Ethambutol Hcl 275 mg, Isoniazid 75 mg, Rifampicin 150 mg Tablets

ETHAMBUTOL HCL, following a single oral dose of 25 mg/kg of body weight, attains a peak of 2 to 5 mcg/mL in serum 2 to 4 hours after administration. When the drug is administered daily for longer periods of time at this dose, serum levels are similar. The serum level of ETHAMBUTOL HCL falls to undetectable levels by 24 hours after the last dose except in some patients with abnormal renal function. The intracellular concentrations of erythrocytes reach peak values approximately twice those of plasma and maintain this ratio throughout the 24 hours.

During the 24-hour period following oral administration of ETHAMBUTOL HCl approximately 50 percent of the initial dose is excreted unchanged in the urine, while an additional 8 to 15 percent appears in the form of metabolites. The main path of metabolism appears to be an initial oxidation of the alcohol to an aldehydic intermediate, followed by conversion to a dicarboxylic acid. From 20 to 22 percent of the initial dose is excreted in the feces as unchanged drug. No drug accumulation has been observed with consecutive single daily doses of 25 mg/kg in patients with normal kidney function, although marked accumulation has been demonstrated in patients with renal insufficiency.

ETHAMBUTOL HCl diffuses into actively growing Mycobacterium cells such as tubercle bacilli. ETHAMBUTOL HCl appears to inhibit the synthesis of one or more metabolites, thus causing impairment of cell metabolism, arrest of multiplication, and cell death. No cross resistance with other available antimycobacterial agents has been demonstrated.

ETHAMBUTOL HCl has been shown to be effective against strains of Mycobacterium tuberculosis but does not seem to be active against fungi, viruses, or other bacteria. Mycobacterium tuberculosis strains previously unexposed to ETHAMBUTOL HCL have been uniformly sensitive to concentrations of 8 or less mcg/mL, depending on the nature of the culture media. When ETHAMBUTOL HCl has been used alone for treatment of tuberculosis, tubercle bacilli from these patients have developed resistance to ETHAMBUTOL HCl (ethambutol hydrochloride) by in vitro susceptibility tests; the development of resistance has been unpredictable and appears to occur in a step-like manner. No cross resistance between ETHAMBUTOL HCl and other antituberculous drugs has been reported. ETHAMBUTOL HCl has reduced the incidence of the emergence of mycobacterial resistance to isoniazid when both drugs have been used concurrently. An agar diffusion microbiologic assay, based upon inhibition of Mycobacterium smegmatis (ATCC 607) may be used to determine concentrations of ETHAMBUTOL HCl in serum and urine.

Within 1 to 2 hours after oral administration, isoniazid produces peak blood levels which decline to 50 percent or less within 6 hours. It diffuses readily into all body fluids (cerebrospinal, pleural and ascitic fluids), tissues, organs and excreta (saliva, sputum and feces). The drug also passes through the placental barrier and into milk in concentrations comparable to those in the plasma. From 50 to 70 percent of a dose of isoniazid is excreted in the urine in 24 hours.

Isoniazid is metabolized primarily by acetylation and dehydrazination. The rate of acetylation is genetically determined. Approximately 50 percent of Blacks and Caucasians are "slow inactivators" and the rest are "rapid inactivators"; the majority of Eskimos and Orientals are rapid inactivators."

The rate of acetylation does not significantly alter the effectiveness of isoniazid. However, slow acetylation may lead to higher blood levels of the drug and, thus, to an increase in toxic reactions.

Pyridoxine (vitamin B6) deficiency is sometimes observed in adults with high doses of isoniazid and is considered probably due to its competition with pyridoxal phosphate for the enzyme apotryptophanase.

Isoniazid inhibits the synthesis of mycoloic acids, an essential component of the bacterial cell wall. At therapeutic levels isoniazid is bactericidal against actively growing intracellular and extracellular Mycobacterium tuberculosis organisms.

Resistance to isoniazid occurs because of mutations in the katG, inhA, kasA and ahpC genes. Resistance in M. tuberculosis develops rapidly when isoniazid monotherapy is administered.

For specific information regarding susceptibility test criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: www.fda.gov/STIC.

Rifampin is readily absorbed from the gastrointestinal tract. Peak serum concentrations in healthy adults and pediatric populations vary widely from individual to individual. Following a single 600 mg oral dose of rifampin in healthy adults, the peak serum concentration averages 7 mcg/mL but may vary from 4 to 32 mcg/mL. Absorption of rifampin is reduced by about 30% when the drug is ingested with food.

Rifampin is widely distributed throughout the body. It is present in effective concentrations in many organs and body fluids, including cerebrospinal fluid. Rifampin is about 80% protein bound. Most of the unbound fraction is not ionized and, therefore, diffuses freely into tissues.

In healthy adults, the mean biological half-life of rifampin in serum averages 3.35 ± 0.66 hours after a 600 mg oral dose, with increases up to 5.08 ± 2.45 hours reported after a 900 mg dose. With repeated administration, the half-life decreases and reaches average values of approximately 2 to 3 hours. The half-life does not differ in patients with renal failure at doses not exceeding 600 mg daily, and consequently, no dosage adjustment is required. The half-life of rifampin at a dose of 720 mg daily has not been established in patients with renal failure. Following a single 900 mg oral dose of rifampin in patients with varying degrees of renal insufficiency, the mean half-life increased from 3.6 hours in healthy adults to 5.0, 7.3, and 11.0 hours in patients with glomerular filtration rates of 30 to 50 mL/min, less than 30 mL/min, and in anuric patients, respectively. Refer to the WARNINGS section for information regarding patients with hepatic insufficiency.

After absorption, rifampin is rapidly eliminated in the bile, and an enterohepatic circulation ensues. During this process, rifampin undergoes progressive deacetylation so that nearly all the drug in the bile is in this form in about 6 hours. This metabolite has antibacterial activity. Intestinal reabsorption is reduced by deacetylation, and elimination is facilitated. Up to 30% of a dose is excreted in the urine, with about half of this being unchanged drug.

Mechanism of Action — Rifampin inhibits DNA-dependent RNA polymerase activity in susceptible Mycobacterium tuberculosis organisms. Specifically, it interacts with bacterial RNA polymerase but does not inhibit the mammalian enzyme.

Resistance — Organisms resistant to rifampin are likely to be resistant to other rifamycins.

In the treatment of both tuberculosis and the meningococcal carrier state (see INDICATIONS AND USAGE ), the small number of resistant cells present within large populations of susceptible cells can rapidly become predominant. In addition, resistance to rifampin has been determined to occur as single-step mutations of the DNA-dependent RNA polymerase. Since resistance can emerge rapidly, appropriate susceptibility tests should be performed in the event of persistent positive cultures.

Activity in vitro and in vivo — Rifampin has bactericidal activity in vitro against slow and intermittently growing M tuberculosis organisms.

Rifampin has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections (see INDICATIONS AND USAGE ).

For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.