Thre

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.

In the treatment of both tuberculosis and the meningococcal carrier state, the small number of resistant cells present within large populations of susceptible cells can rapidly become the predominant type. Bacteriologic cultures should be obtained before the start of therapy to confirm the susceptibility of the organism to rifampinand they should be repeated throughout therapy to monitor the response to treatment. Since resistance can emerge rapidly, susceptibility tests should be performed in the event of persistent positive cultures during the course of treatment. If test results show resistance to rifampin and the patient is not responding to therapy, the drug regimen should be modified.

Thre 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 TuberculosisCholestatic pruritus, MRSA Infection, Prosthetic Joint Infection, Asymptomatic Neisseria meningitidis carrier of the nasopharynx, Initial phase Tuberculosis, Late phase Tuberculosis, Antibacterial therapy

How Thre 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.

Rifampin acts via the inhibition of DNA-dependent RNA polymerase, leading to a suppression of RNA synthesis and cell death.

Dosage

Thre 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

Rifampin can be administered by the oral route or by IV infusion. IV doses are the same as those for oral.

Tuberculosis:

• Adults: 10 mg/kg, in a single daily administration, not to exceed 600 mg/day, oral or IV
• Pediatric Patients: 10–20 mg/kg, not to exceed 600 mg/day, oral or IV

It is recommended that oral rifampin be administered once daily, either 1 hour before or 2 hours after a meal with a full glass of water.

Rifampin is indicated in the treatment of all forms of tuberculosis. A three-drug regimen consisting of rifampin, isoniazid, and pyrazinamide is recommended in the initial phase of shortcourse therapy which is usually continued for 2 months. The Advisory Council for the Elimination of Tuberculosis, the American Thoracic Society, and theCenters for Disease Control and Preventionrecommend that either streptomycin or ethambutol be added as a fourth drug in a regimen containing isoniazid (INH), rifampin and pyrazinamide for initial treatment of tuberculosis unless the likelihood of INH resistance is very low. The need for a fourth drug should be reassessed when the results of susceptibility testing are known. If community rates of INH resistance are currently less than 4%, an initial treatment regimen with less than four drugs may be considered.

Following the initial phase, treatment should be continued with rifampin and isoniazid for at least 4 months. Treatment should be continued for longer if the patient is still sputum or culture positive, if resistant organisms are present, or if the patient is HIV positive.

Should be taken with food.

Should be taken on an empty stomach. Best taken on an empty stomach 1 hr before or 2 hr after meals.

Preparation Of Solution For IV Infusion: Reconstitute the lyophilized powder by transferring 10 mL of sterile water for injection to a vial containing 600 mg of rifampin for injection. Swirl vial gently to completely dissolve the antibiotic. The reconstituted solution contains 60 mg rifampin per mL and is stable at room temperature for up to 30 hours. Prior to administration, withdraw from the reconstituted solution a volume equivalent to the amount of rifampin calculated to be administered and add to 500 mL of infusion medium. Mix well and infuse at a rate allowing for complete infusion within 3 hours. Alternatively, the amount of rifampin calculated to be administered may be added to 100 mL of infusion medium and infused in 30 minutes.

Dilutions in dextrose 5% for injection (D5W) are stable at room temperature for up to 8 hours and should be prepared and used within this time. Precipitation of rifampin from the infusion solution may occur beyond this time. Dilutions in normal saline are stable at room temperature for up to 6 hours and should be prepared and used within this time. Other infusion solutions are not recommended.

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

Facial flushing and itching, with or without a rash, flu-like syndrome characterised by episodes of fever, chills, headache, dizziness, bone pain, shortness of breath, and malaise; GI adverse effects (e.g. nausea, vomiting, anorexia, diarrhoea, epigastric distress), pseudomembranous colitis, eosinophilia, leucopenia, haemolytic anaemia; alterations in kidney function and renal failure, menstrual disturbances, oedema, myopathy, muscular weakness; orange-red discolouration of the urine, faeces, sweat, saliva, sputum, tears, and other body fluids; thrombophlebitis, local irritation and inflammation after prolonged IV infusion. Rarely, eye irritation and visual disturbances, anaphylaxis or shock.

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.

LD₅₀=1570 mg/kg (rat), chronic exposure may cause nausea and vomiting and unconsciousness

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.

Rifampicin has been shown to produce liver dysfunction. Fatalities associated with jaundice have occurred in patients with liver disease and in patients taking rifampin with other hepatotoxic agents. Patients with impaired liver function should be given rifampin only in cases of necessity and then with caution and under strict medical supervision. In these patients, careful monitoring of liver function, especially SGPT/ALT and SGOT/AST should be carried out prior to therapy and then every 2 to 4 weeks during therapy. If signs of hepatocellular damage occur, rifampin should be withdrawn.

In some cases, hyperbilirubinemia resulting from competition between rifampin and bilirubin for excretory pathways of the liver at the cell level can occur in the early days of treatment. An isolated report showing a moderate rise in bilirubin and/or transaminase level is not in itself an indication for interrupting treatment; rather, the decision should be made after repeating the tests, noting trends in the levels, and considering them in conjunction with the patient's clinical condition.

Rifampin has enzyme-inducing properties, including induction of delta amino levulinic acid synthetase. Isolated reports have associated porphyria exacerbation with rifampin administration.

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.

May accelerate the metabolism and reduce the effect of drugs that are metabolised by CYP450 enzymes (e.g. quinidine, phenytoin, theophylline). Decreased concentrations of atovaquone and increased concentrations of rifampicin when taken concomitantly. Concurrent use of ketoconazole and rifampicin may result in decreased serum concentrations of both drugs. May decrease serum concentrations of enalaprilat. Reduced absorption by antacids. Increased risk of hepatotoxicity with halothane or isoniazid.

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.

Well absorbed from gastrointestinal tract.

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.

3.35 (+/- 0.66) hours

Clearance

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

• 0.19 +/- 0.06 L/hr/kg [300 mg IV]
• 0.14 +/- 0.03 L/hr/kg [600 mg IV]

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.

Less than 30% of the dose is excreted in the urine as rifampin or metabolites.

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

Pregnancy: When administered during the last few weeks of pregnancy, rifampin can cause post natal hemorrhages in the mother and infant for which treatment with vitamin K may be indicated.

Nursing Mothers: Because of the potential for tumorigenicity shown for rifampin in animal studies, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

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.

Rifampicin is contraindicated in patients with a history of hypersensitivity to rifampin or any of the components, or to any of the rifamycins. Rifampin is contraindicated in patients who are also receiving ritonavir-boosted saquinavir due to an increased risk of severe hepatocellular toxicity.

Rifampin is contraindicated in patients who are also receiving atazanavir, darunavir, fosamprenavir, saquinavir, or tipranavir due to the potential of rifampin to substantially decrease plasma concentrations of these antiviral drugs, which may result in loss of antiviral efficacy and/or development of viral resistance.

Special Warning

Geriatric Use: Clinical studies of Rifampicin did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Caution should therefore be observed in using rifampin in elderly patients.

Acute Overdose

Nausea, vomiting, abdominal pain, pruritus, headache, and increasing lethargy will probably occur within a short time after ingestion; unconsciousness may occur when there is severe hepatic disease. Transient increases in liver enzymes and/or bilirubin may occur. Brownish-red or orange discoloration of the skin, urine, sweat, saliva, tears, and feces will occur, and its intensity is proportional to the amount ingested.

Liver enlargement, possibly with tenderness, can develop within a few hours after severe overdosage; bilirubin levels may increase and jaundice may develop rapidly. Hepatic involvement may be more marked in patients with prior impairment of hepatic function. Other physical findings remain essentially normal. A direct effect upon the hematopoietic system, electrolyte levels, or acid-base balance is unlikely.

Facial or periorbital edema has also been reported in pediatric patients. Hypotension, sinus tachycardia, ventricular arrhythmias, seizures and cardiac arrest were reported in some fatal cases.

Storage Condition

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

Store between 15-30° C. Avoid excessive heat and protect from light.

Innovators Monograph

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