Co-Ripyso Paed 75/50/150 mg Dispersible tablet

CO-RIPYSO PAED 75/50/150 is indicated for pulmonary tuberculosis in children.

Posology
The South African TB control programme defines daily dosage as 5 days per week. CO - RIPYSO PAED 75/50/150 is recommended in the initial intensive phase of the short course treatment of pulmonary tuberculosis. During this phase, which lasts for 2 months, CO-RIPYSO PAED 75/50/150 should be administered on a continuous daily basis. When indicated, other antituberculosis medicines such as streptomycin may be added. 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
Pyrazinamide 35 mg/kg (30-40) , 2 g
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 +
Chemoprophylaxis: Children less than 5 years of age in close household contact with a smear positive case of pulmonary TB should be treated with rifampicin/isoniazid for a period of 3 months. Routine chemoprophylaxis of those older than 5 years is not recommended.

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. CO-RIPYSO PAED 75/50/150 should be taken at least 1 hour before aluminium containing antacids are used.

• CO-RIPYSO PAED 75/50/150 is contraindicated in patients with a history of hypersensitivity to rifamycins or isoniazid or pyrazinamide and other chemically related medicines or to any of the excipients of CO-RIPYSO PAED 75/50/150, listed in Section 6.1.
• It is contra-indicated in the presence of jaundice or in patients with hepatic impairment.
• Pregnancy and lactation (see section 4.6)
• CO-RIPYSO PAED 75/50/150 is contraindicated in patients with moderate to severe renal or hepatic impairment, diabetes mellitus, chronic alcoholism, a history of gout, patients suffering from convulsive disorders and porphyria.
• The concomitant use of CO-RIPYSO PAED 75/50/150 and nevirapine, saquinavir, ritonavir is contraindicated.

Rifampicin:
u2022 Patients with impaired liver function should not be given CO-RIPYSO PAED 75/50/150. Should CO-RIPYSO PAED 75/50/150 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, CO-RIPYSO PAED 75/50/150 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.
u2022 Liver function should be checked before and during treatment with CO-RIPYSO PAED 75/50/150 and special care should be taken in alcoholic patients or those with pre-existing liver disease should CO-RIPYSO PAED 75/50/150 be the only treatment option (see Section 4). 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. If other serious complications arise e.g. renal failure or haemolytic anaemia, CO-RIPYSO PAED 75/50/150 should be stopped and never restarted.
u2022 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.
u2022 Rifampicin has enzyme induction properties that can enhance the metabolism of endogeneous substrates including adrenal hormones, thyroid hormones and vitamin D.
Isoniazid:
u2022 Use of isoniazid as contained in CO-RIPYSO PAED 75/50/150 is contra-indicated in patients with chronic liver disease or renal dysfunction. Should CO-RIPYSO PAED 75/50/150 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 CO-RIPYSO PAED 75/50/150 in these cases may cause a more severe form of liver damage (see Section 4.3).
u2022 Liver function should be checked before and during treatment with CO-RIPYSO PAED 75/50/150 and special care should be taken in alcoholic patients or those with pre-existing liver disease should CO-RIPYSO PAED 75/50/150 be the only treatment option (see Section 4.3).
u2022 Periodic eye examinations during CO-RIPYSO PAED 75/50/150 treatment have been suggested.
u2022 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.
u2022 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.
Pyrazinamide:
Pyrazinamide as contained in CO-RIPYSO PAED 75/50/150 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. Liver function should be assessed before and regularly during treatment in all patients. Caution should be observed in patients with impaired renal function. Diabetes mellitus may become difficult to control in patients who are receiving CO-RIPYSO PAED 75/50/150.
Excipients
CO-RIPYSO PAED 75/50/150 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 CO-RIPYSO PAED 75/50/150 and nevirapine is contraindicated. When CO-RIPYSO PAED 75/50/150 is given concomitantly with the combination of saquinavir/ritonavir, the potential for hepatotoxicity is increased. Therefore, concomitant use of 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 CO-RIPYSO PAED 75/50/150. Patients using oral contraceptives should be advised to change to non-hormonal methods of birth control during therapy with CO-RIPYSO PAED 75/50/150. Magnesium trisilicate, aluminium hydroxide or sodium bicarbonate reduce the bioavailability of CO-RIPYSO PAED 75/50/150. 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 CO-RIPYSO PAED 75/50/150 can induce the metabolism of zidovudine, the NNRTIu2019s delavirdine, efavirenz and nevirapine (see Section 4.3 CONTRAINDICATIONS) 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 CO-RIPYSO PAED 75/50/150 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 CO-RIPYSO PAED 75/50/150. 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 CO-RIPYSO PAED 75/50/150 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 CO-RIPYSO PAED 75/50/150. 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 CO-RIPYSO PAED 75/50/150 is reduced by aluminium-containing antacids; RIPSO PAED 75/50 should be given at least 1 hour before the antacid. Concurrent use of CO-RIPYSO PAED 75/50/150 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. CO-RIPYSO PAED 75/50/150 should be used with caution with stavudine and zalcitabine as stavudine, zalcitabine and isoniazid have been associated with causing peripheral neuropathy. The use of CO-RIPYSO PAED 75/50/150 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 CO-RIPYSO PAED 75/50/150.
Pyrazinamide: Combinations containing any of the following medicines may also interact with pyrazinamide as contained in CO - RIPYSO PAED 75/50/150: Sulfinpyrazone, allopurinol, colchicine and probenecid: Pyrazinamide may increase serum uric acid concentrations and decrease the efficacy of the gout therapy of allopurinol, colchicine, probenecid or sulfinpyrazone. Dosage adjustments of these medicines may be necessary to control hyperuricaemia and gout when antigout medicines are used concurrently with CO - RIPYSO PAED 75/50/150. Ciclosporin: Concurrent use with CO - RIPYSO PAED 75/50/150 may decrease the serum concentrations of ciclosporin, leading to inadequate immunosuppression. Ciclosporin serum concentrations should be monitored when used concurrently with CO - RIPYSO PAED 75/50/150.

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, isoniazid and pyrazinamide cross the placenta and both are excreted in breastmilk.

CO-RIPYSO PAED 75/50/150 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 Frequency Adverse reactions class Blood and lymphatic system disorders Less frequent Blood dyscrasias, unusual bleeding or bruising, thrombocytopenia, purpura, haemolysis, eosinophilia, leucopenia, haemolytic anaemia. Immune system disorders Frequency unknown 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 Frequency 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. Frequency Unknown alopecia, urticaria Musculoskeletal and connective tissue disorders Frequency Unknown A rheumatic syndrome, hyperreflexia Renal and urinary disorders Less frequent Urinary retention Reproductive system and breast disorders: Less frequent Gynaecomastia Pyrazinamide MedDRA System organ class Frequency Adverse reactions Blood and lymphatic system disorders Less frequent Sideroblastic anaemia, thrombocytopenia. Immune system disorders Less frequent Hypersensitivity reaction. Metabolism and nutritional disorders Less frequent Pellagra Gastrointestinal disorders Frequent Anorexia, nausea, vomiting, aggravation of peptic ulcer. Hepatobiliary disorders Frequent Hepatotoxicity (frequency appears to be dose related). Skin and subcutaneous tissue disorders Less frequent Photosensitivity, skin rash, pruritus. Musculoskeletal and connective tissue disorders Frequent Arthralgia, which is related to hyperuricaemia. Less frequent Gouty arthritis Renal and urinary disorders Less frequent Dysuria General disorders and administrative site conditions Less frequent Malaise, fever 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.
Pyrazinamide Symptoms may be the exacerbation of side effects.
Treatment of overdose
General: In cases of overdosage with CO-RIPYSO PAED 75/50/150 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.