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
|
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:
- 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
- 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
- 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.
- 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
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 tuberculosis | 0.005 - 0.200 |
| Staphylococcus aureus | 0.008 - 0.060 |
| Neisseria meningitidis | 0.015 - 1.000 |
| Haemophilus influenzae | 0.250 - 1.000 |
| Legionella pneumophila | 0.015 - 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
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