Ripyso Paed 75 mg and 50 mg Dispersible tablet

RIPYSO PAED 75/50 is indicated for pulmonary tuberculosis in children.

Posology

RIPYSO PAED 75/50 is recommended in the continuation phase of the treatment of pulmonary tuberculosis. During this phase RIPYSO PAED 75/50 should be administered on a continuous daily basis.

The total dosage requirement is as follows:

• Daily Maximum daily dose
• Rifampicin 15 mg/kg (10 to 20) 600 mg
• Isoniazid 10 mg/kg (7 to 15) 300 mg

The daily dosage is calculated from the recommended daily requirement given above and to closely regulate dosage according to body mass.

Table 1: Dosage calculation

• Number of tablets For infants/children with body mass (kg)
• 1 tablet 4 - 7
• 2 tablets 8 - 11
• 3 tablets 12 - 15
• 4 tablets 16 - 24
• Adult dosages recommended 25 +

Method of administration

Oral use

The tablets can either be dispersed in as little as 5 ml of water, or chewed, and should preferably be taken on an empty stomach as a single dosage. RIPYSO PAED 75/50 should be taken at least 1 hour before aluminium containing antacids are used.

• RIPYSO PAED 75/50 is contra-indicated in patients with a history of hypersensitivity to rifamycins or isoniazid and other chemically related medicines or to any of the excipients of RIPYSO PAED 75/50 listed in Section 6.1.
• It is contra-indicated in the presence of jaundice or in patients with hepatic impairment.
• RIPYSO PAED 75/50 is contra-indicated in patients with impaired renal or liver function, diabetes mellitus, chronic alcoholism, a history of gout, patients suffering from convulsive disorders and porphyria.
• The concomitant use of RIPYSO PAED 75/50 and nevirapine is contra-indicated.
• RIPYSO PAED 75/50 is contra-indicated when given concurrently with the combination of saquinavir/ritonavir (see Section 4.5).
• Pregnancy and lactation (see section 4.6)

Rifampicin:

• Patients with impaired liver function should not be given RIPYSO PAED 75/50. Should RIPYSO 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 If signs of hepatocellular damage occur, RIPYSO PAED 75/50 should be withdrawn (see section 4.3).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 patientu2019s clinical condition.
• Liver function should be checked before and during treatment with RIPYSO PAED 75/50 and special care should be taken in alcoholic patients or those with pre-existing liver disease should RIPYSO 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, RIPYSO 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 RIPYSO PAED 75/50 is contra-indicated in patients with chronic liver disease or renal dysfunction. Should RIPYSO 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 RIPYSO 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 RIPYSO PAED 75/50 and special care should be taken in alcoholic patients or those with pre-existing liver disease should RIPYSO PAED 75/50 be the only treatment option (see Section 4.3). Periodic eye examinations during RIPYSO 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

RIPYSO 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 RIPYSO PAED 75/50 and nevirapine is contraindicated.

When RIPYSO PAED 75/50 is given concomitantly with the combination of saquinavir/ritonavir, the potential for hepatotoxicity is increased. Therefore, concomitant use of RIPYSO 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 RIPYSO PAED 75/50. Patients using oral contraceptives should be advised to change to non-hormonal methods of birth control during therapy with RIPYSO PAED 75/50.

Magnesium trisilicate, aluminium hydroxide or sodium bicarbonate reduce the bioavailability of RIPYSO 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 RIPYSO PAED 75/50 can induce the metabolism of zidovudine, the NNRTIu2019s 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 RIPYSO 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 RIPYSO 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 RIPYSO 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 RIPYSO 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 triazolam and 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 RIPYSO PAED 75/50 is reduced by aluminium-containing antacids; RIPYSO PAED 75/50 should be given at least 1 hour before the antacid. Concurrent use of RIPYSO PAED 75/50 with chronically used paracetamol, alcohol and other hepatotoxic medicines may increase the potential for isoniazid induced hepatotoxicity.

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

RIPYSO 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

MedDRA System organ class Frequency Adverse reactions

• Blood and lymphatic system disorders Less frequent Blood dyscrasias, unusual bleeding or bruising, thrombocytopenia, purpura, haemolysis, eosinophilia, leucopenia, haemolytic anaemia.
• Immune system disorders Less frequent Anaphylaxis and shock.
• Nervous system disorders Less frequent Confusion, drowsiness, headache, ataxia, dizziness, peripheral neuropathy and generalised numbness.
• Eye disorders Less frequent Blurred vision, eye irritation.
• Ear and labyrinth disorders Less frequent Transient hearing loss
• Respiratory, thoracic and mediastinal disorders Unknown Pulmonary fibrosis, pneumonitis, shortness of breath and wheezing.
• Gastrointestinal disorders Frequent Nausea, vomiting, anorexia, diarrhoea and epigastric distress. Less frequent Pseudomembranous colitis. Unknown Ulcerative colitis, gastrointestinal bleeding,
• Hepatobiliary disorders Less frequent Hepatitis (which may be fatal), hepatitis prodromal symptoms which include loss of appetite, nausea or vomiting, unusual tiredness or weakness. A rise in serum transaminase levels.
• Skin and subcutaneous tissue disorders Frequent Cutaneous reactions, which typically consist of flushing and itching, with or without a rash. Less frequent More serious hypersensitivity cutaneous reactions, toxic epidermal necrolysis, exfoliative dermatitis, erythema multiforme including Stevens-Johnson syndrome and vasculitis, drug reaction with eosinophilia and system symptoms (DRESS).
• Musculoskeletal and connective tissue disorders Frequent Muscle weakness and myopathy.
• Renal and urinary disorders Less frequent Interstitial nephritis, renal failure.
• Reproductive system and breast disorders Less frequent Disturbances of the menstrual cycle, reduction of effectiveness of oral contraceptives.
• General disorders and administration site conditions Frequent Reddish - orange to reddish - brown discolouration of the urine, faeces, saliva, sputum, sweat and tears. Soft contact lenses may be permanently stained. Less frequent Intermittent, interrupted or repeated treatment of rifampicin may increase the chance of a patient developing flu syndrome, a febrile reaction with influenza-like symptoms, fungal overgrowth i.e. sore mouth or tongue. Unknown Oedema

Isoniazid

MedDRA System organ class Frequency Adverse reactions

• Blood and lymphatic system disorders Less frequent Various haematological disturbances including eosinophilia, agranulocytosis, thrombocytopenia and various anaemias
• Immune system disorders Less frequent Hypersensitivity reactions including various skin eruptions, fever, lymphadenopathy and vasculitis, lupus-like reactions.
• Metabolism and nutritional disorders Less frequent Hyperglycaemia, metabolic acidosis
• Psychiatric disorders Less frequent Psychotic reactions (characterised by delusions, hallucinations and confusion), memory impairment.
• Nervous system disorders Frequent Peripheral neuropathy. Less frequent Polyneuritis associated with paraesthesia, muscle weakness, loss of tendon reflexes, convulsions, increase in frequency of fits in epileptic patients, ataxia.
• Eye disorders Less frequent Optic neuritis (blurred vision or loss of vision, with or without eye pain).
• Ear and labyrinth disorders Less frequent Vertigo
• Gastrointestinal disorders Frequent Diarrhoea, nausea and vomiting, stomach pain, constipation, dry mouth, pancreatitis.
• Hepatobiliary disorders Frequent Hepatitis (sometimes fatal), hepatitis prodromal symptoms (loss of appetite, nausea or vomiting, unusual tiredness or weakness). Transient increases in liver enzymes.
• Skin and subcutaneous tissue disorders Less frequent Skin reactions, acne, pellagra, Stevens - Johnsons syndrome, exfoliative dermatitis. Unknown alopecia, urticaria
• Musculoskeletal and connective tissue disorders Unknown A rheumatic syndrome, hyperreflexia
• Renal and urinary disorders Less frequent Urinary retention
• Reproductive system and breast disorders: Less frequent Gynaecomastia

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 u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8.

Symptoms of overdose

Rifampicin: Acute overdosage with rifampicin has produced a characteristic bright-red discolouration of the skin and mucous membranes, sometimes referred to as u201cthe red-man syndromeu201d, mental obtundation, periorbital or facial oedema and generalised pruritus.

Isoniazid: Symptoms are more likely to be related to isoniazid. These include hyperglycaemia and metabolic acidosis, slurred speech, convulsions, coma, hallucinations, respiratory distress, central nervous system depression; fatalities can occur.

Treatment of overdose

General: In cases of overdosage with RIPYSO PAED 75/50 activated charcoal slurry into the stomach may help absorb any remaining medicine from the gastrointestinal tract. Antiemetic medication may be required to control severe nausea and vomiting. Intensive supportive measures should be instituted and individual symptoms treated as they arise. Further treatment is symptomatic and supportive.

If acute overdose is suspected, even in asymptomatic patients, the administration of intravenous pyridoxine (vitamin B6) should be considered. In patients with seizures not controlled with pyridoxine, anticonvulsant therapy should be administered. Sodium bicarbonate should be given to control metabolic acidosis. Haemodialysis is advised for refractory cases: if this is not available, peritoneal dialysis can be used along with forced diuresis.