Composition
Each chewable tablet Rimactazid® Paed 75/50 contains rifampicin 75 mg and isoniazid 50 mg.
Therapeutic Indication
For treatment tuberculosis due to strains of Mycobacterium tuberculosis sensitive to rifampicin and INH.
Dosage and Administration
Each Rimactazid® Paed 75/50 chewable tablet contains Rifampicin (R), and Isoniazid (H) in such a ratio that administration of 15 mg/kg body weight (R) and 10 mg/kg body weight (H) can be achieved by giving 1 tablet per 5 kg body weight, i.e. which is given daily for 4 months after intensive phase.
1 tablet to children of 5 kg, 2 tablets to children of 10 kg, 3 tablets to children of 15 kg, 4 tablets to children of 20 kg, 5 tablets to children of 25 kg body weight.
No child should take more than 6 Rimactazid® Paed tablets per day.
The daily dosage is calculated from the recommended daily requirement given above and the tablets can be halved to more regulate dosage according to body weight.
Contraindications
Known or suspected hypersensitivity to rifampicin and/or to INH, as well as a history of drug-induced hepatitis; acute liver diseases, regardless of their origin, peripheral neuritis, jaundice; optic neuritis, renal dysfunction, epilepsy, chronic alcoholism.
Special warnings and special precautions
The presence of rifampicin means that, if treatment with Rimactazid® Paed is withdrawn for a while and then resumed again, or if the medication is not taken regularly, potentially serious side effects can occur (see under rifampicin in "Undesirable effects"). For this reason, both temporary interruptions of treatment and noncompliance should it possible be avoided. Where temporary withdrawal of the medication is unavoidable, the two components rifampicin and INH should be administered separately when resuming the treatment, because rifampicin should then be given in an incremental dosage. A start should be made with approx. 75-150 mg rifampicin on the first day, and the desired therapeutic dose should be reached within 3 - 4 days.
During this time the patient's renal function should be closely monitored. Corticosteroids may prove useful in attenuating possible immunopathological reactions. INH should be given in its normal dosage from the first day onwards.
If severe acute hypersensitivity reactions set in, such as thrombocytopenia, purpura, haemolytic anaemia, dyspnoea and asthma-like attacks, shock, or renal failure (these being side effects which rifampicin may provoke in exceptional cases), Rimactazid® Paed should be withdrawn at once.
Patients developing such complications should never again be treated with rifampicin.
If other signs of hypersensitivity appear, such as drug fever or skin reactions, Rimactazid® Peed should likewise be withdrawn. For safety reasons, treatment should not be continued with rifampicin; instead, another anti tuberculous agent should be prescribed. Where INH is considered indispensable for combined medication and is therefore not withdrawn, treatment with it should be resumed in low doses and under strict surveillance.
Liver diseases undernourishment, alcoholism
In patients with chronic liver disease, as well as in chronic alcoholics and undernourished patients, the therapeutic benefits of treatment with Rimactazid® Paed must be weighed against the possible risks if the treatment is considered necessary, the dosage of two components must be correspondingly reduced; it is only possible to arrive at a correct adaptation of the dosage by administering rifampicin and INH separately.
Porphyria
Owing to its enzyme-inducing effect, rifampicin must be employed with extreme caution in patients with porphyria, because activation of delta-aminolaevulinic acid synthetase may lead to an acute manifestation of the porphyria.
Patients with epilepsy
Owing to the neurotoxic action of INH, patients with epilepsy must be kept under special observation during treatment with Rimactazid® Paed (see also references to interactions with anticonvulsants in chapter Interaction).
Neuropathy Pyridoxine (vit. B6) may be useful for attenuating any neuropathy due to INH.
Neuropathy
Pyridoxine may be useful in preventing the occurrence of peripheral neuritis.
Caution is given on patients with severe nutrition deficiency and elderly patients. For elderly patient additional pyridoxine may be indicated to reduce the occurrence of nutrition deficiency cause by INH.
Renal dysfunction
In case of severe renal dysfunction the excretion of isoniazid can be delayed.
Alcohol
Patients should abstain from alcohol while under treatment with Rimactazid® Paed (see also "Interaction with other medicaments and other forms of Interaction
Test to be performed
Blood count and liver function test (SGOT, SGPT) should be performed periodically, and at baseline if possible.
Patient have to take anti TB drug regularly as TB treatment regimen schedule especially on the initial treatment phase.
To avoid treatment failure (after receiving TB treatment phase completely, microscopic sputum test still AFB positive) and occurrence of relapse (microscopic sputum test still AFB positive once again after being declared cured). Motivate the patient to complete the TB treatment regimens as recommended.
Interaction with other medicaments and other forms of interaction
Rifampicin
Antacids, opiates, anticholinergic drugs and ketoconazole reduce the bioavailability of rifampicin when it is given concomitantly "by mouth. The same applies to PAS preparations containing bentonite. To avoid this interaction, rifampicin must be administered a few hours before these preparations.
Owing to its enzyme-inducing effect, rifampicin accelerates the metabolism of many concomitantly administered drugs, whose activity Clay thus is reduced and the success of treatment with their Jeopardised.
The activity of the following drugs may be impaired, and their dosage must therefore be reassessed during and after treatment with rifampicin.
Oral anticoagulants: oral antidiabetic agents; digitalis preparations; antiarrhythmic agents (disopyramide, pirmenol, quinidine; mexiletine, tocainide, lorcainid, propaferone); methadone (withdrawal ogres may set in); hydantoins (phenytoin (see also under isoniazid), ethotoin, mephenytoin); hexobarbital; nodriptyline; benzodiazepines; corticosteroids (Addison patients may develop a-crisis; exacerbation of pemphigus may occur; treatment for corticoid-dependent asthma patients may become more difficult or impossible); sex hormones (menstrual disorders may appear); oral contraceptives (their effect can no longer be relied upon); theophyllines; dapsone; chloramphenicol; azole antifungal agents (ketoconazole, itraconazole); cyclosporin A, azathioprine (transplants may be rejected); beta blockers; calcium-channel blockers (nifedipine, verapamil); analapril; cimetidine.
Although concurrent use of isoniazid, pyrazinamide, and rifampicin is common and therapeutically valuable, hepatic toxicity may be increased. Rifampicin can delay the Whittier excretion of contrast media employed to xray the gall-blader. Microbiological. Techniques for assaying folio acid and vitamin B12 in tile serum are unsuitable for use during treatment with Rimactazid® Paed.
Rifampicin causes temporary competitive inhibition of bromsulphthalein execration. To guard against false positive results the bromsulphthalein test should be performed in the morning before administration of Rimactazid® Paed.
Isoniazid
The absorption of isoniazid is reduced by antacids.
Isoniazid retards the metabolism of various concomitantly administered drugs, whose toxicity thus becomes increased Clinically relevant interactions of this kind can occur with hydantoins (phenytoin, ethotoin, and mephenytoin), carbamazepine, primidone, and valproic acid, the dosage of which may have to be reduced. Concurrent administration of disulfiram may lead to mental disturbances; the mechanism underlying this interaction has not been clarified. It is not advisable to employ disulfiram concomitantly with isoniazid. Concomitant use of halothane and isoniazid (and possibly rifampicin) may increase the risk of hepatotoxic reactions.
As alcohol tolerance is decreased under isoniazid, the consumption of alcoholic beverages should be avoided. The metabolism of isoniazid is increased in chronic alcoholics.
Undesirable effects
Frequency estimates: frequent › 10%, occasional 1% - 10%,rare 0.001%-1% isolated cases ‹ 0.001%.
Rifampicin
Rifampicin may cause reddish discoloration of body fluid and occasionally other body secretions, e.g. urine, Sputum, lacrimal fluid, feces, saliva, sweats. It may permanently discolor soft contact lenses.
Unwanted effects which may occur during continuous daily or intermittent therapy:
Skin and appendices
Occasionally flushing, itching with or without skin rash, urticaria and reddening of the eyes.
Isolated cases: severe signs and symptoms, such as exudative conjunctivitis or generalized hypersensitivity Reactions involving the skin, (such as exfoliative dermatitis, Lyell's syndrome) and pemphigoid reactions
Gastrointestinal tract
Occasionally: anorexia, nausea, abdominal pains, gaseous distension rarely: vomiting or diarrhoea; isolated cases: of erosive gastritis and pseudomembronous colitis.
Liver:
Frequently: an asymptomatic increase in liver enzymes; rarely: hepatitis or jaundice; induction of porphyria in isolated cases.
Central and peripheral nervous system
Occasionally: tiredness, drowsiness, headache, lightheadedness, dizziness; rarely: ataxia, mental confusion.
Isolated cases: muscular weakness, visual disturbances.
Blood
Isolated cases: of transient leucopenia; eosinophilia; thrombocytopenia and thrombocytopenic purpura are encountered more frequently under intermittent therapy than on continuous daily treatment, during which they occur only in isolated cases.
Endocrine reactions
Rarely: disturbances in the menstrual cycle; induction of a crisis in Addison patients (see "Interactions with other medicaments and other forms of interaction"). Unwanted effects chiefly occurring during intermittent therapy or upon resumption of treatment after temporary
Interruption:
In patients taking rifampicin other than on a daily basis or in those resuming treatment with the drug after a temporary interruption, on Influenza-like syndrome ("flu syndrome") may occur, this being very probably of immunopathological origin. It is characterized by fever, shivering, and possibly headache, dizziness, and musculoskeletal pain. In rare cases the Flu syndrome" may be followed by thrombocytopenia, purpura, dyspnoea, asthma like attacks, haemolytic anaemia, shock, and acute renal failure. These serious complications may, however, also set in suddenly with no preceding "flu syndromes, chiefly when treatment is resumed after a temporary interruption or when rifampicin is given only once a week in high doses (25 mg/kg or more). When rifampicin is administered in lower doses (600 mg) 2-3 times a week, the syndrome is only rarely encountered, its incidence then being comparable to that observed during daily medication.
Isoniazid
Central and peripheral nervous system
Frequently: peripheral neuropathy (dose-dependent and more common in undernourished patients, in alcoholics, and in diabetics).
Rare: damage to the optic nerve, convulsions, psychoses, dizziness, lightheadedness, and headache.
Isolated cases: toxic encephalopathy. High doses may increase the frequency of seizures in epileptics.
Gastrointestinal tract
Occasionally: nausea, vomiting, epigastric distress.
Liver
Frequently: disturbances of liver function (usually transient), rarely: hepatitis, which in Isolated Instances may be severe, the frequency of hepatitis rises with increasing age.
Haematological reaction
Isolated cases: of agranulocytosis, eosinophilia, and thrombocytopenia, anaemia (haemolytic, hypoplastic).
Allergic and miscellaneous reactions
Occasionally: drug rash and fever, rarely: dryness of the mouth, heartburn, disorders of micturition, rheumatic syndrome, lupus erythematosus-like signs and symptoms, pellagra. Isolated cases: gynoecomastia, vasculitis.
Severe adverse drug reactions of FDCs to warrant withdrawal of drugs generally occur in only 3 - 6% of patients on tuberculosis treatment. These may be more common in patients co-infected with HIV.
Overdose
Signs and symptoms
Rifampicin
Reddish-brown or orange discoloration of the skin, saliva, lacrimal fluid, sweat, feces ('red man syndromes'); nausea, vomiting, abdominal pains; enlargement of the flyer, Jaundice, elevated liver enzyme levels; possibly acute pulmonary oedema, lethargy, including of consciousness, convulsions.
Isoniazid
In mild poisoning: ataxia, symptoms of polyneuritis, disturbed articulation, swimming before the eyes.
In severe poisoning: hallucination, epileptiform tonic clonic attacks, respiratory depression, coma, severe metabolic acidosis, hyperglycoemia, acetonuria.
Pharmacological properties
Pharmacodynamic properties
Rimactazid® Paed is a fixed combination for the treatment of tuberculosis.
Rifampicin
Rifampicin is a rifamycin antibiotic which in vivo has a bactericidal effect on strains of Mycobacterium tuberculosis located not only in the extracellular spaces but also intracellularly.
Of particular clinical significance in the treatment of tuberculosis is its rapid onset of action.
Mechanism of action: Rifampicin inhibits the DNAdependent RNA polymerase of sensitive bacterial strains, but without affecting the corresponding mammalian enzyme.
Isoniazid
Isoniazid is a specific antituberculous agent exerting a strong bactericidal effect mainly on rapidly growing populations of Mycobacterium tuberculosis. Its mechanism of action is probably based chiefly on inhibition of mycolic acid synthesis, mycolic acid being an important constituent of the mycobacterial cell wall.
Pharmacokinetic properties
The bioavailability of both active ingredients, rifampicin and isoniazid, is the some when administered as a fixed combination or when given separately. Neither component interferes with the pharmacokinetics of the other when administered simultaneously.
Absorption
After oral administration of the fixed combination on an empty stomach, the two active substances are well absorbed. Rifampicin, following a single dose of 600 mg, reaches mean peak plasma concentrations of 9.4 μg/ml after 2-3 hours. Isoniazid, following a single dose of 300 mg, reaches mean peak plasma concentration of 6.1 g/ml after 0.5 - 2 hours. However, plasma concentrations vary interindividually, depending on the acetylator status of the patient.
Concomitant intake of food reduces the absorption of both active components.
Distribution
Rifampicin: Binding to serum protein amounts to 80%. Isoniazid: The apparent distribution volume is 0.57-0.76 L/kg. Isoniazid is not appreciably bound to serum proteins.
Rifampicin and Isoniazid penetrate rapidly into various body fluids and tissues, including bone tissue (rifampicin) and cerebrospinal timid, in therapeutically active concentrations.
Rifampicin crosses the blood brain barrier in the case of inflamed meninges only, but concentrations in the cerebrospinal fluid may remain above the MIC for Mycobacterium tuberculosis for up to two months with continuous therapy of 600 mg/day orally.
Biotransformation
Rifampicin is metabolized in the liver, the principal metabolize being 25 - O - deacetylrifampicin, which is microbiologically active, and like rifampicin, subject to enterohepatic circulation.
Rifampicin induces its own metabolism.
Isoniazid is acetylated and hydrolyzed in the liver. Acetylation is the most important metabolic pathway and is subject to genetic predisposition (fast and slow acetylators).
Elimination/ Excretion
Rifampicin
The plasma elimination half life increases with increasing doses, and amounts to 2.5 h. 3-4 hand about 5 h after single doses of 300 mg, 600 mg, and 900 mg respectively. After a few days of repeated daily administration, the bioavailability of rifampicin diminishes, and the half-life value following repeated doses of 600 mg falls to 1-2 hours.
Owing to its enzyme inducing effect in the liver, rifampicin accelerates its own metabolism, with the result that its systemic clearance, which amounts to approx. 6 l/h after the first dose, rises to approx. 9 l/h after repeated dosing.
Although the bulk of the drug is eliminated in the bile, 80% of the quantity excreted being accounted for by the Deacetylrifampicin metabolize, rifampicin also appears in the urine. In a dosage range of 150-900 mg, 4-18% of dose is excreted dose dependently in the urine in unchanged form.
Isoniazid
The plasma elimination half-life is 0.6-1.8 hours in test acetylators and 1.8-6.7 hours in slow acetylators. Within 24 hours 75-95% of the dose administered is excreted in the urine, mainly as metabolizes. N-Acetylisoniazid is eliminated in the urine together with other metabolises. The quantity appearing in the urine as unchanged Isoniazid is equivalent to 12% of tire dose in fast acetylators and to 27% in slow acetylators.
Characteristics in patients
Rifampicin
In elderly patients plasma concentrations are similar to those in adults.
With impaired renal function, the elimination half-life becomes prolonged only at doses exceeding 600 mg daily. Provided that hepatic excretory function is normal, the dosage in-patients with impaired renal function do not need to be reduced below 600 mg daily.
Rifampicin is eliminated by peritoneal or haemodialysis.
Dosage adjustment is not necessary during dialysis. In patients with impaired liver function the plasma concentrations are raised and the elimination half-life prolonged. In the presence of severe hepatic dysfunction the dosage may hove to be adjusted accordingly.
Isoniazid
Elderly patients: In fast acetylators, old age has no significant influence on the rate at which the drug is eliminated. However, clearance and elimination half-life varies significantly in elderly slow acetylators, so that it might be necessary to adjust the dosage accordingly.
In slow acetylators with severely impaired renal function, accumulation of isoniazid may occur. In such cases, the serum concentration of isoniazid should be monitored and, if necessary, the dosage reduced. In the presence of impaired liver function the elimination half-life of isoniazid is prolonged. To avoid unwanted effects it may therefore be necessary to adapt the dosage accordingly.
Storage
Do not store above 30°C, protect from light and moisture.
Drugs should be kept out of the reach of children.
To be dispensed only on the prescription of a physician.
Packages
Rimactazid® Paed 75/50 : Box of 5 blisters of 10 chewable tablets,
Reg. No. DKL0230411463A1
HARUS DENGAN RESEP DOKTER
Manufactured by PT Novartis Indonesia
Citeureup, Bogor, Indonesia
under license of Sandoz GmbH, Kundl, Austria
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