Rifampicin 75 mg and isoniazid 50 mg
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INSTRUCTION for medical use of the medicinal product Rifampicin 75 mg and Isoniazid 50 mg (Rifampicin 75 mg and Isoniazid 50 mg)
Composition:
Active substances: rifampicin, isoniazid;
One dispersible tablet contains 75 mg of rifampicin and 50 mg of isoniazid;
Excipients: microcrystalline cellulose, crospovidone, povidone, shellac, sodium croscarmellose, aspartame (E 951), raspberry flavor, magnesium stearate.
Pharmaceutical form. Dispersible tablets.
Main physico-chemical properties: round, biconvex, uncoated tablets of reddish-brown color with speckles, deeply scored on one side and smooth on the other.
Pharmacotherapeutic group. Combined antituberculosis agents.
ATC code J04AM02.
Pharmacological Properties
Pharmacodynamics
Mechanism of Action
Rifampicin
In vitro, rifampicin exerts bactericidal activity against a broad spectrum of microorganisms, including Mycobacterium tuberculosis. Its action is based on inhibition of DNA-dependent RNA polymerase, thereby suppressing transcription. In tuberculosis, rifampicin acts bactericidally on both intracellular and extracellular microorganisms. Bacterial resistance may develop, resulting from alterations in the key enzyme (RNA polymerase).
Isoniazid
Isoniazid demonstrates high activity against Mycobacterium tuberculosis. It exerts bactericidal effects in vitro and in vivo against mycobacteria. Its mechanism of action is associated with inhibition of synthesis of long-chain mycolic acids, which are components of the mycobacterial cell wall. Resistance to isoniazid develops rapidly when it is used as monotherapy for clinical diseases caused by mycobacteria.
Pharmacokinetics
Rifampicin
Absorption
Rifampicin is rapidly absorbed from the gastrointestinal tract. Its bioavailability is 90–95% in adults, but may be lower in children. Concomitant food intake delays absorption and reduces peak concentration, but does not reduce rifampicin bioavailability.
It is known that after a single dose of 2 tablets of rifampicin/isoniazid 75 mg/50 mg, the mean (±SD) Cmax of rifampicin was 2160 ng/mL (±516), and the corresponding AUC value was 10495 ng*h/mL (±2153). The mean (±SD) tmax of rifampicin was 1.20 (±0.50) hours.
Distribution
Rifampicin is 60–90% bound to plasma proteins, with a volume of distribution of approximately 0.9 L/kg. The concentration of rifampicin in cerebrospinal fluid is similar to that of unbound rifampicin in plasma. Rifampicin readily crosses the placental barrier.
Metabolism
Rifampicin is metabolized via hydrolysis and deacetylation into several metabolites, including the active metabolite deacetyl-rifampicin. Rifampicin induces its own metabolism; after repeated dosing, bioavailability decreases to approximately 70%, and systemic clearance increases.
Elimination
The elimination half-life of rifampicin after a single dose is approximately 3 hours. After repeated doses, this value decreases to approximately 1–2 hours. Rifampicin and its metabolites are primarily excreted via bile, and rifampicin undergoes enterohepatic recirculation. Approximately 25% of the dose is excreted in urine.
Special Patient Populations
The elimination half-life of rifampicin is prolonged in patients with hepatic dysfunction or biliary obstruction.
Isoniazid
Absorption
After oral administration, isoniazid is rapidly absorbed, with bioavailability ≥80%, and peak serum concentration is achieved within 1–2 hours. The rate and extent of absorption are reduced when isoniazid is administered with food. Isoniazid undergoes significant presystemic (first-pass) metabolism in the intestinal wall and liver.
After a single dose of 2 tablets of rifampicin/isoniazid 75 mg/50 mg, the mean (±SD) Cmax of isoniazid was 2043 ng/mL (±739), and the corresponding AUC value was 7348 ng*h/mL (±3733). The mean (±SD) tmax of isoniazid was 0.57±0.34 hours.
Distribution
Isoniazid is distributed throughout the body with a volume of distribution ranging from 0.57 to 0.76 L/kg. Plasma protein binding is very low (0–10%).
Metabolism
Isoniazid undergoes extensive metabolism in the mucosal cells of the small intestine and in the liver. It is primarily inactivated by acetylation. Acetyl-isoniazid is subsequently hydrolyzed. Acetylation of isoniazid depends on genetically determined metabolic phenotypes of individual patients, known as fast or slow acetylators (related to genetic polymorphism in the metabolic enzyme N-acetyltransferase). Different ethnic groups have varying proportions of acetylator phenotypes. Acetylator status is a key determinant of isoniazid efficacy at a given dose.
Efficacy in fast acetylators is approximately half that in slow acetylators when isoniazid is administered at the same dose.
Elimination
Up to 95% of isoniazid is excreted in urine within 24 hours, primarily as inactive metabolites. Less than 10% of the dose is excreted in feces. The main urinary excretion products are N-acetyl-isoniazid and isonicotinic acid.
Pharmacokinetics in Renal Impairment
Information on the pharmacokinetics of isoniazid and its metabolites in patients with renal impairment is incomplete. In slow acetylators, the elimination half-life of isoniazid is prolonged and exposure is increased. Exposure to (inactive) metabolites of isoniazid is likely increased in both fast and slow acetylators.
Clinical characteristics.
Indications.
The medicinal product is indicated for the treatment of tuberculosis caused by Mycobacterium tuberculosis in children with body weight less than 25 kg during the continuation phase.
Contraindications.
The medicinal product is contraindicated:
- in patients with hypersensitivity to the active substances or to any of the excipients of the product;
- in hepatic insufficiency;
- in patients with porphyria;
- during surgical procedures under general anaesthesia;
- when co-administered with bictegravir, cobicistat, daclatasvir, dasabuvir, delamanid, grazoprevir/elbasvir, protease inhibitors boosted with ritonavir, isavuconazole, ledipasvir, lurasidone, midostaurin, ombitasvir/paritaprevir, praziquantel, rilpivirine, sofosbuvir, velpatasvir, voriconazole, voxilaprevir (see section "Interaction with other medicinal products and other types of interactions").
Interaction with other medicinal products and other types of interactions.
Antimicrobial agents and INR (International Normalized Ratio – standard measure of prothrombin time)
Numerous cases of increased vitamin K antagonist activity have been reported in patients receiving antibacterial agents. Risk factors include severe infectious or inflammatory diseases, age, and the patient's general condition. Under these circumstances, it is difficult to distinguish between the infectious pathology and its treatment when a coagulation imbalance occurs.
Concomitant use of rifampicin with other antibiotics causing vitamin K-dependent coagulopathy, such as cefazolin (or other cephalosporins with an N-methylthiotetrazole side chain), should be avoided, as this may lead to serious coagulation disorders potentially resulting in fatal outcomes (especially at high doses). If concomitant use is necessary, intensified INR monitoring is recommended.
Enzyme induction
Rifampicin is a potent inducer of metabolic enzymes, including cytochrome P450 (CYP450) 1A2, 2B6, 2C8, 2C9, 2C19, and 3A4, and UDP-glucuronosyltransferases (UGT). In vitro and in vivo studies have shown that rifampicin also induces transporters such as P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance-associated protein 2 (MRP2). Many medicinal products are substrates for at least one or more of these enzymes and/or transporters. Rifampicin may accelerate metabolism and thus reduce the activity of certain co-administered drugs, or increase the activity of co-administered prodrugs (when metabolic activation is required), potentially leading to clinically significant interactions with numerous drugs from various therapeutic classes. Dose adjustments of these drugs may be required at the initiation or discontinuation of treatment, considering that the inducing effect reaches its maximum after approximately 15 days and persists for 1–2 weeks after stopping rifampicin.
Contraindicated combinations (see section "Contraindications")
Interactions related to rifampicin:
Bictegravir
Very significant reduction in bictegravir concentration, potentially leading to loss of efficacy.
Cobicistat
Risk of reduced cobicistat efficacy due to enhanced metabolism by rifampicin.
Daclatasvir
Reduction in daclatasvir plasma concentration due to enhanced hepatic metabolism by rifampicin.
Dasabuvir
Risk of reduced dasabuvir plasma concentration due to rifampicin.
Delamanid
Reduction in delamanid plasma concentration due to enhanced hepatic metabolism by rifampicin.
Protease inhibitors boosted with ritonavir (amprenavir, atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, saquinavir, tipranavir)
Very significant reduction in protease inhibitor plasma concentration due to enhanced hepatic metabolism by rifampicin.
For the combination (saquinavir + ritonavir): risk of severe hepatocellular toxicity.
Grazoprevir/elbasvir
Risk of reduced concentrations of grazoprevir and elbasvir under the influence of rifampicin, potentially affecting their efficacy.
Isavuconazole
Reduction in isavuconazole plasma concentration due to enhanced hepatic metabolism by rifampicin.
Ledipasvir
Significant reduction in ledipasvir plasma concentration due to enhanced hepatic metabolism by rifampicin.
Lurasidone
Reduction in lurasidone concentration via enhanced hepatic metabolism by rifampicin. Rifampicin at a dose of 600 mg has been shown to significantly reduce lurasidone plasma concentration compared to lurasidone alone. Lurasidone should not be co-administered with rifampicin.
Midostaurin
Reduction in midostaurin concentration under the influence of rifampicin.
Ombitasvir/paritaprevir
Reduction in plasma concentration with dual therapy due to enhanced hepatic metabolism by rifampicin.
Praziquantel
Very significant reduction in praziquantel plasma concentration with risk of treatment inefficacy due to enhanced hepatic metabolism by rifampicin.
Rilpivirine
Significant reduction in rilpivirine plasma concentration due to enhanced hepatic metabolism by rifampicin.
Sofosbuvir
Risk of reduced sofosbuvir plasma concentration due to reduced intestinal absorption by rifampicin.
Velpatasvir
Reduction in velpatasvir plasma concentration under the influence of rifampicin, potentially affecting efficacy.
Voriconazole
Significant reduction in voriconazole plasma concentration with risk of loss of efficacy due to enhanced hepatic metabolism by rifampicin.
Voxilaprevir
Reduction in voxilaprevir plasma concentrations under the influence of rifampicin with risk of loss of efficacy.
Not recommended combinations (see section "Special precautions for use")
Interactions related to isoniazid:
Carbamazepine
Increased plasma concentration of carbamazepine with signs of overdose due to inhibition of its hepatic metabolism.
Disulfiram
Behavioral and coordination disturbances.
Interactions related to rifampicin:
Abiraterone
Significant reduction in abiraterone plasma concentration with risk of reduced efficacy.
Apixaban, dabigatran, rivaroxaban
Reduction in plasma concentrations of apixaban, dabigatran, or rivaroxaban under the influence of rifampicin with risk of reduced therapeutic effect.
Apixaban
Reduction in apremilast plasma concentration due to enhanced metabolism by rifampicin.
Apixaban
Very significant reduction in aprepitant concentration.
Atorvastatin, simvastatin
Very significant reduction in atorvastatin or simvastatin plasma concentration due to enhanced hepatic metabolism by rifampicin.
Atovaquone
Reduction in atovaquone plasma concentration by enzyme inducer.
Bedaquiline
Reduction in bedaquiline plasma concentration due to enhanced metabolism by rifampicin.
Bosentan
Risk of reduced bosentan plasma concentration, significant for rifampicin.
Clopidogrel
Strong induction of CYP2C19 leading to both increased plasma concentration of clopidogrel's active metabolite and enhanced platelet inhibition, potentially increasing the risk of bleeding. As a precaution, concomitant use of clopidogrel and rifampicin is not recommended.
Cyclophosphamide
Risk of increased plasma concentrations of cyclophosphamide's active metabolite under the influence of rifampicin, and thus increased toxicity.
Cyproterone used as hormonal contraceptive
Risk of reduced cyproterone efficacy. An additional barrier method of contraception (condom) should be used throughout the duration of combination therapy and for one cycle after discontinuation of rifampicin.
Docetaxel
Reduction in cytotoxic drug concentration due to enhanced metabolism by rifampicin with risk of reduced efficacy.
Dolutegravir in case of resistance to integrase inhibitors
Reduction in dolutegravir plasma concentration due to enhanced metabolism by rifampicin.
Dronedarone
Significant reduction in dronedarone concentration via enhanced metabolism without significant change in active metabolite.
Estrogen and progestin contraceptives
Reduced contraceptive efficacy due to enhanced hepatic metabolism of hormonal contraceptives by rifampicin. An additional barrier method of contraception (condom) should be used throughout the period of concomitant use and for one menstrual cycle after discontinuation of rifampicin.
Etoposide
Reduction in etoposide plasma concentration by rifampicin. If combination is necessary, clinical monitoring and possible dose adjustment of etoposide are required during concomitant use and 1–2 weeks after discontinuation of rifampicin.
Fentanyl
Reduction in fentanyl plasma concentration due to enhanced hepatic metabolism by rifampicin. Another opioid should be preferred during rifampicin use.
Fluconazole
Reduction in plasma concentration and efficacy of both antimicrobial agents (enzyme induction by rifampicin and reduced intestinal absorption due to azole antifungal action).
Idelalisib
Reduction in idelalisib plasma concentration due to enhanced hepatic metabolism by rifampicin.
5-alpha-reductase inhibitors (dutasteride, finasteride)
Reduction in plasma concentrations of 5-alpha-reductase inhibitors under the influence of rifampicin. If combination cannot be avoided, careful clinical monitoring is required.
Metabolized tyrosine kinase inhibitors
Reduction in plasma concentration and efficacy of tyrosine kinase inhibitor due to enhanced metabolism by rifampicin.
Irinotecan
Likely reduction in plasma concentrations of irinotecan's active metabolite with risk of ineffective cytotoxic therapy.
Itaconazole
Reduction in plasma concentration and efficacy of both antimicrobial agents (enzyme induction by rifampicin and reduced intestinal absorption due to azole antifungal action).
Ivacaftor
Significant reduction in ivacaftor plasma concentration with risk of loss of efficacy.
Ketoconazole
Reduction in plasma concentration and efficacy of both antimicrobial agents (enzyme induction by rifampicin and reduced intestinal absorption due to azole antifungal action).
Macitentan
Reduction in macitentan plasma concentration via enhanced metabolism by rifampicin.
Mianserin
Risk of loss of mianserin efficacy.
Midazolam
Risk of lack of midazolam effect due to very significant reduction in its plasma concentration due to enhanced hepatic metabolism.
Naloxegol
Reduction in naloxegol concentration under the influence of rifampicin.
Nevaripine
Reduction in nevirapine plasma concentration due to enhanced hepatic metabolism by rifampicin.
Nimodipine
Reduction in calcium antagonist plasma concentration due to enhanced hepatic metabolism. Clinical monitoring of the patient and possible dose adjustment of the calcium antagonist are required during rifampicin treatment and after its discontinuation.
Olaparib
Reduction, possibly very significant, in olaparib plasma concentration via enhanced hepatic metabolism by rifampicin.
Oxycodone
Reduction in oxycodone plasma concentration due to enhanced metabolism by rifampicin. Possible dose adjustment of oxycodone.
Paclitaxel
Reduction in cytotoxic drug concentration due to enhanced metabolism by rifampicin with risk of reduced efficacy.
Posaconazole
Reduction in plasma concentration and efficacy of both antimicrobial agents (enzyme induction by rifampicin and reduced intestinal absorption by azole antifungal).
Quetiapine
Very significant reduction in quetiapine plasma concentration due to enhanced hepatic metabolism by enzyme inducer, with risk of inefficacy.
Quinine
Risk of loss of quinine efficacy due to enhanced hepatic metabolism by rifampicin.
Raltegravir
Reduction in raltegravir concentration under the influence of rifampicin. If combination cannot be avoided, doubling the raltegravir dose may be considered.
Ranolazine
Very significant reduction in ranolazine concentration.
Regorafenib
Reduction in regorafenib plasma concentration due to enhanced metabolism by rifampicin.
Rolapitant
Very significant reduction in rolapitant concentration with risk of loss of efficacy.
Sertraline
Risk of ineffective antidepressant treatment.
Tenofovir alafenamide
Reduction in tenofovir alafenamide plasma concentration due to reduced absorption by rifampicin. Clinical monitoring should be performed during combination therapy and 1–2 weeks after discontinuation of rifampicin.
Telithromycin
Very significant reduction in telithromycin plasma concentration with risk of ineffective antimicrobial treatment due to enhanced hepatic metabolism by rifampicin.
Tickagrelor
Significant reduction in ticagrelor plasma concentration due to enhanced hepatic metabolism by rifampicin with risk of reduced therapeutic effect.
Ulipristal
Risk of reduced ulipristal effect due to enhanced hepatic metabolism by rifampicin. An alternative medicinal product, whose metabolism is not affected or minimally affected by rifampicin, should be preferred.
Vemurafenib
Risk of reduced vemurafenib plasma concentration with reduced efficacy.
Vinca alkaloid cytotoxics
Rifampicin reduces vinca alkaloid plasma concentrations with possible impact on efficacy.
Vismodegib
Risk of reduced vismodegib plasma concentration due to enhanced hepatic metabolism by rifampicin.
Zidovudine
Reduction in zidovudine plasma concentration by half via enhanced metabolism by rifampicin. If combination use cannot be avoided, intensified clinical and biological monitoring is required.
Combinations requiring precautions for use
Interactions related to isoniazid:
Halogenated volatile anaesthetics
Potentiation of isoniazid hepatotoxicity with enhanced formation of toxic isoniazid metabolites. As a precaution in case of planned surgery, isoniazid treatment should be discontinued one week before surgery and resumed only 15 days later.
Glucocorticoids (except hydrocortisone in replacement therapy)
When co-administered with prednisolone, reduced isoniazid plasma concentration has been observed. This effect is due to increased hepatic metabolism of isoniazid and reduced glucocorticoid levels. Clinical and biological monitoring is required.
Ketoconazole
Reduction in ketoconazole plasma concentration.
It is recommended to separate the doses of both antimicrobial agents by at least 12 hours. Ketoconazole plasma concentration should be monitored and dose adjusted if necessary.
Phenytoin and fosphenytoin
Overdose of phenytoin (reduced metabolism) has been observed when co-administered with isoniazid. Careful clinical monitoring, determination of phenytoin plasma concentration, and possible dose adjustment during and after isoniazid treatment are required.
Pyrazinamide
Enhanced hepatotoxic effects may occur when co-administered. Clinical and biological monitoring is required.
Rifampicin
Enhanced hepatotoxic effect of isoniazid (enhanced formation of toxic isoniazid metabolites – see sections "Special precautions for use" and "Adverse reactions"). Clinical and biological monitoring of this combination is required. In case of hepatitis, isoniazid administration should be discontinued.
Stavudine
Increased risk of peripheral neuropathy due to additive adverse effects. Regular clinical and biological monitoring, especially at the beginning of treatment, is required.
Interactions related to rifampicin:
Valproic acid and valpromide
Risk of seizures due to enhanced hepatic metabolism of valproate by rifampicin. Clinical and biological monitoring and possible dose adjustment of the anticonvulsant during and after rifampicin treatment are required.
Afatinib
Reduction in afatinib plasma concentration due to enhanced metabolism by rifampicin. Clinical monitoring is required during combination therapy and 1–2 weeks after its discontinuation.
Albendazole
Significant reduction in albendazole and its active metabolite plasma concentrations under the influence of rifampicin with risk of reduced efficacy. Clinical monitoring of therapeutic response and possible dose adjustment of albendazole during and after rifampicin treatment are required.
Androgens (androstanolone, norethandrolone, testosterone)
Risk of reduced androgen plasma concentration and thus reduced efficacy due to enhanced hepatic metabolism by rifampicin. Clinical and biological monitoring during combination therapy and 1–2 weeks after discontinuation of rifampicin are required.
Calcium channel antagonists (except nimodipine)
Reduction in calcium antagonist plasma concentration due to enhanced hepatic metabolism. Clinical observation and possible dose adjustment of the calcium antagonist during and after rifampicin treatment are required.
Class IA antiarrhythmics (disopyramide, hydroquinidine, quinidine)
Reduction in plasma concentration and efficacy of antiarrhythmic agent (enhanced hepatic metabolism).
Clinical monitoring, ECG, and possibly monitoring of antiarrhythmic plasma concentration are required. Doses of antiarrhythmic agent may need to be adjusted during and after rifampicin treatment (due to risk of antiarrhythmic overdose).
Vitamin K antagonists (warfarin, acenocoumarol, fluindione)
Reduced effect of vitamin K antagonist due to enhanced hepatic metabolism by rifampicin. More frequent INR monitoring is required. Dose adjustment of vitamin K antagonist may be necessary during rifampicin treatment and 8 days after its discontinuation.
Aripiprazole
Reduction in aripiprazole plasma concentration. Clinical observation and possible dose adjustment of aripiprazole during combination therapy and 1–2 weeks after discontinuation of rifampicin are required.
Bazedoxifene
Reduction in bazedoxifene plasma concentrations under the influence of rifampicin. Monitoring for any signs indicating loss of efficacy (bleeding) is required.
Buspirone
Reduction in buspirone plasma concentration via enhanced hepatic metabolism by rifampicin. Clinical monitoring and possible dose adjustment of buspirone during and after rifampicin treatment are required.
Carbamazepine
Reduction in plasma concentration and efficacy of carbamazepine due to enhanced hepatic metabolism by rifampicin. Clinical monitoring, plasma concentration control, and dose adjustment of carbamazepine during and after rifampicin treatment are required.
Carvedilol
Significant reduction in carvedilol plasma concentration due to enhanced hepatic metabolism by rifampicin. Regular clinical monitoring and dose adjustment of carvedilol during rifampicin treatment are required. After discontinuation of rifampicin, there is a risk of significant increase in carvedilol plasma concentration, requiring dose reduction and careful clinical observation.
Caspo fungin
Reduction in caspofungin plasma concentration. Two weeks after repeated administration of rifampicin, caspofungin plasma concentrations were 30% lower than in adults receiving caspofungin alone. During rifampicin treatment starting on day 2, the dose should be maintained at 70 mg daily.
Clarithromycin
Reduction in clarithromycin plasma concentration and risk of reduced efficacy, especially in HIV-infected patients, due to enhanced hepatic metabolism by rifampicin. Regular clinical and biological monitoring is required.
Clozapine
Risk of ineffective antipsychotic therapy (reduced clozapine plasma concentration due to enhanced hepatic metabolism). Clinical monitoring and possible dose increase of clozapine during rifampicin treatment are required.
Cyproterone used as antiandrogen
Risk of reduced cyproterone efficacy. Clinical monitoring and possible dose adjustment of cyproterone during and after combination therapy are required.
Dapsone
Increased effect of hydroxylamine metabolite responsible for adverse effects including methemoglobinemia, hemolytic anemia, agranulocytosis, and hemolysis.
Deferasirox
Risk of reduced deferasirox plasma concentration. Serum ferritin should be monitored during and after rifampicin treatment. Dose adjustment of deferasirox is recommended if necessary.
Digoxin
Moderate reduction in digoxin concentration. Clinical monitoring and ECG are required.
Disopyramide
Risk of reduced disopyramide concentration by rifampicin. Clinical monitoring and possible dose adjustment of disopyramide during combination therapy and 1–2 weeks after discontinuation of rifampicin are required.
Dolutegravir, in absence of resistance to integrase inhibitors
Dose adjustment of dolutegravir to 50 mg twice daily during combination therapy and one week after its discontinuation.
Reduction in dolutegravir plasma concentration due to enhanced metabolism by rifampicin.
Efavirenz
Reduction in plasma concentration and efficacy of efavirenz due to enhanced hepatic metabolism by rifampicin. Regular clinical and biological monitoring, especially at the beginning of combination therapy, are required.
Enalapril
Reduced effect of enalapril active metabolites. If required by the patient's clinical condition, dose adjustment may be necessary.
Glucocorticoids
Reduction in plasma concentration and efficacy of corticosteroids due to enhanced hepatic metabolism by rifampicin; consequences are particularly significant in Addison's disease patients treated with hydrocortisone and in transplantation. Clinical and biological monitoring and dose adjustment of corticosteroids during and after rifampicin treatment are required.
There is a risk of reduced hydrocortisone efficacy due to enhanced metabolism, with serious consequences if hydrocortisone is used as replacement therapy or in transplantation. Clinical and biological monitoring and dose adjustment of hydrocortisone during combination therapy and after rifampicin discontinuation are required.
Haloperidol
Risk of reduced haloperidol plasma concentration and therapeutic efficacy due to enhanced hepatic metabolism by rifampicin. Clinical observation and, if necessary, dose adjustment during and after rifampicin treatment are required.
Thyroid hormones (described for phenytoin, rifampicin, carbamazepine)
Risk of clinical hypothyroidism in hypothyroid patients due to enhanced metabolism of T3 and T4 hormones. Monitoring of serum T3 and T4 concentrations and, if necessary, adjustment of thyroid hormone dose during and after rifampicin treatment are required.
Immunosuppressants
Reduction in blood concentration and efficacy of immunosuppressants due to enhanced hepatic metabolism by rifampicin. Dose increase of immunosuppressant under blood concentration control is recommended, with dose reduction after discontinuation of rifampicin.
Isoniazid
Increased hepatotoxicity of isoniazid (enhanced formation of toxic isoniazid metabolites). Clinical and biological monitoring of this combination is required. In case of hepatitis, isoniazid administration should be discontinued.
Ivabradine
Risk of reduced ivabradine efficacy due to enhanced metabolism by rifampicin. Clinical monitoring and dose adjustment of ivabradine during combination therapy and after rifampicin discontinuation are required.
Levonorgestrel
When levonorgestrel is used for emergency contraception, significant reduction in levonorgestrel plasma concentration with risk of loss of efficacy is observed. If the enzyme inducer has been used within the last 4 weeks, non-hormonal emergency contraception (copper intrauterine device (IUD)) should be considered. If IUD use is not possible, double dose of levonorgestrel should be administered.
Linezolid
Risk of reduced linezolid efficacy due to enhanced hepatic metabolism by rifampicin. Clinical monitoring and possible dose increase of linezolid during rifampicin treatment are required.
Maraviroc
Reduction in maraviroc concentration under the influence of rifampicin in absence of concomitant use with a strong CYP3A4 inhibitor. In such case, maraviroc dose should be increased to 600 mg twice daily.
Methadone
Reduction in methadone plasma concentration with risk of withdrawal syndrome due to enhanced hepatic metabolism. Frequency of methadone administration should be increased (2–3 times daily instead of once).
Metronidazole
Reduction in metronidazole plasma concentration due to enhanced hepatic metabolism by rifampicin. Clinical monitoring and possible dose adjustment of metronidazole during and after rifampicin treatment are required.
Mifepristone
Reduced mifepristone concentration. Rifampicin has been shown to reduce the area under the curve (AUC) of mifepristone by 6.3 times and the AUC of its metabolites 22-hydroxymifepristone and N-desmethylmifepristone by 20 times and 5.9 times, respectively. Therefore, reduced efficacy is expected when mifepristone is co-administered with rifampicin. If co-administration is necessary, mifepristone dose should be increased.
Mineralocorticoids
Reduction in plasma concentration and efficacy of corticosteroids due to enhanced hepatic metabolism by rifampicin; consequences are particularly significant in Addison's disease patients treated with hydrocortisone and in transplantation.
Clinical and biological monitoring and dose adjustment of corticosteroids during and after rifampicin treatment are required.
Montelukast
Risk of reduced montelukast efficacy due to enhanced hepatic metabolism by rifampicin. Clinical monitoring and possible dose adjustment of antiasthmatic agents during and after rifampicin treatment are required.
Morphine
Reduction in plasma concentration and efficacy of morphine and its active metabolite. Clinical monitoring and possible dose adjustment of morphine during and after rifampicin treatment are required.
Nintedanib
Reduction in nintedanib plasma concentration due to reduced absorption by rifampicin. Clinical monitoring during combination use is required.
Paracetamol
Concomitant use of paracetamol and rifampicin may increase the risk of hepatotoxicity.
Pioglitazone
Reduction in glitazone plasma concentration due to enhanced metabolism by rifampicin. Clinical and biological monitoring and dose adjustment of glitazone during and after rifampicin treatment are required.
Non-contraceptive progestins (with or without estrogen)
Reduced progestagen efficacy. Clinical monitoring and possible dose adjustment of hormonal therapy during and after inducer use are required.
Propafenone
Reduction in propafenone plasma concentration due to enhanced hepatic metabolism by rifampicin. Clinical monitoring and ECG. Dose adjustment of propafenone during combination therapy and after discontinuation of rifampicin may be necessary.
Terbinafine
Reduction in plasma concentration and efficacy of terbinafine due to enhanced hepatic metabolism by rifampicin.
Clinical monitoring is required. Dose adjustment of terbinafine during rifampicin treatment is recommended if necessary.
Theophylline and aminophylline
Reduction in plasma concentration and efficacy of theophylline (enhanced metabolism via enzyme induction).
Clinical observation is recommended. Dose adjustment of theophylline during and after rifampicin treatment may be necessary.
Tiagabine
Reduction in tiagabine plasma concentration via enhanced hepatic metabolism. Dose increase of tiagabine may be required when combined with rifampicin.
Vitamin D
Reduced vitamin D concentration has been observed during rifampicin treatment. Dose adjustment of vitamin D may be necessary.
Zolpidem
Reduction in plasma concentration and efficacy of zolpidem due to enhanced hepatic metabolism by rifampicin. Clinical monitoring is required. If possible, another hypnotic medicinal product should be used.
Zopiclone
Reduction in plasma concentration and efficacy of zopiclone due to enhanced hepatic metabolism by rifampicin. Clinical monitoring is required. If possible, another hypnotic medicinal product should be used.
Interactions requiring consideration
Interactions related to rifampicin
Bortezomib
Reduction in cytotoxic drug concentration due to enhanced metabolism by rifampicin with risk of reduced efficacy.
Cabazitaxel
Reduction in cytotoxic drug concentration due to enhanced metabolism by rifampicin with risk of reduced efficacy.
Exemestane
Risk of reduced exemestane efficacy due to enhanced hepatic metabolism by rifampicin.
Metformin
Reduction in metformin concentration under the influence of rifampicin.
Metoprolol, propranolol
Reduction in plasma concentration and efficacy of beta-blocker (enhanced hepatic metabolism).
Perampanel
Significant reduction (up to two thirds) in perampanel concentration.
Tamoxifen
Risk of inefficacy of tamoxifen due to enhanced metabolism by rifampicin.
Special precautions for use.
The use of rifampicin and isoniazid may cause liver function impairment.
Isoniazid may cause seizures in cases of overdose (in slow acetylators) or in patients predisposed to seizures. Patients should be closely monitored, and anticonvulsant therapy should be administered if necessary.
Isoniazid may increase blood phenytoin levels and cause signs of toxicity, including nystagmus, ataxia, and confusion (see section "Interaction with other medicinal products and other forms of interaction").
Cases of cerebellar syndrome (including cerebellar ataxia, dysdiadochokinesia, speech disorders, balance disturbances, nystagmus, dysmetria) have been reported during isoniazid treatment, primarily in patients with chronic renal failure. Reversal of cerebellar syndrome symptoms has been observed after discontinuation of treatment, with or without corrective therapy. Therefore, the physician should determine whether a treatment interruption and/or reduction of isoniazid dose is necessary.
Hepatitis in severe form, sometimes fatal, may occur during treatment with isoniazid and even several months after treatment. The risk of hepatitis development depends on the patient's age.
Patients should immediately inform their physician about symptoms of liver injury or other adverse effects if they occur, particularly: unexplained anorexia, nausea, vomiting, malaise, persistent fatigue, and/or weakness lasting more than 3 days. If such symptoms or signs indicating liver injury appear, the drug should be discontinued immediately, as continued use in these cases may lead to more severe liver damage. Careful monitoring is required when prescribing isoniazid to patients with chronic liver disease or severe renal failure.
Cases of moderate to severe cholestasis have been reported during rifampicin treatment. Patients should seek immediate medical attention if they experience symptoms such as pruritus, loss of appetite, nausea, vomiting, abdominal pain, yellowing of the eyes or skin, or darkening of urine. If cholestasis is confirmed, the drug should be discontinued.
Hypersensitivity
Rifampicin may cause a hypersensitivity syndrome, including flu-like symptoms and/or manifestations affecting internal organs.
The risk of developing hypersensitivity reactions and other adverse reactions increases with intermittent treatment regimens or when resuming treatment after interruption.
In case of severe, acute signs of rifampicin hypersensitivity (such as thrombocytopenia, purpura, hemolytic anemia, dyspnea, shock, or acute renal failure), the drug should be discontinued immediately. Re-administration of rifampicin is not recommended in such patients. If rifampicin treatment is temporarily discontinued, resumption should be under close supervision, starting with a reduced dose. In such cases, the drug is not recommended for use.
Serious bullous reactions: Cases of serious bullous reactions, such as Stevens-Johnson syndrome, Lyell’s syndrome (toxic epidermal necrolysis), sometimes fatal, have been reported during antituberculosis therapy (see section "Adverse reactions"). Patients should be warned about signs and symptoms of skin reactions and closely monitored. Patients should be informed about the necessity of immediate medical consultation if signs or symptoms of Stevens-Johnson syndrome or toxic epidermal necrolysis appear (progressive rashes, often accompanied by blistering and mucosal lesions). The medicinal product should be permanently discontinued if the etiology of such manifestations cannot be established.
Severe systemic hypersensitivity reactions, including fatal cases such as drug reaction with eosinophilia and systemic symptoms (DRESS), have been observed during antituberculosis therapy (see section "Adverse reactions").
It is important to note that early signs of hypersensitivity, such as fever, lymphadenopathy, or laboratory abnormalities (including eosinophilia, liver function abnormalities), may occur without apparent skin manifestations.
If such signs or symptoms appear, patients should be informed about the necessity of immediate medical consultation.
The drug should be discontinued if the cause of the signs and symptoms cannot be established.
Cross-sensitivity. Patients with increased sensitivity to ethionamide, pyrazinamide, niacin (nicotinic acid), or other chemically similar medicinal products may also have increased sensitivity to isoniazid.
Intermittent therapy
Hypersensitivity reactions are frequently, if not exclusively, associated with periodic (intermittent) administration or repeated discontinuation of rifampicin (see section "Adverse reactions").
Paradoxical reaction
After initial improvement in tuberculosis, symptoms may worsen again. In these patients, clinical or radiological worsening of existing tuberculosis lesions or development of new lesions has been observed. These reactions typically occur within the first weeks or months of antituberculosis treatment. Cultures are usually negative, and such reactions generally do not indicate treatment inefficacy.
The cause of this paradoxical reaction is still unknown, but an excessive immune response is considered a likely cause. In case of suspected paradoxical reaction, symptomatic treatment to reduce the excessive immune response should be initiated if necessary. Furthermore, continuation of standard antituberculosis therapy is recommended.
Patients should seek immediate medical attention if their symptoms worsen. Symptoms are usually characteristic of the affected tissues. Possible general symptoms include cough, fever, fatigue, dyspnea, headache, loss of appetite, weight loss, or weakness (see section "Adverse reactions").
Interstitial lung disease (ILD)/pneumonia
Cases of ILD or pneumonia have been reported in patients receiving this medicinal product for tuberculosis treatment. ILD/pneumonia are life-threatening conditions. A thorough evaluation should be performed in all patients with sudden onset and/or unexplained worsening of pulmonary symptoms (dyspnea with dry cough) and fever to confirm the diagnosis of ILD/pneumonia. If ILD/pneumonia is diagnosed, the drug should be permanently discontinued in cases of severe manifestations (respiratory failure and acute respiratory distress syndrome), and appropriate treatment should be initiated if necessary.
Rifampicin is a potent inducer of transporters and enzymes responsible for drug metabolism. This may reduce or increase the effect of concomitantly administered medicinal products and thus affect their efficacy and safety (see section "Interaction with other medicinal products and other forms of interaction"). Therefore, patients are not recommended to take any other medicinal products without prior consultation with a physician.
Hepatotoxicity
Rifampicin and isoniazid may cause hepatotoxicity. The drug should be prescribed to patients with liver function impairment only if absolutely necessary, with caution and under close medical supervision.
Regular clinical and laboratory monitoring of patients is required due to the risk of increased hepatotoxicity when isoniazid and rifampicin are used in combination:
Complete blood count (including platelet count), e.g., on day 8, at the end of the first month, then at longer intervals (once every 2 months), and liver function monitoring (transaminases, bilirubin).
Treatment with the drug should be discontinued if signs of hepatocellular injury (hepatitis) appear.
Since cases of hepatitis associated with isoniazid use occur more frequently in patients aged 35 years and older, this patient group is recommended to have transaminase levels measured at the beginning of treatment and then at least once a month during treatment.
Other factors increasing the risk of hepatitis development:
- Daily alcohol consumption;
- Active chronic liver disease;
- Intravenous drug use;
- Women belonging to African and Latin American ethnic groups.
In some cases, hyperbilirubinemia may occur in the first days of treatment due to competition at the cellular level between rifampicin and bilirubin for hepatic excretion. Isolated and mild hyperbilirubinemia by itself is not an indication for discontinuation of treatment; the decision to discontinue the drug should be made after repeat testing based on observed trends and taking into account the patient's clinical condition (see section "Adverse reactions").
In addition to monthly symptom assessment, liver enzyme levels (especially AST and ALT) should be monitored before starting and periodically during treatment with the drug.
Elevations in liver function tests are common during treatment with the drug.
If liver test levels increase more than 3–5 times, the drug must be discontinued.
After hepatotoxicity occurs during treatment, re-treatment may be considered if appropriate, but only after symptom resolution and normalization of laboratory parameters. In case of re-treatment, the drug is not recommended. In such cases, rifampicin and isoniazid should be prescribed separately, as individual medicinal products, with gradual dose escalation, or alternative drugs should be used.
Peripheral neuropathy
Isoniazid may cause symptomatic pyridoxine deficiency, manifesting as neuropathy, particularly in undernourished children receiving antiretroviral therapy. In adults, the frequency depends on dose and predisposing conditions such as malnutrition, alcoholism, and especially in elderly patients. These patient categories are recommended to receive concomitant pyridoxine (vitamin B6) at a dose of 5–10 mg daily for prophylaxis and 50–75 mg daily for treatment of peripheral neuropathy.
Regular clinical neurological examinations are recommended.
Renal function impairment
In patients with renal function impairment, especially slow acetylators, the risk of adverse reactions (e.g., peripheral neuropathy) may increase after isoniazid administration. The condition of such patients should be closely monitored. As with other patients, pyridoxine should be administered at an appropriate dosage (see above) to reduce the risk of neurotoxicity.
Coagulation disorders (see section "Adverse reactions")
Cases of coagulation disorders have been reported during rifampicin use, especially in combination with cephalosporin-class drugs (including cefazolin). Appropriate monitoring should be performed in patients at risk (patients with risk factors causing vitamin K deficiency or affecting other coagulation mechanisms). If necessary, additional vitamin K administration should be considered (e.g., in cases of established vitamin K deficiency, hypoprothrombinemia).
Effect on adrenal gland function
Drug administration may decompensate latent adrenal insufficiency controlled by corticosteroid therapy (see section "Adverse reactions"). Therefore, monitoring of such patients is recommended, and adrenal cortex function analysis should be performed in case of any suspicion.
Drug interactions
The drug is generally not used in combination with:
abiraterone, apixaban, atovaquone, apremilast, aprepitant, atorvastatin, bedaquiline, bosentan, certain anticoagulant drugs such as clopidogrel (for vitamin K antagonists, see section "Interaction with other medicinal products and other forms of interaction"), carbamazepine, cyclophosphamide, cyproterone (used as a hormonal contraceptive), dabigatran, disulfiram, docetaxel, dolotegravir (only in cases of integrase inhibitor resistance), dronedarone, etoposide, fentanyl, fluconazole, idelalisib, dutasteride, finasteride, metabolized tyrosine kinase inhibitors, irinotecan, itraconazole, ivacaftor, ketoconazole, macitentan, mianserin, midazolam, naloxegol, nevirapine, nimodipine, olaparib, oxycodone, paclitaxel, posaconazole, quetiapine, quinine, raltegravir, ranolazine, regorafenib, rifamycin, symvastatin, teicoplanin, apitant, ticagrelor, telithromycin, ulipristal, combined hormonal and progestin contraceptives, vemurafenib, cytotoxic vinca alkaloids, vismodegib, and zidovudine (see section "Interaction with other medicinal products and other forms of interaction").
Contraception
Oral contraceptives do not provide adequate protection against pregnancy when used concomitantly with the drug. This likely also applies to other forms of hormonal contraceptives (such as contraceptive patches, transdermal implants).
A barrier method of contraception and other non-hormonal contraceptive methods should be used.
Discoloration of teeth and body fluids
The use of the drug may cause discoloration of teeth, urine, sweat, sputum, and tears to yellow, orange, red, or brown. Patients should be informed about this. Permanent discoloration of soft contact lenses is possible. This is due to the action of rifampicin and does not require treatment.
Effect on clinical test results
Rifampicin may delay the biliary excretion of contrast agents used for radiographic examination of the gallbladder.
Microbiological methods for determining plasma folate and vitamin B12 concentrations should not be used during rifampicin treatment.
Rifampicin temporarily competes with bilirubin and bromosulfophthalein (BSP). To avoid false-positive results, the BSP test should be performed in the morning before taking rifampicin.
Since cross-reaction with false-positive urine opiate test results has been reported in patients taking rifampicin, particularly when using the KIMS (kinetic interaction of microparticles in solution) method, it is recommended to verify results using methods such as gas chromatography/mass spectrometry.
Excipients. This medicinal product contains aspartame, a derivative of phenylalanine. This may be dangerous for patients with phenylketonuria.
Use during pregnancy or breastfeeding.
Pregnancy
Rifampicin
Animal studies have shown teratogenic effects in rats and mice at high doses.
To date, clinical use of rifampicin during a limited number of pregnancies has not caused specific developmental abnormalities or fetotoxic effects. Although rifampicin is known to cross the placental barrier and appears in umbilical cord blood, further studies are needed to assess the consequences of exposure during pregnancy. Therefore, the use of rifampicin during pregnancy should be considered only if no therapeutic alternative is available.
Isoniazid
Animal studies have not revealed teratogenic effects of isoniazid. In the absence of teratogenic effects in animals, a malformative effect in humans is not expected. Substances causing developmental defects in humans have been found to be teratogenic in animals in properly conducted studies on two species. Clinical use of isoniazid in a limited number of pregnant women has not revealed specific developmental abnormalities or fetotoxic effects. However, additional studies are needed to assess the consequences of exposure during pregnancy.
Therefore, the use of this combination during pregnancy should be considered only if necessary, keeping in mind that effective treatment of active tuberculosis in pregnant women should continue as prescribed before pregnancy. The drug should preferably be used concomitantly with pyridoxine due to the effects of isoniazid.
When used at the end of pregnancy, this combination may lead to early bleeding in both mother and newborn. The use of rifampicin increases the risk of bleeding. Prophylactic administration of vitamin K1 to the mother during the month preceding delivery and appropriate administration to the newborn after birth are effective. Concomitant use with pyridoxine is recommended.
Breastfeeding period
Rifampicin and isoniazid pass into breast milk.
Isoniazid is minimally protein-bound in plasma, and penetration into breast milk has been demonstrated, with concentrations equivalent to those in maternal plasma. Due to the potential risk of acetylation defect in the newborn and considering the neurotoxicity and hepatotoxicity of isoniazid, breastfeeding is not recommended.
Fertility
There are no data on the effect of the drug on fertility in men or women.
Ability to affect reaction speed when driving vehicles or operating machinery.
Adverse reactions associated with isoniazid use, such as dizziness, visual disturbances, and psychotic reactions, have been reported (see section "Adverse reactions"). Patients should be informed about this and warned that if the aforementioned symptoms occur, they should not drive, operate machinery, or engage in any activity where these symptoms could endanger themselves or others.
Dosage and Administration.
For oral use.
Dosage regimen for the treatment of tuberculosis in the continuation phase:
| Body weight |
Number of tablets |
| 4–7 kg |
1 |
| 8–11 kg |
2 |
| 12–15 kg |
3 |
| 16–24 kg |
4 |
For children with a body weight of 25 kg or more, the adult dosage is recommended.
Intermittent treatment regimens should not be used.
The required number of dispersible tablets should be dissolved in approximately 50 mL of water and taken within 10 minutes. After administration, an additional volume of water should be consumed immediately.
Rifampicin 75 mg and Isoniazid 50 mg dispersible tablets should be taken on an empty stomach (at least 1 hour before or 2 hours after meals). If the drug is taken with food to improve gastrointestinal tolerability, impaired bioavailability of the drug may occur.
If dose reduction or discontinuation of one of the active substances is required, individual medicinal products containing rifampicin and/or isoniazid should be used.
If a dose is missed, it should be taken as soon as possible, and the next dose should be taken at the usual time. However, if the next dose is due within the following 6 hours, the missed dose should not be taken. Instead, wait and take the next dose at the usual time.
Double doses should not be taken to compensate for a missed dose.
Renal impairment.
In most cases, dose adjustment is not required in patients with renal impairment. However, patients should be closely monitored for signs of isoniazid toxicity, particularly symptoms of peripheral neuropathy. Patients showing signs of isoniazid toxicity who are slow acetylators and have severe renal insufficiency (creatinine clearance <25 mL/min) may require dose reduction to 2/3 of the normal daily dose. In such cases, individual rifampicin and isoniazid preparations should be prescribed.
Hepatic impairment.
Limited data indicate that the pharmacokinetics of rifampicin and isoniazid are altered in patients with hepatic insufficiency. Therefore, patients with liver dysfunction should be carefully monitored for signs of toxicity. The drug should not be administered to patients with severe liver disease.
Children.
The drug should not be administered to children with body weight below 4 kg.
Overdose.
Symptoms.
In adults, symptoms of overdose have been reported following ingestion of 9 g of rifampicin, and fatal overdoses have occurred after ingestion of 14 g of rifampicin.
Symptoms observed are mostly related to isoniazid overdose, the lethal dose of which is 200 mg/kg.
Anorexia, nausea, vomiting, dizziness, hallucinations and/or visual disturbances, skin and urine red discoloration (due to rifampicin content), hyperbilirubinemia, hepatomegaly, mild elevation of alkaline phosphatase and transaminases occurring within 30 minutes to 3 hours after isoniazid ingestion.
In cases of rifampicin overdose, arterial hypotension, sinus tachycardia, ventricular arrhythmias, seizures, and cardiac arrest have been reported, some of which were fatal. Facial edema or periorbital swelling have also been observed. The minimal acute lethal or toxic dose has not been precisely established. The minimal lethal dose varies significantly, particularly depending on the presence of concomitant conditions (hepatic insufficiency, alcohol abuse). Seizures, coma, and hypoxia may occur, which can lead to fatal outcome.
Typical laboratory findings in overdose include metabolic acidosis, ketonuria, and hyperglycemia.
Treatment.
Gastric lavage in a specialized facility, measures to counteract acidosis, cardiopulmonary resuscitation, administration of anticonvulsants and high doses of pyridoxine are required. In severe cases, treatment may include hemodialysis.
Adverse reactions.
The frequency of all adverse reactions is defined as follows: common (≥ 1/10), uncommon (≥1/100, < 1/10), rare (≥ 1/1000, < 1/100), very rare (≥ 1/10000, < 1/1000), not known.
Adverse reactions associated with rifampicin and isoniazid use.
Rifampicin and isoniazid are generally well tolerated at recommended doses.
General disorders and administration site reactions
Common: paradoxical reaction (recurrence or new appearance of tuberculosis symptoms, clinical and radiological signs in a patient who previously showed improvement after appropriate antituberculosis treatment, referred to as a paradoxical reaction). This reaction is diagnosed after excluding poor patient adherence to treatment regimen, drug resistance, adverse reactions to treatment, and secondary bacterial/fungal infections.
Adverse reactions associated with rifampicin use
Reactions to rifampicin occurring during continuous or intermittent therapy:
Infections and infestations
Frequency not known: pseudomembranous colitis, influenza-like syndrome and bone pain, most commonly occurring between the 3rd and 6th month of treatment. The frequency of the syndrome varies but may occur in up to 50 percent of patients receiving treatment once weekly at doses of 25 mg/kg or higher.
Blood and lymphatic system disorders
Common: thrombocytopenia with or without purpura, usually associated with intermittent therapy. This phenomenon is reversible if treatment is discontinued at the first signs of purpura.
Uncommon: leukopenia.
Frequency not known: disseminated intravascular coagulation, sometimes fatal, eosinophilia, agranulocytosis, haemolytic anaemia, coagulation disorders.
Immune system disorders
Frequency not known: anaphylactic reactions (urticaria, bronchospasm, angioneurotic oedema), anaphylactic shock.
Endocrine disorders
Frequency not known: decompensation of latent or corticosteroid-treated compensated adrenal insufficiency, leading to manifestations of acute adrenal insufficiency (see section "Special precautions for use").
Metabolism and nutrition disorders
Frequency not known: decreased appetite.
Psychiatric disorders
Frequency not known: isolated cases of psychiatric or psychological disorders have been reported.
Nervous system disorders
Common: headache, dizziness.
Frequency not known: rifampicin should be discontinued in cases of purpura development, as fatal cerebral haemorrhages have been reported upon continuation or re-administration.
Eye disorders
Frequency not known: change in tear fluid colour. Rifampicin may permanently stain contact lenses.
Vascular disorders
Frequency not known: shock, vasomotor reactions, vasculitis, haemorrhages.
Respiratory, thoracic and mediastinal disorders
Frequency not known: dyspnoea, respiratory and asthmatic disorders, abnormal sputum pigmentation, interstitial lung disease (including pneumonia).
Gastrointestinal disorders
Common: nausea, vomiting.
Uncommon: diarrhoea.
Frequency not known: other gastrointestinal disorders such as abdominal pain, flatulence, change in tooth colour (may be irreversible).
Hepatobiliary disorders
Frequency not known: hepatitis, hyperbilirubinaemia, cholestasis (see section "Special precautions for use").
Hepatic injury or hepatitis may occur as a manifestation of hypersensitivity reaction to rifampicin, most commonly during the first month of treatment. Direct hepatotoxic effects of rifampicin may also occur (see section "Special precautions for use").
Transient hyperbilirubinaemia may occur during the first days of treatment (see section "Special precautions for use").
Skin and subcutaneous tissue disorders
Frequency not known: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), drug hypersensitivity syndrome with eosinophilia and systemic symptoms (DRESS syndrome) (see section "Special precautions for use"), skin hypersensitivity reactions, pruritus with or without rash, urticaria, allergic dermatitis, pemphigoid reactions, change in sweat pigmentation.
Musculoskeletal and connective tissue disorders
Frequency not known: muscle weakness, myopathy, bone pain.
Renal and urinary disorders
Frequency not known: acute renal failure due to tubular necrosis or tubulointerstitial nephritis, chromaturia (change in urine colour). Cortical necrosis has also been reported.
Pregnancy, puerperium and perinatal period
Frequency not known: postpartum haemorrhage.
Reproductive system and breast disorders
Frequency not known: menstrual cycle disturbances.
Congenital, familial and genetic disorders
Frequency not known: porphyria.
General disorders and administration site reactions
Very common: febrile episodes (fever), chills.
Frequency not known: oedema.
Investigations
Common: increased blood bilirubin levels, increased aspartate aminotransferase (AST) and alanine aminotransferase (ALT).
Frequency not known: decreased blood pressure, increased blood creatinine levels, increased plasma liver enzymes.
Adverse reactions associated with isoniazid use
Reproductive system and breast disorders
Gynaecomastia.
Skin and subcutaneous tissue disorders
Drug hypersensitivity syndrome with eosinophilia and systemic symptoms (DRESS syndrome) (see section "Special precautions for use"), rash, acne, toxic epidermal necrolysis (Lyell's syndrome), Stevens-Johnson syndrome (see section "Special precautions for use"), exfoliative dermatitis, bullous eruption.
Gastrointestinal disorders
Nausea, vomiting, epigastric pain.
Frequency not known: pancreatitis.
Hepatobiliary disorders
Hepatotoxicity: relatively frequent elevation of transaminase levels, bilirubinuria, rare acute hepatitis (with or without jaundice), some of which may be severe and occasionally fatal.
Hepatotoxicity is enhanced by interaction with rifampicin due to enzyme induction mechanisms. Other enzyme inducers may have similar effects (e.g., barbiturates).
Vascular disorders
Frequency not known: vasculitis.
Nervous system disorders
Neurotoxicity (likely due to the active substance itself related to pyridoxine deficiency): peripheral neuropathy manifested by distal paraesthesias, particularly in slow acetylators, malnourished patients, and those suffering from alcoholism.
Convulsions.
Frequency not known: cerebellar syndrome including cerebellar ataxia, dysdiadochokinesia, imbalance, nystagmus, speech disorders, dysmetria.
Psychiatric disorders
Psychiatric disorders resembling neuropsychiatric excitation: hyperactivity, euphoria, insomnia.
In predisposed individuals, particularly during concomitant use of ethionamide, manic episodes, acute delirium or depression have been observed.
Anorexia.
Eye disorders
Optic neuritis and optic atrophy.
General disorders and administration site reactions
Fever.
Musculoskeletal and connective tissue disorders
Myalgia, arthralgia.
In special cases: rheumatoid syndrome, algodystrophy (shoulder-hand syndrome), lupus-like syndrome.
Immune system disorders
Many toxic effects are associated with hypersensitivity and/or use of high doses (more than 10 mg/kg).
Hypersensitivity reactions
Rare: fever, rash, acne, jaundice or hepatitis, lymphadenopathy, eosinophilia, blood dyscrasias.
Reporting suspected adverse reactions
Reporting suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients or their legal representatives should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.
Shelf life.
2 years.
Storage conditions.
Store at temperatures not exceeding 25 °C in the original packaging.
Keep out of reach and sight of children.
Packaging.
28 tablets in a blister pack, 3 blisters in a cardboard box.
Prescription status.
Prescription only.
Manufacturer.
Macleods Pharmaceuticals Limited.
Manufacturer's address and location of manufacturing site.
Phase II, Plot No. 12, 15, 21, 23, 24, 25, 26, 27, 28 and 30, Survey No. 366, Premier Industrial Estate, Kachigam, Daman, 396210, India.