Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2023 Publisher: Aventis Pharma Limited, 410 Thames Valley Park Drive, Reading, Berkshire, RG6 1PT, UK Trading as: Sanofi, 410 Thames Valley Park Drive, Reading, Berkshire, RG6 1PT, UK
Rifadin is contraindicated in:
Rifampicin should be given under the supervision of a respiratory or other suitably qualified physician.
Cautions should be taken in case of renal impairment if dose >600 mg/day.
All tuberculosis patients should have pre-treatment measurements of liver function.
Adults treated for tuberculosis with rifampicin should have baseline measurements of hepatic enzymes, bilirubin, serum creatinine, a complete blood count, and a platelet count (or estimate).
Baseline tests are unnecessary in children unless a complicating condition is known or clinically suspected.
Patients with impaired liver function should only be given rifampicin in cases of necessity, and then with caution and under close medical supervision. In these patients, lower doses of rifampicin are recommended and careful monitoring of liver function, especially serum alanine aminotransferase (ALT) and serum aspartate aminotransferase (AST) should initially be carried out prior to therapy, weekly for two weeks, then every two weeks for the next six weeks. If signs of hepatocellular damage occur, rifampicin should be withdrawn.
Rifampicin should also be withdrawn if clinically significant changes in hepatic function occur. The need for other forms of antituberculosis therapy and a different regimen should be considered. Urgent advice should be obtained from a specialist in the management of tuberculosis. If rifampicin is re-introduced after liver function has returned to normal, liver function should be monitored daily.
In patients with impaired liver function, elderly patients, malnourished patients, and possibly, children under two years of age, caution is particularly recommended when instituting therapeutic regimens in which isoniazid is to be used concurrently with Rifadin. If the patient has no evidence of pre-existing liver disease and normal pre-treatment liver function, liver function tests need only be repeated if fever, vomiting, jaundice or other deterioration in the patient’s condition occur.
Patients should be seen at least monthly during therapy and should be specifically questioned concerning symptoms associated with adverse reactions.
In some patients hyperbilirubinaemia can occur in the early days of treatment. This results from competition between rifampicin and bilirubin for hepatic excretion. An isolated report showing a moderate rise in bilirubin and/or transaminase level is not in itself an indication for interrupting treatment; rather the decision should be made after repeating the tests, noting trends in the levels and considering them in conjunction with the patient’s clinical condition.
Because of the possibility of immunological reaction including anaphylaxis (see section 4.8 Undesirable effects) occurring with intermittent therapy (less than 2 to 3 times per week) patients should be closely monitored. Patients should be cautioned against interrupting treatment.
Rifampicin has enzyme induction properties that can enhance the metabolism of endogenous substrates including adrenal hormones, thyroid hormones and vitamin D. Isolated reports have associated porphyria exacerbation with rifampicin administration.
Severe, systemic hypersensitivity reactions, including fatal cases, such as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome have been observed during treatment with anti-tuberculosis therapy (See section 4.8).
Rifadin capsules should be discontinued if an alternative etiology for the signs and symptoms cannot be established.
Severe cutaneous adverse reactions (SCARs) including Steven-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), which can be life-threatening or fatal, have been reported with a not known frequency in association with Rifadin capsules treatment.
After initial improvement of tuberculosis under therapy with Rifadin capsules, the symptoms may worsen again. In affected patients, clinical or radiological deterioration of existing tuberculous lesions or the development of new lesions have been detected. Such reactions have been observed within the first few weeks or months of initiation of tuberculosis therapy. Cultures are usually negative, and such reactions do not usually indicate treatment failure.
The cause of this paradoxical reaction is still unclear, but an exaggerated immune reaction is suspected as a possible cause. In case a paradoxical reaction is suspected, symptomatic therapy to suppress the exaggerated immune reaction should be initiated if necessary. Furthermore, continuation of the planned tuberculosis combination therapy is recommended.
Patients should be advised to seek medical advice immediately if their symptoms worsen. The symptoms that occur are usually specific to the affected tissues. Possible general symptoms include cough, fever, tiredness, breathlessness, headache, loss of appetite, weight loss or weakness (see section 4.8).
At the time of prescription patients should be advised of the signs and symptoms and monitored closely for skin reactions.
It is important to note that early manifestations of hypersensitivity, such as fever, lymphadenopathy or biological abnormalities (including eosinophilia, liver abnormalities) may be present even though rash is not evident. If such signs or symptoms are present, the patient should be advised to consult immediately their physician.
If signs and symptoms suggestive of these reactions appear, Rifadin capsules should be withdrawn immediately and an alternative treatment considered (as appropriate).
Most of these reactions occurred within 2 days to 2 months after treatment initiation; the time to onset can vary depending on the conditions.
Rifadin capsules may produce a discoloration (yellow, orange, red, brown) of the teeth, urine, sweat, sputum and tears, and the patient should be forewarned of this. Soft contact lenses have been permanently stained (see section 4.8).
Rifadin capsules are a well characterized and potent inducer of drug metabolizing enzymes and transporters and might therefore decrease or increase concomitant drug exposure, safety and efficacy (see Section 4.5). Therefore, potential drug interactions should be considered whenever beginning or discontinuing rifampicin treatment.
Rifampicin may cause vitamin K dependent coagulopathy and severe bleeding (see Section 4.8). Monitoring of occurrence of coagulopathy is recommended for patients at particular bleeding risk. Supplemental vitamin K administration should be considered when appropriate (vitamin K deficiency, hypoprothrombinemia).
There have been reports of interstitial lung disease (ILD) or pneumonitis in patients receiving Rifadin Capsules for treatment of tuberculosis (see section 4.8). ILD/pneumonitis is a potentially fatal disorder. Careful assessment of all patients with an acute onset and/or unexplained worsening of pulmonary symptoms (dyspnoea accompanied by dry cough) and fever should be performed to confirm the diagnosis of ILD/pneumonitis. If ILD/pneumonitis is diagnosed, Rifadin Capsules should be permanently discontinued in case of severe manifestations (respiratory failure and acute respiratory distress syndrome) and appropriate treatment initiated as necessary.
All patients with abnormalities should have follow up examinations, including laboratory testing, if necessary.
Sodium: This medicine contains less than 1 mmol sodium (23 mg) per daily dose, that is to say essentially ‘sodium-free’.
Therapeutic levels of rifampicin have been shown to inhibit standard microbiological assays for serum folate and Vitamin B12. Thus, alternative assay methods should be considered. Transient elevation of BSP and serum bilirubin has been reported. Rifampicin may impair biliary excretion of contrast media used for visualization of the gallbladder, due to competition for biliary excretion. Therefore, these tests should be performed before the morning dose of rifampicin.
When rifampicin is given concomitantly with the combination saquinavir/ritonavir, the potential for hepatotoxicity is increased. Therefore, concomitant use of Rifadin with saquinvir/ritonavir is contraindicated (see section 4.3 Contraindications).
When rifampicin is given concomitantly with either halothane or isoniazid, the potential for hepatotoxicity is increased. The concomitant use of rifampicin and halothane should be avoided. Patients receiving both rifampicin and isoniazid should be monitored closely for hepatotoxicity.
The concomitant use of rifampicin with other antibiotics causing vitamin K dependent coagulopathy such as cefazolin (or other cephalosporins with N-methyl-thiotetrazole side chain) should be avoided as it may lead to severe coagulation disorders, which may result in fatal outcome (especially in high doses).
Rifadin capsules are a well characterized and potent inducer of drug metabolizing enzymes and transporters. Enzymes and transporters reported to be affected by Rifadin capsules include cytochromes P450 (CYP) 1A2, 2B6, 2C8, 2C9, 2C19, and 3A4, UDP-glucuronyltransferases (UGT), sulfotransferases, carboxylesterases, and transporters including Pglycoprotein (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 by Rifadin capsules simultaneously. Therefore, Rifadin capsules may accelerate the metabolism and decrease the activity of certain co-administered drugs or increase the activity of a co-administered pro-drug (where metabolic activation is required), and has the potential to perpetuate clinically important drug-drug interactions against many drugs and across many drug classes (Table 1). To maintain optimum therapeutic blood levels, dosages of drugs may require adjustment when starting or stopping concomitantly administered Rifadin capsules.
Examples of drugs or drug classes affected by rifampicin:
Enalapril: Decrease enalapril active metabolite exposure. Dosage adjustments should be made if indicated by the patient’s clinical condition.
Hepatitis-C antiviral drugs (e.g, daclatasvir, simeprevir, sofosbuvir, telaprevir): Concurrent use of treatment of hepatitis-C antiviral drugs and rifampicin should be avoided.
Morphine: Plasma concentrations of morphine may be reduced by rifampicin. The analgesic effect of morphine should be monitored, and doses of morphine adjusted during and after treatment of rifampicin.
Clopidogrel: Increases active metabolite exposure. Rifadin strongly induces CYP2C19, resulting in both an increased level of clopidogrel active metabolite and platelet inhibition, which in particular might potentiate the risk of bleeding. As a precaution, concomitant use of clopidogrel and rifampicin should be discouraged.
Dapsone: Rifampicin has also been shown to increase the clearance of dapsone and the production of the hydroxylamine metabolite of dapsone which could increase the risk of methaemoglobinaemia, haemolytic anaemia, agranulocytosis, and haemolysis.
Systemic hormonal contraceptives including oestrogens and progestogens: Rifampicin treatment reduces the systemic exposure of oral contraceptives. Patients on oral contraceptives should be advised to use alternative, non-hormonal methods of birth control during Rifadin therapy.
Antidiabetic (e.g. chlorpropamide, tolbutamide, sulfonylureas, rosiglitazone): diabetes may become more difficult to control.
Antifungals (e.g. fluconazole, itraconazole, ketoconazole, voriconazole): Concurrent use of ketoconazole and rifampicin has resulted in decreased serum concentrations of both drugs.
If p-aminosalicylic acid and rifampicin are both included in the treatment regimen, they should be given not less than eight hours apart to ensure satisfactory blood levels.
Antacids: Concomitant antacid administration may reduce the absorption of rifampicin. Daily doses of rifampicin should be given at least 1 hour before the ingestion of antacids.
Paracetamol: Concomitant use of paracetamol with rifampicin may increase the risk of hepatotoxicity.
When the two drugs were taken concomitantly, decreased concentrations of atovaquone and increased concentrations of rifampicin were observed.
At very high doses in animals rifampicin has been shown to have teratogenic effects. There are no well controlled studies with rifampicin in pregnant women. Although rifampicin has been reported to cross the placental barrier and appear in cord blood, the effect of rifampicin, alone or in combination with other antituberculosis drugs, on the human foetus is not known. Therefore, Rifadin should be used in pregnant women or in women of child bearing potential only if the potential benefit justifies the potential risk to the foetus. When Rifadin is administered during the last few weeks of pregnancy it may cause post-natal haemorrhages in the mother and infant for which treatment with Vitamin K1 may be indicated.
Rifampicin is excreted in breast milk, patients receiving rifampicin should not breast feed unless in the physician’s judgement the potential benefit to the patient outweighs the potential risk to the infant.
No studies on the effects on the ability to drive and use machines have been performed.
The following CIOMS frequency rating is used, when applicable: Very common ≥10%; Common ≥1 and <10%; Uncommon ≥0.1 and <1%; Rare ≥0.01 and <0.1%; Very rare <0.01%, Unknown (cannot be estimated from available data).
Reactions occurring with either daily or intermittent dosage regimens include:
Unknown: Pseudomembranous colitis, Influenza
Common: Thrombocytopenia with or without purpura, usually associated with intermittent therapy, but is reversible if drug is discontinued as soon as purpura occurs.
Uncommon: Leukopenia
Unknown: Disseminated intravascular coagulation, Eosinophilia, Agranulocytosis, Hemolytic anemia, Vitamin K dependent coagulation disorders
Unknown: Anaphylactic reaction
Unknown: Adrenal insufficiency in patients with compromised adrenal function have been observed
Unknown: Decreased appetite
Unknown: Psychotic disorder
Common: Headache, Dizziness
Unknown: Cerebral hemorrhage and fatalities have been reported when rifampicin administration has been continued or resumed after the appearance of purpura
Unknown: Tear discolouration
Unknown: Shock, Flushing, Vasculitis, Bleeding
Unknown: Dyspnoea, Wheezing, Sputum discoloured
Common: Nausea, Vomiting
Uncommon: Diarrhea
Unknown: Gastrointestinal disorder, Abdominal discomfort, Tooth discolouration (which may be permanent)
Unknown: Hepatitis, Hyperbilirubinaemia (see section 4.4)
Unknown: Erythema multiforme, Stevens-Johnson syndrome (SJS), Toxic epidermal necrolysis (TEN), Drug reaction with eosinophilia and systemic symptoms (DRESS), Acute generalized exanthematous pustulosis (AGEP) (see section 4.4), Skin reaction, Pruritus, Rash pruritic, Urticaria, Dermatitis allergic, Pemphigoid, Sweat discoloration
Unknown: Muscle weakness, Myopathy, Bone pain
Unknown: Acute kidney injury usually due to renal tubular necrosis or tubulointerstitial nephritis, Chromaturia
Unknown: Post-partum haemorrhage, Fetal-maternal haemorrhage
Unknown: Menstrual disorder
Unknown: Porphyria
Very common: Pyrexia, Chills
Common: Paradoxical drug reaction (Recurrence or appearance of new symptoms of tuberculosis, physical and radiological signs in a patient who had previously shown improvement with appropriate antituberculosis treatment is called a paradoxical reaction, which is diagnosed after excluding poor compliance of the patient to treatment, drug resistance, side effects of antitubercular therapy, secondary bacterial/fungal infections).*
Unknown: Edema
Common: Blood bilirubin increased, Aspartate aminotransferase increased, Alanine aminotransferase increased
Unknown: Blood pressure decreased, Blood creatinine increased, Hepatic enzyme increased
* Incidence of paradoxical drug reaction: Lower frequency is reported as 9.2% (53/573) (data between October 2007 and March 2010) and higher frequency is reported as 25% (19/76) (data between 2000 and 2010).
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
None stated.
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