MT-3

Uses

Rifampin, isoniazid, and pyrazinamide is used for the initial phase of the short-course treatment of pulmonary tuberculosis. During this phase, which should last 2 months, this drug should be administered on a daily, continuous basis.

Following the initial phase and treatment with this drug, treatment should be continued with rifampin and isoniazid for at least 4 months. Treatment should be continued for a longer period of time if the patient is still sputum or culture positive, if resistant organisms are present, or if the patient is HIV positive.

In the treatment of tuberculosis, the small number of resistant cells present within large populations of susceptible cells can rapidly become the predominant type. Since resistance can emerge rapidly, susceptibility tests should be performed in the event of persistent positive cultures during the course of treatment. Bacteriologic smears or cultures should be obtained before the start of therapy to confirm the susceptibility of the organism to rifampin, isoniazid, and pyrazinamide and they should be repeated throughout therapy to monitor response to the treatment. If test results show resistance to any of the components of this drug and the patient is not responding to therapy, the drug regimen should be modified.

MT-3 is also used to associated treatment for these conditions: Active Tuberculosis, Mycobacterium kansasii infection, Late phase TuberculosisActive Tuberculosis, Pulmonary Tuberculosis (TB)Cholestatic pruritus, MRSA Infection, Prosthetic Joint Infection, Asymptomatic Neisseria meningitidis carrier of the nasopharynx, Initial phase Tuberculosis, Late phase Tuberculosis, Antibacterial therapy

How MT-3 works

Isoniazid is a prodrug and must be activated by bacterial catalase. Specficially, activation is associated with reduction of the mycobacterial ferric KatG catalase-peroxidase by hydrazine and reaction with oxygen to form an oxyferrous enzyme complex. Once activated, isoniazid inhibits the synthesis of mycoloic acids, an essential component of the bacterial cell wall. At therapeutic levels isoniazid is bacteriocidal against actively growing intracellular and extracellular Mycobacterium tuberculosis organisms. Specifically isoniazid inhibits InhA, the enoyl reductase from Mycobacterium tuberculosis, by forming a covalent adduct with the NAD cofactor. It is the INH-NAD adduct that acts as a slow, tight-binding competitive inhibitor of InhA.

Pyrazinamide diffuses into active M. tuberculosis that express pyrazinamidase enzyme that converts pyrazinamide to the active form pyrazinoic acid. Pyrazinoic acid can leak out under acidic conditions to be converted to the protonated conjugate acid, which is readily diffused back into the bacilli and accumulate intracellularly. The net effect is that more pyrazinoic acid accumulates inside the bacillus at acid pH than at neutral pH. Pyrazinoic acid was thought to inhibit the enzyme fatty acid synthase (FAS) I, which is required by the bacterium to synthesise fatty acids. However, this theory was thought to have been discounted. However, further studies reproduced the results of FAS I inhibition as the putative mechanism first in whole cell assay of replicating M. tuberculosis bacilli which have shown that pyrazinoic acid and its ester inhibit the synthesis of fatty acids. This study was followed by in vitro assay of tuberculous FAS I enzyme that tested the activity with pyrazinamide, pyrazinoic acid and several classes of pyrazinamide analogs. Pyrazinamide and its analogs inhibited the activity of purified FAS I.

It has also been suggested that the accumulation of pyrazinoic acid disrupts membrane potential and interferes with energy production, necessary for survival of M. tuberculosis at an acidic site of infection. Pyrazinoic acid has also been shown to bind to the ribosomal protein S1 (RpsA) and inhibit trans-translation. This may explain the ability of the drug to kill dormant mycobacteria.

Rifampin acts via the inhibition of DNA-dependent RNA polymerase, leading to a suppression of RNA synthesis and cell death.

Dosage

MT-3 dosage

Total Dosage Requirement:

• Rifampicin: 10 (8-12) mg/kg body mass/day.
• Isoniazid: 5 (4-6) mg/kg body mass/day.
• Pyrazinamide: 25 (20-30) mg/kg body mass/day.

Pediatric Patients:

The ratio of the drugs may not be appropriate in pediatric patients under the age of 15 (e.g., higher mg/kg doses of isoniazid are usually given in pediatric patients than adults).

The tablets should be given as a single dose, preferably on an empty stomach, at least 30 min before breakfast to ensure a high peak serum concentration.

Tablets are recommended in the initial intensive phase of the short course treatment of tuberculosis. During this phase which lasts for 2 months

Should be taken on an empty stomach. Best taken on an empty stomach 1 hr before or 2 hr after meals.

Preparation Of Solution For IV Infusion: Reconstitute the lyophilized powder by transferring 10 mL of sterile water for injection to a vial containing 600 mg of rifampin for injection. Swirl vial gently to completely dissolve the antibiotic. The reconstituted solution contains 60 mg rifampin per mL and is stable at room temperature for up to 30 hours. Prior to administration, withdraw from the reconstituted solution a volume equivalent to the amount of rifampin calculated to be administered and add to 500 mL of infusion medium. Mix well and infuse at a rate allowing for complete infusion within 3 hours. Alternatively, the amount of rifampin calculated to be administered may be added to 100 mL of infusion medium and infused in 30 minutes.

Dilutions in dextrose 5% for injection (D5W) are stable at room temperature for up to 8 hours and should be prepared and used within this time. Precipitation of rifampin from the infusion solution may occur beyond this time. Dilutions in normal saline are stable at room temperature for up to 6 hours and should be prepared and used within this time. Other infusion solutions are not recommended.

Side Effects

Unwanted effects which may occur during continuous daily or intermittent therapy: Rifampicin: Rifampicin may cause reddish discolouration of body fluids and occasionally other body secretions eg, urine, sputum, lacrimal fluid, faeces, saliva and sweat. It may permanently discolour soft contact lenses.

Hepatic Effects: Very common (>10%) is an asymptomatic increase in liver enzymes; severe life-threatening hepatic reactions eg, hepatic failure and acute fulminant hepatitis are uncommon (>0.1% and <1%). In isolated cases (<0.01 %), a fatal outcome was observed.

Gastrointestinal Effects: Nausea, abdominal pains, vomiting or diarrhoea, pseudomembranous colitis.

Central and Peripheral Nervous System Effects: Tiredness, drowsiness, headache, dizziness, ataxia, mental confusion, muscular weakness, visual disturbances.

Haematological Changes: Leucopenia, eosinophilia, thrombocytopenia and thrombocytopenic purpura.

Effects on Skin and Appendages: Flushing, itching with or without skin rash, urticaria, reddening of the eyes, exudative conjunctivitis or generalised hypersensitivity reactions involving the skin eg, exfoliative dermatitis, Lyell's syndrome and pemphigoid reactions.

Endocrine Effects: Disturbances in the menstrual cycle, induction of crisis in Addison patients.

Unwanted effects chiefly occurring during intermittent therapy or upon resumption of treatment after temporary interruption

Toxicity

LD₅₀ 100 mg/kg (Human, oral). Adverse reactions include rash, abnormal liver function tests, hepatitis, peripheral neuropathy, mild central nervous system (CNS) effects. In vivo, Isoniazid reacts with pyridoxal to form a hydrazone, and thus inhibits generation of pyridoxal phosphate. Isoniazid also combines with pyridoxal phosphate; high doses interfere with the coenzyme function of the latter.

Side effects include liver injury, arthralgias, anorexia, nausea and vomiting, dysuria,malaise and fever, sideroblastic anemia, adverse effects on the blood clotting mechanism or vascular integrity, and hypersensitivity reactions such as urticaria, pruritis and skin rashes.

LD₅₀=1570 mg/kg (rat), chronic exposure may cause nausea and vomiting and unconsciousness

Precaution

Caution is advised in patients with impaired renal or liver function, diabetes mellitus, chronic alcoholism and undernourished patients, patients with a history of gout and patients suffering from convulsive disorders and acute porphyria. Precautions need to be taken: Blood counts and liver function tests (SGPT, SGOT) should be performed periodically (especially in prolonged treatment) and at baseline, if possible.

Patients with current chronic liver disease or impaired liver function should be treated with caution and under strict medical supervision. Careful monitoring of liver function should be carried out and attention should be paid to possible prodromal symptoms of hepatitis eg, fatigue, weakness, malaise, anorexia, nausea or vomiting. If these symptoms appear or if signs suggestive of hepatic damage are detected, treatment should be discontinued promptly. The occurrence of severe and sometimes fatal hepatitis associated may develop even after many months of treatment.

Interaction

Rifampicin may reduce effectivity of hormonal contraceptives, ACE inhibitors (e.g. enalapril, imidapril), antiemetics (e.g. aprepitant), antineoplastics (e.g. imatinib), diuretics (e.g. eplerenone), drugs for erectile dysfunction (e.g. tadalafil), oral hypoglycaemics (e.g. nateglinide, repaglinide), NSAIDs (e.g. etoricoxib). Rifampicin may reduce serum levels of atovaquone, ketoconazole. Antacids may reduce absorption of rifampicin. Anaesthetics and halothane may increase risk for hepatotoxicity with rifampicin and isoniazid.

Isoniazid may increase serum levels of phenytoin and theophylline; and may decrease carbamazepine metabolism. Stavudine may increase risk of distal sensory neuropathy with isoniazid. Antacids may reduce isoniazid absorption. May increase plasma levels of isoniazid with para-aminosalicylic acid. Increased risk of CNS toxicity when isoniazid is used concomitantly with cycloserine.

Pyrazinamide antagonizes the effects of probenecid and sulfinpyrazone.

Potentially Fatal: Concominant use with saquinavir/ritonavir may increase risk of severe hepatotoxicity. May reduce antiviral efficacy of atazanavir, darunavir, fosamprenavir, saquinavir, or tipranavir

Elimination Route

Readily absorbed following oral administration; however, may undergo significant first pass metabolism. Absorption and bioavailability are reduced when isoniazid is administered with food.

Rapidly and well absorbed from the gastrointestinal tract.

Well absorbed from gastrointestinal tract.

Half Life

Fast acetylators: 0.5 to 1.6 hours. Slow acetylators: 2 to 5 hours.

9-10 hours (normal conditions)

3.35 (+/- 0.66) hours

Clearance

• 0.19 +/- 0.06 L/hr/kg [300 mg IV]
• 0.14 +/- 0.03 L/hr/kg [600 mg IV]

Elimination Route

From 50 to 70 percent of a dose of isoniazid is excreted in the urine within 24 hours.

Approximately 70% of an oral dose is excreted in the urine, mainly by glomerular filtration within 24 hours

Less than 30% of the dose is excreted in the urine as rifampin or metabolites.

Pregnancy & Breastfeeding use

Pregnancy Category C. Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks

Contraindication

Known or suspected hypersensitivity to rifamycins and/or to isoniazid and to pyrazinamide and/or to any of the excipients including a history of drug-induced hepatitis, acute liver diseases regardless of their origin, and peripheral neuritis.

Special Warning

Usage in Children: Pyrazinamide regimens employed in adults are probably equally effective in children. Pyrazinamide appears to be well tolerated in children.

Geriatric Use: Clinical studies of Pyrazinamide did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. 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 or renal function, and of concomitant disease or other drug therapy.It does not appear that patients with impaired renal function require a reduction in dose. It may be prudent to select doses at the low end of the dosing range, however.

Renal Dose Adjustments: The manufacturer recommends to start therapy at low end of dosage range and monitor patient closely.For the treatment of active tuberculosis, the CDC, ATS, and IDSA recommend against daily dosing. For patients with CrCl less than 30 mL/min or patients receiving hemodialysis the recommended dose is 25 to 35 mg/kg per dose three times per week.

Liver Dose Adjustments: Monitor patients closely.

Dose Adjustments: 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 or renal function, and of concomitant disease or other drug therapy.

If organism is susceptible to isoniazid and rifampin, pyrazinamide is continued for the first 2 months of a 6-month course of therapy (9-months if HIV positive). If primary drug resistance is shown, drug regimens should be adjusted as needed and continued for at least 6 months, or 3 months beyond culture conversion (9 months, or 6 months beyond culture conversion if HIV positive). If multiple-drug resistance is demonstrated, therapy should be continued for 12 to 24 months following culture conversion.

Geriatric Use: Clinical studies of Rifampicin 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. Caution should therefore be observed in using rifampin in elderly patients.

Acute Overdose

Overdosage experience is limited. In one case report of overdose, abnormal liver function tests developed. These spontaneously reverted to normal when the drug was stopped. Clinical monitoring and supportive therapy should be employed. Pyrazinamide is dialyzable.

Nausea, vomiting, abdominal pain, pruritus, headache, and increasing lethargy will probably occur within a short time after ingestion; unconsciousness may occur when there is severe hepatic disease. Transient increases in liver enzymes and/or bilirubin may occur. Brownish-red or orange discoloration of the skin, urine, sweat, saliva, tears, and feces will occur, and its intensity is proportional to the amount ingested.

Liver enlargement, possibly with tenderness, can develop within a few hours after severe overdosage; bilirubin levels may increase and jaundice may develop rapidly. Hepatic involvement may be more marked in patients with prior impairment of hepatic function. Other physical findings remain essentially normal. A direct effect upon the hematopoietic system, electrolyte levels, or acid-base balance is unlikely.

Facial or periorbital edema has also been reported in pediatric patients. Hypotension, sinus tachycardia, ventricular arrhythmias, seizures and cardiac arrest were reported in some fatal cases.

Storage Condition

Should be stored in cool and dry place

Innovators Monograph

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