Combunex

Uses

Ethambutol is used for the treatment of pulmonary tuberculosis. It should not be used as the sole antituberculous drug, but should be used in conjunction with at least one other antituberculous drug. Selection of the companion drug should be based on clinical experience, considerations of comparative safety, and appropriate in vitro susceptibility studies. In patients who have not received previous antituberculous therapy, ie, initial treatment, the most frequently used regimens have been the following:

• Ethambutol plus isoniazid
• Ethambutol plus isoniazid plus streptomycin.

In patients who have received previous antituberculous therapy, mycobacterial resistance to other drugs used in initial therapy is frequent. Consequently, in such retreatment patients, Ethambutol should be combined with at least one of the second line drugs not previously administered to the patient and to which bacterial susceptibility has been used by appropriate in vitro studies. Antituberculous drugs used with Ethambutol have included cycloserine, ethionamide, pyrazinamide, viomycin and other drugs. Isoniazid, aminosalicylic acid, and streptomycin have also been used in multiple drug regimens. Alternating drug regimens have also been utilized.

Isoniazid is used for the treatment of all forms of tuberculosis in which organisms are susceptible.

Combunex is also used to associated treatment for these conditions: Mycobacterium Infections, Mycobacterium avium complex infection, Pulmonary Tuberculosis (TB)Active Tuberculosis, Mycobacterium kansasii infection, Late phase Tuberculosis

How Combunex works

Ethambutol diffuses into Mycobacterium cells. Once inside the cell, ethambutol inhibits the arabinosyltransferases (embA, embB, and embC), preventing formation of the cell wall components arabinogalactan and lipoarabinomannan, and preventing cell division. Decreased concentrations of arabinogalactan in the cell wall reduces the number of binding sites for mycolic acid, leading to the accumulation of mycolic acid, trehalose monomycolate, and trehalose dimycolate. Lipoarabinomannan is a component of a cell surface molecule involved in the interaction with host cells. Reduced levels of lipoarabinomannan may interfere with mycobacterial interaction with host cells.

Isoniazid is a prodrug and must be activated by bacterial catalase. Specficially, activation is associated with reduction of the mycobacterial ferric KatG catalase-peroxidase by hydrazine and reaction with oxygen to form an oxyferrous enzyme complex. Once activated, isoniazid inhibits the synthesis of mycoloic acids, an essential component of the bacterial cell wall. At therapeutic levels isoniazid is bacteriocidal against actively growing intracellular and extracellular Mycobacterium tuberculosis organisms. Specifically isoniazid inhibits InhA, the enoyl reductase from Mycobacterium tuberculosis, by forming a covalent adduct with the NAD cofactor. It is the INH-NAD adduct that acts as a slow, tight-binding competitive inhibitor of InhA.

Dosage

Combunex dosage

Ethambutol should not be used alone, in initial treatment or in retreatment. Ethambutol should be administered on a once every 24-hour basis only.Absorptionis not significantly altered by administration with food. Therapy, in general, should be continued until bacteriological conversion has become permanent and maximal clinical improvement has occurred.

Ethambutol is not recommended for use in pediatric patients under thirteen years of age since safe conditions for use have not been established.

Initial Treatment:In patients who have not received previous antituberculous therapy, administer Ethambutol 15 mg/kg of body weight, as a single oral dose once every 24 hours. In the more recent studies, isoniazid has been administered concurrently in a single, daily, oral dose.

Retreatment:In patients who have received previous antituberculous therapy, administer Ethambutol 25 mg/kg of body weight, as a single oral dose once every 24 hours. Concurrently administer at least one other antituberculous drug to which the organisms have been demonstrated to be susceptible by appropriatein vitrotests. Suitable drugs usually consist of those not previously used in the treatment of the patient. After 60 days of Ethambutol administration, decrease the dose to 15 mg/kg of body weight, and administer as a single oral dose once every 24 hours.

During the period when a patient is on a daily dose of 25 mg/kg, monthly eye examinations are advised.

Renal Impairment: Dose adjustment may be needed as determined by blood levels of ethambutol.

Adult:

• Active tuberculosis: 5 mg/kg/day. Max: 300 mg/day or 15 mg/kg up to 900 mg/day, 2 or 3 times wkly.
• Latent tuberculosis: 300 mg/day for 6 mth. Nontuberculous mycobacterial infections 5 mg/kg/day for at least 12 mth of culture-negative sputum. Max: 300 mg/day.

Child:10-15 mg/kg/day, max 300 mg/day q 12-24 hourlyWith directly observed biweekly therapy, dosage is 20-30 mg/kg, max 900 mg/dose twice weekly

Should be taken with food.

Side Effects

Retrobulbar neuritis with reduction in visual acuity, constriction of visual field, central or peripheral scotoma and green-red colour blindness of 1 or both eyes. Reduced renal clearance of urate and may precipitate acute gout. Confusion, disorientation, hallucinations, headache, dizziness, malaise, jaundice or transient liver dysfunction, peripheral neuropathy, thrombocytopenia, pulmonary infiltrates, eosinophilia and GI disturbances (e.g. nausea, vomiting, anorexia, abdominal pain). Rarely, retinal haemorrhage, hypersensitivity reactions including rashes, pruritus, leucopenia, fever, and joint pains.

Peripheral neuropathy (dose-related incidence, 10-20% incidence with 10 mg/kg/d), Loss of appetite, Nausea, Vomiting, Stomach pain, Weakness 1-10%, Dizziness, Slurred speech, Lethargy, Progressive liver damage (increases with age; 2.3% in pts > 50 yo), Hyperreflexia, Agranulocytosis, Anemia, Megaloblastic anemia, Thrombocytopenia, Systemic lupus erythematosus, Seizure

Toxicity

Patients experiencing a chronic overdose of ethambutol may present with disturbances in colour vision and reduced visual acuity as symptoms of optic neuropathy. In these cases, ethambutol should be stopped. Data regarding acute overdose of ethambutol are not readily available. Patients experiencing an acute overdose of ethambutol may be experience an increased risk and severity of adverse effects such as pruritus, joint pain, gastrointestinal upset, abdominal pain, malaise, headache, dizziness, mental confusion, disorientation, and possible hallucinations. Patients should be treated with symptomatic and supportive measures.

LD₅₀ 100 mg/kg (Human, oral). Adverse reactions include rash, abnormal liver function tests, hepatitis, peripheral neuropathy, mild central nervous system (CNS) effects. In vivo, Isoniazid reacts with pyridoxal to form a hydrazone, and thus inhibits generation of pyridoxal phosphate. Isoniazid also combines with pyridoxal phosphate; high doses interfere with the coenzyme function of the latter.

Precaution

Patient with ocular defects (e.g. cataracts, recurrent ocular inflammatory conditions, diabetic neuropathy). Renal impairment. Pregnancy and lactation.

Renal or hepatic impairment; convulsive disorders; history of psychosis; patients at risk of neuropathy or pyridoxine deficiency eg, diabetic, alcoholic, malnourished, uraemic, infected with HIV. Careful monitoring of hepatic function is necessary for black and hispanic women. Check hepatic function before and during treatment. Pregnancy and lactation.

Interaction

Delayed or reduced absorption with aluminium hydroxide.

Inhibit the hepatic metabolism of antiepileptics (e.g. carbamazepine, ethosuximide, primidone, phenytoin), benzodiazepines (e.g. diazepam, triazolam), chlorzoxazone, theophylline, disulfiram, sometimes leading to increased toxicity. Increased metabolism of enflurane, resulting in potentially nephrotoxic levels of fluoride. Increased concentrations and enhanced effects or toxicity of clofazimine, cycloserine and warfarin. Reduced absorption with Al-containing antacids. Increased risk of peripheral neuropathy with zalcitabine and stavudine.

Volume of Distribution

Patients coinfected with tuberculosis and HIV have an estimated ethambutol volume of distribution of 76.2 L.

Elimination Route

Oral ethambutol is approximately 75-80% orally bioavailable. A 25 mg/kg oral dose of ethambutol reaches a C_max of 2-5 µg/mL, with a T_max of 2-4 hours. In a separate study, the AUC_0-8 varied from 6.3 ± 5.5 h*mg/L to 10.8 ± 7.6 h*mg/L depending on CYP1A2 genetic polymorphisms.

Readily absorbed following oral administration; however, may undergo significant first pass metabolism. Absorption and bioavailability are reduced when isoniazid is administered with food.

Half Life

Ethambutol has a half life of 3.3 hours in patients with normal renal function. In patients with renal failure, the half life could be 7 hours or longer.

Fast acetylators: 0.5 to 1.6 hours. Slow acetylators: 2 to 5 hours.

Clearance

Patients coinfected with tuberculosis and HIV have an estimated ethambutol oral clearance of 77.4 L/h.

Elimination Route

Ethambutol is 50% eliminated in the urine as the unmetabolized parent compound and 8-15% as inactive metabolites. 20-22% of a dose is eliminated unchanged in the feces.

From 50 to 70 percent of a dose of isoniazid is excreted in the urine within 24 hours.

Pregnancy & Breastfeeding use

Category C: Either studies in animals have revealed adverse effects on the foetus (teratogenic or embryocidal or other) and there are no controlled studies in women or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the foetus.

Pregnancy Category C. Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks

Lactation: distributed into milk but safe for nursing infants

Contraindication

Ethambutol is contraindicated in patients who are known to be hypersensitive to this drug. It is also contraindicated in patients with known optic neuritis unless clinical judgment determines that it may be used. Ethambutol is contraindicated in patients who are unable to appreciate and report visual side effects or changes in vision.

Acute liver disease or history of hepatic damage during INH therapy; hypersensitivity.

Storage Condition

Store between 20-25°C. Protect from light, moisture and excessive heat.

Innovators Monograph

You find simplified version here Combunex