RISOPET Film coated tablet Ref.[115165] Active ingredients: Ethambutol Isoniazid Pyrazinamide Rifampicin

Liver function should be assessed before and regularly during treatment as each active ingredient contained in RISOPET has been associated with liver dysfunction.

In cases of known acetylation phenotypes, patients with extremely fast or extremely slow acetylating capability should receive the four components of RISOPET separately in order to facilitate dose adjustment of isoniazid.

Hypersensitivity

Treatment should be discontinued permanently should shock, renal failure, haemolytic anaemia, dyspnoea and asthma-like attacks, thrombocytopenia or purpura occur as these are side effects that rifampicin may provoke in exceptional cases. Patients developing such reactions must never again be treated with rifampicin. Patients should be advised against interrupting treatment. Use of RISOPET after interruption has been associated with increased risk of serious adverse effects. Treatment with RISOPET tablets should be stopped immediately and the patient evaluated should rash and fever occur.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)

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 section 4.8). 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. RISOPET should be permanently discontinued if an alternative aetiology for the signs and symptoms cannot be established.

Impaired liver function, undernourishment, alcoholism

Rifampicin, isoniazid, pyrazinamide and ethambutol are metabolised in the liver. Elevated transaminase levels, above the upper limit of normal (ULN), commonly occur. Liver dysfunction that may occur in the first few weeks of treatment usually returns to the normal range spontaneously, without interruption of treatment, and usually by the third month of treatment.

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.

A moderate rise in bilirubin and/or transaminase levels is not in itself an indication for interrupting treatment; rather, the decision should be made after repeating these liver function tests, noting trends in the levels, and considering them in conjunction with the patient’s clinical condition.

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.

Treatment with RISOPET tablets should be stopped immediately and the patient evaluated in the following cases: jaundice or elevated liver enzymes associated with the clinical signs of hepatitis since continued use of the medicine in these cases has been reported to cause a more severe form of liver damage.

Special care should be exercised in alcoholic patients, the elderly (patients of 50 years and older have the highest incidence of hepatitis with the use of isoniazid) or those with pre-existing hepatic disease.

Risk of neuropathy or pyridoxine deficiency, including those who are alcoholic, malnourished, diabetic, uremic, HIV infected or pregnant, supplementation with pyridoxine (in a 10 mg to 50 mg daily dose) is usually required under these circumstances.

Medicine reaction with eosinophilia and systemic symptoms (“DRESS”)

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 section 4.8). 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. RISOPET should be discontinued if an alternative aetiology for the signs and symptoms cannot be established.

Impaired renal function

Impaired kidney function: dosage adjustment may be necessary according to the ethambutol serum concentration.

In severe renal insufficiency, the elimination of isoniazid, pyrazinamide and ethambutol can be delayed leading to a higher systemic exposure, which can result in an increase in adverse events. RISOPET should be used with caution in patients with moderate renal impairment (creatinine clearance 30-60 ml/min).

Gout

In patients with a history of gout, regular monitoring of serum uric acid should be undertaken. RISOPET treatment should be stopped in gouty arthritis.

Haematology

Full blood count should be monitored during prolonged treatment and in patients with hepatic disorders. Rifampicin should be withdrawn permanently if thrombocytopenia or purpura occur. The possibility of pyrazinamide having an undesirable effect on blood clotting time or vascular integrity should be borne in mind in patients with haemoptysis.

Diabetes mellitus

Pyrazinamide may interfere with the measurement of urine ketone levels (see section 4.5).

Increased difficulty has been reported in controlling diabetes mellitus when such patients are given isoniazid.

Epilepsy/psychosis

Caution should be observed with the use of RISOPET in patients with

• Epilepsy, as convulsions may be triggered
• History of psychosis

Visual defects

Should visual disturbances arise during treatment with RISOPET tablets (especially in the elderly, and in children in whom evaluation of changes in visual acuity may be difficult), it must be reported immediately, and the medicine discontinued pending visual evaluation. Periodic eye examinations during treatment are suggested.

Contraception

The efficacy of oral contraceptives may be affected by rifampicin; patients should be advised to change to non-hormonal methods for effective birth control (see section 4.5).

Antacids

The absorption of rifampicin may be reduced by antacids, but this interaction can be overcome by giving RISOPET an hour before any antacid. Similarly, RISOPET and preparations containing bentonite (e.g. some amino-salicylic acid preparations) should be given 8 hours apart (see section 4.5).

Discolouration of teeth, body fluids and contact lenses

Treatment with RISOPET tablets may lead to reddish-orange colouration of faeces, saliva, sputum, urine, tears and sweat. Soft contact lenses may be stained irreversibly. Avoid the wearing of soft contact lenses during treatment.

Influence of other medicines on RISOPET

Antacids reduce the bioavailability of rifampicin, isoniazid and ethambutol. To avoid this interaction, RISOPET should be taken at least 1 hour before antacids (see section 4.4). Glucocorticosteroids may increase hepatic metabolism and/or excretion of isoniazid.

Influence of RISOPET on other medicines

Rifampicin and isoniazid

Cytochrome P-450 enzyme interaction

Rifampicin induces and isoniazid inhibits certain cytochrome P-450 enzymes. Care should be taken when RISOPET tablets are prescribed with medicines metabolised by cytochrome P-450. To maintain optimum therapeutic plasma levels, the dosages of medicines metabolised by cytochrome P-450 enzymes may require adjustment when initiating or stopping concomitant administration of RISOPET tablets.

Some medicines are affected in the opposite direction by rifampicin and isoniazid, e.g. phenytoin, warfarin and theophylline. The net effect cannot be predicted and may change over time.

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 with rifampicin.

Medicines that are eliminated by metabolism should only be used concomitantly with RISOPET if the plasma concentrations or clinical response/undesirable effects can be monitored and the dose can be adequately adjusted. Monitoring should be performed regularly during RISOPET therapy and for 2-3 weeks after discontinuation of the therapy.

The enzyme inducing effects of rifampicin reach a peak within 10 days and gradually decrease over a period of 2 or more weeks after discontinuation of rifampicin treatment, factors that must be taken into account if the dose of other medicinal products is increased during treatment with RISOPET.

Rifampicin

Combinations contraindicated

Enzyme induction:

When RISOPET is given concurrently with the combination saquinavir/ritonavir, the potential for hepatotoxicity is increased. Concomitant use with voriconazole and saquinavir/ritonavir, protease inhibitors, except ritonavir when given at full dose or 600 mg twice daily is contraindicated (see section 4.3).

Combinations not recommended

Use of the following medicines concomitantly with RISOPET is not recommended: nevirapine, simvastatin, oral contraceptives and ritonavir (when given in low doses as a booster a marked reduction of plasma concentration might occur) (see section 4.4).

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.

Combinations requiring precaution

Rifampicin increases the rate of metabolism of certain medicines by inducing microsomal enzymes, resulting in decreases in the plasma levels of such medicines.

Examples of medicines metabolised by cytochrome P-450 enzymes include analgesics (e.g. methadone, narcotic analgesics, morphine, etoricoxib, rofecoxib), antidysrhythmics (e.g. disopyramide, mexiletine, quinidine, propafenone, tocainide, verapamil), antibacterials (e.g. chloramphenicol, clarithromycin, dapsone, doxycycline, fluoroquinolones, telithromycin, linezolid, p-aminosalicylic acid) anticoagulants (e.g. warfarin), anticonvulsants (e.g. phenytoin, tiagabine, carbamazepine), antiestrogens (e.g. tamoxifen, toremifene, gestrinone), antifungals (e.g. fluconazole, itraconazole, ketoconazole, voriconazole, terbinafine), antipsychotics (e.g. haloperidol, clozapine, aripiprazole), antiretrovirals (e.g. zidovudine, delavidine, saquinavir, indinavir, efavirenz and protease inhibitors), atovaquone, 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, nimodipine, isradipine, nicardipine, nisoldipine, amlodipine), cardiac glycosides (e.g. digoxin), cimetidine, clofibrate, clofazimine, co-trimoxazole, cytotoxics (e.g. imatinib, geftinib, irinotecan), diuretics (e.g. eplerenone), systemic hormonal contraceptives, corticosteroids, estrogens, fexofenadine, , oral hypoglycaemic agents (sulfonylureas), immunosuppressive agents (e.g. azathioprine, cyclosporine, tacrolimus), irinotecan, levothyroxine, losartan, imidapril, enalapril, praziquantel, progestins, quinine, riluzole, selective 5-HT3 receptor antagonists (e.g. ondansetron), statins metabolised by CYP 3A4, fluvastatin, sulphasalazine, thiazolidinediones (e.g. rosiglitazone), theophylline, thyroid hormone (e.g. levothyroxine), tricyclic antidepressants (e.g. amitriptyline). It may be necessary to adjust the dosages of these medicines if they are given concurrently with rifampicin.

The effectiveness of estrogen-containing oral preparations is reduced. Patients using systemic hormonal contraceptives should be advised to use additional precautions or to switch to non-hormonal methods of contraception during rifampicin therapy (see section 4.4).

Concurrent use of alcohol, isoniazid, paracetamol, and other hepatotoxic medicines may increase the incidence of rifampicin-induced hepatotoxicity.

Concurrent use of 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.

Interference with laboratory and diagnostic tests:

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. RISOPET 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.

Isoniazid

Combinations requiring precaution

Chronic use of isoniazid may decrease the plasma clearance and prolong the duration of action of alfentanil, benzodiazepines (diazepam, triazolam), carbamazepine, chlorzoxazone, coumarin anticoagulants, ethosuximide, primidone, theophylline, disulfiram and phenytoin. 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 alcohol, paracetamol, rifampicin and other hepatotoxic agents, may increase the potential for isoniazid-induced hepatotoxicity.

Aluminium-containing antacids may delay absorption and decrease serum concentrations of isoniazid.

Glucocorticosteroids 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, cycloserine and other neurotoxic medicines may increase the potential for CNS toxicity.

Isoniazid may increase the formation of potentially nephrotoxic inorganic fluoride metabolites when used concomitantly with enflurane.

Interactions with miconazole and ketoconazole have been reported.

Copper sulphate urine glucose tests may show false positive reactions.

Consumption of red wine, cured meat, beer and certain types of cheese e.g. Swiss or Cheshire (tyramine-containing foods), or foods containing histamine e.g. fish such as tuna, skipjack, other tropical fish, salmon, mackerel may result in chills or headache, sweating, flushing, hypotension, itching of the skin and a rapid or pounding heart. Tyramine-and histamine-containing foods should be avoided by patients on RISOPET therapy.

Pyrazinamide

Combinations requiring precaution

Pyrazinamide may decrease the efficacy of medicines used in the treatment of gout (e.g. allopurinol, colchicine, probenecid or sulphinpyrazone). Dosage adjustments of these medicines may be necessary.

The dosage of pyrazinamide may be decreased by zidovudine.

Pyrazinamide may interfere with the measurement of urine ketone levels in patients with diabetes (see section 4.4).

Ethambutol

Combinations requiring precaution

Concurrent use of ethambutol with neurotoxic medicines may potentiate neurotoxic effects such as optic and peripheral neuritis.

Pregnancy

The safety of RISOPET tablets in pregnancy 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.

Breastfeeding

All components of RISOPET tablets are excreted in breast milk.

The safety of RISOPET tablets in breast feeding has not been established.

RISOPET can cause side-effects such as confusion, disorientation, dizziness or drowsiness and visual disturbances. RISOPET may impair your ability to drive and use machinery. Patients should be advised to not drive, operate machinery, or do anything else that could be dangerous until they know how RISOPET affects them.

Tabulated summary of adverse reactions

Side effects associated with rifampicin:

Side effects associated with pyrazinamide:

Side effects associated with ethambutol:

The adverse effects for each of the active ingredients as listed above are possible side effects when taking the combination tablet RISOPET.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions to SAHPRA via the online service for adverse drug reaction reporting by following the link: https://www.sahpra.org.za/Publications/Index/8.

An email can be sent directly to the company, pharmacovigilance@pharmadynamics.co.za to ensure safety of the product.

Not applicable.