4d Plus

Uses

Treatment of both pulmonary and extrapulmonary tuberculosis in the intensive initial phase of treatment.

4d Plus 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 TuberculosisActive Tuberculosis, Pulmonary Tuberculosis (TB)Cholestatic pruritus, MRSA Infection, Prosthetic Joint Infection, Asymptomatic Neisseria meningitidis carrier of the nasopharynx, Initial phase Tuberculosis, Late phase Tuberculosis, Antibacterial therapy

How 4d Plus 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.

Pyrazinamide diffuses into active M. tuberculosis that express pyrazinamidase enzyme that converts pyrazinamide to the active form pyrazinoic acid. Pyrazinoic acid can leak out under acidic conditions to be converted to the protonated conjugate acid, which is readily diffused back into the bacilli and accumulate intracellularly. The net effect is that more pyrazinoic acid accumulates inside the bacillus at acid pH than at neutral pH. Pyrazinoic acid was thought to inhibit the enzyme fatty acid synthase (FAS) I, which is required by the bacterium to synthesise fatty acids. However, this theory was thought to have been discounted. However, further studies reproduced the results of FAS I inhibition as the putative mechanism first in whole cell assay of replicating M. tuberculosis bacilli which have shown that pyrazinoic acid and its ester inhibit the synthesis of fatty acids. This study was followed by in vitro assay of tuberculous FAS I enzyme that tested the activity with pyrazinamide, pyrazinoic acid and several classes of pyrazinamide analogs. Pyrazinamide and its analogs inhibited the activity of purified FAS I.

It has also been suggested that the accumulation of pyrazinoic acid disrupts membrane potential and interferes with energy production, necessary for survival of M. tuberculosis at an acidic site of infection. Pyrazinoic acid has also been shown to bind to the ribosomal protein S1 (RpsA) and inhibit trans-translation. This may explain the ability of the drug to kill dormant mycobacteria.

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

Dosage

4d Plus dosage

Adults: 3 tablets/day for an average body weight of 50 kg.

Patients weighing-

• >70 kg: 5 tablets
• 55-70 kg: 4 tablets
• 38-54 kg: 3 tablets
• 30-37 kg: 2 tablets

All doses to be taken once daily for 2 months on intensive phase.

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

Rifampicin: Reddish discolouration of body fluids, asymptomatic increase in liver enzymes, elevations of BUN & uric acid, hemolysis, hematuria, intestinal nephritis, renal insufficiency, Gl discomfort, CNS effects, hematological changes, skin rash, endocrine effects.

Isoniazid: Disturbances of liver function, hepatitis, Gl disturbances, peripheral neuropathy, dizziness, lightheadedness, hematological changes, allergic reactions.

Pyrazinamide: Transient rise in serum transaminases, hepatotoxicity, hepatomegaly, jaundice, hyperuricemia, intestinal nephritis, dysuria, Gl disturbances, hematological changes, allergic reactions.

Ethambutol: Confusion, disorientation, headache, visual disturbances, jaundice, transient liver dysfunction, Gl disturbances, hematological changes, allergic effects, acute gout (rare).

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.

Side effects include liver injury, arthralgias, anorexia, nausea and vomiting, dysuria,malaise and fever, sideroblastic anemia, adverse effects on the blood clotting mechanism or vascular integrity, and hypersensitivity reactions such as urticaria, pruritis and skin rashes.

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

Precaution

Impaired renal or liver function, DM, chronic alcoholism, undernourishment, history of gout, patients with convulsive disorders, acute porphyria. Elderly. Pregnancy & lactation. Perform periodic blood counts & liver function tests. Avoid use with soft contact lenses.

Children <8 year or patients who are not able to communicate visual disturbances. Check visual ability before starting treatment & monitor during treatment.

Interaction

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

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

Pyrazinamide: Decreases efficacy of gout therapy agents.

Ethambutol: Neurotoxic agents.

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.

Rapidly and well absorbed from the gastrointestinal tract.

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.

9-10 hours (normal conditions)

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.

Approximately 70% of an oral dose is excreted in the urine, mainly by glomerular filtration within 24 hours

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

Pregnancy & Breastfeeding use

Rifampicin: Since rifampicin has been reported to cross the placental barrier and appear in cord blood and in maternal milk, neonates and newborns of rifampicin-treated mothers should be carefully observed for any evidence of untoward effects.

Ethambutol: While administration of ethambutol to pregnant human patients has produced no detectable effect upon the fetus, the possible teratogenic potential in women capable of bearing children would be weighed carefully against the benefits of therapy. There are published reports of 5 women who received ethambutol during pregnancy without apparent adverse effect upon the fetus.

Contraindication

Hypersensitivity to rifampicin, isoniazid, pyrazinamide or ethambutol.

Isoniazid: Previous isoniazid-associated hepatic injury; severe adverse reactions to isoniazid eg, fever, chills and arthritis; acute liver disease of any etiology, a history of previous hypersensitivity reaction to isoniazid including drug-induced hepatitis.

Special Warning

Use in children: Ethambutol is not recommended for use in children <13 years since safe conditions for use have not been established.

Acute Overdose

Overdosage experience is limited. In one case report of overdose, abnormal liver function tests developed. These spontaneously reverted to normal when the drug was stopped. Clinical monitoring and supportive therapy should be employed. Pyrazinamide is dialyzable.

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 at temperatures not exceeding 30°C.

Innovators Monograph

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