rifampin 300 MG / isoniazid 150 MG Oral Capsule

WARNINGS

Rifampin and isoniazid capsules are a combination of two drugs, each of which has been associated with liverdysfunction.

Liver function tests should be performed prior to therapy with rifampin/isoniazid and periodicallyduring treatment.

Rifampin Rifampin has been shown to produce liver dysfunction.

There have been fatalities associated with jaundice inpatients with liver disease or receiving rifampin concomitantly with other hepatoxic agents.

Since an increased riskmay exist for individuals with liver disease, benefits must be weighed carefully against the risk of further liver damage.

Several studies of tumorigenicity potential have been done in rodents.

In one strain of mice known to be particularlysusceptible to the spontaneous development of hepatomas, rifampin given at a level 2-10 times the maximumdosage used clinically resulted in a significant increase in the occurrence of hepatomas in female mice of this strainafter one year of administration.

There was no evidence of tumorigenicity in the males of this strain, in males or females of another mouse strain, orin rats.

Isoniazid See the boxed warning .

OVERDOSAGE

Rifampin Signs and Symptoms: Nausea, vomiting and increasing lethargy will probably occur within a short time after ingestion;actual unconsciousness may occur with severe hepatic involvement.

Brownish-red or orange discoloration ofthe skin, urine, sweat, saliva, tears, and feces is proportional to amount ingested.

Liver enlargement, possibly with tenderness, can develop within a few hours after severe overdosage, and jaundicemay develop rapidly.

Hepatic involvement may be more marked in patients with prior impairment of hepatic function.Other physical findings remain essentially normal.

Direct and total bilirubin levels may increase rapidly with severe overdosage; hepatic enzyme levels may be affected, especially with prior impairment of hepatic function.

A direct effect upon hemopoietic system, electrolyte levels, or acid-base balance is unlikely.

Isoniazid Signs and Symptoms: Isoniazid overdosage produces signs and symptoms within 30 minutes to 3 hours.

Nausea, vomiting, dizziness, slurring of speech, blurring of vision, visual hallucinations (including bright colors and strangedesigns), are among the early manifestations.

With marked overdosage, respiratory distress and CNS depression, progressing rapidly from stupor to profound coma, are to be expected, along with severe, intractable seizures.Severe metabolic acidosis, acetonuria, and hyperglycemia are typical laboratory findings.

Treatment The airway should be secured and adequate respiratory exchange established.

Only then should gastric emptying(lavage-aspiration) be attempted; this may be difficult because of seizures.

Since nausea and vomiting are likely tobe present, gastric lavage is probably preferable to induction of emesis.

Activated charcoal slurry instilled into the stomach following evacuation of gastric contents can help absorb anyremaining drug in the GI tract.

Antiemetic medication may be required to control severe nausea and vomiting.

Blood samples should be obtained for immediate determination of gases, electrolytes, BUN, glucose, etc.

Bloodshould be typed and cross matched in preparation for possible hemodialysis.

Rapid control of metabolic acidosis is fundamental to management.

Intravenous sodium bicarbonate should begiven at once and repeated as needed, adjusting subsequent dosage on the basis of laboratory findings (i.e., serumsodium, pH, etc.).

At the same time, anticonvulsants should be given intravenously (i.e., barbiturates, diphenylhydantoin, diazepam) as required, and large doses of intravenous pyridoxine.

Forced osmotic diuresis must be started early and should be continued for some hours after clinical improvementto hasten renal clearance of drug and help prevent relapse.

Fluid intake and output should be monitored.

Bile drainage may be indicated in presence of serious impairment of hepatic function lasting more than 24-48hours.

Under these circumstances and for severe cases, extracorporeal hemodialysis may be required; if this is notavailable, peritoneal dialysis can be used along with forced diuresis.

Along with measures based on initial and repeated determination of blood gases and other laboratory tests as needed,meticulous respiratory and other intensive care should be utilized to protect against hypoxia, hypotension, aspiration,pneumonitis, etc.

In patients with previously adequate hepatic function, reversal of liver enlargement and impaired hepatic excretoryfunction probably will be noted within 72 hours, with rapid return toward normal thereafter.

Untreated or inadequately treated cases of gross isoniazid overdosage can terminate fatally, but good response hasbeen reported in most patients brought under adequate treatment within the first few hours after drug ingestion.

DESCRIPTION

Rifampin/Isoniazid is a combination capsule containing 300 mg rifampin and 150 mg isoniazid.

Each capsule for oral administration, contain the following inactive ingredients: colloidal silicon dioxide, corn starch, lactose monohydrate,magnesium stearate, and pregelatinized starch.

Capsule shell contains: FD&C blue #1, FD&C red #40, gelatin and titanium dioxide.

The printing ink contains: ammonium hydroxide, isopropyl alcohol, N-butyl alcohol, pharmaceutical glaze, propylene glycol, simethicone, and titanium dioxide.

Rifampin is a semisynthetic antibiotic derivative of rifamycin B.

The chemical name for rifampin is 3-(4-methyl-1-piperazinyliminomethyl) rifamycin SV.

Isoniazid is the hydrazide of isonicotinic acid.

It exists as colorless or white crystals or as a white crystalline powderthat is water soluble, odorless and slowly affected by exposure to air and light.

HOW SUPPLIED

Rifampin and Isoniazid Capsules USP, 300 mg/150 mg are supplied as red powder filled No.

0 Scarlet Opaque HardGelatin Capsules; printed “IsonaRif™” on one end and “VP/017” on the other end in white ink; bottles of 60 capsules (NDC#61748-017-60).

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

Keep tightly closed.

Store in a dry place.

Avoid excessive heat.

Store at 20-25°C (68-77°F) [See USP Controlled Room Temperature].

Protect from light and moisture.

Manufactured for: VersaPharm Incorporated Marietta, GA 30062 Manufactured by: West-ward Pharmaceutical Corp Eatontown, NJ 07724 Rev.

Feb.

2007

INDICATIONS AND USAGE

For pulmonary tuberculosis in which organisms are susceptible, and when the patient has been titrated on theindividual components and it has therefore been established that this fixed dosage is therapeutically effective.

This fixed-dosage combination drug is not recommended for initial therapy of tuberculosis or for preventive therapy.

In the treatment of tuberculosis, small numbers of resistant cells, present within large populations of susceptiblecells, can rapidly become the predominating type.

Since rapid emergence of resistance can occur, culture andsusceptibility tests should be performed in the event of persistent positive cultures.

This drug is not indicated for the treatment of meningococcal infections or asymptomatic carriers of N.

meningitides to eliminate meningococci from the nasopharynx.

BOXED WARNING

WARNING Severe and sometimes fatal hepatitis associated with isoniazid therapy may occur and may develop even after many months of treatment.

The risk of developing hepatitis is age related.

Approximate case rates by age are: 0 per 1,000 for persons under 20 years of age, 3 per 1,000 for persons in the 20-34 year age group, 12 per 1,000 for persons in the 35-49 year age group, 23 per 1,000 for persons in the 50-64 year age group, and 8 per 1,000 for persons over 65 years of age.

The risk of hepatitis is increased with daily consumption of alcohol.

Precise data to provide a fatality rate for isoniazid-related hepatitis is not available; however, in a U.S.

Public Health Service Surveillance Study of 13,838 persons taking isoniazid, there were 8 deaths among 174 cases of hepatitis.

Therefore, patients given isoniazid should be carefully monitored and interviewed at monthly intervals.

Serum transaminase concentration becomes elevated in about 10-20 percent of patients, usually during the first few months of therapy, but it can occur at any time.

Usually enzyme levels return to normal despite continuance of drug, but in some cases progressive liver dysfunction occurs.

Patients should be instructed to report immediately any of the prodromal symptoms of hepatitis, such as fatigue, weakness, malaise, anorexia, nausea, or vomiting.

If these symptoms appear or if signs suggestive of hepatic damage are detected, isoniazid should be discontinued promptly, since continued use of the drug in these cases has been reported to cause a more severe form of liver damage.

Patients with tuberculosis should be given appropriate treatment with alternative drugs.

If isoniazid must be reinstituted, it should be reinstituted only after symptoms and laboratory abnormalities have cleared.

The drug should be restarted in very small and gradually increasing doses and should be withdrawn immediately if there is any indication of recurrent liver involvement.

Treatment should be deferred in persons with acute hepatic diseases.

DOSAGE AND ADMINISTRATION

In general, therapy should be continued until bacterial conversion and maximal improvement have occurred.

Adults: Two Rifampin and Isoniazid Capsules, USP (600 mg rifampin, 300 mg isoniazid) once daily, administeredone hour before or two hours after a meal.

Concomitant administration of pyridoxine (B6) is recommended in the malnourished, in those predisposed toneuropathy (e.g., diabetic), and in adolescents.

Susceptibility Testing, Rifampin Rifampin susceptibility powders are available for both direct and indirect methods of determining the susceptibility of strains of mycobacteria.

The MIC’s of susceptible clinical isolates when determined in 7H10 or other non-eggcontainingmedia have ranged from 0.1 to 2 mcg/mL.

Quantitative methods that require measurement of zonediameters give the most precise estimates of antibiotic susceptibility.

One such procedure has been recommendedfor use with discs for testing susceptibility to rifampin.

Interpretations correlate zone diameters from the disc testwith MIC (minimal inhibitory concentration) values for rifampin.