Rifampicin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT RIFAMPIN (RIFAMPIN)

Composition:

Active substance: rifampicin;

1 vial contains rifampicin 600 mg;

Excipients: sodium formaldehyde sulfoxylate, sodium hydroxide.

Pharmaceutical form. Lyophilized powder for solution for infusion.

Main physicochemical properties: lyophilized powder or red-colored lump.

Pharmacotherapeutic group.
Antituberculosis agents. ATC code J04AB02.

Pharmacological Properties.

Pharmacodynamics.

Rifampicin is an active bactericidal antituberculosis agent, particularly effective against rapidly growing extracellular organisms, and also exerts bactericidal activity against intracellular pathogens. Rifampicin is active against slowly and intermittently growing M. tuberculosis.

Rifampicin inhibits 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.

Pharmacokinetics.

After intravenous administration of a 300 or 600 mg dose of rifampicin infused over 30 minutes in healthy male volunteers (n = 12), mean peak plasma concentrations were 9.0 and 17.5 µg/mL, respectively. Mean plasma concentrations remained detectable for 8 and 12 hours, respectively.

Pharmacokinetics (oral and intravenous administration) in children is similar to that in adults.

In healthy volunteers, the mean elimination half-life of rifampicin in blood serum is approximately 3 hours after a 600 mg dose and increases to 5.1 hours after a 900 mg dose. With repeated administration, the half-life decreases and reaches average values of approximately 2–3 hours. At doses up to 600 mg/day, pharmacokinetics do not differ in patients with renal insufficiency, and therefore dose adjustment is not required.

Rifampicin is rapidly excreted in bile, resulting in enterohepatic circulation. During this process, rifampicin undergoes progressive deacetylation, so that nearly all of the drug in bile is in this form within about 6 hours. This metabolite retains practically full antibacterial activity. Deacetylation reduces intestinal reabsorption and facilitates elimination. Up to 30% of the administered dose is excreted in urine, with approximately half of this amount remaining unchanged.

Rifampicin is widely distributed throughout the body. It reaches effective concentrations in many organs and body fluids, including cerebrospinal fluid. Rifampicin is approximately 80% protein-bound. The majority of the unbound fraction is non-ionized, allowing free diffusion into tissues.

Clinical characteristics.

Indications.

Rifampicin for infusion is indicated for the treatment of acute cases of disease when oral administration of the drug is not possible (postoperative or comatose state of patients), as well as for the treatment of patients with gastrointestinal absorption disorders.

Tuberculosis: Rifampicin, used in combination with other antituberculosis agents, is indicated for the treatment of all forms of tuberculosis, including initial, severe, chronic, and cases resistant to other antibiotics. Rifampicin is also effective against most atypical strains of mycobacteria.

Leprosy: Rifampicin, used in combination with at least one other antileprosy agent, is indicated for the treatment of multibacillary and paucibacillary leprosy to convert an infectious state into a non-infectious one.

Other infections: Rifampicin is indicated for the treatment of brucellosis, Legionnaires' disease, and severe staphylococcal infections. To prevent the emergence of resistant strains of infectious organisms, rifampicin should be used in combination with another antibiotic appropriate to the infection.

Contraindications.

Rifampicin for infusion is contraindicated in patients with hypersensitivity to rifamycins or to any of the excipients.

Although the medicinal product is not recommended for use in patients with jaundice, the benefit and potential risks associated with treatment should be carefully weighed.

Rifampicin for infusion is contraindicated when used concomitantly with the combination of saquinavir/ritonavir.

Interaction with other medicinal products and other forms of interaction.

Pharmacodynamic interaction

Concomitant use of rifampicin with the combination of saquinavir/ritonavir increases the risk of hepatotoxicity. Therefore, concomitant administration of rifampicin with saquinavir/ritonavir is contraindicated.

Concomitant use of rifampicin with halothane or isoniazid increases the risk of hepatotoxicity. Concomitant use of rifampicin and halothane should be avoided. Patients receiving rifampicin and isoniazid should be closely monitored for hepatotoxicity.

Concomitant use of rifampicin with other antibiotics that cause vitamin K-dependent coagulopathy, such as cefazolin (or other cephalosporins with an N-methyl-thiotetrazole side chain), should be avoided, as this may lead to serious coagulation disorders and fatal outcomes (especially at high doses).

Effect of the drug on other medicinal products

Enzyme and transporter induction

Rifampicin is a potent inducer of enzymes and transporters involved in drug metabolism. Enzymes and transporters affected by rifampicin include cytochrome P450 (CYP) 1A2, 2B6, 2C8, 2C9, 2C19, and 3A4, UDP-glucuronosyltransferases (UGT), sulfotransferases, carboxylesterases, and transporters including P-glycoprotein (P-gp) and multidrug resistance-associated protein 2 (MRP2). Most drugs are substrates for one or more of these enzyme or transporter pathways, and these pathways may be induced simultaneously by rifampicin infusion. Thus, rifampicin infusion may accelerate the metabolism and reduce the activity of certain concomitantly administered drugs, or increase the activity of prodrugs requiring metabolic activation, and has the potential to cause clinically significant drug interactions with many drugs and across multiple drug classes. Dose adjustments of these medicinal products may be required at the start of rifampicin treatment or after its discontinuation to maintain their optimal therapeutic blood concentrations.

Examples of drugs or drug classes affected by rifampicin:

• antiarrhythmics (e.g., disopyramide, mexiletine, quinidine, propafenone, tocainide);

• antiepileptic drugs (e.g., phenytoin);

• hormone antagonists (anti-estrogens, e.g., tamoxifen, toremifene, gestrinone);

• antipsychotic agents (e.g., haloperidol, aripiprazole);

• anticoagulants (e.g., coumarins);

• antifungal agents (e.g., fluconazole, itraconazole, ketoconazole, voriconazole);

• antiviral agents (e.g., saquinavir, indinavir, efavirenz, amprenavir, nelfinavir, atazanavir, lopinavir, nevirapine);

• barbiturates;

• beta-blockers (e.g., bisoprolol, propranolol);

• anxiolytics and hypnotics (e.g., diazepam, benzodiazepines, zopiclone, zolpidem);

• calcium channel blockers (e.g., diltiazem, nifedipine, verapamil, nimodipine, isradipine, nicardipine, nisoldipine);

• antibacterial agents (e.g., chloramphenicol, clarithromycin, dapsone, doxycycline, fluoroquinolones, telithromycin);

• corticosteroids;

• cardiac glycosides (digoxin, digitoxin);

• clofibrate;

• systemic hormonal contraceptives, including estrogens and progestogens;

• oral antidiabetic agents (sulfonylureas and derivatives, e.g., chlorpropamide, tolbutamide, rosiglitazone);

• immunosuppressive agents (e.g., cyclosporine, sirolimus, tacrolimus);

• irinotecan;

• thyroid hormones (e.g., levothyroxine);

• losartan;

• analgesics (e.g., methadone, narcotic analgesics);

• praziquantel;

• quinine;

• riluzole;

• selective 5-HT3 receptor antagonists (e.g., ondansetron);

• statins metabolized by CYP3A4 (e.g., simvastatin);

• theophylline;

• tricyclic antidepressants (e.g., amitriptyline, nortriptyline);

• cytostatics (e.g., imatinib);

• diuretics (e.g., eplerenone);

• enalapril: reduced exposure to the active metabolite enalaprilat. Dose adjustment may be required based on the patient's clinical condition;

• antiviral agents for the treatment of hepatitis C (e.g., daclatasvir, simeprevir, sofosbuvir, telaprevir): concomitant use of antiviral agents for hepatitis C and rifampicin should be avoided;

• morphine: rifampicin may reduce plasma concentrations of morphine. Analgesic efficacy of morphine should be monitored and dose adjusted during and after rifampicin treatment;

• clopidogrel: increased exposure to active metabolites. Rifampicin strongly induces CYP2C19. This leads to both increased levels of clopidogrel's active metabolite and enhanced platelet inhibition, thereby increasing the risk of bleeding. Therefore, concomitant use of clopidogrel and rifampicin is not recommended.

Rifampicin treatment reduces systemic exposure to oral contraceptives. Alternative non-hormonal contraceptive methods should be recommended to patients using oral contraceptives during rifampicin therapy. Also, the use of the drug may complicate the management of diabetes mellitus.

Concomitant administration of ketoconazole and rifampicin has resulted in decreased serum concentrations of both drugs.

If para-aminosalicylic acid and rifampicin are included in the treatment regimen, the interval between their administration should be at least 8 hours to ensure adequate blood concentrations of both drugs.

Effect of other medicinal products on rifampicin

Concomitant use of antacids may reduce the absorption of rifampicin. Rifampicin should be taken at least 1 hour before antacids.

Other medicinal interactions

Concomitant use has been observed to decrease atovaquone concentrations and increase rifampicin concentrations.

Laboratory and diagnostic tests

Therapeutic levels of rifampicin have been shown to interfere with results obtained by standard microbiological methods for determining serum concentrations of folic acid and vitamin B12. Therefore, alternative quantitative methods should be considered. Transient increases in serum bromsulphthalein and bilirubin levels have also been observed. Rifampicin may interfere with the excretion of contrast media used for gallbladder visualization. Therefore, these tests should be performed before the daily administration of rifampicin.

Special precautions for use.

Rifampicin should be administered under the supervision of a pulmonologist or other qualified physician.

When using doses of rifampicin exceeding 600 mg per day, renal function must be monitored.

For all patients with tuberculosis, a complete assessment of liver function should be performed before initiating treatment.

In adult patients receiving anti-tuberculosis therapy with rifampicin, levels of liver enzymes, bilirubin, creatinine in blood, and a complete blood count including platelet count should be determined.

Initial testing is not required in children unless there are known complicating factors or clinically expected complications.

Rifampicin may be administered to patients with moderate to severe hepatic impairment only in extreme cases and under continuous medical supervision. Lower doses of rifampicin are recommended for such patients, along with careful monitoring of liver function, especially serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Monitoring should be performed prior to initiation of therapy, then weekly during the first two weeks, and thereafter every two weeks for an additional six weeks. If signs of hepatotoxicity occur, the drug should be discontinued.

Treatment should also be discontinued if clinically significant abnormalities in liver function develop. Consideration should be given to alternative forms of anti-tuberculosis therapy. Consultation with a qualified specialist is advised. If therapy with rifampicin is continued after normalization of liver function, it should be monitored daily.

Therapeutic regimens combining isoniazid and rifampicin should be prescribed with caution in patients with impaired liver function, elderly patients, debilitated patients, and children under 2 years of age. If the patient has no prior history of liver disease and liver function is normal, liver function tests should be repeated only if fever, vomiting, jaundice, or other clinical deterioration occurs.

Patients should be monitored for at least one month during treatment, and questioned regarding symptoms related to adverse reactions.

In the first few days of treatment, hyperbilirubinemia may occur due to competition between rifampicin and bilirubin for hepatic excretion. In one case, mild elevations in bilirubin and/or transaminases were observed, which do not necessarily require discontinuation of treatment. Decisions should be based on repeat testing, considering the trend in levels and clinical status of the patient.

Patients must be closely monitored, as intermittent dosing regimens (less than 2–3 times per week) increase the risk of immunological reactions, including anaphylactic shock (see section "Adverse reactions"). Patients should be warned about the consequences of interrupting treatment.

Rifampicin induces enzymes that accelerate the metabolism of endogenous substrates such as adrenal hormones, thyroid hormones, and vitamin D.

Cases of porphyria exacerbations associated with rifampicin therapy have been reported.

Severe systemic hypersensitivity reactions, including fatal cases such as drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), have been observed during anti-tuberculosis therapy.

Infusion of rifampicin should be discontinued if an alternative etiology for signs and symptoms cannot be established.

Cases of severe skin adverse reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), and acute generalized exanthematous pustulosis, have been reported in association with intravenous rifampicin. These adverse reactions may be fatal. The frequency of these reactions is unknown.

Paradoxical drug reaction

After initial clinical improvement during rifampicin infusion therapy, symptoms may worsen again. Clinical or radiological worsening of existing tuberculosis lesions or development of new lesions has been observed in patients. These reactions typically occur within the first few weeks or months of initiating tuberculosis treatment. Such reactions usually do not indicate treatment failure.

The cause of this paradoxical reaction is not fully understood but may involve an enhanced immune response. If a paradoxical reaction is suspected, symptomatic therapy to suppress the heightened immune response should be initiated as needed. Additionally, continuation of the planned combined tuberculosis therapy is recommended.

Patients should be advised to seek immediate medical attention if symptoms worsen. Symptoms are usually specific to the affected tissues. General symptoms may include cough, fever, fatigue, dyspnea, headache, loss of appetite, weight loss, or weakness.

When prescribing treatment, patients should be informed about signs and symptoms and advised to carefully monitor for skin reactions.

It is important to note that early signs of hypersensitivity, such as fever, lymphadenopathy, or laboratory abnormalities (including eosinophilia and liver abnormalities), may be present even in the absence of visible rash. Patients experiencing such signs or symptoms should seek immediate medical advice.

If symptoms suggestive of these reactions occur, rifampicin infusion should be discontinued immediately, and alternative treatment should be considered.

Most of these reactions occur between 2 days and 2 months after initiation of treatment; the onset time may vary depending on the condition.

Rifampicin for infusion solution is intended for intravenous use only and must not be administered intramuscularly or subcutaneously. Extravasation of the drug should be avoided during administration. Irritation and inflammation at the injection site due to extravasation and infiltration have been observed. In such cases, infusion should be stopped and restarted at another site.

During treatment with rifampicin, urine, sweat, sputum, and tears may turn orange-red. The drug may permanently stain soft contact lenses (see section "Adverse reactions").

Rifampicin is a well-documented potent inducer of drug-metabolizing enzymes and transporters, and therefore may decrease or increase exposure, safety, and efficacy of concomitant medications. Potential drug interactions should be considered whenever initiating or discontinuing rifampicin therapy.

Rifampicin may cause vitamin K-dependent coagulopathy and severe bleeding. Monitoring for coagulopathy is recommended in patients at increased risk of bleeding. Consideration should be given to supplemental vitamin K administration (in cases of vitamin K deficiency, hypoprothrombinemia).

All patients with underlying conditions should continue to be monitored as needed, including laboratory testing.

This medicinal product contains 1.6 mmol (or 36.8 mg) of sodium. Caution is advised when administering to patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding.

Pregnancy

At high doses, rifampicin has shown teratogenic effects in animals. There are no adequate and well-controlled studies on the effects of rifampicin in pregnant women. Rifampicin crosses the placental barrier and has been detected in umbilical cord blood. The effect of rifampicin on the human fetus, when used alone or in combination with other anti-tuberculosis drugs, is unknown. Therefore, use during pregnancy is possible only in exceptional cases and when strictly indicated, if the expected benefit to the mother's health outweighs the potential risk to the fetus.

Administration of rifampicin in the last weeks of pregnancy increases the risk of bleeding in newborns and postpartum women, which may be treated with vitamin K.

Breastfeeding

Rifampicin is excreted in breast milk. If use of the drug is necessary, breastfeeding should be discontinued.

Ability to affect the reaction rate while driving or operating machinery.

Unknown.

Administration and Dosage.

The medicinal product should be administered intravenously by drip infusion. To prevent the development of microbial resistance, Rifampicin must be used in combination with other antibacterial agents.

Tuberculosis treatment:

Adults: intravenous infusion of 600 mg over 2–3 hours once daily is effective and well tolerated. Serum concentrations after this dosing regimen are similar to those observed after oral administration of 600 mg.

Children: the usual pediatric dose is a single daily dose of up to 20 mg/kg/day (maximum daily dose should not exceed 600 mg).

Leprosy treatment:

The recommended dose is 10 mg/kg/day; the usual daily dose is 450 mg for patients with body weight less than 50 kg, and 600 mg for patients with body weight of 50 kg or more. An alternative regimen is a single oral dose of 600 mg of rifampicin. For leprosy treatment, rifampicin must be used in combination with at least one other antileprosy agent.

Brucellosis, Legionnaires' disease, and severe staphylococcal infections:

For adults, the recommended dose is 600–1200 mg daily in 2–4 divided doses. Should be used in combination with other antibacterial agents with similar properties to prevent emergence of resistant strains.

The duration of treatment is determined individually by the physician.

Hepatic impairment:

For patients with impaired liver function, the daily dose should not exceed 8 mg/kg.

Use in elderly patients:

In elderly patients, renal excretion of rifampicin decreases proportionally to the physiological decline in renal function; however, due to compensatory increase in hepatic excretion, the terminal half-life in serum is similar to that in younger patients. Nevertheless, since elevated serum levels of rifampicin have been observed in elderly patients in one study, caution should be exercised when administering rifampicin to such patients, especially if there are signs of impaired liver function.

When patients are able to take medications orally, they should be switched to oral formulations of rifampicin.

For preparation of the solution for intravenous administration, dissolve each 600 mg in 10 ml of water for injections, shaking vigorously until completely dissolved; the resulting solution should then be mixed with 500 ml of 5% glucose solution. The infusion rate is 60–80 drops/min.

Children.

Rifampicin may be used for treatment of children aged 1 year and older.

Overdose.

Symptoms: nausea, vomiting, abdominal pain, pruritus, headache, and increased fatigue may occur shortly after ingestion of a large dose; loss of consciousness in the presence of severe liver disease, increased levels of bilirubin and hepatic transaminases in plasma; brownish-red or orange discoloration of the skin, urine, sweat, saliva, tears, and feces proportional to the administered dose; periorbital or facial edema in children.

Some fatal cases have been reported, involving hypotension, sinus tachycardia, ventricular arrhythmias, seizures, and cardiac arrest.

The minimum lethal or toxic dose has not been established. However, non-fatal acute overdoses in adults have been reported at doses ranging from 9 to 12 g of rifampicin. Fatal severe overdoses in adults have been reported at doses ranging from 14 to 60 g. In some reports of fatal and non-fatal cases, alcohol presence in the body or chronic alcohol abuse was noted.

Reports of non-critical overdoses in children aged 1 to 4 years have been received following ingestion of one (100 mg/kg) or two doses.

Treatment: intensive supportive measures should be applied and individual symptoms treated as they arise. In cases of nausea and vomiting, gastric lavage should be performed. After gastric emptying, activated charcoal should be administered to eliminate any remaining drug in the gastrointestinal tract. Antiemetics may be required to control severe nausea and vomiting. Forced diuresis promotes drug elimination. Hemodialysis may be beneficial for some patients.

Adverse reactions.

Adverse effects have been classified according to their frequency of occurrence: very common — ≥ 1/10; common — ≥ 1/100 and < 1/10; uncommon — ≥ 1/1000 and < 1/100; rare — ≥ 1/10,000 and < 1/1000; very rare — < 1/10,000; frequency not known (cannot be estimated from the available data).

Rifampicin is generally well tolerated by patients, although cases of hypersensitivity reactions have been reported, and fever, skin rash, and nausea/vomiting have been observed in some patients.

There have been reports of phlebitis and pain at the injection site.

Reactions occurring with either daily or intermittent dosing regimens:

Infections and infestations: frequency not known — pseudomembranous colitis, influenza-like symptoms.

Blood and lymphatic system disorders: common — thrombocytopenia, with or without purpura (more frequent with intermittent therapy, reversible upon discontinuation of the drug); uncommon — leukopenia; frequency not known — disseminated intravascular coagulation, eosinophilia, agranulocytosis, hemolytic anemia, vitamin K-dependent coagulation disorders.

Immune system disorders: frequency not known — anaphylactic reaction.

Endocrine disorders: frequency not known — adrenal insufficiency in patients with impaired adrenal function.

Metalbolism and nutrition disorders: frequency not known — decreased appetite.

Psychiatric disorders: frequency not known — psychotic disorder.

Nervous system disorders: common — headache, dizziness; frequency not known — cerebral hemorrhage and fatal outcomes have been reported when treatment with rifampicin was continued or resumed after development of purpura.

Eye disorders: frequency not known — change in tear color.

Vascular disorders: frequency not known — shock, inflammation, vasculitis, bleeding.

Respiratory, thoracic and mediastinal disorders: frequency not known — dyspnea, wheezing, discoloration of sputum.

Gastrointestinal disorders: common — nausea, vomiting; uncommon — diarrhea; frequency not known — gastrointestinal disturbances, abdominal discomfort, tooth discoloration which may be irreversible.

Hepatobiliary disorders: frequency not known — hepatitis, hyperbilirubinemia.

Skin and subcutaneous tissue disorders: frequency not known — erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), acute generalized exanthematous pustulosis, skin reactions, pruritus, urticaria, allergic dermatitis, pemphigoid (bullous) reaction, change in sweat color.

Musculoskeletal and connective tissue disorders: frequency not known — muscle weakness, myopathy, bone pain.

Renal and urinary disorders: frequency not known — acute kidney injury, usually due to tubular necrosis or interstitial nephritis, chromaturia.

Pregnancy, puerperium and perinatal conditions: frequency not known — postpartum hemorrhage, fetomaternal hemorrhage.

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 conditions: very common — fever, chills; common — paradoxical drug reaction (recurrence or appearance of new symptoms of tuberculosis, clinical and radiological signs in a patient who previously showed improvement under appropriate anti-tuberculosis treatment, known as a paradoxical reaction, diagnosed after excluding poor patient compliance, drug resistance, adverse effects of anti-tuberculosis therapy, or secondary bacterial/fungal infections)*; frequency not known — edema.

Investigations: common — increased blood bilirubin levels, increased aspartate aminotransferase levels, increased alanine aminotransferase levels; frequency not known — decreased blood pressure, increased blood creatinine levels, increased liver enzyme levels.

* Frequency of paradoxical drug reactions: the lowest reported frequency was 9.2% (53/573) (data from October 2007 to March 2010), and the highest was 25% (19/76) (data between 2000 and 2010).

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua/.

Shelf life. 2 years.

Storage conditions.

Store in a protected from light and inaccessible to children place at a temperature not exceeding 25 °C.

The prepared solution is stable for 24 hours at a temperature not exceeding 25 °C.

Incompatibilities.

Do not use solvents not specified in the section "Instructions for use and dosage".

Packaging.

600 mg of powder in a vial; 1 vial per cardboard box.

Prescription status. Prescription only.

Manufacturer.

MYLAN LABORATORIES LIMITED – Sterile Products Division

Manufacturer's address and place of business.

Opp IIM, Bilekahalli, Bannerghatta Road, Bangalore, IN-560076, India

Marketing Authorization Holder.

M.BIOTECH LIMITED

Address of the Marketing Authorization Holder.

Gladstone House, 77-79 High Street, Egham TW20 9HY, Surrey, United Kingdom