İHALE DÜNYASI
İHALE DÜNYASI
MYCOBUTIN Capsules for oral administration contain 150 mg of the rifamycin antimycobacterial agent rifabutin, 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 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 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
MYCOBUTIN Capsules are indicated for the prevention of disseminated Mycobacterium avium complex (MAC) disease in patients with advanced HIV infection.
It is recommended that MYCOBUTIN 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 MYCOBUTIN 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 MYCOBUTIN by 50%, if toxicity is suspected. No dosage adjustment is required for patients with mild to moderate renal impairment. Reduction of the dose of MYCOBUTIN 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.
MYCOBUTIN Capsules are contraindicated in patients who have had clinically significant hypersensitivity to rifabutin or to any other rifamycins.
Adverse Reactions from Clinical Trials MYCOBUTIN 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 MYCOBUTIN, compared to 8% of patients receiving placebo in these trials. Primary reasons for discontinuation of MYCOBUTIN 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 MYCOBUTIN in studies 023 and 027. Table: 3 Clinical Adverse Experiences Reported in ?1% of Patients Treated With MYCOBUTIN Adverse event MYCOBUTIN (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 <1% OF PATIENTS WHO RECEIVED MYCOBUTIN Considering data from the 023 and 027 pivotal trials, and from other clinical studies, MYCOBUTIN 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 MYCOBUTIN, but an etiologic role has not been established: seizure, paresthesia, aphasia, confusion, and non-specific T wave changes on electrocardiogram. When MYCOBUTIN was administered at doses from 1050 mg/day to 2400 mg/day, generalized arthralgia and uveitis were reported. These adverse experiences abated when MYCOBUTIN was discontinued. Mild to severe, reversible uveitis has been reported less frequently when MYCOBUTIN is used at 300 mg as monotherapy in MAC prophylaxis versus MYCOBUTIN in combination with clarithromycin for MAC treatment (see also WARNINGS ). Uveitis has been infrequently reported when MYCOBUTIN 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 MYCOBUTIN are administered in combination with these agents, the incidence of uveitis is higher. FDA proposes moving this paragraph from below with some revisions. 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 MYCOBUTIN and ophthalmologic evaluation are recommended. In most mild cases, MYCOBUTIN may be restarted; however, if signs or symptoms recur, use of MYCOBUTIN 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 MYCOBUTIN 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 Laboratory abnormalities MYCOBUTIN (n = 566) % PLACEBO (n = 580) % Includes grades 3 or 4 toxicities as specified: Chemistry Increased alkaline phosphatase All values >450 U/L <1 3 Increased SGOT All values >150 U/L 7 12 Increased SGPT 9 11 Hematology Anemia All hemoglobin values <8.0 g/dL 6 7 Eosinophilia 1 1 Leukopenia All WBC values <1,500/mm 3 17 16 Neutropenia All ANC values <750/mm 3 25 20 Thrombocytopenia All platelet count values <50,000/mm 3 5 4 The incidence of neutropenia in patients treated with MYCOBUTIN was significantly greater than in patients treated with placebo (p = 0.03). Although thrombocytopenia was not significantly more common among patients treated with MYCOBUTIN in these trials, MYCOBUTIN has been clearly linked to thrombocytopenia in rare cases. One patient in Study 023 developed thrombotic thrombocytopenic purpura, which was attributed to MYCOBUTIN. 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: 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.
Tuberculosis MYCOBUTIN 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 MYCOBUTIN should be evaluated immediately, so that those with active disease may be given an effective combination regimen of anti-tuberculosis medications. Administration of MYCOBUTIN as a single agent to patients with active tuberculosis is likely to lead to the development of tuberculosis that is resistant both to MYCOBUTIN and to rifampin. There is no evidence that MYCOBUTIN is an effective prophylaxis against M. tuberculosis . Patients requiring prophylaxis against both M. tuberculosis and Mycobacterium avium complex may be given isoniazid and MYCOBUTIN 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 MYCOBUTIN is used concomitantly with clarithromycin for MAC treatment, a decreased dose of MYCOBUTIN is recommended due to the increase in plasma concentrations of MYCOBUTIN (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 MYCOBUTIN therapy for signs and/or symptoms of hypersensitivity reactions. If these symptoms occur, administer supportive measures and discontinue MYCOBUTIN. Uveitis Due to the possible occurrence of uveitis, patients should also be carefully monitored when MYCOBUTIN 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 MYCOBUTIN should be suspended (see also ADVERSE REACTIONS ). Clostridium difficile Associated Diarrhea Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including MYCOBUTIN (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 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 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.
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 MYCOBUTIN 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 ? indicates increase; ? indicates decrease; ? indicates no significant change QD- once daily; BID- twice daily; TID - thrice daily ND - No Data AUC - Area under the Concentration vs. Time Curve; C max - Maximum serum concentration ANTIVIRALS Amprenavir 1200 mg BID × 10 days 300 mg QD × 10 days Healthy male subjects (6) ? AUC by 193%, ? Cmax by 119% ? Reduce rifabutin dose by at least 50%. Monitor closely for adverse reactions. Delavirdine 400 mg TID 300 mg QD HIV-infected patients (7) ? AUC by 230%, ? Cmax by 128% ? AUC by 80%, ? Cmax by 75%, ? Cmin by 17% CONTRAINDICATED Didanosine 167 or 250 mg BID × 12 days 300 or 600 mg QD × 1 HIV-infected patients (11) ? ? Fosamprenavir/ ritonavir 700 mg BID plus ritonavir 100 mg BID × 2 weeks 150 mg every other day × 2 weeks Healthy subjects (15) ? AUC compared to rifabutin 300 mg QD alone ? Cmax by 15% ? AUC by 35% compared to historical control (fosamprenavir/ritonavir 700/100 mg BID) , ? Cmax by 36%, ? Cmin by 36%, Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with fosamprenavir/ritonavir combination. Indinavir 800 mg TID × 10 days 300 mg QD × 10 days Healthy subjects (10) ? AUC by 173%, ? Cmax by 134% ? AUC by 34%, ? Cmax by 25%, ? Cmin by 39% Reduce rifabutin dose by 50%, and increase indinavir dose from 800 mg to 1000 mg TID. Lopinavir/ ritonavir 400/100 mg BID × 20 days 150 mg QD × 10 days Healthy subjects (14) ? AUC by 203% also taking zidovudine 500 mg QD ? Cmax by 112% ? Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with lopinavir/ritonavir combination. Monitor closely for adverse reactions. Reduce rifabutin dosage further, as needed. Saquinavir/ ritonavir 1000/100 mg BID × 14 or 22 days 150 mg every 3 days × 21-22 days Healthy subjects ? AUC by 53% compared to rifabutin 150 mg QD alone ? Cmax by 88% (n=11) ? AUC by 13%, ? Cmax by 15%, (n=19) Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with saquinavir/ritonavir combination. Monitor closely for adverse reactions. Ritonavir 500mg BID × 10 days 150 mg QD × 16 days Healthy subjects (5) ? AUC by 300%, ? Cmax by 150% ND Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with lopinavir/ritonavir combination. Monitor closely for adverse reactions. Reduce rifabutin dosage further, as needed. Tipranavir/ ritonavir 500/200 BID × 15 doses 150 mg single dose Healthy subjects (20) ? AUC by 190%, ? Cmax by 70% ? Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with tipranavir/ritonavir combination. Monitor closely for adverse reactions. Reduce rifabutin dosage further, as needed. Nelfinavir 1250 mg BID × 7-8 days 150 mg QD × 8 days HIV-infected patients (11) ? AUC by 83%, compared to rifabutin 300 mg QD alone ? Cmax by 19% ? Reduce rifabutin dose by 50% (to 150 mg QD) and increase the nelfinavir dose to 1250 mg BID Zidovudine 100 or 200 mg q4h 300 or 450 mg QD HIV-infected patients (16) ? ? AUC by 32%, ? Cmax by 48%, Because zidovudine levels remained within the therapeutic range during coadministration of rifabutin, dosage adjustments are not necessary. ANTIFUNGALS Fluconazole 200 mg QD × 2 weeks 300 mg QD × 2 weeks HIV-infected patients (12) ? AUC by 82%, ? Cmax by 88% ? Monitor for rifabutin associated adverse events. Reduce rifabutin dose or suspend MYCOBUTIN use if toxicity is suspected. Posaconazole 200 mg QD × 10 days 300 mg QD × 17 days Healthy subjects (8) ? AUC by 72%, ? Cmax by 31% ? AUC by 49%, ? Cmax by 43% If co-administration of these two drugs cannot be avoided, patients should be monitored for adverse events associated with rifabutin administration, and lack of posaconazole efficacy. Itraconazole 200 mg QD 300 mg QD HIV-Infected patients (6) ? data from a case report ? AUC by 70%, ? Cmax by 75%, If co-administration of these two drugs cannot be avoided, patients should be monitored for adverse events associated with rifabutin administration, and lack of itraconazole efficacy. In a separate study, one case of uveitis was associated with increased serum rifabutin levels following co-administration of rifabutin (300 mg QD) with itraconazole (600-900 mg QD). Voriconazole 400 mg BID × 7 days (maintenance dose) 300 mg QD × 7 days Healthy male subjects (12) ? AUC by 331%, ? Cmax by 195% ? AUC by ~100%, ? Cmax by ~100% compared to voriconazole 200 mg BID alone CONTRAINDICATED ANTI-PCP (Pneumocystis carinii pneumonia) Dapsone 50 mg QD 300 mg QD HIV-infected patients (16) ND ? AUC by 27 -40% Sulfamethoxazole- Trimethoprim 800/160 mg 300 mg QD HIV-infected patients (12) ? ? AUC by 15-20% ANTI-MAC (Mycobacterium avium intracellulare complex) Azithromycin 500 mg QD × 1 day, then 250 mg QD × 9 days 300 mg QD Healthy subjects (6) ? ? Clarithromycin 500 mg BID 300 mg QD HIV-infected patients (12) ? AUC by 75% ? AUC by 50% Monitor for rifabutin associated adverse events. Reduce dose or suspend use of MYCOBUTIN if toxicity is suspected. Alternative treatment for clarithromycin should be considered when treating patients receiving rifabutin ANTI-TB (Tuberculosis) Ethambutol 1200 mg 300 mg QD × 7 days Healthy subjects (10) ND ? Isoniazid 300 mg 300 mg QD × 7 days Healthy subjects (6) ND ? OTHER Methadone 20 - 100 mg QD 300 mg QD × 13 days HIV-infected patients (24) ND ? Ethinylestradiol (EE)/Norethindrone (NE) 35 mg EE / 1 mg NE × 21 days 300 mg QD × 10 days Healthy female subjects (22) ND EE: ? AUC by 35%, ? C max by 20% NE: ? AUC by 46% Patients should be advised to use additional or alternative methods of contraception. Theophylline 5 mg/kg 300 mg × 14 days Healthy subjects (11) ND ? Other drugs The structurally similar drug, rifampin, is known to reduce the plasma concentrations of a number of other drugs (see prescribing information for rifampin). Although a weaker enzyme inducer than rifampin, rifabutin may be expected to have some effect on those drugs as well.