Ributin

Ributin uses

• Description
• Clinical pharmacology
• Clinical studies
• Microbiology
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Animal toxicology
• Overdosage
• Dosage and administration
• How supplied
• Ributin reviews

DESCRIPTION

Ributin Capsules for oral administration contain 150 mg of the rifamycin antimycobacterial agent Ributin, USP, per capsule, along with the inactive ingredients microcrystalline cellulose, magnesium stearate, red iron oxide, silica gel, sodium lauryl sulfate, titanium dioxide, and edible white ink.

The chemical name for Ributin 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. Ributin has a molecular formula of C₄₆H₆₂N₄O₁₁, a molecular weight of 847.02 and the following structure:

Ributin is a red-violet powder soluble in chloroform and methanol, sparingly soluble in ethanol, and very slightly soluble in water (0.19 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).

Chemical Structure

CLINICAL PHARMACOLOGY

Pharmacokinetics

Absorption

Following a single oral dose of 300 mg to nine healthy adult volunteers, Ributin was readily absorbed from the gastrointestinal tract with mean peak plasma levels (C_max) of 375 (±267) ng/mL (range: 141 to 1033 ng/mL) attained in 3.3 (±0.9) hours (T_max 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 Ributin dose is absorbed from the gastrointestinal tract. The bioavailability of Ributin 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-C_max 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, Ributin 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 Ributin steady-state trough levels (C_p,min ^ss; 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. Ributin 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 Ributin 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 Ributin 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 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 CL_s/F.

Pharmacokinetics in Special Populations

Geriatric

Compared to healthy volunteers, steady-state kinetics of Ributin are more variable in elderly patients.

Pediatric

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

Renal Impairment

The disposition of Ributin 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 (Cr_cl) between 61–74 mL/min. In patients with mild to moderate renal impairment (Cr_cl between 30–61 mL/min), the AUC increased by about 41%. In patients with severe renal impairment, carefully monitor for Ributin associated adverse events. A reduction in the dosage of Ributin is recommended for patients with Cr_cl <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 Ributin 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. Drug serum concentrations data from AIDS patients with varying disease severity (based on CD4+ counts) suggests that Ributin absorption is not influenced by progressing HIV disease.

Drug-Drug Interactions

Multiple dosing of Ributin has been associated with induction of hepatic metabolic enzymes of the CYP3A subfamily. Rifabutin's predominant metabolite (25-desacetyl Ributin: LM565), may also contribute to this effect. Metabolic induction due to Ributin 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 Ributin.

CLINICAL STUDIES

Two randomized, double-blind clinical trials compared Ributin (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:

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

MAC Bacteremia

Participants who received Ributin 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 Ributin and 22% for patients randomized to placebo. In Study 027, these rates were 13% and 28% for patients receiving Ributin 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 Ributin 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 Ributin and 77% for the placebo group. In Study 027, the one-year survival rates were 77% for the group receiving Ributin and 70% for the placebo group.

These differences were not statistically significant.

MICROBIOLOGY

Mechanism of Action

Ributin 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, Ributin, like rifampin, did not inhibit this enzyme. It is not known whether Ributin inhibits DNA-dependent RNA polymerase in Mycobacterium avium or in M. intracellulare which comprise M. avium complex.

Susceptibility Testing

In vitro susceptibility testing methods and diagnostic products used for determining minimum inhibitory concentration (MIC) values against M. avium complex (MAC) organisms have not been standardized. Breakpoints to determine whether clinical isolates of MAC and other mycobacterial species are susceptible or resistant to Ributin have not been established.

In Vitro Studies

Ributin 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 Ributin 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.

Ributin 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. Ributin was also shown to be active against phagocytized, M. avium complex in a mouse macrophage cell culture model.

Ributin 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 Ributin concentrations of ≤0.125 µg/mL.

Cross-resistance between rifampin and Ributin is commonly observed with M. tuberculosis and M. avium complex isolates. Isolates of M. tuberculosis resistant to rifampin are likely to be resistant to Ributin. Rifampicin and Ributin 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).

Ributin 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.

INDICATIONS AND USAGE

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

CONTRAINDICATIONS

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

WARNINGS

Tuberculosis

Ributin 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 Ributin should be evaluated immediately, so that those with active disease may be given an effective combination regimen of anti-tuberculosis medications. Administration of Ributin as a single agent to patients with active tuberculosis is likely to lead to the development of tuberculosis that is resistant both to Ributin and to rifampin.

There is no evidence that Ributin is an effective prophylaxis against M. tuberculosis. Patients requiring prophylaxis against both M. tuberculosis and Mycobacterium avium complex may be given isoniazid and Ributin 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 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 Ributin is used concomitantly with clarithromycin for MAC treatment, a decreased dose of Ributin is recommended due to the increase in plasma concentrations of Ributin (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. There have been reports of anaphylaxis with the use of rifamycins.

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

Uveitis

Due to the possible occurrence of uveitis, patients should also be carefully monitored when Ributin 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 Ributin should be suspended (see also ADVERSE REACTIONS ).

Clostridium difficile Associated Diarrhea

Clostridium difficile associated diarrhea has been reported with use of nearly all antibacterial agents, including Ributin (rifabutin) Capsules, USP, 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.

Protease Inhibitor Drug Interaction

Protease inhibitors act as substrates or inhibitors of CYP3A4 mediated metabolism. Therefore, due to significant drug-drug interactions between protease inhibitors and Ributin, 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 Ributin dose, and depending on the protease inhibitor, an adjustment of the antiviral drug dose. Increased monitoring for adverse events is recommended when using these drug combinations (see PRECAUTIONS-Drug Interactions ). For further recommendations, please refer to current, official product monographs of the protease inhibitor or contact the specific manufacturer.

PRECAUTIONS

General

Because treatment with Ributin Capsules may be associated with neutropenia, and more rarely thrombocytopenia, physicians should consider obtaining hematologic studies periodically in patients receiving prophylaxis with Ributin.

Information for Patients

Patients should be advised of the signs and symptoms of both MAC and tuberculosis, and should be instructed to consult their physicians if they develop new complaints consistent with either of these diseases. In addition, since Ributin may rarely be associated with myositis and uveitis, patients should be advised to notify their physicians if they develop signs or symptoms suggesting either of these disorders.

Urine, feces, saliva, sputum, perspiration, tears, and skin may be colored brown-orange with Ributin and some of its metabolites. Soft contact lenses may be permanently stained. Patients to be treated with Ributin should be made aware of these possibilities.

Diarrhea is a common problem caused by antibacterials which usually ends when the antibacterial is discontinued. Sometimes, after starting treatment with antibacterials, patients can develop watery and bloody stools even as late as two or more months after having taken the last dose of the antibacterial. If this occurs, patients should contact their physician as soon as possible.

Drug Interactions

Effect of Ributin on the Pharmacokinetics of Other Drugs

Ributin 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 Ributin Pharmacokinetics

Some drugs that inhibit CYP3A may significantly increase the plasma concentration of Ributin. Therefore, carefully monitor for Ributin associated adverse events in those patients also receiving CYP3A inhibitors, which include fluconazole and clarithromycin. In some cases, the dosage of Ributin 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 Ributin. 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.

Other drugs

The structurally similar drug, rifampin, is known to reduce the plasma concentrations of a number of other drugs. Although a weaker enzyme inducer than rifampin, Ributin may be expected to have some effect on those drugs as well.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term carcinogenicity studies were conducted with Ributin in mice and in rats. Ributin was not carcinogenic in mice at doses up to 180 mg/kg/day, or approximately 36 times the recommended human daily dose. Ributin was not carcinogenic in the rat at doses up to 60 mg/kg/day, about 12 times the recommended human dose.

Ributin was not mutagenic in the bacterial mutation assay using both rifabutin-susceptible and resistant strains. Ributin was not mutagenic in Schizosaccharomyces pombe P₁ and was not genotoxic in V-79 Chinese hamster cells, human lymphocytes in vitro, or mouse bone marrow cells in vivo.

Fertility was impaired in male rats given 160 mg/kg (32 times the recommended human daily dose).

Pregnancy

Ributin 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 Ributin 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), Ributin 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), Ributin caused maternotoxicity and increase in fetal skeletal anomalies. Because animal reproduction studies are not always predictive of human response, Ributin 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 Ributin 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.

Pediatric Use

Safety and effectiveness of Ributin for prophylaxis of MAC in children have not been established. Limited safety data are available from treatment use in 22 HIV-positive children with MAC who received Ributin in combination with at least two other antimycobacterials for periods from 1 to 183 weeks. Mean doses for these children were: 18.5 (range 15.0 to 25.0) for infants 1 year of age, 8.6 (range 4.4 to 18.8) for children 2 to 10 years of age, and 4.0 (range 2.8 to 5.4) for adolescents 14 to 16 years of age. There is no evidence that doses greater than 5 mg/kg daily are useful. Adverse experiences were similar to those observed in the adult population, and included leukopenia, neutropenia, and rash. In addition, corneal deposits have been observed in some patients during routine ophthalmologic surveillance of HIV-positive pediatric patients receiving Ributin as part of a multiple-drug regimen for MAC prophylaxis. These are tiny, almost transparent, asymptomatic peripheral and central corneal deposits which do not impair vision. Doses of Ributin may be administered mixed with foods such as applesauce.

Geriatric Use

Clinical studies of Ributin did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy (see CLINICAL PHARMACOLOGY ).

ADVERSE REACTIONS

Adverse Reactions from Clinical Trials

Ributin 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 Ributin, compared to 8% of patients receiving placebo in these trials. Primary reasons for discontinuation of Ributin were rash, 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 Ributin in studies 023 and 027.

CLINICAL ADVERSE EVENTS REPORTED IN <1% OF PATIENTS WHO RECEIVED Ributin

Considering data from the 023 and 027 pivotal trials, and from other clinical studies, Ributin 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 Ributin, but an etiologic role has not been established: seizure, paresthesia, aphasia, confusion, and non-specific T wave changes on electrocardiogram.

When Ributin was administered at doses from 1050 mg/day to 2400 mg/day, generalized arthralgia and uveitis were reported. These adverse experiences abated when Ributin was discontinued.

Mild to severe, reversible uveitis has been reported less frequently when Ributin is used at 300 mg as monotherapy in MAC prophylaxis versus Ributin in combination with clarithromycin for MAC treatment (see also WARNINGS ).

Uveitis has been infrequently reported when Ributin is used at 300 mg/day as montherapy in MAC prophylaxis of HIV-infected persons, even with the concomitant use of fluconazole and/or macrolide antibacterials. However, if higher doses of Ributin 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 Ributin and ophthalmologic evaluation are recommended. In most mild cases, Ributin may be restarted; however, if signs or symptoms recur, use of Ributin 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 Ributin 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.

The incidence of neutropenia in patients treated with Ributin was significantly greater than in patients treated with placebo (p = 0.03). Although thrombocytopenia was not significantly more common among patients treated with Ributin in these trials, Ributin has been clearly linked to thrombocytopenia in rare cases. One patient in Study 023 developed thrombotic thrombocytopenic purpura, which was attributed to Ributin.

Adverse Reactions from Post-Marketing Experience

Adverse reactions identified through post-marketing surveillance by system organ class 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: Clostridium difficile colitis/ Clostridium 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 number of skin discoloration have been reported.

Rifamycin hypersensitivity reactions

Hypersensitivity to rifamycins have been reported including flu-like symptoms, bronchospasm, hypotension, urticaria, angioedema, conjunctivitis, thrombocytopenia or neutropenia.

ANIMAL TOXICOLOGY

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.

OVERDOSAGE

No information is available on accidental overdosage in humans.

Treatment

While there is no experience in the treatment of overdose with Ributin 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.

Ributin 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 Ributin from the body in a patient with an overdose of Ributin.

DOSAGE AND ADMINISTRATION

It is recommended that Ributin 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 Ributin 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 Ributin by 50%, if toxicity is suspected. No dosage adjustment is required for patients with mild to moderate renal impairment. Reduction of the dose of Ributin 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 Ributin in patients with moderate and severe hepatic impairment is not known.

HOW SUPPLIED

Ributin (rifabutin) Capsules, USP are supplied as hard gelatin capsules having an opaque red-brown cap and body, imprinted with MYCOBUTIN/PHARMACIA & UPJOHN in white ink, each containing 150 mg of Ributin, USP.

Ributin is available as follows:

NDC 0013-5301-17 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°–30°C (59°–86°F).

LAB-0217-7.0

August 2016

Logo

Pfizer

NDC 0013-5301-17

Ributin ^®

Ributin capsules, USP

150 mg

capsules

100 Capsules

Rx only

Ributin pharmaceutical active ingredients containing related brand and generic drugs:

• Rifabutin

Ributin available forms, composition, doses:

• Capsules; Oral; Rifabutin 150 mg

Ributin destination | category:

• Human:
• Antibiotics
• Antileprotics
• Antituberculosis agents

Ributin Anatomical Therapeutic Chemical codes:

• N/A

Ributin pharmaceutical companies:

• Lupin Pharmaceuticals

References

1. Dailymed."MYCOBUTIN (RIFABUTIN) CAPSULE [PHARMACIA AND UPJOHN COMPANY LLC]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
2. Dailymed."RIFABUTIN: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
3. "RIFABUTIN". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Depending on the reaction of the Ributin after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Ributin not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology