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Rimactane

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Rimactane
Rimactane®

Composition
Each sugar coated tablet contains Rifampicin 450 mg and 600 mg; each capsule contains Rifampicin 150 and 300 mg; each 5 ml syrup 2% contains Rifampicin 100 mg.

Pharmaceutical forms
Capsules (150 mg and 300 mg Rifampicin).
Sugar Coated Tablets (450 mg and 600 mg Rifampicin).
Oral Suspension (20 mg/ml).

Therapeutic Indications
Mycobacterial infections
Tuberculosis (all forms).
Rimactane® must always be combined with at least one other antituberculosis agents.

Leprosy
In combination with Dapsone and Clofazimine as treatment for multibacillary forms of leprosy (Lepromatous (LL), Borderline Lepromatous (BL), Borderline (BB)). In combination with Dapsone as treatment for paucibacillary forms of leprosy (Tuberculoid (TT), Borderline Tuberculoid (BT)).

Posology and Method of Administration
Mycobacterial Infections Tuberculosis
Adults weighing less than 50 kg : 450 mg Rimactane® daily. Adults weighing 50 kg or more: 600 mg Rimactane® daily. Children; 10-20 mg/kg Rimactane® daily. Maximum permissible daily dose: 600 mg. The chemotherapeutic agents usually employed today as combined therapy for tuberculosis are Rifampicin (Rimactane®) (RMP), Isoniazide (INH), Pyrazinamide (PZA), Ethambutol (EMB), Streptomycin (STM). The dosages as recommended by WHO are as follows:

Drug
Daily
2 or 3 times a week
mg/kg
Max.mg
mg/kg
Max.mg
RMP
10
600
10
600
INH
8
400
15
750
PZA
30
2000
50
3500
EMB
20
1200
40
2000
STM
15
1000
15
1000

For the treatment of sputum-positive pulmonary tuberculosis, preference is nowadays given to the following regimens:

Continuous Therapy (7 times a week)
Total duration 9 months:
Initial phase for 2 months: RMP + INH + EMB or STM.
Continuation phase for 7 months; RMP + INH.
The short terms antituberculosis drug for adults (15 years and above), with alternatives as follows:
  1. Category I
    • Initial phase for 2 months daily (60 times taking the drug): RMP 450 mg + INH 300 mg + PZA 1500 mg + EMB 750 mg
    • Continuation phase for 4 months, three times a week (54 times taking the drug): RMP 450 mg + INH 600 mg
  2. Category II
    • Initial phase for 3 months, daily (90 times taking the drug): RMP 450 mg + INH 300 mg + PZA 1500 mg + EMB 750 mg + STM 750 mg.
    • Streptomycin is only given in the first 2 months.
    • Continuation phase for 5 months, three times a week (66 times taking the drug): RMP 450 mg + INH 600 mg + EMB 1250 mg
  3. Category III
    • Initial phase for 2 months daily (60 times taking the drug): RMP 450 mg + INH 300 mg + PZA 1500 mg.
    • Continuation phase for 4 months, three times a week [54 times taking the drug): RMP 450 mg + INH 600 mg.
  4. Insertion
    • If the treatment of category 1 and 2 in the end of initial phase/ intensive still Acid Resistant Bacillus positive, insertion treatment is given during 1 month daily.
    • The daily dosage for 1 month (30 times taking the drug): RMP 450 mg + INH 300 mg + PZA 1500 mg + EMB 750 mg
In the case of all regimens administered twice or three times weekly, the patient should be monitored with directly observed therapy (i.e. administration of tablets under supervision). The same applies for
relapses and treatment failures. Dosage recommendations for sputum-negative pulmonary tuberculosis and extra pulmonary tuberculosis, and dosage recommendations for elderly and/or undernourished patients and those with severe liver damage can be found in the relevant literature.

Leprosy
For the treatment of leprosy the WHO recommends the following regimens;
Multi bacillary forms (LL, BL, BB):
Adults : Rifampicin (Rimactane®) 600 mg once a month under supervision + Dapsone 100 mg once daily + Clofazimine (Lamprene®) 300 mg once a month under supervision + 50 mg once a day.
Children : Rifampicin (Rimactane®) 10 mg/kg once a month under supervision + Dapsone 1- 2 mg/ kg daily + Clofazimine (Lamprene®) 200 mg once a month under supervision + 50 mg on alternate days.
Duration of treatment: at least 2 years, preferably until negative skin smears are obtained.

Paucibacillary forms (TT, BT):
Adults : Rifampicin (Rimactane®) 600 mg once a month under supervision + Dapsone 100 mg (1 - 2 mg/ kg) once a day.
Children : Rifampicin (Rimactane®) 10 mg/kg once a month under supervision + Dapsone 1 -2 mg/ kg/ daily. Duration of treatment at least 6 months.

Method of administration
Oral Forms
To ensure optimum absorption, Rimactane® should preferably be taken on an empty stomach, i.e. at least one hour before or two hours after a meal. The syrup should be well shaken before used.

Contraindications
Known or suspected hyper-sensitivity to Rifampicin; jaundice.
Additionally for the oral suspension: known hyper-sensitivity to parabens.

Special warnings and special precautions for use
Resistance
To prevent the emergence of resistant bacteria, Rifampicin must always be combined with other antibiotics/ chemotherapeutic agents when employed to treat infections.

Intermittent Therapy
The "flu syndrome" (see "Undesirable Effects") is chiefly encountered during intermittent therapy and may be a prelude to serious complications such as thrombocytopenia, purpura, haemolytic
anaemia, dyspnoea and asthma-like attacks, shock, and renal failure. In the event of its onset, therefore, one should consider the possibility of switching to daily medication. Such a switch must always be made where the "flu syndrome" assumes a relatively severe form, and, if the aforementioned serious complications occur, the medication must be withdrawn at once and never re-instituted. When changing over from intermittent to daily therapy, an incremental dosage must be employed, starting with approximately 75-150 mg on the first day. The desired therapeutic dose should be reached within 3 - 4 days. During this time the patient renal function should be closely monitored. Corticosteroids may prove useful in attenuating possible immunopathological reactions.

Resumption of therapy after its interruption
Since severe reactions such as shock and renal failure may occur in rare cases upon resumption of therapy, incremental dosing under close surveillance is mandatory (see "Intermittent therapy").

Premature and newborn infants
These patients should be treated only in cases of emergency and with extreme caution, because in these infants the liver enzyme system is not yet fully developed. Data are not available for determination of dosage for children under 5 years.

Liver diseases, undernourished, alcoholism
In patients with chronic liver diseases, as well as in chronic alcoholics and undernourished patients, the therapeutic benefits of combined treatment with Rifampicin must be weighed against the possible risks.
This applies particularly to combination of Isoniazide and/or Pyrazinamide with Rifampicin. In the presence of severely impaired liver function the dosage may have to be reduced.

Porphyria
Owing to its enzyme-inducing effect, Rifampicin must be employed with extreme cautions in patients with porphyria, because activation of delta aminolaevulinic acid synthetase may lead to an acute
manifestation of the porphyria.
Rimactane® must not be employed to treat an overt meningococcal infection.

Contraception
To preclude all possibility of pregnancy during treatment with Rimactane® non-hormonal means of contraception must be employed (see "Interactions with other medicaments and other forms of interaction").

Test to be performed
During prolonged treatment blood counts and liver functions tests should be performed periodically and at baseline if possible.

Pregnancy and Lactation
In mice and rats, Rifampicin proved teratogenic in daily doses of over 150 mg/kg, insofar as on increased occurrence of spine bifida and "cleft palate" was observed. In rabbits it had no teratogenic effect. In all three animal species, unspecific embryotoxic effects occurred after doses 150 mg/kg. In humans, no significant increase in malformation rate was observed in the offspring of over 300 women exposed to Rifampicin during pregnancy. Rimactane® should not be given during pregnancy unless the potential benefit justifies the potential risk to the fetus. Administration of Rifampicin during the last few weeks of pregnancy can cause post-natal haemorrhage in the mother and newborn infant, which may necessitate treatment with vitamin K preparations. Although Rifampicin passes into the breast milk, no adverse effects on breast-fed infants have been observed. It is therefore not necessary to wean the infant. Anti tuberculosis drugs must be administered regularly according to the treatment schedule especially in the initial phase of treatment. The use of Rifampicin, INH and Pyrazinomide in the long term may increase the incidence of liver function disorder especially in patients with signs of liver damage before the treatment and alcoholism. In these cases, the potential
risk has to be compared to the potential benefit. If the treatment have to be employed, the dosage should be reduced. It is recommended to closely supervise and to conduct blood count and liver function test (especially SGOT and SGPT) and renal function test before the treatment and continues to every 2-4 weeks. Because of this drug contains of INH, cautions should also be given to patients with renal function disorder and in patients with the low threshold of spasm. If there is emergence symptoms of hepatocellular damage, treatment with combination of RMP + INH + PZA + EMB have to be stopped and not to be employed anymore. The same cautions should also be given in severe undernourished patients and elderly patients.
For elderly patients, addition of vitamin B6 is indicated to reduce the incidence of deficiency because of administration of INH. Patients should be informed not to stop the treatment during the period of
treatment. Discontinuation of treatment with drugs contain of Rifampicin may cause the incidence of immunological risks which sometimes might be serious. If the discontinuation of treatment could not be avoided, the risks might be reduced with the administration of Rifampicin, INH and Pyrazinamide separately. Patient with the history of gout disease should be warned. Rifampicin may cause reddish
discoloration of body fluids, and it may permanently discolor soft contact lens.

Interactions with other medicaments and other forms of interaction
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 may thus be reduced and the success of treatment with them Jeopardized. The activity of the following drugs may be impaired, and their dosage must therefore be reassessed drug and after treatment with Rifampicin:
Oral anticoagulants; oral antidiabetic agents; digitalis preparations; antiarrhythmic agents (Disopyramide, Pirmenol, Quinidine; Mexiletine, Tocainide; Lorcainide, Propafenon); methadone (withdrawal of signs may set in); hydantoins (Fenitoin, Ethotoin, Mefenitoin); Heksobarbital; Nortriptyline; Benzodiazepine; Corticosteroid (patient Addison 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 (transplant may be rejected); beta blockers; calcium-channel blockers ( Nifedipine, Verapamil); Enalapril; Cimetidine.
Although concurrent use of Isoniazide, Pyrazinamide, and Rifampicin is common and therapeutically valuable, hepatic toxicity may be increased. Rifampicin can delay the biliary excretion of contrast media employed to x-ray the gall bladder. Microbiological techniques for assaying folic acid and vitamin B12 in the serum are unsuitable for use during treatment with Rimactane®. Rifampicin causes temporary competitive inhibition of bromsulphthalein excretion. To guard against false positive results, the bromsulphthalein test should be performed in the morning before administration of Rimactane®.

Undesirable Effects
Frequency estimates: frequent 10%, occasional 1 - 10%, rare 0.001-1%, isolated cases 0.001%.
Rifampicin may cause reddish discoloration of body fluids, and occasionally other body secretions, e.g. urine, sputum, lachrymal fluid, feces, saliva, sweat. It may permanently dis-colour soft contact lenses.
Unwanted effects which may occur during continuous daily or intermittent therapy:

Skin and appendages
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 ( e.g. exfotiative dermatitis, Lyell's syndrome and pemphigoid reactions).

Gastro intestinal Tract
Occasionally: anorexia, nausea, abdominal pains, gaseous distension; rarely: vomiting or diarrhoea; isolated cases: erosive gastritis and pseudomembranous colitis.

Liver
Frequently: an asymptomatic increase in liver enzymes ; rarely: hepatitis or jaundice; here account should also be taken of the liver toxicity of chemotherapeutic agents, e.g. Isoniazide or Pyrazinamide,
employed in combination with Rifampicin, 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: 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
In rare: instances disturbances in the menstrual cycle; induction of a crisis in Addison patients (see "Interactions with other medicaments and other Terms 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, an 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 syndrome", 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 Rimactane® 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.

Overdose
Signs and Symptoms
Reddish-brown or orange discoloration of the skin, sputum, lachrymal fluid, sweat, feces ("red man syndrome"); nausea, vomiting, abdominal pains; enlargement of the liver, jaundice, elevated liver
enzyme levels; possibly acute pulmonary oedema, lethargy, clouding of consciousness, convulsions.

Treatment
Gastric lavage together with the administration of an activated charcoal suspension via the stomach tube; general supportive measures to maintain vital functions; forced diuresis; haemodialysis; in
the presence of severe liver damage, bile drainage if necessary. Bear in mind that other drugs used in combination with Rimactane® may also have been taken in an overdose and necessitate additional
specific measures.

Pharmacological properties
Pharmacodynamic properties
Rifampicin is a rifamycin antibiotic, which exerts, both in vitro and in vivo, a bactericidal effect on Mycobacterium tuberculosis, whereas its activity against other atypical species of Mycobacterium varies. The spectrum of its bactericidal action also includes M. Leprae, as well as various other Gram-positive and Gram-negative bacteria. Minimum inhibitory concentrations (mg/ml) in vitro:

Mycobacterium tuberculosis0.005 - 0.200
Staphylococcus aureus0.008 - 0.060
Neisseria meningitidis0.015 - 1.000
Haemophilus influenzae0.250 - 1.000
Legionella pneumophila0.015 - 0.030
Mycobacterium leprae (Mouse footpad)0.300

In vivo it exerts its bactericidal effect not only on micro-organisms in the extracellular spaces but also on those located intracellularly.
Mechanism of action:Rifampicin inhibits the DNA-dependent RNA polymerase of sensitive bacterial strains, but without affecting the corresponding mammalian enzyme. Since relatively rapid "one step"
selection of resistant bacteria occurs with rifampicin, the drug must not be employed as mono therapy to treat overt infections. Bacteria resistant to rifampicin display no cross-resistance to other antibiotics with the exception of the rifamycins.

Pharmacokinetic properties
Absorption
The active substance, rifampicin, is absorbed from the capsules, coated tablets, and oral suspension. Following a single dose of 600 mg Rifampicin on an empty stomach the peak serum concentrations of approx. 10 mg/ml ore attained after 2 - 3 hours. Concomitant intake of food reduces the absorption of rifampicin.

Distribution
Volume of distribution at steady state were 0.66±0.14 and 0.64±0.11 l/kg for the 300 and 600 mg i.v. doses respectively. Binding to serum proteins amounts to 80. Rifampicin penetrates rapidly into various body fluids and tissues, including bone tissue and cerebrospinal fluid. 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 two months with continuous therapy of 600 mg/day orally.

Rifampicin crosses the human placenta and is secreted in human breast milk. However, a breast-fed infant would receive not more than 1 of the usual therapeutic dose.

Biotransformation
Rifampicin is metabolized in the liver, the principal metabolite being 25-0-deacetylrifampicin, which is microbiologically active, and "like unchanged Rifampicin" subject to enterohepatic circulation.
Rifampicin induces its own metabolism.

Elimination/ Excretion
The plasma elimination half-life of Rifampicin increases with increasing doses, and amounts to 2.5 h. 3-4 h and 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. Although the bulk of the drug is eliminated in the bile, 80 of the quantity excreted being accounted for by the deacetylrifampicin metabolite, Rifampicin also appears in the urine. In a dosage range of 150- 900 mg, 4-18 of a dose is excreted dose-dependently in the urine in unchanged form.

Characteristic in patients
In elderly patients plasma concentrations are comparable to those in young patients. 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 does not need to be reduced below 600 mg daily. Rifampicin is eliminated by peritoneal of haemodialysis. Dosage adjustment is not necessary during dialysis. In patients with impaired liver function, the plasma concentrations raised and the elimination half-life prolonged. In the presence of severe hepatic dysfunction the dosage may have to be adjusted accordingly.

Preclinical Safety Data
Carcinogenicity
There is only limited evidence as to the carcinogenicity potential of Rifampicin in animals. After oral administration to two mouse strains, a significant increase in benign and malignant liver-cell tumors was observed after 1 year of treatment with Rifampicin in quantities equivalent to 2 - 10 times the maximum clinical doses in female animals of one strain (known to be susceptible to hepatomas) only. No evidence of carcinogenicity was observed in females of the other strain or in male animals of both strains, as well as in rats of both sexes treated for 2 years.

Mutagenicity
In various short-term in vitro and in vivo tests in Rifampicin did not induce mutagenic effects. A slight increase in the occurrence aberrations may be seen in human blood cell cultures, according to the evaluation methods used.

Compatibilities and incompatibilities
The reconstituted solution is miscible with the following infusion solutions: NaCl 0.9%, Ringer solution (lactate or acetate), glucose 5% or 10%, mannitol 10% or 20%, sodium hydrogen carbonate 1.4%. Not miscible with : sodium hydrogen carbonate 5%, Ringer solution (acetate) + glucose. The reconstituted solution, diluted in glucose or NaCl solution, is miscible with the following chemotherapeutic agents/antibiotics : Isoniazide, Ethambutol, PAS; most cephalosporins, such as cephalotin, cephacetril cefsulodin, cefuroxime; aminoglycosides such as Gentamyicin, Tobramycin, Amikacin; Oxytetracycline and Erythromycin. Not miscible with : Cephamide, Tetracycline, Rolitetracycline, Doxycycline.

Storage
Capsules and coated tablets: do not store above 30°C, protect from light and moisture.
Oral suspension: do not store above 25°C, protect from light and moisture.
Drugs should be kept out of the reach of children.

Instruction for Use / handling
See "Posology and method of administration"
Oral suspension: shake well before use.

Package
Rimactane® 150 mg, pack of 5 x 10 capsules,
Reg. No. DKL 9930407901 A1
Rimactane® 300 mg, pack of 5 x 10 capsules,
Reg. No.DKL 9930407901 B1
Rimactane® 450 mg, pack of 5 x 10 sugar-coated tablets and pack of 25 x 4 sugar-coated tablets,
Reg. No.DKL9930408008 A1
Rimactane® 600 mg, pack of 5 x 10 sugar-coated tablets and pack of 25 x 4 sugar-coated tablets,
Reg. No. DKL9930408008 B1
Rimactane® syrup, bottle of 50 ml and 100 ml,
Reg. No. DKL9930408137 A1

HARUS DENGAN RESEP DOKTER

PRESCRIPTION ONLY

Manufactured by PT Novartis Indonesia, Citeureup, Bogor, Indonesia
under license of Novartis Pharma AG, Basel, Switzerland

Rimcure Paed

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Rimcure Paed
RIMCURE® PAED 75/50/150

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

Rimactazid Paed Tablet

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Rimactazid Paed Tablet
Rimactazid® Paed 75/50

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

Ethambutol

12:30 Add Comment
Ethambutol
ETHAMBUTOL

KOMPOSISI:
Ethambutol Tablet Salut Selaput 500 mg, tiap tablet salut selaput mengandung: Ethambutol HCl 500 mg.

DESKRIPSI:
Ethambutol dengan zat aktif Ethambutol HCl tersedia dalam bentuk tablet salut selaput 500 mg.

FARMAKOLOGI:
Merupakan tuberkulostatik dengan mekanisme kerja menghambat sintesa RNA. Pada pemberian oral dosis tunggal 25 mg/kg BB, diperoleh kadar 2 - 5 mcg/ml di dalam serum setelah 2 - 4 jam. Ekskresi sebagian besar melalui ginjal, hanya lebih kurang 10% diubah menjadi metabolit inaktif.

INDIKASI:
Untuk pengobatan tuberkulosa dalam kombinasi dengan antituberkulosis lain.

DOSIS DAN CARA PEMBERIAN :
Dosis lazim: 15 - 25 mg/kg BB sehari sebagai dosis tunggal.
Pengobatan awal: Penderita yang belum pernah mendapat pengobatan antituberkulosis sebelumnya, dosis Ethambutol adalah: 15 mg/kg BB dalam dosis tunggal setiap 24 jam . Dapat diberikan bersamaan dengan isoniazid oral dosis tunggal.
Pengobatan ulang: Pada penderita yang pernah mendapat pengobatan antituberkulosa sebelumnya, dosis Ethambutol adalah : 25 mg/kg BB dalam dosis tunggal sekali setiap  24 jam. Secara bersamaan diberikan antituberkulosa lain yang peka. Biasanya bukan obat yang pernah diberikan sebelumnya.


KONTRAINDIKASI :
  • Penderita yang hipersensitif obat ini.
  • Penderita neuritis optik.

PERINGATAN DAN PERHATIAN :
  • Pemeriksaan mata harus dilakukan sebelum pengobatan.
  • Tidak dianjurkan untuk anak-anak dibawah usia 13 tahun.
  • Penggunaan Ethambutol harus dihentikan apabila terjadi gangguan penglihatan dan segera menghubungi dokter.
  • Pada pengobatan jangka panjang agar dilakuken pemeriksaan fungsi ginjal, hati, dan hematopoetik secara periodik.
  • Hati-hati penggunaan pada penderita dengan gangguan fungsi ginjal, harus ada penyesuaian dosis.
  • Tidak dianjurkan penggunaan pada wanita hamil dan menyusui karena data keamanannya belum diketahui.

EFEK SAMPING :
  • Efek samping obat yang harus diperhatikan adalah toksisitas okuler yang tergantung pada dosis dan lamanya pengobatan.
  • Bisa terjadi neuritis retrobulbar bilateral dengan gejala terjadi penurunan ketajaman penglihatan, kehilangan kemampuan membedakan warna penyempitan lapangan pandang, skotoma sentral dan perifer.
  • Efek samping lain yang dilaporkan: reaksi anafilaksis pruritis, gangguan gastrointestinal, nyeri sendi, malaise, sakit kepala, pusing, gelisah.
  • Walaupun jarang, dapat timbul rasa kaku dan kesemutan pada ekstremitas yang disebabkan karena neuritis perifer.

KEMASAN:
Ethambutol Tablet Salut Selaput 500 mg
Dus, 10 strip @ 10 tablet salut selaput
No. Hag.: GKL930231n17A1

SIMPAN DIBAWAH SUHU 30°C

HARUS DENGAN RESEP DOKTER

Diproduksi oleh:
PT. BERNOFARM
Sidoarjo - Indonesia

Pyrazinamide

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Pyrazinamide
PYRAZINAMIDE

Komposisi:
Tiap kaplet mengandung:
Pyrazinamide .................... 500 mg

Cara Kerja Obat:
Pyrazinamide merupakan antituberkulosis sekunder. Secara in vitro Pyrazinamide aktif dalam suasana asam terhadap mikrobakterium. Bersifat bakterisid terutama pada hasil tuberkulosa intraselular. Pada pemberian oral Pyrazinamide mudah diserap dan tersebar luas keseluruh jaringan tubuh. Kadar puncak dalam serum tercapai dalam waktu kurang lebih 2 jam dan waktu paruh antara 10-16 jam. Pyrazinamide mengalami hidrolisis dan hidroksilasi menjadi asam hidroksi Pyrazinoat yang merupakan metabolit utamanya dan diekskresi melalui filtrasi glomerulus.

Indikasi:
Terapi tuberkulosis (sebagai tuberkulostatik sekunder) diberikan bersama tuberkulostatik lain.

Posologi:
20-30 mg/kg BB/hari dalam dosis tunggal atau terbagi (maksimum 2 gram/hari)

Peringatan dan Perhatian:
  • Hati-hati terhadap efek hepatotoksik, sebaiknya dilakukan pemantauan SGPT dan SGOT tiap 2-4 minggu selama pemberian obat.
  • Bila timbul gejala sedangkan terapi tidak dapat dihentikan, berikan probenesid 2 kali 0,5 gram sehari.
  • Keamanan penggunaan pada anak-anak, wanita hamil dan menyusui belum terbukti.
  • Hati-hati pemakaian pada penderita dengan riwayat gout.
  • Dianjurkan untuk penderita yang akan dibedah paru-parunya dan penderita yang sudah resisten terhadap pilihan pertama pengobatan harus di rumah sakit.

Efek samping:
  • Efek samping berupa artralgia, anoreksia, nausea, disuria, malaise, dan demam.
  • Porphyria, Hepatomegali, dan Splenomegali, jaundice, kerusakan sel hati, fatal hemolysis, sideroblastik anemia, tukak lambung, trombocytopenia, rash, urtikaria, pruritus, acne, photosensitivitas, dan interstitial nephritis.

Kontra indikasi:
  • Penderita dengan gangguan fungsi hati.
  • Hyperuricaemia dan atau gout
  • Hipoglycemia
  • Diabetes
  • Penderita dengan gangguan fungsi ginjal
  • Hipersensitif

Interaksi Obat:
Tidak ada

Cara penyimpanan:
Simpan pada suhu di bawah 30° C, dan terlindung cahaya

Kemasan:
Dus,10 strip @ 10 kaplet.
No. Reg: GKL9817105110A1

HARUS DENGAN RESEP DOKTER

HOLI PHARMA
Jl. Leuwigajah No. 100, Cimindi Cimahi
Bandung 40521, INDONESIA
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