| PRESCRIPTION ONLY |
Composition
Each chewable tablet RIMCURE® Paed 75/50/150 contains rifampicin 75 mg, isoniazid 50 mg and pyrazinamide 150 mg.
Therapeutic Indication
For treatment tuberculosis due to strains of Mycobacterium tuberculosis sensitive to rifampicin, INH and pyrazinamide.
Dosage and Administration
Each RIMCURE® Paed 75/50/150 chewable tablet contains Rifampicin (R), Isoniazid (H) and pyrazinamide (Z) in such a ratio that administration of 15 mg/kg body weight (R), 10 mg/kg body weight (H) and 30 mg/kg body weight (Z) 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 RIMCURE® 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.
Contraindication
Known or suspected hypersensitivity to rifampicin and/or to INH and/or to pyrazinamide, 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The presence of rifampicin means that, if treatment with RIMCURE® Paed is withdrawn for a while and then resumed again, or if the medication is not taken regularly, potentially serious side effects can occur (see under rifampicin in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 non-compliance should it possible be avoided. Where temporary withdrawal of the medication is unavoidable, the three components rifampicin, INH and pyrazinamide should be administered separately when resuming the treatment, because rifampicin should then be given in on 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 squid be closely monitored.
Corticosteroids may prove useful in attenuating possible immunopathological reactions. INH and pyrazinamide 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), RIMCURE® 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, RIMCURE® Paed 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 RIMCURE® Paed must be weighed against the possible risks. If the treatment is considered necessary, the dosage of three components must be correspondingly reduced; it is only possible to arrive at a correct adaptation of the dosage by administering rifampicin, INH and pyrazinamide 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 RIMCURE® 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.
Gout
Pyrazinamide should be used with caution in patients with a history of gout.
If hyperuricaemia accompanied by an acute gouty arthritis occurs, the patient should be transferred to a regimen not containing pyrazinamide
Diabetes mellitus
Increased difficulty has been reported in controlling diabetes mellitus when diabetes mellitus are given pyrazinamide.
Alcohol
Patients should abstain from alcohol while under treatment with RIMCURE® 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.
Patients have to take anti TB drug regularly as TB treatment regimen schedule especially on the initial treatment phase.
To ovoid 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 ketoconozole 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 x-ray the gall-blader. Microbiological. Techniques for assaying folio acid and vitamin B12 in tile serum are unsuitable for use during treatment with RIMCURE® 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 RIMCURE® 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
Pyrazinamide
Pyrazinamide may interfere with the Acetes and Ketostix Urine Test for ketones.
The action of uricosuric drugs such as probenecid and sulphinpyrazones is antagonised by pyrazinamide.
Allopurinol increases the plasma concentration of pyrazinamide. Pyrazinamide may interfere with the effect of oral anti diabetics. These drug interactions have to be taken into consideration in the management of patients with hyperuricaemia, gout and diabetes mellitus.
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 pseudomembranous colitis.
Liver
Frequently: on 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 ore 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 o 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 riles 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: gynaecomastia, vasculitis.
Pyrazinamide
Liver
The liver toxicity of pyrazinamide depends on the dosage, the duration of treatment and concomitant therapy. It can vary from occasional mild liver disorders, such as a transient increase in serum transaminase levels to isolated cases of acute yellow atrophy of the liver.
Gastro-intestinal tract
Gastro-intestinal side effects may occur, including nausea, anorexia, vomiting, diarrhoea and abdominal pain.
Urogenital system
Decreased renal excretion of uric acid, resulting in hyperuricaemia, may occur with pyrazinamide in dosage exceeding 2.0 g/day.
Occasionally arthralgia and rarely attacks of gout have been reported; these always proved reversible after the drug had been withdrawn or the dosage decreases and appropriate of therapy given.
Blood
Rarely sideroblastic anaemia, thrombocytopenia and attack porphyria.
Vaculatian of erythrocytes and increased serum iron concentration have occurred with this drug rarely.
Central nervous system
Mild fever and malaise may occur.
Skin
Allergic skin reactions, including urticaria, rash, flushing, pruritis, burning sensations, and photosensitivity have been observed.
General
Fever, porphyria, myalgia, gout and dysuria have rarely been reported.
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, hyperglycaemia, acetonuria.
Pyrazinamide
In the case of over dosage the stomach should be emptied by emesis or gastric lavage.
Short-acting barbiturates may be given for manifestations of CNS stimulation,
analeptic for coma and artificial respiration and oxygen for respiratory failure. In the event of shock a vasopressor agent should be given.
Abnormal liver function test, these spontaneously reverted to normal when the drug was stopped.
Pharmacological properties
Pharmacodynamic properties
RIMCURE® Paed is a fixed combination for the treatment of tuberculosis.
Rifampicin
Rifampicin is a rifamycin antibiotic which in vivo has o 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 DNA-dependent 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 on important constituent of the mycobacterial cell wall.
Pyrazinamide
Pyrazinamide is bactericidal for Mycobacterium tuberculosis hominis at an acidic pH. Clinically, pyrazinamide has been shown to be active against mycobacteria growing slowly in on acidic environment, e.g. caseous foci, pulmonary cavities. The minimal inhibitory concentration far Mycobocterium tuberculosis at pH 5.5 in vitro is 20-50 mg/ml.
In order to avoid inducing bacterial resistance, a risk inherent in all tuberculostatics when administered as monotherapy, pyrazinamide should always be given together with other antituberculous agent, the standard core combination being pyrazinamide, Isoniazid and rifampicin.
Pharmocokinetic properties
The bioavailability of three active ingredients, rifampicin, isoniazid and pyrazinamide, is the same 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 three 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 μg/ml after 0.5 - 2 hours. Pyrazinamide is well absorbed from gastro-intestinal tract and attains peak plasma concentrations within 2 hours. Plasma concentrations generally range from 30 to 50 mg/ml with doses of 20 to 25 mg/kg. However, plasma concentrations vary interindividually, depending on the acetylator status of the patient.
Concomitant intake of food reduces the absorption of three 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.
Pyrazinamide does not bind to human serum protein. The volume of distribution amounts to 1.65 L/kg. Pyrazinamide penetrates the blood-brain barrier, reaching concentration in the cerebrospinal fluid comparable to those in the serum. It passes into the breast milk in quantities which measurable, but small as compared with those in the serum.
Biotransformation
Rifampicin is metabolized in the liver, the principal metabolize being 25 - 0 - 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).
Pyrazinamide is converted to pyrazinoic acid by hepatic microsomal pyrazinamide deaminidase, which is then further oxidised by xanthine oxidase to 5-hydroxypyrazinoic acid (5-OH-PA).
Elimination/ Excretion
Rifampicin
The plasma elimination halt 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. 61/h after the first dose, rises to approx. 91/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 Deocetylrifampicin 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 lest 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-Acetylisaniazid 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.
Pyrazinamide
Approximately 20 % of the administered pyrazinamide dose was excreted as pyrazinoic acid and 5-OH-PA, this value reaching 40% by 24 hours. Only 1% of pyrazinamide was excreted in the free unaltered form.
Characteristics in patients
Rifampicin
In elderly patients plasma concentrations ore 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 have 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 acetylotors 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.
Pyrazinamide
Elderly patients: no age related differences were observed for this drug.
Storage
Do not store above 30°C, protect from heat, light and moisture.
Drugs should be kept out of the reach of children.
Packages
RIMCURE® Paed 75/50/150: Box of 6 blisters of 10 chewable tablets,
Reg. No. DKL0230411563A1
| HARUS DENGAN RESEP DOKTER |
Manufactured by
PT Novartis Indonesia,
Citeureup, Bogor, Indonesia
under license of
Sandoz GmbH, Kundl, Austria
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