AFARIS PAED 75/50 Tablet Ref.[115239] Active ingredients: Isoniazid Rifampicin

Rifampicin

• Patients with impaired liver function should not be given AFARIS PAED 75/50. Should AFARIS PAED 75/50 be the only treatment option in these patients, careful monitoring of liver function, especially serum glutamic pyruvic transaminase ALT and serum glutamic oxaloacetic transaminase AST, should be carried out prior to therapy and repeated every two to four weeks during therapy. If signs of hepatocellular damage occur, AFARIS PAED 75/50 should be withdrawn (see section 4.3). A report showing a moderate rise in bilirubin and/or transaminase level in itself is not an indication for interruption of treatment. This decision should rather be made after repeating the tests, noting trends in the levels and considering them in conjunction with the patient’s clinical condition.
• Liver function should be checked before and during treatment with AFARIS PAED 75/50 and special care should be taken in alcoholic patients or those with pre-existing liver disease should AFARIS PAED 75/50 be the only treatment option (see Section 4.3). Dosage adjustment is necessary where there is evidence of hepatic function impairment and treatment may need to be changed where there is more serious liver toxicity. Blood counts should be monitored during prolonged treatment and in patients with hepatic disorders (see section 4.3). If other serious complications arise e.g. renal failure or haemolytic anaemia, AFARIS PAED 75/50 should be stopped and never restarted.
• Because of the possibility of immunological reactions including anaphylaxis 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.
• Patients should be advised that discolouration of the urine, faeces, saliva, sputum, sweat and tears may occur. Patients should be further advised that soft contact lenses may be permanently stained.
• Rifampicin has enzyme induction properties that can enhance the metabolism of endogeneous substrates including adrenal hormones, thyroid hormones and vitamin D.

Isoniazid

• Use of isoniazid as contained in AFARIS PAED 75/50 is contra-indicated in patients with chronic liver disease or renal dysfunction. Should AFARIS PAED 75/50 be the only treatment option, these patients should be carefully monitored. Severe and sometimes fatal hepatitis associated with isoniazid therapy may occur and may even develop after many months of treatment. The risk of developing hepatitis is age related. Patients should be monitored for 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, treatment should be discontinued promptly. Continued use of AFARIS PAED 75/50 in these cases may cause a more severe form of liver damage and may exacerbate convulsive disorders (see Section 4.3).
• Liver function should be checked before and during treatment with AFARIS PAED 75/50 and special care should be taken in alcoholic patients or those with pre-existing liver disease should AFARIS PAED 75/50 be the only treatment option (see Section 4.3). Periodic eye examinations during AFARIS PAED 75/50 treatment have been suggested.
• Vitamin B6 in a dose of 15 to 50 mg per day should be administered with isoniazid therapy to minimise adverse reactions in malnourished patients and those predisposed to neuropathy.
• Use of isoniazid should be carefully monitored in patients with slow acetylators status (see section 5.2), history of psychosis, history of peripheral neuropathy and HIV infection.

Excipients

AFARIS PAED 75/50 contains 3,13 mg aspartame in each tablet.

Aspartame is a source of phenylalanine. It may be harmful if you have phenylketonuria (PKU), a rare genetic disorder in which phenylalanine builds up because the body cannot remove it properly.

Rifampicin

The concomitant use of AFARIS PAED 75/50 and nevirapine is contraindicated.

When AFARIS PAED 75/50 is given concomitantly with the combination of saquinavir/ritonavir, the potential for hepatotoxicity is increased. Therefore, concomitant use of AFARIS PAED 75/50 with saquinavir/ritonavir is contraindicated.

Halogenated inhalation anaesthetics, when given concomitantly with rifampicin has been reported to increase the hepatotoxicity of both rifampicin and isoniazid.

Ketaconazole has been reported to diminish the serum concentrations of both medicines when given concomitantly.

Rifampicin has liver-enzyme inducing properties and may reduce the activity of azathioprine, chloramphenicol, cimetidine, clofibrate, corticosteroids, coumarin anticoagulants, ciclosporin, dapsone, diazepam, doxycycline, fluconazole, haloperidol, hexobarbitone, itraconazole, ketoconazole, methadone, oral hypoglycaemic medicines, phenytoin, quinine, sulphasalazine, thyroid hormones, theophylline, zidovudine, and several cardiovascular medicines including beta-adrenoceptor blocking medicines, digoxin, and antidysrhythmic medicines such as disopyramide, lorcainide, mexiletine, propafenone, quinidine, tocainide, and verapamil and other calcium-channel blocking medicines, oral contraceptives, narcotics, analgesics and barbiturates.

It may be necessary to adjust the dosage of these medicines if they are given concurrently with AFARIS PAED 75/50. Patients using oral contraceptives should be advised to change to non-hormonal methods of birth control during therapy with AFARIS PAED 75/50.

Magnesium trisilicate, aluminium hydroxide or sodium bicarbonate reduce the bioavailability of AFARIS PAED 75/50.

Alcohol

Concurrent daily consumption of alcohol may increase the risk of rifampicin-induced hepatotoxicity and increased metabolism of rifampicin. Dosage adjustments of rifampicin may be necessary and patients should be monitored closely for signs of hepatotoxicity.

Corticosteroids

Concurrent use with rifampicin may enhance the metabolism of corticosteroids by induction of hepatic microsomal enzymes, resulting in a decrease in corticosteroid plasma concentration. Dosage adjustment of the corticosteroid may be required.

Anti-retroviral medicines

Rifampicin as contained in AFARIS PAED 75/50 can induce the metabolism of zidovudine, the NNRTI’s delavirdine, efavirenz and nevirapine (see section 4.3) and the HIV-protease inhibitors, resulting in subtherapeutic plasma concentrations. Furthermore, HIV-protease inhibitors inhibit the metabolism of rifampicin resulting in elevated plasma-rifampicin concentrations and an increased incidence of adverse effects.

Rifampicin as contained in AFARIS PAED 75/50 decreases the concentration of efavirenz and it is recommended that the dose of efavirenz be increased in patients weighing more than 60 kg; no dose modification is required for rifampicin as contained in AFARIS PAED 75/50.

Isoniazid

Isoniazid is known to inhibit and rifampicin to induce certain cytochrome P-450 enzymes. In general, the impact of the competing effects of rifampicin and isoniazid on the metabolism of medicines that undergo biotransformation through the affected pathways is unknown. Therefore, caution should be used when prescribing AFARIS PAED 75/50 with medicines metabolised by cytochrome P-450. To maintain optimum therapeutic blood levels, the dosages of these medicines metabolised by these enzymes may require adjustment when starting or stopping AFARIS PAED 75/50.

As isoniazid is an inhibitor of hepatic metabolism of medicines it may therefore enhance the effects of some medicines taken concomitantly.

Adverse reactions have occurred when isoniazid has been given with phenytoin, primidone, carbamazepine, ethosuximide, benzodiazepines such as diazepam or triazolamand warfarin. Appropriate adjustments of the doses of the anticonvulsants should be made.

Theophylline plasma concentrations can be increased.

Increased central nervous system adverse effects have occurred when isoniazid is given with cycloserine and disulfiram.

Isoniazid can be affected by compounds such as alcohol, alfentanil, aminosalicylic acid, corticosteroids, ketoconazole, propranolol and large doses of pyridoxine.

Oral absorption of isoniazid as contained in AFARIS PAED 75/50 is reduced by aluminium-containing antacids; AFARIS PAED 75/50 should be given at least 1 hour before the antacid.

Concurrent use of AFARIS PAED 75/50 with chronically used paracetamol, alcohol and other hepatotoxic medicines may increase the potential for isoniazid induced hepatotoxicity.

Anti-retroviral medicines

The clearance of isoniazid is approximately doubled when given concomitantly with zalcitabine. AFARIS PAED 75/50 should be used with caution with stavudine and zalcitabine as stavudine, zalcitabine and isoniazid have been associated with causing peripheral neuropathy. The use of AFARIS PAED 75/50 with stavudine has been reported to increase the incidence of peripheral neuropathy.

Food interactions

Due to some monoamine oxidase inhibiting activity of isoniazid, 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 AFARIS PAED 75/50.

Pregnancy

Safety and efficacy in pregnancy has not been established (see section 4.3).

Breastfeeding

Safety and efficacy in lactation has not been established (see section 4.3). Rifampicin and isoniazid cross the placenta and both are excreted in breastmilk.

Fertility

No data is available on the effect on fertility.

AFARIS PAED 75/50 may cause dizziness, impaired concentration, and/or drowsiness. Patients should be instructed that if they experience these symptoms they should avoid potentially hazardous tasks such as driving or operating machinery.

Tabulated list of adverse reactions

Rifampicin:

Isoniazid:

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. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the “6.04 Adverse Drug Reactions Reporting Form”, found online under SAHPRA’s publications: https://www.sahpra.org.za/Publications/Index/8.

Not applicable.