Rifabutin

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

DOSAGE AND 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. Doses of Rifabutin capsules may be administered mixed with foods such as applesauce. 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.

CONTRAINDICATIONS Rifabutin capsules are contraindicated in patients who have had clinically significant hypersensitivity to rifabutin or to any other rifamycins. Rifabutin capsules are contraindicated in patients being treated with cabotegravir/rilpivirine prolonged-release injectable suspension ( see PRECAUTIONS-Drug Interactions, Table 2 ).

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 450 U/L 2 All values >150 U/L 3 All hemoglobin values <8.0 g/dL 4 All WBC values < 1,500/mm 3 5 All ANC values <750/mm 3 6 All platelet count values <50,000/mm 3 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 The incidence of neutropenia in patients treated with rifabutin was significantly greater than in patients treated with placebo (p = 0.03). Although thrombocytopenia was not significantly more common among patients treated with rifabutin in these trials, rifabutin has been clearly linked to thrombocytopenia in rare cases. One patient in Study 023 developed thrombotic thrombocytopenic purpura, which was attributed to rifabutin. Adverse Reactions from Post-Marketing Experience Adverse reactions identified through post-marketing surveillance by system organ class (SOC) are listed below: Blood and lymphatic system disorders: White blood cell disorders (including agranulocytosis, lymphopenia, granulocytopenia, neutropenia, white blood cell count decreased, neutrophil count decreased), platelet count decreased. Immune system disorders: Hypersensitivity, bronchospasm, rash, and eosinophilia. Gastrointestinal disorders: Clostridiodes difficile colitis/ Clostridiodes difficile associated diarrhea. Pyrexia, rash and other hypersensitivity reactions such as eosinophilia and bronchospasm might occur, as has been seen with other antibacterials. A limited occurrence of skin discoloration have been reported. Severe cutaneous adverse reactions (SCARs): Rifabutin capsules has been associated with the occurrence of DRESS as well as other SCARs such as SJS, TEN, and AGEP (see WARNINGS ). Rifamycin hypersensitivity reactions: Hypersensitivity to rifamycins have been reported including flu-like symptoms, bronchospasm, hypotension, urticaria, angioedema, conjunctivitis, thrombocytopenia or neutropenia.

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%, ↑ C max by 119% ↔ Reduce rifabutin dose by at least 50%. Monitor closely for adverse reactions. Atazanavir/Ritonavir 300/100 mg once daily 150 mg twice weekly Healthy adult subjects 48% ↑ in AUC, 149% ↑ C max of rifabutin. 990% ↑ in AUC, 677% ↑ C max of 25-O-desacetyl-rifabutin. No significant change in pharmacokinetics. A reduction in the dose of rifabutin (to 150 mg every other day or 3 times a week) is recommended. Increased monitoring for adverse reactions is warranted. Bictegravir 75 mg once a day 300 mg once a day (fasted) Healthy subjects ND ↓ AUC 38% ↓ C min 56 % ↓ C max 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 Darunavir/Ritonavir 600/100 mg twice a day for 12 days 150 mg every other day for 12 days Healthy HIV negative adults No significant change in rifabutin pharmacokinetics. 881% ↑ in AUC, 377% ↑ C max of 25-O-desacetyl-rifabutin. 57% ↑ in AUC, 42% ↑ C max of darunavir. 66% ↑ in AUC, 68% C max of ritonavir. A reduction in the dose of rifabutin (to 150 mg every other day or 3 times a week) is recommended. Increased monitoring for adverse reactions is warranted. Delavirdine 400 mg three times a day 300 mg once a day HIV-infected patients (7) ↑ AUC by 230%, ↑ C max by 128% ↓ AUC by 80%, ↓ C max by 75%, ↓ C min 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) ↔ ↔ Dolutegravir 50 mg daily for 14 days 300 mg daily for 14 days Healthy adult subjects ND No significant change in dolutegravir pharmacokinetics at steady state Doravirine 100 mg single dose 300 mg once a day for 16 days Healthy subjects (12) ND ↓ 50% in AUC, ↓ 68% in C 24 ↔ in C max If concomitant use is necessary, increase the doravirine dosage as instructed in the doravirine-containing product prescribing information. Elvitegravir/Cobicistat 150/50 mg daily 300 mg daily Or 150 mg every other day Healthy subjects (12) No significant change in rifabutin pharmacokinetics. 6.3-fold ↑in AUC, 4.8-fold ↑ C max of 25-O-desacetly-rifabutin. No change in elvitegravir except 67% ↓ C trough of elvitegravir. No change in cobicistat exposure. Co-administration of rifabutin with elvitegravir/cobicistat is not recommended due to an expected decrease in elvitegravir exposure. Etravirine 800 mg twice daily for 21 days 300 mg daily on days 8 …

Mechanism of Action Rifabutin inhibits DNA-dependent RNA polymerase in susceptible strains of Escherichia coli and Bacillus subtilis but not in mammalian cells. In resistant strains of E. coli , rifabutin, like rifampin, did not inhibit this enzyme. It is not known whether rifabutin inhibits DNA-dependent RNA polymerase in Mycobacterium avium or in M. intracellulare which comprise M. avium complex (MAC).

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

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 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 Capsules, USP are available as follows: NDC: 70518-4594-00 NDC: 70518-4594-01 NDC: 70518-4594-02 PACKAGING: 60 in 1 BOTTLE PLASTIC PACKAGING: 50 in 1 BOX PACKAGING: 1 in 1 POUCH 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]. Repackaged and Distributed By: Remedy Repack, Inc. 625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762