Mycobutin (Rifabutin)

MYCOBUTIN®

Pharmacia & Upjohn

Rifabutin

Antibacterial Agent

Action And Clinical Pharmacology: Rifabutin is a derivative of rifamycin S, belonging to the class of ansamycins. The rifamycins owe their antimycobacterial efficacy to their ability to penetrate the cell wall and to their ability to complex with and to inhibit DNA-dependent RNA polymerase. Rifabutin has been found to interact with and to penetrate the outer layers of the mycobacterial envelope.

Rifabutin inhibits DNA-dependent RNA polymerase in susceptible strains of E. coli and B. 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 M. avium or in M. intracellulare which constitutes M. avium complex (MAC). Rifabutin inhibited incorporation of thymidine into DNA of rifampin-resistant M. tuberculosis suggesting that rifabutin may also inhibit DNA synthesis which may explain its activity against rifampin-resistant organisms.

Pharmacokinetics: Following oral administration, at least 53% of rifabutin dose is rapidly absorbed with rifabutin peak plasma concentrations attained in 2 to 4 hours. High-fat meals slow the rate without influencing the extent of absorption of rifabutin from the capsule dosage form.

The mean (±SD) absolute bioavailability assessed in HIV positive patients in a multiple dose study was 20% (±16%, n=5) on day 1 and 12% (±5%, n=7) on day 28.

In healthy adult volunteers administered a single oral dose of 300 mg of rifabutin, the mean (±SD) peak plasma concentration (Cmax) was 375 (±267) ng/mL (range: 141 to 1 033 ng/mL). Mean rifabutin steady-state trough levels (Cp, mins 24-hour post dose) ranged from 50 to 65 ng/mL in HIV positive patients and in healthy normal volunteers. Pharmacokinetic dose-proportionality over the 300 to 900 mg single dose range has been demonstrated in early symptomatic HIV positive patients and in healthy normal volunteers over the 300 to 600 mg single dose range.

Rifabutin appears to be widely distributed throughout the body and has been detected in all tissues and body fluids examined. Several times higher concentrations than those achieved in plasma have been observed in lung parenchyma, gallbladder and the small intestinal wall. The apparent volume of distribution at steady-state (Vss) estimated in early symptomatic HIV positive male patients following i.v. dosing was large (8 to 9 L/kg), suggesting extensive distribution of rifabutin into the tissues. About 85% of the drug is bound to plasma proteins over a concentration range of 50 to 1 000 ng/mL. Binding is predominantly to human serum albumin, is concentration independent and does not appear to be influenced by renal or hepatic dysfunction.

Rifabutin undergoes extensive oxidative metabolism. Of the 5 metabolites that have been identified, 25-O-deacetyl and 31-hydroxy are the most predominant and show a plasma metabolite:parent area under the curve ratio of 0.10 for 25-O-deacetyl and 0.07 for 31-hydroxy metabolite. The 25-O-deacetyl metabolite has antimycobacterial activity equal to the parent drug and contributes up to 10% to the total antimicrobial activity. The 31-hydroxy metabolite has some antimicrobial activity (1/16 that of parent drug), but, considering its concentration in plasma, it is probably not contributing significantly to the therapeutic activity of rifabutin. Rifabutin can induce its own metabolism on multiple dosing. The area under the plasma concentration-time curve (AUC) following multiple dosing decreased by 38%, but its terminal half-life remained unchanged.

The plasma elimination profile of rifabutin is biphasic with an initial half-life of approximately 4 hours followed by a mean terminal half-life 45 (±17) hours (range: 16 to 69 hours). Mean systemic clearance in healthy adult volunteers following a single oral dose was 0.69 (±0.32) L/hour/kg (range: 0.46 to 1.34 L/hour/kg). Rifabutin is mainly excreted in the urine, primarily as metabolites and to a lesser extent in the feces. Fifty-three percent (53%) of the oral dose of 4-labelled drug was recovered in the urine by 5 days post-dose and 30% was recovered in the feces over the same period. Renal and biliary excretion of unchanged drug each contribute approximately 5% to the systemic clearance.

The pharmacokinetic profile of rifabutin is not significantly modified by age or by hepatic dysfunction, although the inter-individual variability in elderly subjects (71 to 80 years) was slightly higher. Rifabutin steady-state pharmacokinetics in early symptomatic HIV positive patients are similar to those in healthy normal volunteers but the variability between individuals is higher in the HIV positive patients. Renal insufficiency was correlated to a decrease in rifabutin urinary excretion. Other pharmacokinetic parameters did not appear to differ in a clinically relevant way between patients with various degrees of renal insufficiency and patients with normal renal function. Care is recommended when treating patients with severe renal insufficiency. No rifabutin disposition information is currently available in children or adolescents under 18 years of age.

Indications And Clinical Uses: For the prevention of disseminated M. avium complex (MAC) disease in patients with advanced HIV infection (CD4+ cell count £200/mmwith an AIDS defining diagnosis, or CD4+ cell count £100/mmwithout an AIDS defining diagnosis).

Contra-Indications: In patients who have had clinically significant hypersensitivity to this drug, or to any other rifamycins.

Manufacturers’ Warnings In Clinical States: Rifabutin prophylaxis must not be administered to patients with active tuberculosis. Among HIV positive patients, tuberculosis is common and may present with atypical or extrapulmonary findings. Patients are likely to have a nonreactive purified protein derivative (PPD) test 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.

Patients who develop signs and symptoms consistent with active tuberculosis while on rifabutin prophylaxis should be evaluated immediately, so that those with active disease may be given an effective combination regimen of antituberculosis medications. Administration of rifabutin, as a single-agent, to patients with active tuberculosis is likely to lead to the development of tuberculosis which is resistant both to rifabutin and to rifampin.

There is no evidence that rifabutin provides effective prophylaxis against M. tuberculosis infections. Patients requiring prophylaxis against both M. tuberculosis and M. avium complex may be given isoniazid and rifabutin concurrently.

Precautions: General: Because rifabutin may be associated with neutropenia, and more rarely thrombocytopenia, physicians should consider obtaining hematologic studies periodically in patients receiving rifabutin prophylaxis.

Geriatrics: Rifabutin administered as a single dose has been evaluated in 24 healthy, elderly (71 to 80 years) volunteers. The pharmacokinetic profile of rifabutin is not significantly modified by age, although the inter-individual variability in this age group was slightly higher when compared to younger (25 to 37 years) volunteers.

Children: The safety and effectiveness of rifabutin for prophylaxis of MAC disease in children and adolescents under 18 years of age have not been established. However, limited safety data are available from 22 HIV positive children who received rifabutin as treatment for disseminated MAC disease, in combination with at least 2 other antimycobacterials for periods ranging from 1 to 183 weeks.

The mean daily doses (mg/kg) for these children were: infants 1 year of age, 18.5 (range 15.0 to 25.0); children 2 to 10 years, 8.6 (range 4.4 to 18.8); adolescents 14 to 16 years, 4.0 (range 2.8 to 5.4). Rifabutin was generally safe in this treatment group. Adverse experiences were similar to those observed in the adult population, and included leukopenia, neutropenia and skin rash. Doses of rifabutin may be administered mixed with foods such as applesauce.

Pregnancy: There are no adequate and well-controlled studies of rifabutin use in pregnant women. No teratogenic effects were observed in reproduction studies carried out in rats and rabbits. 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.

Lactation: It is not known whether rifabutin is excreted in human milk. Because many drugs are excreted in human milk and given 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 nursing mother.

Renal Impairment: In a study of 18 patients with increasing degrees of renal insufficiency, rifabutin was administered as a single 300 mg dose. Renal insufficiency was correlated to a decrease in rifabutin urinary excretion. Other pharmacokinetic parameters did not appear to differ in a clinically relevant way between patients with various degrees of renal insufficiency and patients with normal renal function. Care is recommended when treating patients with severe renal insufficiency.

Hepatic Impairment: The pharmacokinetics of single-dose rifabutin have been studied in 12 patients with alcoholic liver disease. Hepatic impairment did not significantly modify the overall pharmacokinetic profile of rifabutin.

Drug Interactions: In 10 healthy adult volunteers and 8 HIV positive patients, steady-state plasma levels of zidovudine (ZDV), an antiretroviral agent which is metabolized mainly through glucuronidation, were decreased after repeated rifabutin dosing. The mean zidovudine decrease in Cmax was 48% and in the AUC, 32%. In vitro studies have demonstrated that rifabutin does not affect the inhibition of HIV by ZDV.

Steady-state kinetics in 12 HIV positive patients show that both the rate and extent of systemic availability of didanosine (ddI), was not altered after repeated dosing of rifabutin.

Possible drug-drug interaction between rifabutin and fluconazole was also evaluated in HIV positive patients. Preliminary results from the Phase I study did not show any alterations in the steady-state fluconazole plasma kinetics following multiple rifabutin dosing.

Rifabutin has liver enzyme-inducing properties. The related drug rifampin is known to reduce the activity of a number of drugs, including dapsone, narcotics (including methadone), anticoagulants, corticosteroids, cyclosporine, cardiac glycoside preparations, quinidine, oral contraceptives, oral hypoglycemic agents (sulfonylureas), and analgesics. Rifampin has also been reported to decrease the effects of concurrently administered ketoconazole, barbiturates, diazepam, verapamil, beta-adrenergic blockers, clofibrate, progestins, disopyramide, mexiletine, theophylline, chloramphenicol and anticonvulsants. Because of the structural similarity of rifabutin and rifampin, rifabutin may be expected to have some effect on these drugs as well. However, unlike rifampin, rifabutin appears not to affect the acetylation of isoniazid. When the effects of rifabutin on hepatic microsomal enzyme activity were compared to those of rifampin in a study with 8 healthy normal volunteers, rifabutin appeared to be a less potent enzyme inducer than rifampin. The significance of this finding for clinical drug interactions is not known. Dosage adjustment of drugs listed above may be necessary if they are given concurrently with rifabutin.

Patients using oral contraceptives should consider changing to nonhormonal methods of birth control.

Information for the Patient: Mycobutin is used for the prevention of serious disease caused by M. avium complex (MAC) organisms in patients with advanced HIV infection. Mycobutin should not be given to patients with active tuberculosis. Patients should ask their physicians to advise them of the signs and symptoms of both MAC disease and tuberculosis. Patients should consult their physician if they develop new complaints suggestive of either MAC disease or tuberculosis.

Mycobutin should be taken as a single dose (two 150 mg capsules) once daily with or without food. For those patients who experience nausea, vomiting or other stomach upsets, it may be useful to split the Mycobutin dose in half (one 150 mg capsule) twice a day with food.

The most common side effect of Mycobutin is that urine may be colored brown-orange. Similar discoloration may affect stools, saliva, sputum, perspiration, tears or the skin. Contact lenses may be permanently stained.

Other side effects associated with Mycobutin include: a reduction in the number of white blood cells which fight infections, skin rashes, and gastrointestinal complaints such as indigestion, belching, flatulence, nausea, vomiting and abdominal pain. Very rarely, Mycobutin may cause muscle aches, inflammation of the inside of the eye (uveitis), and generalized joint pains.

Adverse Reactions: Rifabutin was generally well tolerated in the controlled clinical trials involving 566 patients treated with rifabutin and 580 patients treated with placebo. The most serious adverse reaction to rifabutin was neutropenia.

The most common adverse events, reported more frequently in the rifabutin treated patients than in the placebo group were: urine discoloration, neutropenia, skin rash, nausea and/or vomiting, and abdominal pain. The incidence of urine discoloration and neutropenia in patients treated with rifabutin were significantly greater than in patients treated with placebo (Fisher’s Test, p
Sixteen percent (16%) of rifabutin treated patients discontinued therapy due to an adverse event as compared to 8% of placebo-treated patients. The primary reasons for discontinuation of rifabutin were: skin rash (4%), gastrointestinal intolerance (3%) and neutropenia (2%).

Table I enumerates adverse experiences that occurred at a frequency of 1% or greater among the patients treated with rifabutin and those treated with placebo in the Phase III clinical trials.

Considering data from the Phase III clinical 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 the treated patients: arthralgia, chest pressure or pain with dyspnea, hemolysis, hepatitis, myositis, and skin discoloration.

The following adverse events have occurred in more than 1 patient receiving rifabutin, but an etiologic role for rifabutin has not been established: aphasia, confusion, non-specific T wave changes on the ECG, and seizures.

When rifabutin was administered at doses from 1 050 mg/day to 2 400 mg/day, generalized arthralgia and uveitis were reported. These adverse experiences abated when rifabutin was discontinued.

Laboratory Test Abnormalities: Table II enumerates the changes in laboratory values that were considered as laboratory test abnormalities in the Phase III clinical trials.

Although thrombocytopenia was not significantly more common among rifabutin treated patients in the Phase III trials, rifabutin has been clearly linked to thrombocytopenia in rare cases. One patient in the Phase III trials developed thrombotic thrombocytopenic purpura which was attributed to rifabutin.

Symptoms And Treatment Of Overdose: Symptoms: No information is available on accidental overdosage in humans.

Treatment: While there is no experience in the treatment of overdose with rifabutin, clinical experience with rifamycins suggest 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). As unchanged drug, rifabutin is not primarily excreted via the urinary route (less than 10%), therefore, neither hemodialysis nor forced diuresis is expected to enhance the systemic elimination of unchanged rifabutin from the body in a patient with rifabutin overdose.

Dosage: It is recommended that 300 mg of rifabutin be administered once daily with or without food. For those patients who experience nausea, vomiting or other gastrointestinal upsets, it may be useful to split the rifabutin dose in half (one 150 mg capsule) twice a day with food.

Availability And Storage: Each hard gelatin capsule having an opaque red-brown cap and body, imprinted with PHARMACIA/ MYCOBUTIN, in white ink, contains: rifabutin 150 mg. Nonmedicinal ingredients: microcrystalline cellulose, magnesium stearate, red iron oxide, silica gel, sodium lauryl sulfate, titanium dioxide and edible white ink. Bottles of 60, 100 and 250. Store at controlled room temperature, 15 to 30°C. Keep container tightly closed.

MYCOBUTIN® Pharmacia & Upjohn Rifabutin Antibacterial Agent

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