Rifabutin

Rifabutin is an Antitubercular belonging to antimycobacterial.

Rifabutin is used in the Treatment of Mycobacterium avium complex (MAC), prophylaxis. It is so used to treat M. avium complex infection treatment; Tuberculosis, latent Tuberculosis treatment (drug susceptible) (excludes meningitis).

Rifabutin is readily but incompletely absorbed from the GI tract. Food may delay absorption and get Widely distributed in body tissues and fluids. Volume of distribution: 9.32 L/kg. The Plasma protein binding: Approx 70% and Undergoes rapid hepatic metabolism by CYP3A4 isoenzyme to active 25-O-deacetyl and 31-hydroxy metabolites.It gets excreted Via urine (approx 53%, mainly as metabolites) and faeces (approx 30%). Mean half-life: Approx 40 hr.

The Tmax of Rifabutin was within 2-4 hours. The Cmax of Rifabutin was ranging from 0.16 µg/mL after administration of a single 150-mg capsule to 0.9 µg/mL after a single 900-mg administration

Rifabutin shows common side effects like Chest pain , coughing or spitting up blood , dark-colored urine, decreased appetite , fever , general feeling of tiredness

Rifabutin is available in the form of Capsule .

Rifabutin is available in India, Germany, Canada, Italy.

Rifabutin acts via the inhibition of DNA-dependent RNA polymerase in gram-positive and some gram-negative bacteria, leading to a suppression of RNA synthesis and cell death. Rifabutin is readily absorbed from the gastrointestinal tract, with an absolute bioavailability averaging 20%.

Rifabutin is used in the Treatment of Mycobacterium avium complex (MAC) prophylaxis. It is so used to treat M. avium complex infection treatment; Tuberculosis, latent Tuberculosis treatment (drug susceptible) (excludes meningitis).

Rifabutin is approved for use in the following clinical indications

● Mycobacterium avium complex (MAC), prophylaxis: Prevention of disseminated MAC disease in patients with advanced human immunodeficiency virus (HIV) infection.

● Although not approved there have been certain off label use documented for Rifabutin which includes:

M. avium complex infection, treatment; Tuberculosis, latent; Tuberculosis, treatment (drug-susceptible) (excludes meningitis)

Rifabutin is available in various strengths as 150 mg.

Rifabutin is available in the form of Capsule

Dosage Adjustment in Kidney Patient

● CrCl ≥30 mL/minute: No dosage adjustment necessary.

● CrCl <30 mL/minute: No dosage adjustment necessary. The manufacturer’s labeling recommends considering a dose reduction of 50% if toxicity is suspected; however, AUC values reported in patients with CrCl <30 mL/minute have been similar to those found in healthy volunteers

Dosage Adjustment in Hepatic impairment Patient

• Mild impairment: No dosage adjustment necessary.
• Moderate to severe impairment: There are no dosage adjustments provided in manufacturer’s labeling

Dosage Adjustment for Pediatric Patients

Mycobacterium avium complex (MAC) infection:

Prophylaxis: Note: Rule out active tuberculosis before initiating rifabutin for prophylaxis .

• HIV-exposed/-infected:

Primary prophylaxis (alternative agent): Children ≥6 years and Adolescents: Oral: 300 mg once daily. Primary prophylaxis may be discontinued in children after ≥6 months of antiretroviral therapy (ART) and upon meeting age-specific CD4 cell count targets for >3 months (≥6 years: >100 cells/mm³); primary prophylaxis may be discontinued in adolescents once effective ART is initiated.

• Chronic maintenance therapy (secondary prophylaxis) (adjunctive agent):

Children ≥6 years: Oral: 5 mg/kg/dose once daily; maximum dose: 300 mg/dose; use as part of an appropriate combination regimen; may discontinue when patient has completed ≥12 months of MAC therapy and ≥6 months of ART, has no signs and symptoms of MAC disease, and has sustained (≥6 months) CD4 cell count above age-specific target (≥6 years: 100 cells/mm³)

Adolescents: Oral: 300 mg once daily as part of an appropriate combination regimen; may discontinue when patient has completed ≥12 months of MAC therapy, has no signs and symptoms of MAC disease, and has sustained (>6 months) CD4 count >100 cells/mm3 in response to ART .

• Non-HIV-exposed or infected: Infants, Children, and Adolescents: Oral: 5 mg/kg/dose once daily; maximum dose: 300 mg/dose.
• Treatment:

Disseminated disease: Note: The addition of rifabutin to standard combination regimen is controversial; it has been suggested for use in patients with severe disease or at higher risk of mortality or emergence of drug resistance.

Infants, Children, and Adolescents: Oral: 10 to 20 mg/kg/dose once daily as part of an appropriate combination regimen for ≥12 months; maximum dose: 300 mg/dose

• Pulmonary disease: Children and Adolescents: Oral: 5 to 10 mg/kg/dose once daily as part of an appropriate combination regimen; maximum dose: 300 mg. Continue treatment until patient is culture negative on therapy for ≥12 months

Tuberculosis, active, drug-susceptible treatment (alternative agent): Limited data available; optimal dose not established:

• Note: Always use in combination with other antitubercular drugs . Any regimens using less than once-daily dosing should be administered as directly observed therapy (DOT). Some experts recommend DOT for all pediatric patients.
• Infants, Children, and Adolescents: Oral: 5 mg/kg/dose once daily or 5-times-weekly (DOT); maximum dose: 300 mg/dose . A higher dose of 10 to 20 mg/kg/dose once daily (maximum dose: 300 mg/dose) has also been recommended .
• Duration of therapy: Treatment regimens consist of an initial 2-month intensive phase of a 4-drug regimen, followed by a 2-drug continuation phase of rifamycin plus isoniazid. Duration of continuation phase is ≥4 months; should be longer for cavitary disease with positive cultures at completion of intensive phase (7 months), bone and joint disease (≥4 to 7 months), and CNS disease.

Concerns related to adverse effects:

• Hepatic effects: Increased risk of hepatic reactions; avoid alcohol intake and other known hepatotoxic drugs, especially in patients with impaired hepatic function. Monitor AST, ALT, alkaline phosphatase, bilirubin, and symptoms of liver dysfunction (eg, fatigue, nausea, anorexia, jaundice, dark urine, liver tenderness, and hepatomegaly) at baseline and monthly during therapy, and as needed. Monitor more frequently if the patient has underlying hepatic disease or is receiving concomitant drugs . Test for viral hepatitis and discontinue other hepatotoxic medications if evidence of new or worsening hepatic disease occurs. Discontinue use if aminotransferase elevations are accompanied by total bilirubin elevation >2 times ULN, aminotransferase elevations are >8 times ULN, or aminotransferase elevations are >5 times ULN and continue for >2 weeks.

Rifabutin may cause liver problems, and using it with substantial quantities of ethanol may increase that risk.

Concentrations in the mother’s milk approach those found in the serum. A decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

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.

High-fat meal may decrease the rate but not the extent of absorption. Management: May administer with meals.

• Common Adverse effects

Rash, GI disturbances, neutropenia, syndrome of polyarthralgia-arthritis at doses >1 g/day

• Less Common Adverse effects:

Uveitis esp in patients receiving clarithromycin or other macrolides, asymptomatic corneal opacities after long-term use, orange-tan skin pigmentation

• Rare Adverse effects

Flu-like syndrome, hepatitis, leucopenia, epigastric pain, erythema, ageusia.

Increased plasma levels w/ clarithromycin (and possibly other macrolides), triazole atifungals (e.g. fluconazole, itraconazole), antivirals (e.g. indinavir, fosamprenavir, ritonavir). May reduce the activity of analgesics, anticoagulants, corticosteroids, ciclosporin, digitalis (although not digoxin), oral hypoglycaemics, narcotics, phenytoin and quinidine. Delayed GI absorption w/ p-aminosalicylic acid. May reduce serum concentration of OC or tacrolimus.

The common side effects of Rifabutin include the following Swelling, Rapid weight gain, Little or no urinating; Severe dizziness, Spinning sensation, Ringing or Roaring

There is no experience with the treatment of acute overdose with Rifabutin . General measures to support basic vital functions including monitoring of vital signs and ECG (QT interval) should be taken in case of deliberate or accidental overdose. Removal of unabsorbed Rifabutin may be achieved by gastric lavage or aided by the administration of activated charcoal. Since Rifabutin is highly protein-bound, dialysis is not likely to significantly remove Rifabutin from plasma.

Pharmacodynamic

Rifabutin is an antibiotic that inhibits DNA-dependent RNA polymerase activity in susceptible cells. Specifically, it interacts with bacterial RNA polymerase but does not inhibit the mammalian enzyme. It is bactericidal and has a very broad spectrum of activity against most gram-positive and gram-negative organisms (including Pseudomonas aeruginosa) and specifically Mycobacterium tuberculosis. Because of the rapid emergence of resistant bacteria, use is restricted to the treatment of mycobacterial infections and a few other indications. Rifabutin is well absorbed when taken orally and is distributed widely in body tissues and fluids, including the CSF. It is metabolized in the liver and eliminated in bile and, to a much lesser extent, in urine, but dose adjustments are unnecessary with renal insufficiency.

Pharmacokinetics

• Absorption: Readily but incompletely absorbed from the GI tract. Food may delay absorption. Time to peak plasma concentration: 2-4 hr.
• Distribution: Widely distributed in body tissues and fluids. Volume of distribution: 9.32 L/kg. Plasma protein binding: Approx 70%.
• Metabolism: Undergoes rapid hepatic metabolism by CYP3A4 isoenzyme to active 25-O-deacetyl and 31-hydroxy metabolites.
• Excretion: Via urine (approx 53%, mainly as metabolites) and faeces (approx 30%). Mean half-life: Approx 40 hr.

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1364710/
• https://reference.medscape.com/drug/colestid-Rifabutin -342452
• https://go.drugbank.com/drugs/DB00375
• https://www.sciencedirect.com/topics/medicine-and-dentistry/Rifabutin
• https://europepmc.org/article/med/6988203