Rifampicin/isoniazid
UkraineTable of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT RIFAMPICIN/ISONIAZID (RIFAMPICIN/ISONIAZID)
Composition:
Active substances: rifampicin, isoniazid;
One film-coated tablet contains: rifampicin 150 mg, isoniazid 75 mg;
Excipients: povidone, shellac, maize starch, sodium lauryl sulfate, crospovidone, sodium starch glycolate (type A), colloidal anhydrous silicon dioxide, magnesium stearate, hypromellose, propylene glycol, diethyl phthalate, titanium dioxide (E 171), talc, Ponceau 4R lake (E 124).
Pharmaceutical form. Film-coated tablets.
Main physico-chemical characteristics: biconvex, round, film-coated tablets ranging in color from brown to reddish-brown, smooth on both sides.
Pharmacotherapeutic group. Combined antituberculosis agents.
ATC code J04AM02.
Pharmacological Properties
Pharmacodynamics
Rifampicin and isoniazid are active bactericidal antituberculosis agents, particularly effective against rapidly growing extracellular organisms, as well as exerting bactericidal effects on intracellular microorganisms. Rifampicin is active against slowly and intermittently growing M. tuberculosis.
Rifampicin inhibits the activity of DNA-dependent RNA polymerase in susceptible cells. Specifically, it interacts with bacterial RNA polymerase but does not inhibit the enzyme in mammals. Cross-resistance to rifampicin has been observed only with other rifamycins.
Isoniazid acts against actively growing tubercle bacilli.
Pharmacokinetics
Rifampicin
Rifampicin is rapidly absorbed from the gastrointestinal tract. Maximum serum concentration of approximately 10 mcg/mL is reached about 2–4 hours after an oral dose of 10 mg/kg body weight taken on an empty stomach.
In healthy volunteers, the biological half-life of rifampicin in serum averages approximately 3 hours after a 600 mg dose and increases to 5.1 hours after a 900 mg dose. With repeated administration, the elimination half-life decreases and reaches average values of approximately 2–3 hours. At doses up to 600 mg per day, the elimination half-life does not differ in patients with renal insufficiency; therefore, dose adjustment is not required.
Following absorption, rifampicin is rapidly excreted into bile, initiating enterohepatic circulation of bile acids. During this process, rifampicin undergoes gradual deacetylation, so that approximately 6 hours after administration, almost the entire drug in bile is present in this form. This metabolite retains nearly full antibacterial activity. Intestinal reabsorption is reduced due to deacetylation, and elimination is facilitated. Up to 30% of the administered dose is excreted in urine, with approximately half of this amount being unchanged drug. Rifampicin absorption is reduced when the drug is taken with food.
Rifampicin penetrates well into tissues and body fluids and reaches therapeutic concentrations in many organs and body fluids, including cerebrospinal fluid. Plasma protein binding is 80%. The majority of the unbound fraction is non-ionized, allowing free diffusion into tissues.
Isoniazid
After oral administration, isoniazid is rapidly absorbed and reaches peak blood levels within 1–2 hours; thereafter, levels decline to 50% or less within 6 hours. The rate and extent of absorption are reduced when isoniazid is taken with food. It is widely distributed throughout the body, penetrating all tissues and fluids (including cerebrospinal, pleural, and ascitic fluids), organs, and secretions (saliva, sputum, feces). Between 50% and 70% of the isoniazid dose is excreted in urine within 24 hours.
Isoniazid is primarily metabolized via acetylation and dehydrogenation. The rate of acetylation is genetically determined.
Pharmacokinetic studies in healthy volunteers have shown that both active ingredients, rifampicin and isoniazid, have comparable bioavailability whether administered together as individual dosage forms or as the fixed-dose combination product Rifampicin/Isoniazid.
Clinical characteristics.
Indications.
Rifampicin/Isoniazid is indicated for the treatment of pulmonary and extrapulmonary tuberculosis during the intensive (initial) and continuation (maintenance) phases of therapy.
Contraindications.
The use of the medicinal product is contraindicated:
- in patients with hypersensitivity to rifampicin, isoniazid, or to any of the excipients of the medicinal product;
- in hepatic insufficiency;
- in patients with porphyria;
- during surgical procedures under general anaesthesia;
- when used concomitantly 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 forms of interaction").
Interaction with other medicinal products and other forms of interaction.
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 antimicrobial agents. Risk factors include severe infectious or inflammatory diseases, age, and the patient's general condition. Under these circumstances, it may be difficult to distinguish between the infectious pathology and the effects of its treatment when an INR 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 that could be fatal (especially at high doses). If concomitant use is necessary, intensified monitoring of INR is recommended.
Enzyme induction
Rifampicin is a potent inducer of metabolic enzymes, including cytochrome P450 (CYP450) isoforms 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 the metabolism of certain co-administered drugs, thereby reducing their activity, or increase the activity of prodrugs requiring metabolic activation. Thus, clinically significant interactions with numerous drugs from various therapeutic classes are likely. Dose adjustments of these drugs may be required at the initiation or discontinuation of rifampicin therapy, considering that the enzyme-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
Reduced plasma concentration of daclatasvir due to enhanced hepatic metabolism by rifampicin.
Dasabuvir
Risk of reduced dasabuvir plasma concentration due to rifampicin.
Delamanid
Reduced plasma concentration of delamanid 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 due to rifampicin, potentially affecting efficacy.
Isavuconazole
Reduced plasma concentration of isavuconazole due to enhanced hepatic metabolism by rifampicin.
Ledipasvir
Significant reduction in ledipasvir plasma concentration due to enhanced hepatic metabolism by rifampicin.
Lurasidone
Reduced plasma concentration of lurasidone due to enhanced hepatic metabolism by rifampicin.
Midostaurin
Reduced midostaurin concentration due to rifampicin.
Ombitasvir/paritaprevir
Reduced plasma concentration with dual therapy due to enhanced hepatic metabolism by rifampicin.
Praziquantel
Very significant reduction in praziquantel plasma concentration, risking 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 caused by rifampicin.
Velpatasvir
Reduced velpatasvir plasma concentration due to rifampicin, potentially affecting efficacy.
Voriconazole
Significant reduction in voriconazole plasma concentration, risking loss of efficacy due to enhanced hepatic metabolism by rifampicin.
Voxilaprevir
Reduced plasma concentrations of voxilaprevir due to rifampicin, risking 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
Impaired behaviour and coordination.
Interactions related to rifampicin:
Abiraterone
Significant reduction in abiraterone plasma concentration, risking reduced efficacy.
Apixaban, dabigatran, rivaroxaban
Reduced plasma concentrations of apixaban, dabigatran, or rivaroxaban due to rifampicin, risking reduced therapeutic effect.
Apomorphine
Reduced plasma concentration of apomorphine due to enhanced metabolism by rifampicin.
Apixaban
Very significant reduction in apixaban concentration.
Atorvastatin, simvastatin
Very significant reduction in atorvastatin or simvastatin plasma concentration due to enhanced hepatic metabolism by rifampicin.
Atovaquone
Reduced atovaquone plasma concentration due to enzyme induction.
Bedaquiline
Reduced 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 the active metabolite of clopidogrel and enhanced platelet inhibition, potentially increasing bleeding risk. As a precaution, concomitant use of clopidogrel and rifampicin is not recommended.
Cyclophosphamide
Risk of increased plasma concentration of the active metabolite of cyclophosphamide due to rifampicin, thus increasing its toxicity.
Cyproterone used as a hormonal contraceptive
Risk of reduced cyproterone efficacy. A barrier method of contraception (e.g., condom) should be used throughout the duration of combination therapy and for one cycle after discontinuation of rifampicin.
Docetaxel
Reduced concentration of cytotoxic agent due to enhanced metabolism by rifampicin, risking reduced efficacy.
Dolutegravir in integrase inhibitor-resistant cases
Reduced dolutegravir plasma concentration due to enhanced metabolism by rifampicin.
Dronedarone
Significant reduction in dronedarone concentration due to enhanced metabolism without significant change in active metabolite.
Estrogen and progestogen contraceptives
Reduced contraceptive efficacy due to enhanced hepatic metabolism of hormonal contraceptives by rifampicin. A barrier method of contraception (e.g., condom) should be used throughout the period of concomitant use and for one menstrual cycle after discontinuation of rifampicin.
Etoposide
Reduced etoposide plasma concentration due to 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
Reduced fentanyl plasma concentration due to enhanced hepatic metabolism by rifampicin. An alternative opioid should be preferred during rifampicin use.
Fluconazole
Reduced plasma concentration and efficacy of both antimicrobial agents (enzyme induction by rifampicin and reduced intestinal absorption due to azole antifungal).
Idelalisib
Reduced idelalisib plasma concentration due to enhanced hepatic metabolism by rifampicin.
5-alpha-reductase inhibitors (dutasteride, finasteride)
Reduced plasma concentrations of 5-alpha-reductase inhibitors due to rifampicin. If combination cannot be avoided, careful clinical monitoring is required.
Tyrosine kinase inhibitors metabolized by CYP3A4
Reduced plasma concentration and efficacy of tyrosine kinase inhibitor due to enhanced metabolism by rifampicin.
Irinotecan
Likely reduction in plasma concentration of active irinotecan metabolite, risking ineffective cytotoxic therapy.
- Itraconazole*
Reduced plasma concentration and efficacy of both antimicrobial agents (enzyme induction by rifampicin and reduced intestinal absorption due to azole antifungal).
Ivacaftor
Significant reduction in ivacaftor plasma concentration, risking loss of efficacy.
Ketoconazole
Reduced plasma concentration and efficacy of both antimicrobial agents (enzyme induction by rifampicin and reduced intestinal absorption due to azole antifungal).
Macitentan
Reduced macitentan plasma concentration due to enhanced metabolism by rifampicin.
Mianserin
Risk of loss of mianserin efficacy.
Midazolam
Risk of lack of midazolam effect due to very significant reduction in plasma concentration due to enhanced hepatic metabolism.
Naloxegol
Reduced naloxegol concentration due to rifampicin.
- Nevirapine*
Reduced nevirapine plasma concentration due to enhanced hepatic metabolism by rifampicin.
Nimodipine
Reduced calcium antagonist plasma concentration due to enhanced hepatic metabolism. Clinical monitoring and possible dose adjustment of calcium antagonist are required during and after rifampicin therapy.
Olaparib
Possibly very significant reduction in olaparib plasma concentration due to enhanced hepatic metabolism by rifampicin.
Oxycodone
Reduced oxycodone plasma concentration due to enhanced metabolism by rifampicin. Dose adjustment of oxycodone may be necessary.
Paclitaxel
Reduced concentration of cytotoxic agent due to enhanced metabolism by rifampicin, risking reduced efficacy.
Posaconazole
Reduced plasma concentration and efficacy of both antimicrobial agents (enzyme induction by rifampicin and reduced intestinal absorption due to azole antifungal).
Quetiapine
Very significant reduction in quetiapine plasma concentration due to enhanced hepatic metabolism by inducer, risking inefficacy.
Quinine
Risk of loss of quinine efficacy due to enhanced hepatic metabolism by rifampicin.
Raltegravir
Reduced raltegravir concentration due to rifampicin. If combination cannot be avoided, doubling the raltegravir dose may be considered.
Ranolazine
Very significant reduction in ranolazine concentration.
Regorafenib
Reduced regorafenib plasma concentration due to enhanced metabolism by rifampicin.
Rolapitant
Very significant reduction in rolapitant concentration, risking loss of efficacy.
Sertraline
Risk of ineffective antidepressant treatment.
Tenofovir alafenamide
Reduced tenofovir alafenamide plasma concentration due to reduced absorption by rifampicin. Clinical monitoring is required during combination therapy and 1–2 weeks after discontinuation of rifampicin.
Telithromycin
Very significant reduction in telithromycin plasma concentration, risking ineffective antimicrobial therapy due to enhanced hepatic metabolism.
Ticagrelor
Significant reduction in ticagrelor plasma concentration due to enhanced hepatic metabolism, risking reduced therapeutic effect.
Ulipristal
Risk of reduced ulipristal effect due to enhanced hepatic metabolism by rifampicin. An alternative medicinal product not affected or minimally affected by rifampicin should be preferred.
Vemurafenib
Risk of reduced vemurafenib plasma concentration and reduced efficacy.
Vinca alkaloid cytotoxics
Rifampicin reduces plasma concentration of vinca alkaloids, potentially affecting efficacy.
Vismodegib
Risk of reduced vismodegib plasma concentration due to enhanced hepatic metabolism by rifampicin.
Zidovudine
Reduced zidovudine plasma concentration by half due to enhanced metabolism by rifampicin. If combination cannot be avoided, intensified clinical and biological monitoring is required.
Combinations requiring caution
Interactions related to isoniazid:
Halogenated volatile anaesthetics
Potentiation of isoniazid hepatotoxicity with increased formation of toxic isoniazid metabolites. As a precaution, isoniazid treatment should be discontinued one week before elective surgery and resumed only 15 days later.
Glucocorticoids (except hydrocortisone in replacement therapy)
Reduced isoniazid plasma concentration when used concomitantly with prednisolone. This effect is due to increased hepatic metabolism of isoniazid and reduced glucocorticoid levels. Clinical and biological monitoring is required.
Ketoconazole
Reduced ketoconazole plasma concentration.
It is recommended to separate the doses of both antimicrobial agents by at least 12 hours. Plasma concentration of ketoconazole should be monitored and dose adjusted if necessary.
Phenytoin and fosphenytoin
Phenytoin overdose (reduced metabolism) has been observed when used concomitantly with isoniazid. Careful clinical monitoring, determination of phenytoin plasma concentration, and possible dose adjustment are required during and after isoniazid therapy.
Pyrazinamide
Possible potentiation of hepatotoxic effects when used concomitantly. Clinical and biological monitoring is required.
Rifampicin
Enhanced hepatotoxicity of isoniazid (increased formation of toxic isoniazid metabolites – see sections "Special precautions for use" and "Adverse reactions"). Clinical and biological monitoring of this combination is required. Isoniazid should be discontinued in case of hepatitis.
Stavudine
Increased risk of peripheral neuropathy due to additive side effects. Regular clinical and biological monitoring, especially at the beginning of treatment.
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 are required during and after rifampicin therapy.
Afatinib
Reduced afatinib plasma concentration due to enhanced metabolism by rifampicin. Clinical monitoring is required during combination therapy and 1–2 weeks after discontinuation.
Albendazole
Significant reduction in albendazole and its active metabolite plasma concentrations due to rifampicin, risking reduced efficacy. Clinical monitoring of therapeutic response and possible dose adjustment of albendazole are required during and after rifampicin therapy.
Androgens (androstanolone, norethandrolone, testosterone)
Risk of reduced androgen plasma concentration and efficacy due to enhanced hepatic metabolism by rifampicin. Clinical and biological monitoring is required during combination therapy and 1–2 weeks after discontinuation.
Calcium channel antagonists (except nimodipine)
Reduced calcium antagonist plasma concentration due to enhanced hepatic metabolism. Clinical monitoring and possible dose adjustment are required during and after rifampicin therapy.
Class IA antiarrhythmics (disopyramide, hydroquinidine, quinidine)
Reduced plasma concentration and efficacy of antiarrhythmic agent (enhanced hepatic metabolism).
Clinical monitoring, ECG, and possibly plasma concentration monitoring are required. Dose adjustment of antiarrhythmic agent may be necessary during and after rifampicin therapy (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 therapy and 8 days after discontinuation.
Aripiprazole
Reduced aripiprazole plasma concentration. Clinical monitoring and possible dose adjustment of aripiprazole are required during combination therapy and 1–2 weeks after discontinuation of rifampicin.
Bazedoxifene
Reduced bazedoxifene plasma concentrations due to rifampicin. Monitoring for signs of loss of efficacy (e.g., bleeding) is required.
Buspirone
Reduced buspirone plasma concentration due to enhanced hepatic metabolism by rifampicin. Clinical monitoring and possible dose adjustment of buspirone are required during and after rifampicin therapy.
Carbamazepine
Reduced plasma concentration and efficacy of carbamazepine due to enhanced hepatic metabolism by rifampicin. Clinical monitoring, plasma concentration control, and dose adjustment of carbamazepine are required during and after rifampicin therapy.
Carvedilol
Significant reduction in carvedilol plasma concentration due to enhanced hepatic metabolism by rifampicin. Regular clinical monitoring and dose adjustment of carvedilol are required during rifampicin therapy. After discontinuation of rifampicin, there is a risk of significant increase in carvedilol plasma concentration, requiring dose reduction and careful clinical observation.
Casposfungin
Reduced caspofungin plasma concentration. During rifampicin treatment, starting from day 2, maintain a dose of 70 mg daily.
Clarithromycin
Reduced 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 are required during rifampicin therapy.
Cyproterone used as antiandrogen
Risk of reduced cyproterone efficacy. Clinical monitoring and possible dose adjustment of cyproterone are required during and after combination therapy.
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 therapy. 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 due to rifampicin. Clinical monitoring and possible dose adjustment of disopyramide are required during combination therapy and 1–2 weeks after discontinuation.
Dolutegravir, in absence of integrase inhibitor resistance
Adjust dolutegravir dose to 50 mg twice daily during combination therapy and for one week after discontinuation.
Reduced dolutegravir plasma concentration due to enhanced metabolism by rifampicin.
Efavirenz
Reduced plasma concentration and efficacy of efavirenz due to enhanced hepatic metabolism by rifampicin. Regular clinical and biological monitoring is required, especially at the beginning of combination therapy.
Enalapril
Reduced effect of enalapril active metabolites. Dose adjustment may be necessary depending on the patient's clinical condition.
Glucocorticoids
Reduced plasma concentration and efficacy of corticosteroids due to enhanced hepatic metabolism by rifampicin; consequences are particularly significant in Addison's disease patients on hydrocortisone and in transplant recipients. Clinical and biological monitoring and dose adjustment of corticosteroids are required during and after rifampicin therapy.
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 are required during combination therapy and after discontinuation of rifampicin.
Haloperidol
Risk of reduced haloperidol plasma concentration and therapeutic efficacy due to enhanced hepatic metabolism by rifampicin. Clinical observation and, if necessary, dose adjustment are required during and after rifampicin therapy.
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, dose adjustment of thyroid hormones are required during and after rifampicin therapy.
Immunosuppressants
Reduced 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. Isoniazid should be discontinued in case of hepatitis.
Ivabradine
Risk of reduced ivabradine efficacy due to enhanced metabolism by rifampicin. Clinical monitoring and dose adjustment of ivabradine are required during combination therapy and after discontinuation of rifampicin.
Levonorgestrel
Significant reduction in levonorgestrel plasma concentration when used for emergency contraception, risking loss of efficacy. If an enzyme inducer has been used within the last 4 weeks, consider using non-hormonal emergency contraception (copper intrauterine device (IUD)). If IUD use is not possible, double the dose of levonorgestrel.
Linezolid
Risk of reduced linezolid efficacy due to enhanced hepatic metabolism by rifampicin. Clinical monitoring and possible dose increase of linezolid are required during rifampicin therapy.
Maraviroc
In the absence of concomitant use with a strong CYP3A4 inhibitor, reduced maraviroc concentration occurs due to rifampicin. In such cases, maraviroc dose should be increased to 600 mg twice daily.
Methadone
Reduced methadone plasma concentration, risking withdrawal symptoms due to enhanced hepatic metabolism. Increase methadone dosing frequency (2–3 times daily instead of once).
Metronidazole
Reduced metronidazole plasma concentration due to enhanced hepatic metabolism by rifampicin. Clinical monitoring and possible dose adjustment of metronidazole are required during and after rifampicin therapy.
Mineralocorticoids
Reduced plasma concentration and efficacy of corticosteroids due to enhanced hepatic metabolism by rifampicin; consequences are particularly significant in Addison's disease patients on hydrocortisone and in transplant recipients.
Clinical and biological monitoring and dose adjustment of corticosteroids are required during and after rifampicin therapy.
Montelukast
Risk of reduced montelukast efficacy due to enhanced hepatic metabolism by rifampicin. Clinical monitoring and possible dose adjustment of anti-asthmatic agents are required during and after rifampicin therapy.
Morphine
Reduced plasma concentration and efficacy of morphine and its active metabolite. Clinical monitoring and possible dose adjustment of morphine are required during and after rifampicin therapy.
Nintedanib
Reduced nintedanib plasma concentration due to reduced absorption by rifampicin. Clinical monitoring is required during combination use.
Paracetamol
Concomitant use of paracetamol and rifampicin may increase the risk of hepatotoxicity.
Pioglitazone
Reduced glitazone plasma concentration due to enhanced metabolism by rifampicin. Clinical and biological monitoring and dose adjustment of glitazone are required during and after rifampicin therapy.
Non-contraceptive progestins (with or without estrogen)
Reduced progestin efficacy. Clinical monitoring and possible dose adjustment of hormonal therapy are required during and after inducer use.
Propafenone
Reduced propafenone plasma concentration due to enhanced hepatic metabolism by rifampicin. Clinical monitoring and ECG. Dose adjustment of propafenone may be necessary during and after combination therapy.
Terbinafine
Reduced plasma concentration and efficacy of terbinafine due to enhanced hepatic metabolism by rifampicin.
Clinical monitoring is required. Dose adjustment of terbinafine is recommended if necessary during rifampicin therapy.
Theophylline and aminophylline
Reduced plasma concentration and efficacy of theophylline (enhanced metabolism via enzyme induction).
Clinical monitoring is recommended. Dose adjustment of theophylline may be necessary during and after rifampicin therapy.
Tiagabine
Reduced tiagabine plasma concentration due to enhanced hepatic metabolism. Dose increase of tiagabine may be required when used with rifampicin.
Vitamin D
Reduced vitamin D concentration has been observed during rifampicin therapy. Dose adjustment of vitamin D may be necessary.
Zolpidem
Reduced plasma concentration and efficacy of zolpidem due to enhanced hepatic metabolism by rifampicin. Clinical monitoring is required. If possible, use an alternative hypnotic agent.
Zopiclone
Reduced plasma concentration and efficacy of zopiclone due to enhanced hepatic metabolism by rifampicin. Clinical monitoring is required. If possible, use an alternative hypnotic agent.
Interactions requiring consideration
Interactions related to rifampicin
Bortezomib
Reduced cytotoxic agent concentration due to enhanced metabolism by rifampicin, risking reduced efficacy.
- Cabazitaxel*
Reduced cytotoxic agent concentration due to enhanced metabolism by rifampicin, risking reduced efficacy.
Exemestane
Risk of reduced exemestane efficacy due to enhanced hepatic metabolism by rifampicin.
Metformin
Reduced metformin concentration due to rifampicin.
Metoprolol, propranolol
Reduced plasma concentration and efficacy of beta-blocker (enhanced hepatic metabolism).
Perampanel
Significant reduction (up to two-thirds) in perampanel concentration.
Tamoxifen
Risk of tamoxifen inefficacy due to enhanced metabolism by rifampicin.
Special precautions for use.
Rifampicin/Isoniazid is a combination of two drugs, each of which may cause hepatic function impairment.
Hepatic function impairment
The drug should be prescribed to patients with hepatic dysfunction only when absolutely necessary, with caution and under close medical supervision.
All patients with tuberculosis should have liver function tests performed before initiating treatment.
Regular clinical and biological monitoring of patients is required due to the risk of increased hepatotoxicity associated with the combination of isoniazid and rifampicin:
complete blood count (including platelet count), e.g., on day 8, at the end of the first month, and then at longer intervals (once every 2 months), and monitoring of liver function (transaminases, bilirubin).
Treatment with the drug should be discontinued if signs of hepatocellular injury (hepatitis) occur.
Since cases of isoniazid-associated hepatitis occur more frequently in patients over 35 years of age, this patient group should have transaminase levels measured at the beginning of treatment and then at least once a month during therapy.
Other factors associated with an increased risk of hepatitis include daily alcohol consumption, chronic liver disease, intravenous drug use, and belonging to African or Latino ethnic groups.
Severe skin adverse reactions, including Stevens-Johnson syndrome and Lyell’s syndrome (toxic epidermal necrolysis), which may be life-threatening or fatal, have been observed during treatment with antituberculosis drugs. Patients should be warned about signs and symptoms of skin reactions and closely monitored. Patients should be advised to seek immediate medical attention if symptoms suggestive of Stevens-Johnson syndrome or toxic epidermal necrolysis occur (progressive rashes, often accompanied by blistering and mucosal lesions). The drug 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 treatment.
It is important to note that early signs of hypersensitivity, such as fever, lymphadenopathy, or laboratory abnormalities (including hyper-eosinophilia, liver function abnormalities), may occur without obvious rash.
If such signs or symptoms occur, patients should be informed about the need to seek immediate medical attention.
The drug should be discontinued if the cause of the signs and symptoms cannot be determined.
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 types of interactions"), carbamazepine, cyclophosphamide, cyproterone (used as a hormonal contraceptive), dabigatran, disulfiram, docetaxel, dolutegravir (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, rivaroxaban, teicoplanin, apitant, ticagrelor, telithromycin, ulipristal, combined hormonal and progestin-only contraceptives, vemurafenib, cytotoxic vinca alkaloids, vismodegib, and zidovudine
- during breastfeeding.
Paradoxical reaction
After initial improvement in tuberculosis during treatment, 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 after initiation of antituberculosis treatment. Cultures are usually negative, and such reactions generally do not indicate treatment failure.
The cause of this paradoxical reaction is still unknown, but an exaggerated immune response is a likely explanation. In case of suspected paradoxical reaction, symptomatic treatment to reduce 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 specific to the affected tissues. Possible general symptoms include cough, fever, fatigue, dyspnea, headache, loss of appetite, weight loss, or weakness.
Interstitial lung disease (ILD)/pneumonia
Cases of ILD or pneumonia have been reported in patients taking this medicinal product for tuberculosis treatment. ILD/pneumonia are life-threatening conditions. All patients with sudden onset and/or unexplained worsening of pulmonary symptoms (dyspnea with dry cough) and fever should undergo thorough evaluation 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.
Peripheral neuropathy
To prevent the development of peripheral neuropathy, regular neurological examinations of patients should be performed, and particular caution should be exercised when prescribing the drug to patients who abuse alcohol.
Pyridoxine (vitamin B6) prevents or resolves rare cases of neuropathy caused by the drug, especially in elderly patients or those with inadequate nutrition.
Effect on adrenal function
The drug may decompensate latent adrenal insufficiency controlled by corticosteroid therapy (see section "Adverse reactions"). Therefore, monitoring of such patients is recommended, and adrenal cortex function testing should be performed at the slightest suspicion.
Rifampicin
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, jaundice, or darkening of urine. If cholestasis is confirmed, the drug should be discontinued.
In some cases, hyperbilirubinemia may occur during the first days of rifampicin treatment due to competitive interaction 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 based on repeat testing, observed trends, and the patient's clinical status.
Rifampicin is a potent inducer of transporters and enzymes responsible for drug metabolism. This may decrease or increase the effects of concomitantly administered drugs, thereby affecting their efficacy and safety (see section "Interaction with other medicinal products and other types of interactions"). Therefore, patients should not take any other medicinal products without prior consultation with a physician.
Coagulation disorders
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 leading to vitamin K deficiency or affecting other coagulation mechanisms). If necessary, additional vitamin K supplementation should be considered (in cases of vitamin K deficiency, hypoprothrombinemia).
Discoloration of teeth, urine, sweat, sputum, and tears
Rifampicin may cause discoloration (yellow, orange, red, brown) of teeth, urine, sweat, sputum, and tears, which should be explained to the patient. Permanent staining of soft contact lenses is possible.
Intermittent therapy
Hypersensitivity reactions are often, if not exclusively, associated with intermittent (intermittent) administration or repeated discontinuation of rifampicin.
Effect on clinical test results
Rifampicin may delay the biliary excretion of contrast agents used in radiographic examination of the gallbladder.
Microbiological methods for determining plasma concentrations of folic acid and vitamin B12 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-reactions with false-positive urine opiate test results have been reported in patients taking rifampicin, particularly with the KIMS (kinetic interaction of microparticles in solution) method, it is recommended to confirm results using methods such as gas chromatography/mass spectrometry.
Isoniazid
Isoniazid use should be carefully monitored in patients with pre-existing chronic liver disease or severe renal dysfunction.
Severe and sometimes fatal hepatitis associated with isoniazid therapy may develop, even after several months of treatment. The risk of hepatitis development depends on the patient's age.
Treatment should be immediately discontinued if signs and symptoms of liver injury occur, such as fatigue, weakness, malaise, anorexia, nausea, or vomiting. Continuing treatment may lead to severe liver damage. Careful monitoring is required in patients with chronic liver disease or severe renal insufficiency during isoniazid therapy.
Isoniazid may cause seizures in cases of overdose (in slow acetylators) or in patients predisposed to seizures. Patient status should be carefully monitored, and anticonvulsant therapy should be administered if necessary.
Isoniazid may increase phenytoin blood levels and cause signs of toxicity, including nystagmus, ataxia, and confusion.
Excipients: This medicinal product contains a dye (Ponceau 4R), which may cause allergic reactions.
The medicinal product contains propylene glycol, which may cause symptoms similar to those caused by alcohol consumption.
Use during pregnancy or breastfeeding.
Pregnancy
Rifampicin
Rifampicin has been shown to have teratogenic effects in rats and mice when administered at high doses. Clinical experience with rifampicin use during a limited number of pregnancies has not revealed any specific developmental malformations or fetotoxic effects. Although rifampicin is known to cross the placental barrier and appears in umbilical cord blood, further studies are needed to evaluate the consequences of exposure during pregnancy. Therefore, the use of rifampicin during pregnancy should be considered only in the absence of therapeutic alternatives.
Isoniazid
Animal studies have not revealed teratogenic effects of isoniazid. In the absence of teratogenic effects in animals, malformative effects in humans are not expected. Substances known to cause developmental defects in humans have been shown to be teratogenic in animals in properly conducted studies on two species. Clinical experience with isoniazid use in a limited number of pregnant women has not revealed any specific developmental malformations or fetotoxic effects. However, additional studies are needed to evaluate the consequences of exposure during pregnancy.
Therefore, the use of this combination during pregnancy should be considered only when 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.
Use at the end of pregnancy 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 are excreted in breast milk.
Isoniazid is weakly bound to plasma proteins, and penetration into breast milk with concentrations equivalent to those in maternal plasma has been demonstrated. Since there is a potential risk of acetylation defects 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 human fertility.
Ability to affect reaction speed when driving or operating machinery.
Isoniazid may cause dizziness, visual disturbances, and psychotic reactions. Patients should be informed about this and warned that if such symptoms occur, they should not drive or operate machinery or participate in any activities where these symptoms may pose a risk to themselves or others.
Dosage and Administration.
For oral use.
Rifampicin/Isoniazid may be administered concurrently with another antituberculosis drug until susceptibility of the infectious agent to rifampicin and isoniazid has been determined.
Rifampicin/Isoniazid 150 mg/75 mg, film-coated tablets, should be taken on an empty stomach (at least 30 minutes before or 2 hours after a meal).
For patients with body weight less than 50 kg: administer 1 tablet once daily.
For patients with body weight of 50 kg and above: administer 4 tablets once daily.
Elderly patients:
these patients should be treated with caution, especially if signs of impaired liver function are present.
Children:
the medicinal product is not recommended for use in children. Alternative medicinal products with appropriate dosing should be used for this patient group.
Overdose.
Signs and symptoms
Non-fatal acute overdose with 9 g of rifampicin in adults has been reported, as well as fatal acute overdose with 14 g of rifampicin in adults.
Symptoms observed are mostly related to isoniazid overdose, the lethal dose of which is 200 mg/kg.
Following overdose, signs and symptoms typically appear within 30 minutes to 3 hours after ingestion and include nausea, vomiting, dizziness, visual disturbances and visual hallucinations (including bright colors and strange patterns), skin and urine reddening (due to rifampicin content), hyperbilirubinemia, hepatomegaly, moderate elevation of alkaline phosphatase and transaminases.
In cases of rifampicin overdose, arterial hypotension, sinus tachycardia, ventricular arrhythmias, seizures, and cardiac arrest have been reported, some with fatal outcomes. Cases of facial or periorbital edema have also been reported.
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 (e.g., hepatic insufficiency, alcohol abuse). Seizures, coma, and hypoxia may occur, potentially leading to a fatal outcome.
Typical laboratory findings in overdose include severe metabolic acidosis, ketonuria, and hyperglycemia.
Treatment
In case of overdose, gastric lavage should be performed in a specialized facility. Measures should be taken to counteract acidosis, and cardiopulmonary resuscitation, anticonvulsant therapy, and high-dose pyridoxine (vitamin B6) should be administered. In severe cases, treatment may include hemodialysis.
Adverse reactions.
Frequency is defined as very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10,000, < 1/1000), very rare (≤ 1/10,000), frequency not known (cannot be estimated based on available data).
Adverse reactions associated with the use of rifampicin and isoniazid.
Rifampicin and isoniazid are generally well tolerated at recommended doses.
| Body systems |
Frequency |
Adverse reactions |
| General disorders and administration site reactions |
common |
Paradoxical reaction (the recurrence or new appearance of tuberculosis symptoms and clinical or radiological signs in a patient who previously showed improvement after appropriate anti-tuberculosis treatment is called a paradoxical reaction. This reaction is diagnosed after excluding poor patient adherence to treatment regimen, treatment resistance, adverse reactions from tuberculosis treatment, and secondary bacterial/fungal infections). |
Adverse reactions associated with the use of rifampicin.
Reactions to rifampicin occurring during continuous or intermittent dosing regimens include:
| Body systems |
Frequency |
Adverse reactions |
| Infections and infestations |
frequency unknown |
pseudomembranous colitis, flu-like syndrome and bone pain, which most commonly occur between the 3rd and 6th month of treatment. The frequency of the syndrome varies but may occur in 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, more frequent during intermittent therapy, but reversible if the drug is discontinued at the first signs of purpura |
| uncommon |
leukopenia |
|
| frequency unknown |
disseminated intravascular coagulation, sometimes with fatal outcome, eosinophilia, agranulocytosis, hemolytic anemia, coagulation disorders |
|
| Immune system disorders |
frequency unknown |
anaphylactic reactions (urticaria, bronchospasm, angioneurotic edema), anaphylactic shock. |
| Endocrine disorders |
frequency unknown |
decompensation of latent adrenal insufficiency or corticosteroid-compensated adrenal insufficiency, leading to manifestations of acute adrenal insufficiency |
| Metabolism and nutrition disorders |
frequency unknown |
decreased appetite |
| Psychiatric disorders |
frequency unknown |
isolated cases of psychiatric or psychological disorders have been reported. |
| Nervous system disorders |
common |
headache, dizziness |
| frequency unknown |
if purpura develops, rifampicin should be discontinued, as cerebral hemorrhages and fatal cases have been reported when rifampicin administration was continued or resumed after onset of purpura |
|
| Eye disorders |
frequency unknown |
change in tear color. Rifampicin may permanently stain contact lenses. |
| Vascular disorders |
frequency unknown |
shock, vasomotor reactions, vasculitis, bleeding |
| Respiratory, thoracic and mediastinal disorders |
frequency unknown |
dyspnea, respiratory and asthmatic disorders, abnormal sputum discoloration, interstitial lung disease (including pneumonia). |
| Gastrointestinal disorders |
common |
nausea, vomiting |
| uncommon |
diarrhea |
|
| frequency unknown |
gastrointestinal disturbances such as abdominal pain, bloating, tooth discoloration (may be permanent) |
|
| Hepatobiliary disorders |
frequency unknown |
hepatitis, hyperbilirubinemia, cholestasis. Liver damage or hepatitis may occur as a symptom of hypersensitivity reaction to rifampicin, most commonly within the first month of treatment. Signs of direct hepatotoxicity of rifampicin may also occur. Transient hyperbilirubinemia may occur during the first days of treatment. |
| Skin and subcutaneous tissue disorders |
frequency unknown |
multiform erythema, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (Lyell's syndrome), drug hypersensitivity syndrome with eosinophilia and systemic symptoms (DRESS), skin hypersensitivity reaction, pruritus, pruritic rash, urticaria, allergic dermatitis, pemphigoid reaction, sweat discoloration |
| Musculoskeletal and connective tissue disorders |
frequency unknown |
muscle weakness, myopathy, bone pain |
| Renal and urinary disorders |
frequency unknown |
acute kidney injury, usually due to renal tubular necrosis or tubulointerstitial nephritis, chromaturia (urine discoloration). Cortical necrosis has also been reported. |
| Pregnancy, postpartum and perinatal period |
frequency unknown |
postpartum hemorrhage, fetal and maternal bleeding. |
| Reproductive system and breast disorders |
frequency unknown |
menstrual cycle disturbances |
| Congenital, familial and genetic disorders |
frequency unknown |
porphyria |
| General disorders and administration site conditions |
very common |
fever, chills |
| frequency unknown |
edema |
|
| Effects on laboratory test results |
common |
increased blood levels of bilirubin, aspartate aminotransferase, and alanine aminotransferase |
| frequency unknown |
decreased blood pressure, increased blood creatinine levels, increased plasma liver enzymes. |
Adverse reactions associated with the use of isoniazid
| Body systems |
Frequency |
Adverse reactions |
| Nervous system disorders |
Neurotoxicity (probably due to the active substance itself due to pyridoxine deficiency): peripheral neuropathy manifested by distal paresthesias, particularly in slow acetylators, patients with nutritional disorders, and patients suffering from alcoholism. Seizures. |
|
| Psychiatric disorders |
Psychiatric disorders of the neuropsychiatric excitation type: hyperactivity, euphoria, insomnia. In predisposed cases, especially during concomitant use of ethionamide, manic episodes, acute delirium, or depression have been observed. Anorexia. |
|
| Eye disorders |
Optic neuritis and optic atrophy. |
|
| Skin and subcutaneous tissue disorders |
frequency unknown |
Drug hypersensitivity syndrome with eosinophilia and systemic symptoms (DRESS), rash, acne, toxic epidermal necrolysis (Lyell's syndrome), Stevens-Johnson syndrome, exfoliative dermatitis, bullous eruption |
| Vascular disorders |
frequency unknown |
vasculitis |
| Gastrointestinal disorders |
nausea, vomiting, epigastric distress, |
|
| frequency unknown |
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 through enzyme induction mechanisms. Other enzyme inducers may have the same effect (barbiturates) |
|
| Reproductive system and breast disorders |
gynecomastia |
|
| Hypersensitivity reactions |
rare |
fever, rash, acne, jaundice or hepatitis, lymphadenopathy, eosinophilia, blood dyscrasias |
| Musculoskeletal disorders |
Myalgia, arthralgia. In special cases: rheumatoid syndrome, algodystrophy (shoulder-hand syndrome), syndrome resembling systemic lupus erythematosus |
|
| General disorders and administration site reactions |
fever |
|
| Immune system disorders |
Many toxic effects are related to hypersensitivity and/or high-dose administration (more than 10 mg/kg) |
Reporting of suspected adverse reactions
Reporting of adverse reactions after the medicinal product has been registered is of great importance. It enables continuous monitoring of the benefit-risk balance of the use of this medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of effectiveness of the medicinal product via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua
Shelf life.
2 years.
Storage conditions.
Store at a temperature not exceeding 25 °C in the original packaging.
Keep out of reach of children.
Packaging.
28 tablets per blister pack. 3 or 24 blisters per cardboard box.
Prescription status.
Prescription only.
Manufacturer.
Macleods Pharmaceuticals Limited.
Manufacturer's address and site of operations.
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.