Rifabutin

Description

DESCRIPTION Rifabutin Capsules for oral administration contain 150 mg of the rifamycin antimycobacterial agent rifabutin, USP, per capsule along with the inactive ingredients, microcrystalline cellulose, sodium lauryl sulfate, colloidal silicon dioxide, magnesium stearate. The hard gelatin capsule contains titanium dioxide, red iron oxide, gelatin, sodium lauryl sulfate and purified water. The imprinting ink contains shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia solution, black iron oxide, potassium hydroxide and purified water. The chemical name for rifabutin is 1',4-didehydro-1-deoxy-1,4-dihydro-5'-(2- methylpropyl)-1-oxorifamycin XIV (Chemical Abstracts Service, 9th Collective Index) or (9 S ,12 E ,14 S ,15 R , 16 S ,17 R ,18 R ,19 R ,20 S ,21 S ,22 E , 24 Z )-6,16,18,20-tetrahydroxy-1'- isobutyl-14-methoxy- 7,9,15,17,19,21,25-heptamethyl-spiro [9,4- (epoxypentadeca[1,11,13]trienimino)-2 H - furo[2',3':7,8]naphth[1,2-d] imidazole-2,4'- piperidine]-5,10,26-(3 H ,9 H )-trione-16-acetate. Rifabutin has a molecular formula of C 46 H 62 N 4 O 11 , a molecular weight of 847.02 and the following structure: Rifabutin is a red-violet powder soluble in methanol, slightly soluble in ethanol, and slightly soluble in water (0.21 mg/mL). Its log P value (the base 10 logarithm of the partition coefficient between n-octanol and water) is 3.2 (n-octanol/water). FDA approved dissolution method differs from the current USP monograph dissolution method. structure

What Is Rifabutin Used For?

INDICATIONS & USAGE Rifabutin Capsules are indicated for the prevention of disseminated Mycobacterium avium complex (MAC) disease in patients with advanced HIV infection.

Dosage and Administration

DOSAGE & ADMINISTRATION It is recommended that Rifabutin Capsules be administered at a dose of 300 mg once daily. For those patients with propensity to nausea, vomiting, or other gastrointestinal upset, administration of Rifabutin at doses of 150 mg twice daily taken with food may be useful. For patients with severe renal impairment (creatinine clearance less than 30 mL/min), consider reducing the dose of Rifabutin by 50%, if toxicity is suspected. No dosage adjustment is required for patients with mild to moderate renal impairment. Reduction of the dose of Rifabutin may also be needed for patients receiving concomitant treatment with certain other drugs (see PRECAUTIONS- Drug Interactions) . Mild hepatic impairment does not require a dose modification. The pharmacokinetics of rifabutin in patients with moderate and severe hepatic impairment is not known.

Side Effects (Adverse Reactions)

ADVERSE REACTIONS Adverse Reactions from Clinical Trials Rifabutin Capsules were generally well tolerated in the controlled clinical trials. Discontinuation of therapy due to an adverse event was required in 16% of patients receiving Rifabutin, compared to 8% of patients receiving placebo in these trials. Primary reasons for discontinuation of Rifabutin were rash (4% of treated patients), gastrointestinal intolerance (3%), and neutropenia (2%). The following table enumerates adverse experiences that occurred at a frequency of 1% or greater, among the patients treated with Rifabutin in studies 023 and 027. Table: 3 Clinical Adverse Experiences Reported in ≥1% of Patients Treated With Rifabutin Adverse event Rifabutin (n = 566) % Placebo (n = 580) % Body as a whole Abdominal pain 4 3 Asthenia 1 1 Chest pain 1 1 Fever 2 1 Headache 3 5 Pain 1 2 Blood and lymphatic system Leucopenia 10 7 Anemia 1 2 Digestive System Anorexia 2 2 Diarrhea 3 3 Dyspepsia 3 1 Eructation 3 1 Flatulence 2 1 Nausea 6 5 Nausea and vomiting 3 2 Vomiting 1 1 Musculoskeletal system Myalgia 2 1 Nervous system Insomnia 1 1 Skin and appendages Rash 11 8 Special senses Taste perversion 3 1 Urogenital system Discolored urine 30 6 CLINICAL ADVERSE EVENTS REPORTED IN <1% OF PATIENTS WHO RECEIVED RIFABUTIN Considering data from the 023 and 027 pivotal trials, and from other clinical studies, Rifabutin appears to be a likely cause of the following adverse events which occurred in less than 1% of treated patients: flu-like syndrome, hepatitis, hemolysis, arthralgia, myositis, chest pressure or pain with dyspnea, skin discoloration, thrombocytopenia, pancytopenia and jaundice. The following adverse events have occurred in more than one patient receiving Rifabutin, but an etiologic role has not been established: seizure, paresthesia, aphasia, confusion, and non-specific T wave changes on electrocardiogram. When Rifabutin was administered at doses from 1050 mg/day to 2400 mg/day, generalized arthralgia and uveitis were reported. These adverse experiences abated when Rifabutin was discontinued. Mild to severe, reversible uveitis has been reported less frequently when Rifabutin is used at 300 mg as monotherapy in MAC prophylaxis versus Rifabutin in combination with clarithromycin for MAC treatment (see also WARNINGS ). Uveitis has been infrequently reported when Rifabutin is used at 300 mg/day as monotherapy in MAC prophylaxis of HIV-infected persons, even with the concomitant use of fluconazole and/or macrolide antibacterials. However, if higher doses of Rifabutin are administered in combination with these agents, the incidence of uveitis is higher. Patients who developed uveitis had mild to severe symptoms that resolved after treatment with corticosteroids and/or mydriatic eye drops; in some severe cases, however, resolution of symptoms occurred after several weeks. When uveitis occurs, temporary discontinuance of Rifabutin and ophthalmologic evaluation are recommended. In most mild cases, Rifabutin may be restarted; however, if signs or symptoms recur, use of Rifabutin should be discontinued (Morbidity and Mortality Weekly Report, September 9, 1994). Corneal deposits have been reported during routine ophthalmologic surveillance of some HIV-positive pediatric patients receiving Rifabutin as part of a multiple drug regimen for MAC prophylaxis. The deposits are tiny, almost transparent, asymptomatic peripheral and central corneal deposits, and do not impair vision. The following table enumerates the changes in laboratory values that were considered as laboratory abnormalities in Studies 023 and 027. Table 4 Percentage of Patients With Laboratory Abnormalities Laboratory abnormalities Rifabutin (n = 566) % PLACEBO (n = 580) % Chemistry Increased alkaline phosphatase 1 <1 3 Increased SGOT 2 7 12 Increased SGPT 2 9 11 Hematology Anemia 3 6 7 Eosinophilia 1 1 Leukopenia 4 17 16 Neutropenia 5 25 20 Thrombocytopenia 6 5 4 Includes grades 3 or 4 toxicities as specified: 1 All...

Drug Interactions

DRUG INTERACTIONS Effect of Rifabutin on the Pharmacokinetics of Other Drugs Rifabutin induces CYP3A enzymes and therefore may reduce the plasma concentrations of drugs metabolized by those enzymes. This effect may reduce the efficacy of standard doses of such drugs, which include itraconazole, clarithromycin, and saquinavir. Effect of Other Drugs on Rifabutin Pharmacokinetics Some drugs that inhibit CYP3A may significantly increase the plasma concentration of rifabutin. Therefore, carefully monitor for rifabutin associated adverse events in those patients also receiving CYP3A inhibitors, which include fluconazole and clarithromycin. In some cases, the dosage of Rifabutin may need to be reduced when it is coadministered with CYP3A inhibitors. Table 2 summarizes the results and magnitude of the pertinent drug interactions assessed with rifabutin. The clinical relevance of these interactions and subsequent dose modifications should be judged in light of the population studied, severity of the disease, patient's drug profile, and the likely impact on the risk/benefit ratio. Table 2 Rifabutin Interaction Studies Coadministered drug Dosing regimen of coadministered drug Dosing regimen of rifabutin Study population (n) Effect on rifabutin Effect on coadministered drug Recommendation ANTIRETROVIRALS Amprenavir 1200 mg twice a day for 10 days 300 mg once a day for 10 days Healthy male subjects (6) ↑ AUC by 193%, ↑ Cmax by 119% Reduce rifabutin dose by at least 50%. Monitor closely for adverse reactions. Bictegravir 75 mg once a day 300 mg once a day (fasted) Healthy subjects ND ↓ AUC 38% ↓ Cmin 56% ↓ Cmax 20% Co-administration of rifabutin with Biktarvy (bictegravir/ emtricitabine/tenofovir alafenamide) is not recommended due to an expected decrease in tenofovir alafenamide in addition to the reported reduction in bictegravir. Refer to Biktarvy prescribing information for additional information. Delavirdine 400 mg three times a day 300 mg once a day HIV infected patients (7) ↑ AUC by 230%, ↑ Cmax by 128% ↓ AUC by 80%, ↓ Cmax by 75%, ↓ Cmin by 17% CONTRAINDICATED Didanosine 167 or 250 mg twice a day for 12 days 300 or 600 mg once a day for 12 days HIV infected patients (11) Doravirine 100 mg single dose 300 mg once a day for 16 days Healthy subjects (12) ND ↓ 50% in AUC, ↓ 68% in C24 ↔ in Cmax If concomitant use is necessary, increase the doravirine dosage as instructed in doravirine-containing product prescribing information. Fosamprenavir/ ritonavir 700 mg twice a day plus ritonavir 100 mg twice a day for 2 weeks 150 mg every other day for 2 weeks Healthy subjects (15) ↔ AUC a ↓ Cmax by 15% ↑ AUC by 35% b , ↑ Cmax by 36%, ↑ Cmin by 36%, Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given With fosamprenavir/ritonavir combination. Indinavir 800 mg three times a day for 10 days 300 mg once a day for 10 days Healthy subjects (10) ↑ AUC by 173%, ↑ Cmax by 134% ↓ AUC by 34%, ↓ Cmax by 25%, ↓ Cmin by...

Contraindications

CONTRAINDICATIONS Rifabutin Capsules are contraindicated in patients who have had clinically significant hypersensitivity to rifabutin or to any other rifamycins.

Pregnancy and Breastfeeding

PREGNANCY Rifabutin should be used in pregnant women only if the potential benefit justifies the potential risk to the fetus. There are no adequate and well-controlled studies in pregnant or breastfeeding women. Reproduction studies have been carried out in rats and rabbits given rifabutin using dose levels up to 200 mg/kg (about 6 to 13 times the recommended human daily dose based on body surface area comparisons). No teratogenicity was observed in either species. In rats, given 200 mg/kg/day, (about 6 times the recommended human daily dose based on body surface area comparisons), there was a decrease in fetal viability. In rats, at 40 mg/kg/day (approximately equivalent to the recommended human daily dose based on body surface area comparisons), rifabutin caused an increase in fetal skeletal variants. In rabbits, at 80 mg/kg/day (about 5 times the recommended human daily dose based on body surface area comparisons), rifabutin caused maternotoxicity and increase in fetal skeletal anomalies. Because animal reproduction studies are not always predictive of human response, rifabutin should be used in pregnant women only if the potential benefit justifies the potential risk to the fetus.

NURSING MOTHERS It is not known whether rifabutin is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Overdosage

OVERDOSAGE No information is available on accidental overdosage in humans. Treatment While there is no experience in the treatment of overdose with Rifabutin Capsules, clinical experience with rifamycins suggests that gastric lavage to evacuate gastric contents (within a few hours of overdose), followed by instillation of an activated charcoal slurry into the stomach, may help absorb any remaining drug from the gastrointestinal tract. Rifabutin is 85% protein bound and distributed extensively into tissues (Vss:8 to 9 L/kg). It is not primarily excreted via the urinary route (less than 10% as unchanged drug); therefore, neither hemodialysis nor forced diuresis is expected to enhance the systemic elimination of unchanged rifabutin from the body in a patient with an overdose of Rifabutin.

How Supplied

HOW SUPPLIED Rifabutin Capsules, USP are supplied as hard gelatin capsule shell with maroon colored cap and body, imprinted with black ink as 041 on cap and Novitium 150 mg (150 mg under Novitium) on body, filled with red-violet powder, each containing 150 mg of Rifabutin, USP. Rifabutin is available as follows: NDC 10135-0738-01 Bottles of 100 capsules Keep tightly closed and dispense in a tight container as defined in the USP. Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Manufactured for/ Distributed by: Marlex Pharmaceuticals, Inc. Rev. 05/22 NP