Source: Health Products Regulatory Authority (ZA) Revision Year: 2018 Publisher: sanofi-aventis south africa (pty) ltd., 2 Bond Street, Midrand, South Africa, 1685
RIFAFOUR e-275 tablets are contraindicated in:
RIFAFOUR e-275 is contraindicated when given concurrently with the combination of saquinavir/ritonavir (see INTERACTIONS).
Rifampicin very markedly reduces ketoconazole levels. Rifampicin levels are halved by ketoconazole (see INTERACTIONS).
RIFAFOUR e-275 tablets is a combination of four medicines, each of which has been associated with liver dysfunction.
Patients with impaired liver function should only be given rifampicin in cases of necessity and then with caution and under strict medical supervision. In these patients, careful monitoring of liver function, especially serum alanine aminotransferase (ALT) and serum aspartate aminotransferase (AST) should be carried out prior to therapy and then every 2 to 4 weeks during therapy. If signs of hepatocellular damage occur, rifampicin should be withdrawn. In some cases, hyperbilirubinaemia resulting from competition between rifampicin and bilirubin for excretory pathways of the liver at cell level can occur in the early days of treatment. 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 the trends in the levels and considering them in conjunction with the patient's clinical condition.
Because of the possibility of immunological reactions, including anaphylaxis (see SIDE EFFECTS), occurring with intermittent therapy (less than 2 to 3 times per week), patients should be closely monitored. Patients should be cautioned against interruption of dosage regimens since these reactions may occur.
Use of isoniazid should be carefully monitored in patients with current chronic liver disease or severe renal dysfunction. Severe and sometimes fatal hepatitis associated with isoniazid therapy may occur and may develop even after months of treatment. The risk of developing hepatitis is age related. Therefore, patients should be monitored for the prodromal symptoms of hepatitis, such as fatigue, weakness, malaise, anorexia, nausea or vomiting. If these symptoms appear or if signs suggestive of hepatic damage are detected isoniazid should be discontinued promptly since continued use of the medicine in these cases has been reported to cause a more severe form of liver damage.
Cases of severe cutaneous reactions including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some with a fatal outcome, have been reported with the use of isoniazid (see SIDE EFFECTS). Patients should be advised of the signs and symptoms and monitored closely for skin reactions. If signs or symptoms of SJS or TEN (e.g. progressive skin rash often with blisters or mucosal lesions) develop, the patient should be advised to consult their doctor immediately. RIFAFOUR e-275 should be permanently discontinued if an alternative aetiology for the signs and symptoms cannot be established.
RIFAFOUR e-275 should be used with caution in patients with a history of gout. If hyperuricaemia accompanied by an acute gouty arthritis occurs, the patient should be transferred to a regimen not containing pyrazinamide.
Severe, systemic hypersensitivity reactions, including fatal cases, such as medicine reaction with eosinophilia and systemic symptoms (DRESS) syndrome have been observed during treatment with anti-tuberculosis therapy (see SIDE EFFECTS).
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 their doctor immediately. RIFAFOUR e-275 should be discontinued if an alternative aetiology for the signs and symptoms cannot be established.
Monitoring:
Adults treated for tuberculosis with RIFAFOUR e-275 should have baseline measurements of hepatic enzymes, bilirubin, serum creatinine, a complete blood count, and a platelet count (or estimate).
Patients should be seen at least monthly during therapy and should be questioned specifically about symptoms associated with adverse reactions. All patients with abnormalities should have follow-up, including laboratory testing, if necessary. However, because there is a higher frequency of isoniazid-associated hepatitis with patients older than 35 years of age, liver function tests should be performed periodically in older persons. Other factors associated with an increased risk of hepatitis include daily use of alcohol, those who are slow acetylators and with chronic liver disease.
Periodic eye examinations during treatment are suggested. Patients with visual defects: should visual disturbances occur during treatment, these must be reported immediately and RIFAFOUR e-275 discontinued pending visual evaluation.
In the following cases, treatment with RIFAFOUR e-275 tablets should be stopped immediately and the patient evaluated: jaundice, rash and fever, elevated liver enzymes associated with the clinical signs of hepatitis, visual impairment. If liver damage is confirmed, the medicine should not be recommenced.
Treatment should be discontinued permanently should thrombocytopenia, purpura, shock or renal failure occur.
Porphyria exacerbation:
Reports have associated porphyria exacerbation with rifampicin administration as a result of induction of delta amino levulinic acid synthetase (see CONTRAINDICATIONS).
Metabolism of endogenous substrates:
Rifampicin has enzyme induction properties that can enhance the metabolism of endogenous substrates including adrenal hormones, thyroid hormones and vitamin D.
Oral contraceptives:
Rifampicin may decrease the effect of oral contraceptives and patients are advised to change to non-hormonal methods of birth control.
Antacid:
Concomitant antacid administration may reduce the absorption of rifampicin by up to about one-third. Daily doses of rifampicin should be given at least 1 hour before the ingestion of antacids (see INTERACTIONS for rifampicin).
Discolouration of teeth, body fluids and contact lenses:
Rifampicin may produce a discolouration (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 SIDE EFFECTS).
Pyridoxine supplementation:
Patients at risk of neuropathy or pyridoxine deficiency, including those who are diabetic, alcoholic, elderly, malnourished, uraemic, have HIV infection or are pregnant: pyridoxine (vitamin B6) supplementation (in a 10 mg to 50 mg daily dose) is usually required.
Caution should be observed with the use of RIFAFOUR e-275 tablets in patients:
Caution should be observed with the use of RIFAFOUR e-275 tablets in patients with diabetes. Pyrazinamide may cause interference with urine ketone determinations.
Caution should be observed with the use of RIFAFOUR e-275 tablets in patients with impaired kidney function: dosage adjustment may be required according to the serum concentration of ethambutol.
Hyperglycaemia and lactose intolerance:
RIFAFOUR e-275 tablets contain lactose, which may have an effect on the glycaemic control of patients with diabetes mellitus. Each tablet contains 54,66 mg lactose monohydrate. Patients with the rare hereditary conditions of galactose intolerance e.g. galactosaemia, Lapp lactase deficiency or glucose-galactose malabsorption should not take RIFAFOUR e-275.
When RIFAFOUR e-275 is given concomitantly with the combination saquinavir/ritonavir, the potential for hepatotoxicity is increased. Therefore, concomitant use of RIFAFOUR e-275 with saquinavir/ritonavir is contraindicated (see CONTRAINDICATIONS).
Rifampicin is known to induce and isoniazid is known to inhibit certain cytochrome P 450 enzymes. Caution should be used when prescribing RIFAFOUR e-275 tablets with medicines metabolised by cytochrome P 450. To maintain optimum therapeutic blood levels, dosages of medicines metabolised by these enzymes may require adjustment when starting or stopping concomitantly administered RIFAFOUR e-275 tablets.
Rifampicin accelerates the metabolism of certain medicines by inducing microsomal enzymes, leading to decreases in plasma concentration of such medicines.
Examples of medicines metabolised by cytochrome P 450 enzymes are: anticonvulsants (e.g. phenytoin), antidysrhythmics (e.g. disopyramide, flecainide, quinidine, propafenone, verapamil), antioestrogens (e.g. tamoxifen, toremifen), antipsychotics (e.g. haloperidol), oral anticoagulants (e.g. warfarin), antifungals (e.g. fluconazole, itraconazole, ketoconazole), antiretroviral medicines (e.g. atazanavir, lopinavir, nevirapine, zidovudine, saquinavir, indinavir, efavirenz), barbiturates (e.g. hexobarbitone), beta-blockers, benzodiazepines (e.g. diazepam), benzodiazepine-related medicines (e.g. zopiclone, zolpidem), calcium channel blockers (e.g. diltiazem, nifedipine, verapamil), chloramphenicol, cimetidine, clarithromycin, corticosteroids, cardiac glycosides (e.g. digoxin), clofibrate, systemic hormonal contraceptives, dapsone, doxycycline, oestrogens, fluoroquinolones (e.g. ciprofloxacin, levofloxacin), gestrinone, oral hypoglycaemic agents (sulfonylureas), immunosuppressive agents (e.g. azathioprine, ciclosporin, sirolimus, tacrolimus), irinotecan, levothyroxine, losartan, narcotic analgesics, methadone, phenytoin, praziquantel, progestins, quinine, riluzole, selective 5-HT3 receptor antagonists (e.g. ondansetron) statins metabolised by CYP3A4 (e.g. atorvastatin, simvastatin), sulfasalazine, telithromycin, theophylline, thiazolidinediones (e.g. pioglitazone), tricyclic antidepressants (e.g. amitriptyline, nortriptyline).
It may be necessary to adjust the dosages of these medicines if they are given concurrently with rifampicin.
The effectiveness of oestrogen-containing oral preparations is reduced. Patients using systemic hormonal contraceptives should be advised to change to non-hormonal methods of birth control during rifampicin therapy (see WARNINGS AND SPECIAL PRECAUTIONS).
When the two medicines were taken concomitantly, decreased concentrations of atovaquone and increased concentrations of rifampicin were observed. Rifampicin reduces serum atovaquone levels by about 50%, whereas atovaquone modestly raises serum rifampicin levels.
Concurrent use of itraconazole, ketoconazole, voriconazole and rifampicin has resulted in decreased serum concentrations of both medicines.
Concurrent use of rifampicin and enalapril has resulted in decreased concentrations of enalaprilat, the active metabolite of enalapril. Dosage adjustments should be made if indicated by the patient's clinical condition.
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.
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.
Concurrent use of alcohol, paracetamol and other hepatotoxic medication may increase the incidence of rifampicin-induced hepatotoxicity.
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 serum bilirubin has also been observed. RIFAFOUR e-275 tablets may impair biliary excretion of contrast media used for visualisation of the gallbladder, due to competition for biliary excretion. Therefore, these tests should be performed before the morning dose of rifampicin.
Chronic use of isoniazid may decrease the plasma clearance and prolong the duration of action of alfentanil, the benzodiazepines diazepam and triazolam, the antiepileptics carbamazepine, phenytoin, ethosuximide and primidone, disulfiram and theophylline.
Appropriate adjustment of the anticonvulsant dose may be required. Isoniazid has been associated with increased concentrations or toxicity of cycloserine and warfarin. Concurrent use of paracetamol, alcohol, rifampicin and other hepatotoxic medication, may increase the potential for isoniazid-induced hepatotoxicity.
Aluminium-containing antacids may delay absorption and decrease serum concentrations of isoniazid.
Glucocorticoid corticosteroids may increase hepatic metabolism and/or excretion of isoniazid. para-Aminosalicylic acid may increase the plasma concentration and elimination half-life of isoniazid.
Concurrent use of ciclosporin, disulfiram and other neurotoxic medicines may increase the potential for CNS toxicity. Interactions with ketoconazole and miconazole have been reported. False positive reactions with copper sulphate urine glucose tests may occur.
Because isoniazid has some monoamine oxidase inhibiting activity, an interaction with tyramine-containing foods (cheese, red wine) may occur. Diamine oxidase may also be inhibited, causing exaggerated response (e.g. headache, sweating, palpitations, flushing, hypotension) to foods containing histamine (e.g. skipjack, tuna, other tropical fish). Tyramine- and histamine-containing foods should be avoided by patients receiving RIFAFOUR-e-275.
Pyrazinamide may decrease the efficacy of gout therapy (e.g. allopurinol, colchicine, probenecid or sulphinpyrazone) and dosage adjustments of this medication may be necessary.
Concurrent administration of neurotoxic medication with ethambutol may potentiate neurotoxic effects such as optic and peripheral neuritis.
Safety in pregnancy has not been established.
All agents of RIFAFOUR e-275 tablets are excreted in breast milk. Safety during lactation has not been established.
Rifampicin has been reported to cross the placental barrier. When administered during the last weeks of pregnancy, rifampicin can cause post-natal haemorrhages in the mother and infant, for which treatment with vitamin K may be indicated.
RIFAFOUR e-275 may cause undesirable effects, e.g. vertigo, dizziness, psychotic reactions and visual disturbances, which may reduce the capacity for the completion of certain tasks (see SIDE EFFECTS). Patients should be informed of the potential for these undesirable effects that may occur and if they experience these symptoms, consideration should be given not to drive or operate machinery.
Side effects associated with rifampicin:
Frequency unknown: pseudomembranous colitis; a 12 hour "flu" syndrome, usually occurring after 3 to 6 months of intermittent treatment and usually with doses of 20 mg/kg or more, may present as fever, chills, bone pain and malaise, shortness of breath and wheezing.
Frequent: thrombocytopenia with or without purpura is usually associated with intermittent regimens but is reversible if the medicine is discontinued as soon as purpura occurs.
Less frequent: leucopenia
Frequency unknown: disseminated intravascular coagulation, eosinophilia, agranulocytosis, haemolytic anaemia, haemolysis
Frequency unknown: anaphylactic reaction, lupus-like syndrome
Frequency unknown: adrenal insufficiency in patients with compromised adrenal function
Frequency unknown: decreased appetite
Frequency unknown: psychotic disorder
Frequency unknown: headache, dizziness, drowsiness, ataxia, numbness, confusion, generalised numbness; cerebral haemorrhage and fatalities have been reported when rifampicin administration has been continued or resumed after the appearance of purpura.
Less frequent: eye irritation visual disturbances
Frequency unknown: tear discolouration, blurred vision, soft contact lenses may be permanently stained (see WARNINGS AND SPECIAL PRECAUTIONS)
Frequency unknown: shock, flushing, vasculitis
Frequency unknown: dyspnoea, wheezing, discoloured sputum
Frequent: nausea, vomiting
Less frequent: diarrhoea
Frequency unknown: gastrointestinal disorder, abdominal discomfort, epigastric distress (which may be alleviated by administration with food), tooth discolouration (which may be permanent)
Frequency unknown: hepatitis and the prodromal symptoms of hepatitis may occur (nausea, vomiting, unusual tiredness/fatigue); hyperbilirubinaemia. Liver function should be monitored (see WARNINGS AND SPECIAL PRECAUTIONS)
Frequency unknown: erythema multiforme including Stevens-Johnson syndrome and toxic epidermal necrolysis, medicine reaction with eosinophilia and systemic symptoms (DRESS) syndrome (see WARNINGS AND SPECIAL PRECAUTIONS); skin reaction, pruritus, pruritic rash, urticaria, erythema, allergic dermatitis, pemphigoid, sweat discolouration
Frequency unknown: muscular weakness, myopathy, bone pain
Frequency unknown: alterations in kidney function, acute kidney injury usually due to renal tubular necrosis or to tubulointerstitial nephritis, chromaturia
Frequency unknown: post-partum haemorrhage, fetal-maternal haemorrhage (see HUMAN REPRODUCTION)
Frequency unknown: menstrual disorder
Frequency unknown: porphyria exacerbation (see CONTRAINDICATIONS and WARNINGS AND SPECIAL PRECAUTIONS)
Frequent: pyrexia, chills
Frequency unknown: oedema
Frequent: increased blood bilirubin, increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT) (see WARNINGS AND SPECIAL PRECAUTIONS)
Frequency unknown: decreased blood pressure, increased blood creatinine, increased hepatic enzyme (see WARNINGS AND SPECIAL PRECAUTIONS)
Side effects associated with isoniazid:
Frequency unknown: eosinophilia, agranulocytosis, thrombocytopenia, anaemia (sideroblastic anaemia, haemolytic anaemia, neutropenia, and less frequently, aplastic anaemia)
Less frequent: hypersensitivity reactions (skin eruptions including erythema multiforme, lymphadenopathy), systemic lupus erythematosus-like syndrome
Frequency unknown: anaphylactic reactions
Frequency unknown: gynecomastia
Frequency unknown: pellagra, hyperglycaemia, metabolic acidosis
Frequency unknown: psychotic reactions
Frequent: peripheral neuropathy (pyridoxine supplementation prevents the development of peripheral neuritis as well as most other nervous system dysfunctions (see WARNINGS AND SPECIAL PRECAUTIONS).
Frequency unknown: polyneuritis presenting as paraesthesia, muscle weakness, loss of tendon reflexes, etc., convulsions (frequency of seizures may be increased in patients with epilepsy), toxic encephalopathy, optic neuritis and atrophy, memory impairment, toxic psychosis
Frequency unknown: vertigo
Frequency unknown: vasculitis
Less frequent: pancreatitis
Frequency unknown: nausea, vomiting, dry mouth, constipation, epigastric distress
Frequency unknown: severe and sometimes fatal hepatitis. Elevated liver enzymes associated with clinical signs of hepatitis such as nausea, vomiting or fatigue may indicate hepatic damage. The incidence of liver damage is highest in patients over 35 years of age, those who are slow acetylators and those who consume alcohol on a daily basis.
Frequency unknown: rash, acne, exfoliative dermatitis, medicine reaction with eosinophilia and systemic symptoms (DRESS) syndrome, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), (see WARNINGS AND SPECIAL PRECAUTIONS), pemphigus, lupus erythematosus-like reactions, purpura, alopecia
Frequency unknown: rheumatoid syndrome
Frequency unknown: urinary retention
Frequency unknown: fever
Side effects associated with pyrazinamide:
Frequency unknown: sideroblastic anaemia, thrombocytopenia with or without purpura
Frequent: hyperuricaemia (may lead to attacks of gout)
Frequency unknown: gout, anorexia
Frequency unknown: nausea, vomiting, aggravation of peptic ulcer
Frequency unknown: hepatitis. The most serious side effect is hepatotoxicity and its frequency appears to be dose-related. It varies from a symptomless abnormality of hepatic cell function through a mild syndrome of fever, malaise and liver tenderness, to more serious reactions such as clinical jaundice and rare cases of acute yellow atrophy and death.
Less frequent: angioedema
Frequency unknown: medicine reaction with eosinophilia and systemic symptoms (DRESS) syndrome (see WARNINGS AND SPECIAL PRECAUTIONS), photosensitivity, pruritus, erythema, rash
Less frequent: arthralgia
Frequency unknown: dysuria
Frequency unknown: malaise, fever
Side effects associated with ethambutol:
Frequency unknown: leucopenia, thrombocytopenia
Frequency unknown: hyperuricaemia
Frequency unknown: confusion, disorientation, hallucinations
Frequency unknown: peripheral neuritis, headache, dizziness
Less frequent: retinal haemorrhage
Frequency unknown: retrobulbar neuritis (with a reduction in visual acuity, constriction of visual field, central or peripheral scotoma, and green-red colour blindness may occur, affecting one or both eyes. The degree of visual impairment appears to depend on the dose and duration of therapy.
Frequency unknown: metallic taste, nausea, vomiting, anorexia, abdominal pain
Frequency unknown: jaundice or transient liver dysfunction
Frequency unknown: medicine reaction with eosinophilia and systemic symptoms (DRESS) syndrome (see WARNINGS AND SPECIAL PRECAUTIONS), hypersensitivity reactions include skin rash, pruritus
Frequency unknown: arthralgia
Frequency unknown: renal clearance of urate may be reduced and acute gout has been precipitated
Frequency unknown: malaise, fever
Frequency unknown: pulmonary infiltrates
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