterium tuberculosis (MTB) infection. As the name implies, reactivation tuberculosis is the reactivation of a previously confined mycobacterial infection. Reactivation tuberculosis is the most frequent active tuberculosis, accounting for 90 percent of cases.

• The lung is the most widely implicated organ. However, other organ systems typically involved are the gastrointestinal system, the musculoskeletal system, the lymphoreticular system, the skin, the liver, and the reproductive system.

What Is Rifapentine?

• Rifapentine belongs to the antimycobacterial drugs.

• It works by destroying the bacteria responsible for the infection.

What Is Rifapentine Used For?

• Rifapentine is used in combination with other drugs to treat active tuberculosis (a severe infection that affects the lungs and occasionally other body parts) in adults and children 12 years and older.

• Rifapentine is also prescribed with Isoniazid to treat latent tuberculosis infection in adults and children two years of age, particularly those in close contact with persons with active tuberculosis.

What to Know Before Using Rifapentine?

Do Not Take Rifapentine:

If a person is allergic to Rifapentine or other ingredients used in the drug. Inform the doctor about current drug allergies or medications the patient is taking.

Before Taking Rifapentine:

• Inform the doctor if the patient is taking hormonal contraception. Rifapentine can reduce the efficacy of hormonal contraceptives. The patient is advised to use another method of birth control. Talk to the doctor regarding birth control options.

• Inform the doctor about active tuberculosis or any other tuberculosis medicines that have not shown improvements.

• Inform the doctor immediately if the patient is pregnant or planning for pregnancy during the treatment.

• Inform the doctor if the patient is using contact lenses or dentures because Rifapentinne causes discoloration of the dentures and lens.

How to Use Rifapentine?

• Rifapentine should be taken along with meals.

What if the Patient Misses a Dose of Rifapentine?

• Take the missing dosage immediately as soon as you remember. However, if it is almost time for the next dosage, ignore the missed dose and proceed with the usual dosing regimen. Take only one dose to make up for a missing one.

What Are the Possible Side Effects?

Rifapentine may have undesirable side effects. Inform the doctor if the patient experiences severe or persistent symptoms:

• Temporary discoloration of the skin, teeth, saliva, urine, feces, sweat, and tears (yellow, eddish-orange, or brown).

• Dizziness.

• Excessive sweat and fainting.

Some serious adverse effects. If the patient suffers any of the following symptoms, contact the doctor as soon as possible:

• Diarrhea (up to two months after therapy) rashes, itching, and hives.

• Coughing with wheezing, breathing problems, eyes are red, itchy, or irritated.

• Fever and blisters on the skin.

• Alterations in thought and behavior.

• Eyes, cheeks, lips, tongue, throat, arms, hands, feet, ankles, or lower legs swelling.

• Irregular heartbeat.

• Nausea and vomiting.

• Chest discomfort.

• Flu-like symptoms include fever, chills, muscular pains, discomfort, fatigue, and headache.

• Stomach ache and loss of appetite.

• Discoloration of the urine.

• Joint pain or swelling and yellowish discoloration of the skin and eyes.

How to Store?

• Keep this medication in its original container, properly sealed, and away from the children. Keep it at room temperature and away from extreme heat and moisture.

• Unused medications should be disposed of in particular ways to ensure that pets, children, and others cannot accidentally consume them.

For Doctors:

What Is Rifapentine?

• Oral administration comprises 150 mg of the active component of Rifapentine per tablet.

• Each 150 mg of Rifapentine tablet contains calcium stearate, disodium EDTA, FD&C Blue No. 2 aluminum lake, hydroxypropyl cellulose, hypromellose USP, microcrystalline cellulose, polyethylene glycol, pregelatinized starch, propylene glycol, sodium ascorbate, sodium lauryl sulfate, sodium starch glycolate, synthetic red iron oxide, and titanium dioxide.

• Rifapentine is a Rifamycin derivative antibiotic with microbiological action equivalent to Rifampin (Rifampicin). The molecular weight is 877.04 and has a molecular formula of C47H64N4O12.

Dosage and Administration:

• The Usual Dose is - 600mg.

• Route of Administration - Oral route.

• Time of Administration:

  • Initial Phase: Twice a week.

  • Continuation Phase: Once a week.

Clinical Pharmacology

Mechanism of Action

In susceptible species, Rifapentine suppresses the production of bacterial RNA by binding to the beta-subunit of DNA-dependent RNA polymerase. It is bactericidal durg.

Pharmacokinetics

Absorption: The total bioavailability of Rifapentine has not been established. Rifapentine has a 70 percent relative bioavailability (using an oral solution as a reference) after a 600 mg dosage in healthy adult volunteers. The highest concentrations were observed five to six hours after taking 600 mg of Rifapentine.

Distribution:

• In healthy participants, Rifapentine binds to plasma proteins 97.7 percent of the time, primarily to albumin. In patients (n = 351) undergoing Rifapentine-based combination treatment for tuberculosis, the distribution volume of Rifapentine was calculated to be 70.2 L.

• The concentrations of Rifapentine in tissue surpassed the plasma concentrations in rats after 8, 24, and 72 hours following oral administration of a 10 mg/kg dosage, except in bone, brain, and testicular tissue. However, the concentrations in the brain were 20 percent less than that of the plasma concentrations.

• In Five Chinese patients with tuberculous meningitis, Cerebrospinal fluid concentrations of Rifapentine were below the detection limit (less than 0.15 mg/L), and mean serum concentrations were 7.2 mg/L 10 hours after oral intake.

Metabolism and Elimination:

• After 600 mg oral dosage of radiolabeled Rifapentine, 87 percent of the total 14C Rifapentine was recovered, 17 percent in the urine, and 70 percent in the feces, respectively. Within seven days, the body eliminated more than 80 percent of the total dose of 14C Rifapentine.

• An esterase enzyme hydrolyses Rifapentine to produce microbiologically active 25-desacetyl Rifapentine 99 percent of the total radioactivity in plasma was responsible for Rifapentine and 25-desacetyl Rifapentine.

• The AUC (0-infinity) and Cmax values of the 25-desacetyl Rifapentine metabolite in plasma were half and one-third of those of Rifapentine, correspondingly.

• Based on relative in vitro activities and AUC (0-infinity) values, Rifapentine and 25-desacetyl Rifapentine may provide 62 percent and 38 percent, respectively, to clinical interventions against M. tuberculosis.

Specific Populations:

• Pregnancy: There have been no appropriate and well-controlled trials of Rifapentine administration during pregnancy. Rifapentine caused fetal damage and was teratogenic in animal reproductive and developmental toxicity evaluation. However, as animal studies do not necessarily reflect human response, Rifapentine should be administered only during pregnancy if the possible benefit outweighs the potential fetal danger.

• Nursing Mothers: It is not established whether Rifapentine is secreted in human milk. Because many medications are secreted in human milk, and there is a risk of significant adverse effects in nursing infants, a choice should be taken whether to quit nursing or stop the drug, considering the drug's benefits to the mother and the advantages of breastfeeding. In addition, because Rifapentine can cause a red-orange staining of bodily fluids, it can cause discoloration of the breast milk.

• Pediatric Use: Rifapentine's safety and efficacy in patients below 12 have not been demonstrated. In a pharmacokinetic investigation of two to twelve years pediatric patients, the exposure to Rifapentine was lower than in healthy adults. Another pharmacokinetic research was carried out on healthy volunteers aged 12 to 15 years, and the pharmacokinetics of Rifapentine were the same as those seen in healthy adults.

• Geriatric Use: Rifapentine clinical trials did not involve a prominent enough number of participants aged 65 and above to assess whether they respond differently than younger people. Other clinical studies have not revealed any variations in responsiveness between elderly and younger patients. In general, for an elderly patient, the dose selection should be carefully made, starting with a low dose, reflecting the increased probability of reduced hepatic, renal, or cardiac function and the presence of concurrent illness or other medication therapy.

What if a Rifapentine Overdose Occurs?

• Overdose symptoms may include - Itching, body ache, stiffness, and blood in the urine (hematuria).

• Single oral doses of up to 1200 mg were given without significant side effects in a pharmacokinetic trial involving healthy volunteers (n=9). Heartburn (3/8), headache (2/8), and increased urine frequency (1/8) were the only side effects observed with the 1200 mg dosage.