Duopic Paed 75 & 50 mg Tablets

DUOPIC PAED is indicated for pulmonary tuberculosis in children.

Posology

DUOPIC PAED is recommended in the continuation phase of the treatment of pulmonary tuberculosis. During this phase DUOPIC PAED 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 dispersible tablets For infants/children with body mass (kg)

• 1 dispersible tablet 4 - 7
• 2 dispersible tablets 8 - 11
• 3 dispersible tablets 12 - 15
• 4 dispersible tablets 16 - 24

Adult dosages recommended 25 +

Method of administration

The dispersible tablets can either be dispersed in as little as 5 mL of water, or chewed, and should preferably be taken orally, on an empty stomach as a single dosage. DUOPIC PAED should be taken at least 1 hour before aluminium containing antacids are used (see section 4.5). For missed doses, the missing dose can be taken as soon as possible, and then take the next dose at its regular time. However, if the next dose is due within 6 hours, do not take the missed dose. Wait and take the next dose at the regular time. A double dose should not be taken to make up for a forgotten tablet.

• Hypersensitivity or a history of hypersensitivity to rifampicin, other rifampicins, isoniazid or to any of the ingredients of DUOPIC PAED (see section 6.1).
• The presence of jaundice or in patients with hepatic impairment.
• 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.
• Concomitant use of DUOPIC PAED and nevirapine is contraindicated (see section 4.5).
• When given concurrently with the combination of saquinavir/ritonavir (see section 4.5).
• Pregnancy and lactation (see section 4.6).

Rifampicin

Hepatic impairment

Patients with impaired liver function should not be given DUOPIC PAED. Should DUOPIC PAED 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, DUOPIC PAED 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 DUOPIC PAED and special care should be taken in alcoholic patients or those with pre-existing liver disease should DUOPIC PAED 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).

Discoloration of bodily fluids

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.

Other

If other serious complications arise e.g. renal failure or haemolytic anaemia (see haematological toxicity), DUOPIC PAED should be stopped and never restarted. Rifampicin has enzyme induction properties that can enhance the metabolism of endogenous substrates including adrenal hormones, thyroid hormones and vitamin D. 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.

Hypersensitivity

Rifampicin may cause a hypersensitivity syndrome including u2018flu-likeu2019 symptoms and/or organ manifestation. The risk is higher in intermittent therapy or if treatment is resumed after discontinuation. If severe, acute signs of rifampicin hypersensitivity do appear (e.g. thrombocytopenia, purpura, haemolytic anaemia, dyspnoea, shock or acute renal failure). DUOPIC PAED should immediately be discontinued. Such patients should not be re-challenged with rifampicin. If rifampicin therapy is temporarily discontinued, rifampicin should be restarted carefully at a reduced dose, and with close monitoring. In this situation, DUOPIC PAED should not be used.

Haematological toxicity

Since rifampicin treatment has been associated with haemolytic anaemia, leukopenia and thrombocytopenia, full blood count should be monitored regularly throughout therapy with DUOPIC PAED. In case of severe haematological disturbances DUOPIC PAED must be discontinued.

Medicine interactions

Rifampicin is a strong inducer of hepatic medicine metabolism, as a result, DUOPIC PAED may reduce exposure and efficacy of many therapeutic medicines, including antiretrovirals, antiepileptic medicines, immunosuppressants and warfarin (see section 4.5).

Porphyria

DUOPIC PAED is contraindicated in patients with porphyria, since the enzyme induction by rifampicin may cause symptoms (see section 4.3).

Isoniazid

Hepatic and renal impairment

Use of isoniazid as contained in DUOPIC PAED is contraindicated in patients with chronic liver disease or renal dysfunction. Should DUOPIC PAED 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 DUOPIC PAED in these cases may cause a more severe form of liver damage (see section 4.3).

Liver function should be checked before and during treatment with DUOPIC PAED and special care should be taken in alcoholic patients or those with pre-existing liver disease, should DUOPIC PAED be the only treatment option (see section 4.3). Patients with renal impairment, particularly those who are slow acetylators (see sections 4.2 and 5.2) may be at increased risk for isoniazid adverse effects such as peripheral neuropathy and should be monitored accordingly. As in other patients, adequate supplementation with pyridoxine (see below) should be given to avoid neurotoxicity.

Use of isoniazid should be carefully monitored in patients with a history of psychosis, history of peripheral neuropathy and HIV infection.

Peripheral neuropathy

Periodic eye examinations during DUOPIC PAED treatment have been suggested as isoniazid may cause symptomatic pyridoxine deficiency, which presents as neuropathy, particularly in severely malnourished children and HIV-positive children on antiretroviral therapy (ART), Vitamin B 6 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.

Cross-sensitivity

Patients hypersensitive to ethionamide, pyrazinamide, niacin (nicotinic acid), or other chemically related medicines may also be hypersensitive to isoniazid.

Diabetes mellitus

Patients with diabetes should be carefully monitored, since blood glucose control may be affected by isoniazid.

Rifampicin/Isoniazid combination

Epilepsy and psychotic disorders

DUOPIC PAED should be used with caution in patients with pre-existing seizure disorders or a history of psychosis.

Nephrotoxicity

DUOPIC PAED should be discontinued in case of clinical signs of nephrotoxicity.

Treatment with corticosteroids

DUOPIC PAED may reduce the efficacy of corticosteroids in Addisonu2019s disease and induce an Addisonian crisis (see section 4.5).

Rifampicin

The concomitant use of DUOPIC PAED and nevirapine is contraindicated (see section 4.3). When DUOPIC PAED is given concomitantly with the combination of saquinavir/ritonavir, the potential for hepatotoxicity is increased. Therefore, concomitant use of DUOPIC PAED with saquinavir/ritonavir is contraindicated (see section 4.3). Halogenated inhalation anaesthetics, when given concomitantly with rifampicin has been reported to increase the hepatotoxicity of both rifampicin and isoniazid. Ketoconazole has been reported to diminish the serum concentrations of both medicines when given concomitantly. Rifampicin is a very potent inducer of the hepatic and intestinal cytochrome P450 enzyme system, as well as of glucuronidation and the P-glycoprotein transport system. Administration of rifampicin with medicines that undergo biotransformation through these metabolic pathways is likely to accelerate elimination of co-administered medicines. These effects approach their maximum after about 10 days of treatment, and gradually return to normal within 2 or more weeks after discontinuation. This must be considered when co-treating with other medicines. To maintain optimum therapeutic blood levels, dosages of medicines metabolised by these enzymes may require adjustment when starting or stopping the concomitant administration of DUOPIC PAED.

As rifampicin has liver-enzyme inducing properties and may reduce the activity of azathioprine, chloramphenicol, cimetidine, clofibrate, corticosteroids, warfarin, 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. Thus, it may be necessary to adjust the dosage of these medicines if they are given concurrently with DUOPIC PAED.

Oral contraceptives

Patients using oral contraceptives should be advised to change to non-hormonal methods of birth control during therapy with DUOPIC PAED.

Minerals

Magnesium trisilicate, aluminium hydroxide or sodium bicarbonate reduce the bioavailability of DUOPIC PAED.

Alcohol

Concurrent daily consumption of alcohol may increase the risk of rifampicin-induced hepatotoxicity and increased the 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 DUOPIC PAED 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 DUOPIC PAED 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 DUOPIC PAED.

Isoniazid

Isoniazid is known to inhibit and rifampicin to induce certain cytochrome P450 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 DUOPIC PAED with medicines metabolised by cytochrome P450. To maintain optimum therapeutic blood levels, the dosages of these medicines metabolised by these enzymes may require adjustment when starting or stopping DUOPIC PAED. 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.

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

Antacids

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

Anti-retroviral medicines

The clearance of isoniazid is approximately doubled when given concomitantly with zalcitabine. DUOPIC PAED should be used with caution with stavudine and zalcitabine as stavudine, zalcitabine and isoniazid have been associated with causing peripheral neuropathy. The use of DUOPIC PAED 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 histamine- or tyramine-containing foods (cheese, FISH, red wine) may occur. Diamine oxidase may also be inhibited, causing exaggerated response (e.g. headache, sweating, palpitations, flushing, hypotension) to foods containing histamine. Tyramine- and histamine-containing foods should be avoided by patients receiving DUOPIC PAED.

Combination rifampicin/isoniazid

In vitro, isoniazid acts as an inhibitor of CYP2C19 and CYP3A4. Therefore, it may increase exposure to medicines mainly eliminated through either of these pathways. However, when co-treating with rifampicin, as when using DUOPIC PAED, these effects are likely to be outweighed by the hepatic enzyme induction due to rifampicin. Insofar as it has been investigated, the net effect of rifampicin and isoniazid on medicine clearance will be an increase due to rifampicin rather than a decrease due to isoniazid. Concurrent use of isoniazid with other hepatotoxic or neurotoxic medicines may increase the hepatotoxicity and neurotoxicity of isoniazid and should be avoided. Mainly due to rifampicin, DUOPIC PAED may interact with a very large number of other medicines, primarily by reducing the exposure to co-administered medicines, reducing their efficacy and increasing the risk of therapeutic failure. For many important therapeutic medicines, no interaction data with rifampicin are available. However, clinically significant reductions in medicine exposure may occur. Whenever co-prescribing any medicine together with DUOPIC PAED, the possibility of a medicine-medicine interaction should be considered. The following list of medicine interactions with DUOPIC PAED is not exhaustive but is a selection of interactions of putative importance. The scope of the table is largely based on the WHO Essential Medicines List.

Pregnancy

Safety during pregnancy has not been established.

Breastfeeding

Safety during lactation has not been established. Rifampicin and isoniazid cross the placenta, and both are excreted in breastmilk.

DUOPIC PAED 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.

Summary of the safety profile

The most important adverse reactions of rifampicin are hepatotoxicity, particularly cholestatic reactions, and skin reactions. Rifampicin may cause subclinical, unconjugated hyperbilirubinemia or jaundice without hepatocellular damage, but occasionally causes hepatocellular injury. It can also potentiate the hepatotoxicity of the other anti-tuberculosis medications. The most important adverse reactions of isoniazid are peripheral and central neurotoxic effects, and hepatotoxicity. Severe and sometimes fatal hepatitis due to isoniazid therapy has been reported. Most cases have occurred within the first three months of therapy, but hepatotoxicity may also develop after a longer duration of treatment.

Tabulated list of adverse effects

Adverse effects for DUOPIC PAED

System Organ Class Frequency Adverse effects

• Blood and lymphatic system disorders Frequency unknown Anaemia (haemolytic, sideroblastic, or aplastic), thrombocytopenia, leukopenia, neutropenia with eosinophilia, agranulocytosis
• Immune system disorders Frequency unknown Allergic reactions with skin manifestations, pruritus, fever, leukopenia, anaphylaxis, allergic pneumonitis, vasculitis, lymphadenopathy, rheumatic syndrome, lupusu2013like syndrome, hypotension, shock
• Metabolism and nutrition disorders Less frequent Aggravated porphyria Frequency unknown Hyperglycaemia, metabolic acidosis, pellagra
• Psychiatric disorders Less frequent Memory impairment, toxic psychosis Frequency unknown Confusion, disorientation, hallucination
• Nervous system disorders Frequent Peripheral neuropathy, usually preceded by paraesthesia of feet and hands Less frequent Headache, lethargy, ataxia, difficulties concentrating, dizziness, seizures, toxic encephalopathy Frequency unknown Tremor, vertigo, insomnia, hyperreflexia, cerebral haemorrhage
• Eye disorders Frequent Ocular redness, permanent discolouration of soft contact lenses Less frequent Exudative conjunctivitis Frequency unknown Optic atrophy or neuritis
• Gastrointestinal disorders Frequent Diarrhoea, abdominal pain, nausea, anorexia, vomiting Less frequent Erosive gastritis, pseudomembranous colitis, pancreatitis Frequency unknown Dry mouth, flatulence, constipation
• Hepato-biliary disorders Frequent Transient increases of serum transaminases Less frequent Increases of serum bilirubin and alkaline phosphatases, hepatitis
• Skin and subcutaneous tissue disorders Frequent Erythema, exanthema, pruritus with or without rash, urticaria Less frequent Photosensitivity reaction, exfoliative dermatitis, pemphigoid reactions, purpura Frequency unknown Lyellu2019s syndrome, Stevens-Johnson syndrome
• Musculoskeletal, connective tissue and bone disorders Frequency unknown Arthralgia, myalgia
• Renal and urinary disorders Less frequent Acute renal failure, interstitial nephritis Frequency unknown Urinary retention
• Reproductive system and breast disorders Frequent Disturbances of the menstrual cycle
• General disorders and administrative site conditions Frequent Flushing, reddish discolouration of body fluids and u2013secretions, such as urine, sputum, tears, saliva and sweat, decrease in blood pressure, shock

Adverse effects of rifampicin

System Organ Class Frequency Adverse effects

• Blood and lymphatic system disorders Less frequent Blood dyscrasias, unusual bleeding or bruising, thrombocytopenia, purpura, haemolysis, eosinophilia, leukopenia, haemolytic anaemia, disseminated intravascular coagulation, eosinophilia, agranulocytosis, haemolytic anaemia, decreased haemoglobin
• Immune system disorders Frequency unknown Anaphylaxis, 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 Frequency unknown Ulcerative colitis, gastrointestinal bleeding
• Hepato-biliary 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 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, vasculitis, drug reaction with eosinophilia and system symptoms (DRESS)
• Musculoskeletal, connective tissue and bone disorders Frequent Muscle weakness, myopathy
• Renal and urinary disorders Less frequent Interstitial nephritis, renal failure
• Reproductive system and breast disorders Frequent Disturbances of the menstrual cycle, reduction of effectiveness of oral contraceptives
• General disorders and administrative 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 Frequency unknown Oedema

Adverse effects for isoniazid

System Organ Class Frequency Adverse effects

• 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 nutrition 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
• Hepato-biliary 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, pellagra, acne, Stevens-Johnsons syndrome, exfoliative dermatitis Frequency unknown Alopecia, urticaria
• Musculoskeletal, connective tissue and bone disorders Frequency unknown Rheumatic syndrome, hyperreflexia
• Renal and urinary disorders Less frequent Urinary retention
• Reproductive system and breast disorders Less frequent Gynecomastia

Signs and symptoms

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.

Management of overdose

In cases of overdosage with DUOPIC PAED 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.