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 (9S,12E,14S,15R, 16S,17R,18R,19R,20S,21S,22E, 24Z)-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)-2H- furo[2',3':7,8]naphth[1,2-d] imidazole-2,4'-piperidine]-5,10,26-(3H,9H)-trione-16-acetate. Rifabutin has a molecular formula of C46H62N4O11, 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.

Pharmacokinetics

Absorption

Following a single oral dose of 300 mg to nine healthy adult volunteers, rifabutin was readily absorbed from the gastrointestinal tract with mean (±SD) peak plasma levels (Cmax) of 375 (±267) ng/mL (range: 141 to 1033 ng/mL) attained in 3.3 (±0.9) hours (Tmax range: 2 to 4 hours). Absolute bioavailability assessed in five HIV-positive patients, who received both oral and intravenous doses, averaged 20%. Total recovery of radioactivity in the urine indicates that at least 53% of the orally administered rifabutin dose is absorbed from the gastrointestinal tract. The bioavailability of rifabutin from the capsule dosage form, relative to an oral solution, was 85% in 12 healthy adult volunteers. High-fat meals slow the rate without influencing the extent of absorption from the capsule dosage form. Plasma concentrations post-Cmax declined in an apparent biphasic manner. Pharmacokinetic dose- proportionality was established over the 300 mg to 600 mg dose range in nine healthy adult volunteers (crossover design) and in 16 early symptomatic human immunodeficiency virus (HIV)-positive patients over a 300 mg to 900 mg dose range.



Distribution

Due to its high lipophilicity, rifabutin demonstrates a high propensity for distribution and intracellular tissue uptake. Following intravenous dosing, estimates of apparent steady-state distribution volume (9.3 ± 1.5 L/kg) in five HIV-positive patients exceeded total body water by approximately 15-fold. Substantially higher intracellular tissue levels than those seen in plasma have been observed in both rat and man. The lung-to-plasma concentration ratio, obtained at 12 hours, was approximately 6.5 in four surgical patients who received an oral dose. Mean rifabutin steady-state trough levels (Cp,minss; 24- hour post-dose) ranged from 50 to 65 ng/mL in HIV-positive patients and in healthy adult volunteers. About 85% of the drug is bound in a concentration-independent manner to plasma proteins over a concentration range of 0.05 to 1 µg/mL. Binding does not appear to be influenced by renal or hepatic dysfunction. Rifabutin was slowly eliminated from plasma in seven healthy adult volunteers, presumably because of distribution-limited elimination, with a mean terminal half-life of 45 (±17) hours (range: 16 to 69 hours). Although the systemic levels of rifabutin following multiple dosing decreased by 38%, its terminal half-life remained unchanged.

Metabolism

Of the five metabolites that have been identified, 25-O-desacetyl and 31-hydroxy are the most predominant, and show a plasma metabolite: parent area under the curve ratio of 0.10 and 0.07, respectively. The former has an activity equal to the parent drug and contributes up to 10% to the total antimicrobial activity.

Excretion

A mass-balance study in three healthy adult volunteers with 14C-labeled rifabutin showed that 53% of the oral dose was excreted in the urine, primarily as metabolites. About 30% of the dose is excreted in the feces. Mean systemic clearance (CLs/F) in healthy adult volunteers following a single oral dose was 0.69 (±0.32) L/hr/kg (range: 0.46 to 1.34 L/hr/kg). Renal and biliary clearance of unchanged drug each contribute approximately 5% to CLs/F.

Pharmacokinetics in Special Populations

Geriatric

Compared to healthy volunteers, steady-state kinetics of Rifabutin are more variable in elderly patients (>70 years).

Pediatric

The pharmacokinetics of Rifabutin have not been studied in subjects under 18 years of age.

Renal Impairment

The disposition of rifabutin (300 mg) was studied in 18 patients with varying degrees of renal function. Area under plasma concentration time curve (AUC) increased by about 71% in patients with severe renal impairment (creatinine clearance below 30 mL/min) compared to patients with creatinine clearance (Crcl) between 61–74 mL/min. In patients with mild to moderate renal impairment (Crcl between 30–61 mL/min), the AUC increased by about 41%. In patients with severe renal impairment, carefully monitor for rifabutin associated adverse events. A reduction in the dosage of rifabutin is recommended for patientswith Crcl <30 mL/min if toxicity is suspected (see DOSAGE AND ADMINISTRATION).

Hepatic Impairment

Mild hepatic impairment does not require a dose modification. The pharmacokinetics of rifabutin in patients with moderate and severe hepatic impairment is not known.

Malabsorption in HIV-Infected Patients

Alterations in gastric pH due to progressing HIV disease has been linked with malabsorption of some drugs used in HIV-positive patients (e.g., rifampin, isoniazid). Drug serum concentrations data from AIDS patients with varying disease severity (based on CD4+ counts) suggests that rifabutin absorption is not influenced by progressing HIV disease.

Drug-Drug Interactions (see also PRECAUTIONS-Drug Interactions)

Multiple dosing of rifabutin has been associated with induction of hepatic metabolic enzymes of the CYP3A subfamily. Rifabutin's predominant metabolite (25-desacetyl rifabutin: LM565), may also contribute to this effect. Metabolic induction due to rifabutin is likely to produce a decrease in plasma concentrations of concomitantly administered drugs that are primarily metabolized by the CYP3A enzymes. Similarly, concomitant medications that competitively inhibit the CYP3A activity may increase plasma concentrations of rifabutin.

Two randomized, double-blind clinical trials (Study 023 and Study 027) compared Rifabutin (300 mg/day) to placebo in patients with CDC-defined AIDS and CD4 counts ≤200 cells/µL. These studies accrued patients from 2/90 through 2/92. Study 023 enrolled 590 patients, with a median CD4 cell count at study entry of 42 cells/µL (mean 61). Study 027 enrolled 556 patients with a median CD4 cell count at study entry of 40 cells/µL (mean 58).

Endpoints included the following:

(1)    MAC bacteremia, defined as at least one blood culture positive for Mycobacterium avium complex (MAC) bacteria.

(2)    Clinically significant disseminated MAC disease, defined as MAC bacteremia accompanied by signs or symptoms of serious MAC infection, including one or more of the following: fever, night sweats, rigors, weight loss, worsening anemia, and/or elevations in alkaline phosphatase.

(3)   Survival.

MAC Bacteremia

Participants who received Rifabutin were one-third to one-half as likely to develop MAC bacteremia as were participants who received placebo. These results were statistically significant (Study 023: p<0.001; Study 027: p = 0.002).

In Study 023, the one-year cumulative incidence of MAC bacteremia, on an intent to treat basis, was 9% for patients randomized to Rifabutin and 22% for patients randomized to placebo. In Study 027, these rates were 13% and 28% for patients receiving Rifabutin and placebo, respectively.

Most cases of MAC bacteremia (approximately 90% in these studies) occurred among participants whose CD4 count at study entry was ≤100 cells/µL. The median and mean CD4 counts at onset of MAC bacteremia were 13 cells/µL and 24 cells/µL, respectively. These studies did not investigate the optimal time to begin MAC prophylaxis.

Clinically Significant Disseminated MAC Disease

In association with the decreased incidence of bacteremia, patients on Rifabutin showed reductions in the signs and symptoms of disseminated MAC disease, including fever, night sweats, weight loss, fatigue, abdominal pain, anemia, and hepatic dysfunction.

Survival

The one-year survival rates in Study 023 were 77% for the group receiving Rifabutin and 77% for the placebo group. In Study 027, the one-year survival rates were 77% for the group receiving Rifabutin and 70% for the placebo group.

These differences were not statistically significant.

Microbiology

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).

Susceptibility Testing

For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

In Vitro Studies

Rifabutin has demonstrated in vitro activity against M. avium complex (MAC) organisms isolated from both HIV-positive and HIV-negative people. While-gene probe techniques may be used to identify these two organisms, many reported studies did not distinguish between these two species. The vast majority of isolates from MAC-infected, HIV-positive people are M. avium, whereas in HIV-negative people, about 40% of the MAC isolates are M. intracellulare.

Various in vitro methodologies employing broth or solid media, with and without polysorbate 80 (Tween 80), have been used to determine rifabutin MIC values for mycobacterial species. In general, MIC values determined in broth are several fold lower than that observed with methods employing solid media. Utilization of Tween 80 in these assays has been shown to further lower MIC values.

However, MIC values were substantially higher for egg-based compared to agar-based solid media.

Rifabutin activity against 211 MAC isolates from HIV-positive people was evaluated in vitro utilizing a radiometric broth and an agar dilution method. Results showed that 78% and 82% of these isolates had MIC99 values of ≤0.25 µg/mL and ≤1.0 µg/mL, respectively, when evaluated by these two methods. Rifabutin was also shown to be active against phagocytized, M. avium complex in a mouse macrophage cell culture model.

Rifabutin has in vitro activity against many strains of Mycobacterium tuberculosis. In one study, utilizing the radiometric broth method, each of 17 and 20 rifampin-naive clinical isolates tested from the United States and Taiwan, respectively, were shown to be susceptible to rifabutin concentrations of ≤0.125 µg/mL.

Cross-resistance between rifampin and rifabutin is commonly observed with M. tuberculosis and M. avium complex isolates. Isolates of M. tuberculosis resistant to rifampin are likely to be resistant to rifabutin. Rifampicin and rifabutin MIC99 values against 523 isolates of M. avium complex were determined utilizing the agar dilution method (Heifets, Leonid B. and Iseman, Michael D. Determination of in vitro susceptibility of Mycobacteria to Ansamycin. Am. Rev. Respir. Dis. 1985; 132(3):710–711).

Table 1 Susceptibility of M. Avium Complex Strains to Rifampin and Rifabutin

Rifabutin in vitro MIC99 values of ≤0.5 µg/mL, determined by the agar dilution method, for M. kansasii, M. gordonae and M. marinum have been reported; however, the clinical significance of these results is unknown.

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

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

Tuberculosis

Rifabutin Capsules must not be administered for MAC prophylaxis to patients with active tuberculosis. Patients who develop complaints consistent with active tuberculosis while on prophylaxis with Rifabutin should be evaluated immediately, so that those with active disease may be given an effective combination regimen of anti-tuberculosis medications. Administration of Rifabutin as a single agent to patients with active tuberculosis is likely to lead to the development of tuberculosis that is resistant both to Rifabutin and to rifampin.

There is no evidence that Rifabutin is an effective prophylaxis against M. tuberculosis. Patients requiring prophylaxis against both M. tuberculosis and Mycobacterium avium complex may be given isoniazid and Rifabutin concurrently.

Tuberculosis in HIV-positive patients is common and may present with atypical or extrapulmonary findings. Patients are likely to have a nonreactive purified protein derivative (PPD) despite active disease. In addition to chest X-ray and sputum culture, the following studies may be useful in the diagnosis of tuberculosis in the HIV-positive patient: blood culture, urine culture, or biopsy of a suspicious lymph node.

MAC Treatment with Clarithromycin

When Rifabutin is used concomitantly with clarithromycin for MAC treatment, a decreased dose of Rifabutin is recommended due to the increase in plasma concentrations of Rifabutin (see PRECAUTIONS-Drug Interactions, Table 2).

Hypersensitivity and Related Reactions

Hypersensitivity reactions may occur in patients receiving rifamycins. Signs and symptoms of these reactions may include hypotension, urticaria, angioedema, acute bronchospasm, conjunctivitis, thrombocytopenia, neutropenia or flu-like syndrome (weakness, fatigue, muscle pain, nausea, vomiting, headache, fever, chills, aches, rash, itching, sweats, dizziness, shortness of breath, chest pain, cough, syncope, palpitations). There have been reports of anaphylaxis with the use of rifamycins.

Monitor patients receiving Rifabutin therapy for signs and/or symptoms of hypersensitivity reactions. If these symptoms occur, administer supportive measures and discontinue Rifabutin.

Uveitis

Due to the possible occurrence of uveitis, patients should also be carefully monitored when Rifabutin is given in combination with clarithromycin (or other macrolides) and/or fluconazole and related compounds (see PRECAUTIONS-Drug Interactions, Table 2). If uveitis is suspected, the patient should be referred to an ophthalmologist and, if considered necessary, treatment with Rifabutin should be suspended (see also ADVERSE REACTIONS).

Clostridioides difficile Associated Diarrhea

Clostridioides difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Rifabutin Capsules and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Severe Cutaneous Adverse Reactions

There have been reports of severe cutaneous adverse reactions (SCAR), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) associated with Rifabutin (see ADVERSE REACTIONS).

If patients develop a skin rash they should be monitored closely, and Rifabutin discontinued if lesions progress. Specifically, for DRESS, a multi-system potential life-threatening SCAR, time to onset of the first symptoms may be prolonged. DRESS is a clinical diagnosis, and its clinical presentation remains the basis for decision making. An early withdrawal of Rifabutin is essential because of the syndrome’s mortality and visceral involvement (e.g., liver, bone marrow or kidney).

Antiretroviral Drug Interactions

Protease inhibitors act as substrates or inhibitors of CYP3A4 mediated metabolism. Therefore, due to significant drug-drug interactions between protease inhibitors and rifabutin, their concomitant use should be based on the overall assessment of the patient and a patient-specific drug profile. The concomitant use of protease inhibitors may require at least a 50% reduction in rifabutin dose, and depending on the protease inhibitor, an adjustment of the antiretroviral drug dose. Increased monitoring for adverse events is recommended when using these drug combinations (see PRECAUTIONS-Drug Interactions).

Rifabutin is a CYP3A inducer. Co-administration with antiretroviral drugs metabolized by CYP3A, including but not limited to products containing bictegravir, rilpivirine, or doravirine may decrease plasma concentrations of those antiretroviral drugs, which may lead to loss of virologic response and possible development of resistance. Therefore, co-administration with antiretroviral drugs metabolized by CYP3A is not recommended or there may be a need to increase the dose of antiretroviral drugs (see PRECAUTIONS-Drug Interactions).

For further recommendations, please refer to the most recent prescribing information of the antiretrovirals or contact the specific manufacturer.

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

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

Includes grades 3 or 4 toxicities as specified:

1 All values >450 U/L

2 All values >150 U/L

3 All hemoglobin values <8.0 g/dL

4 All WBC values <1,500/mm3

5 All ANC values <750/mm3

6 All platelet count values <50,000/mm3

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: Clostridioides difficile colitis/Clostridioides 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 has been reported.

Severe cutaneous adverse reactions (SCARs)

Rifabutin 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.

Liver abnormalities (increased bilirubin and liver weight) occurred in mice, rats and monkeys at doses (respectively) 0.5, 1, and 3 times the recommended human daily dose based on body surface area comparisons. Testicular atrophy occurred in baboons at doses 2 times the recommended human dose based on body surface area comparisons, and in rats at doses 6 times the recommended human daily dose based on body surface area comparisons.

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.

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.

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 70954-041-10                            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 by:

Novitium Pharma LLC

70 Lake Drive, East Windsor

New Jersey, 08520

Issued: 11/2021

Rifabutin Capsules, USP 150 mg

NDC 70954-041-10                            Bottles of 100 capsules