AFDCDT-3^®

AFDCDT®-3 is a combination of Rifampicin, Isoniazid and Pyrazinamide. Rifampicin is bactericidal against a wide range of organisms, including Mycobacterium tuberculosis. It inhibits DNA-dependent RNA polymerase, inhibiting transcription. In tuberculosis, rifampicin is bactericidal for both intracellular and extracellular microorganisms. The bacteria may develop resistance as a result of alterations in the target enzyme (RNA polymerase). Isoniazid is highly active against Mycobacterium tuberculosis. It is bactericidal against actively dividing tubercle bacilli. Its primary action is to inhibit the synthesis of long-chain mycolic acids, which are unique constituents of the mycobacterial cell wall. Resistance to isoniazid develops rapidly if it is used alone in the treatment of mycobacterial infection. Pyrazinamide is a prodrug that is converted into its active form, pyrazinoic acid, by a mycobacterial enzyme, pyrazinamidase, as well as through hepatic metabolism. Pyrazinoic acid is bactericidal to Mycobacterium tuberculosis at acid pH but not at neutral pH. The precise mechanism of action is unknown. Pyrazinamide is inactive against atypical mycobacteria. Resistance develops rapidly if pyrazinamide is used as the sole antituberculosis agent.

No Data

AFDCDT®-3 is indicated for the initial treatment phase of tuberculosis in children, caused by Mycobacterium tuberculosis.

Route of administration: AFDCDTⓇ-3 is for oral use only. It should be taken on an empty

stomach (at least one hour prior to or two hours after a meal). If taken with food to improve gastrointestinal tolerance, oral absorption and bioavailability may be impaired.

Children weighing less than 25 kg:

Children weighing over 25 kg receive adult dosage.

AFDCDT®-3 is not suitable for intermittent treatment regimens. If it is necessary to discontinue or reduce the dose of isoniazid, pyrazinamide or rifampicin then single-component preparations should be used instead of this combination.

Renal impairment

Since dose adjustment may be necessary in patients with renal impairment (creatinine clearance less than 30 ml/minute), separate preparations of rifampicin, isoniazid and pyrazinamide are recommended.

Hepatic impairment

Limited data indicate that the pharmacokinetics of rifampicin and isoniazid are altered in patients with hepatic impairment. Therefore, patients with hepatic impairment should be closely observed for signs of toxicity. AFDCDT -3 must not be used in patients with severe liver disease.

Method of administration

The required number of AFDCDT®-3 should be dispersed in about 50 ml water and the entire mixture should be swallowed. The mixture (of tablets dispersed in water) should be used within 10 minutes.

Pregnancy: No adverse effects of isoniazid or pyrazinamide on the human fetus have been reported. Rifampicin has been reported to cross the placental barrier and appear in cord blood but the effect of rifampicin, alone or with other antituberculosis drugs, on the human fetus is not known. Use of rifampicin in the third trimester has been associated with postnatal hemorrhage in the mother and infant. This combination should be used in pregnancy only if the benefits are considered to outweigh the risks. If this combination is used in the last weeks of pregnancy, the mother and neonate should receive vitamin K supplements.

Lactation: Rifampicin, isoniazid and pyrazinamide appear in breast milk. However, concentrations in breast milk are so low, that breastfeeding cannot be relied upon for adequate tuberculosis prophylaxis or therapy for nursing infants. No adverse effects in the baby have been reported.

Use in children and adolescents

The safety and effectiveness of this combination for patients with a body weight below 4 kg is not recommended.

A Biopen should never be shared between patients, even if the needle is changed. If hyperglycemia or hypoglycemia occurs with changes in insulin regimen, changes need to be made to a patient's insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) under close medical supervision with increased frequency of blood glucose monitoring. Hypoglycemia may be life-threatening. In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended. Accidental mix-ups between insulin products can occur. Patients should be instructed to check insulin labels before injection. Severe, life-threatening, generalized allergy, including anaphylaxis, can occur. On that case, Insulin should be discontinued. The patient should be monitored and treated if indicated. Hypokalemia may be life-threatening. Potassium level in patients at risk of hypokalemia should be monitored and treated if indicated. Fluid retention and heart failure may occur with concomitant use of thiazolidinediones (TZD). Patients should be observed for signs and symptoms of heart failure and dosage reduction or discontinuation be considered of TZD if heart failure occurs.

The most important side effects 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 antituberculosis medications. The common side effects of isoniazid are peripheral and central neurotoxic effects and hepatotoxicity. Severe and sometimes fatal hepatitis due to isoniazid therapy has been reported. The majority of cases have occurred within the first 3 months of therapy, but hepatotoxicity may also develop after a longer duration of treatment. The most important side effect of pyrazinamide is liver damage, ranging from asymptomatic increase of serum transaminases to symptomatic liver dysfunction and in rare cases, fatal liver failure.

This combination is contraindicated in patients with a history of hypersensitivity to rifampicin, isoniazid and pyrazinamide or any other components of this product. It is also contraindicated in patients with history of acute liver disease, icterus or severe liver impairment. Concomitant use with voriconazole or any HIV inhibitors bictegravir, elvitegravir/cobicistat, etravirine, rilpivirine or with several direct-acting antiviral medicines for treating chronic hepatitis C is contraindicated.

Drug interaction with medication: Antacids reduce the bioavailability of rifampicin and isoniazid. To avoid this interaction, it should be taken at least 1 hour before antacids. This combination may reduce the efficacy of corticosteroids in Addison's disease and induce an Addisonian crisis.

Rifampicin: Induces microsomal enzymes (accelerates clearance of methadone, oral anticoagulants, glucocorticoids, estrogen, oral hypoglycemic agents, digitoxin, antiarrhythmics, theophylline, anticonvulsants, azole antifungal, cyclosporin).

Isoniazid: Inhibits metabolism of antiepileptics, benzodiazepines, warfarin, and theophylline. Increases metabolism of enflurane, alcohol, ASA, Al-containing antacids, corticosteroids, ketoconazole, propranolol.

Pyrazinamide: Decreases efficacy of gout therapy agents. Drug interaction with food and others: Concurrent daily use of alcohol may result in an increased incidence of isoniazid induced hepatotoxicity. Patients should be monitored closely for signs of hepatotoxicity and should be strongly advised to restrict intake of alcoholic beverages. Concurrent ingestion of cheese and fish (histamine- or tyramine-rich food) with isoniazid may lead to inhibition of mono-/diamine-oxidases by isoniazid, interfering with the metabolism of histamine and tyramine. Clinically, this may result in redness or itching of the skin, hot feeling, rapid or pounding heartbeat, sweating, chills or clammy feeling, headache, or lightheadedness. Isoniazid may cause a false positive response to copper sulfate glucose tests.

Anorexia, nausea, vomiting, gastrointestinal disturbances, fever, headache, dizziness, slurred speech, hallucinations and/or visual disturbances have occurred within 30 minutes to 3 hours after ingestion of isoniazid. With marked isoniazid overdoses (>80 mg/kg body weight) respiratory distress and CNS depression, progressing rapidly from stupor to profound coma, along with severe intractable seizures are to be expected. Typical laboratory findings are severe metabolic acidosis, acetonuria, and hyperglycemia. When overdosed, rifampicin may cause a reddish-orange discoloration of the skin ('red man syndrome'). Further symptoms include facial edema, pruritus, nausea, vomiting and abdominal tenderness. In adults, a total dose of 14 g has caused cardiopulmonary arrest. Data on pyrazinamide overdose are scarce. However, liver toxicity and hyperuricemia may occur. Emesis, gastric lavage and activated charcoal may be of value started within a few hours of ingestion. Subsequently, pyridoxine (intravenous injection), intravenous diazepam or oral midazolam (if seizures not responding to pyridoxine) and hemodialysis may be of value. Treatment is symptomatic and supportive with special attention to monitoring and support of ventilation and correction of metabolic acidosis. There is no specific antidote.

Rifampicin and/or isoniazid may cause hepatotoxicity. Rifampicin may cause a hypersensitivity syndrome including 'flu-like' symptoms and/or organ manifestations. Isoniazid is associated with vertigo, visual disorders and psychotic reactions. Patients hypersensitive to ethionamide, niacin (nicotinic acid), or other chemically related medications may also be hypersensitive to isoniazid. Peripheral neuropathy is the most common toxic effect of isoniazid. The frequency depends on the dose and on predisposing conditions such as malnutrition, alcoholism or diabetes. Concomitant pyridoxine administration largely reduces the risk of developing neuropathy. Therefore, pyridoxine should be co-administered routinely with this combination, at doses of 10 mg per day. This combination should be used with caution in patients with pre-existing seizure disorders or a history of psychosis. Since rifampicin treatment has been associated with hemolytic anemia, leukopenia and thrombocytopenia, full blood count should be monitored regularly throughout therapy with this combination. In case of severe hematological disturbances, this combination must be discontinued. Pyrazinamide may increase serum levels of uric acid and cause gout. Patients with a history of gout should be carefully monitored. Serum uric acid levels should be determined before starting therapy with this combination. In renal insufficiency, the clearance of pyrazinamide and isoniazid is delayed, leading to increased systemic exposure. In case of renal insufficiency, this combination should not be used, as dose modifications of the active components may be necessary. This combination should be discontinued in case of clinical signs of nephrotoxicity. Patients with diabetes should be carefully monitored, since blood glucose control may be affected by isoniazid. This combination should also be used with caution in patients with porphyria, since the enzyme induction by rifampicin may cause symptoms. This combination may cause a reddish-orange discoloration of body fluids such as urine, sputum and tears. This is due to rifampicin and does not require medical attention. Full blood count, liver function and serum uric acid should be monitored prior to and at regular intervals during treatment with this combination.

Store in a cool (below 30°C) and dry place protected from light. Keep away from the reach of children.

AFDCDT^® -3: Each dispersible tablet contains Rifampicin BP 75 mg, Isoniazid BP 50 mg and Pyrazinamide BP 150 mg.

AFDCDT^® -3: Each box contains 100 tablets in blister pack.