RIFATER

REMEDYREPACK INC.

FULL PRESCRIBING INFORMATION: CONTENTS*

• BOXED WARNING
• RIFATER DESCRIPTION
• INACTIVE INGREDIENT
• CLINICAL PHARMACOLOGY
• WARNINGS
• PHARMACOKINETICS
• MICROBIOLOGY
• MECHANISM OF ACTION
• RIFATER ADVERSE REACTIONS
• RIFATER CONTRAINDICATIONS
• ABUSE
• PRECAUTIONS
• INFORMATION FOR PATIENTS
• LABORATORY TESTS
• DRUG INTERACTIONS
• PREGNANCY
• TERATOGENIC EFFECTS
• NURSING MOTHERS
• PEDIATRIC USE
• GERIATRIC USE
• CLINICAL STUDIES
• OVERDOSAGE
• HOW SUPPLIED
• PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

FULL PRESCRIBING INFORMATION

RIFATER DESCRIPTION

RIFATER (rifampin/isoniazid/pyrazinamide) tablets are combination tablets containing 120 mg rifampin, 50 mg isoniazid, and 300 mg pyrazinamide for use in antibacterial therapy. The tablets also contain as inactive ingredients: povidone, carboxymethylcellulose sodium, calcium stearate, sodium lauryl sulfate, sucrose, talc, acacia, titanium dioxide, kaolin, magnesium carbonate, colloidal silicon dioxide, dried aluminum hydroxide gel, ferric oxide, black iron oxide, carnauba wax, white beeswax, colophony, hard paraffin, lecithin, shellac, and propylene glycol. The RIFATER triple therapy combination was developed for dosing convenience.

Rifampin is a semisynthetic antibiotic derivative of rifamycin SV. Rifampin is a red-brown crystalline powder very slightly soluble in water at neutral pH, freely soluble in chloroform, soluble in ethyl acetate and methanol. Its molecular weight is 822.95 and its chemical formula is C₄₃H₅₈N₄O₁₂. The chemical name for rifampin is either:

3-[[(4-methyl-1-piperazinyl)imino]-methyl]-rifamycin;

INACTIVE INGREDIENT

inactive ingredients:  povidone, carboxymethylcellulose sodium, calcium stearate, sodium lauryl sulfate, sucrose, talc, acacia, titanium dioxide, kaolin, magnesium carbonate, colloidal silicon dioxide, dried aluminum hydroxide gel, ferric oxide, black iron oxide, carnauba wax, white beeswax, colophony, hard paraffin, lecithin, shellac, and propylene glycol. The RIFATER triple therapy combination was developed for dosing convenience.

CLINICAL PHARMACOLOGY

Rifampin is readily absorbed from the gastrointestinal tract. Peak serum levels in normal 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 level averages 7 mcg/mL but may vary from 4 to 32 mcg/mL. Absorption of rifampin is reduced when the drug is ingested with food.

In normal subjects, the biological half-life of rifampin in serum averages about 3 hours after a 600 mg oral dose, with increases up to 5.1 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 half-life increased from 3.6 hours in normal subjects to 5.0, 7.3, and 11.0 hours in patients with glomerular filtration rates of 30–50 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 30percent of a dose is excreted in the urine, with about half as unchanged drug.

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 is diffused freely in tissues.

After oral administration, isoniazid is readily absorbed from the GI tract and produces peak blood levels within 1 to 2 hours. It diffuses readily into all body fluids (cerebrospinal, pleural, and ascitic fluids), tissues, organs, and excreta (saliva, sputum, and feces). Isoniazid is not substantially bound to plasma proteins. The drug also passes through the placental barrier and into milk in concentrations comparable to those in the plasma. The plasma half-life of isoniazid in patients with normal renal and hepatic function ranges from 1–4 hours, depending on the rate of metabolism. From 50percent to 70percent of a dose of isoniazid is excreted in the urine within 24 hours, mostly as metabolites.

Isoniazid is metabolized in the liver mainly by acetylation and dehydrazination. The rate of acetylation is genetically determined. Approximately 50percent of African Americans and Caucasians are "slow inactivators" and the rest are "rapid inactivators"; the majority of Eskimos and Asians 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, an increase in toxic reactions.

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

Pyrazinamide is well absorbed from the gastrointestinal tract and attains peak plasma concentrations within 2 hours. Plasma concentrations generally range from 30 to 50 mcg mL with doses of 20 to 25 mg kg. It is widely distributed in body tissues and fluids including the liver, lungs, and cerebrospinal fluid (CSF). The CSF concentration is approximately equal to concurrent steady-state plasma concentrations in patients with inflamed meninges. Pyrazinamide is approximately 10percent bound to plasma proteins. The plasma half-life of pyrazinamide is 9 to 10 hours in patients with normal renal and hepatic function. The half-life of the drug may be prolonged in patients with impaired renal or hepatic function. Pyrazinamide is hydrolyzed in the liver to its major active metabolite, pyrazinoic acid. Pyrazinoic acid is hydroxylated to the main excretory product, 5-hydroxypyrazinoic acid.

Within 24 hours, approximately 70percent of an oral dose of pyrazinamide is excreted in urine, mainly by glomerular filtration. About 4percent to 14percent of the dose is excreted as unchanged drug; the remainder is excreted as metabolites.

In a single-dose bioavailability study of five RIFATER tablets (Treatment A, n=23) versus RIFADIN 600 mg, isoniazid 250 mg, and pyrazinamide 1500 mg (Treatment B, n=24) administered concurrently in normal subjects, there was no difference in extent of absorption, as measured by the area under the plasma concentration versus time curve (AUC), of all three components. However, the mean peak plasma concentration of rifampin was approximately 18percent lower following the single-dose administration of RIFATER tablets as compared to RIFADIN

WARNINGS

RIFATER is a combination of the three drugs, rifampin, isoniazid, and pyrazinamide. Each of these individual drugs has been associated with liver dysfunction.

Rifampin 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. Because RIFATER contains both rifampin and isoniazid, it should only be given with caution and under strict medical supervision to patients with impaired liver function. In these patients, careful monitoring of liver function, especially serum glutamic pyruvic transaminase (SGPT) and serum glutamic oxaloacetic transaminase (SGOT) should be carried out prior to therapy and then every 2 to 4 weeks during therapy. If signs of hepatocellular damage occur, RIFATER 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.

SEE THE BOXED WARNING

PHARMACOKINETICS

MICROBIOLOGY

MicrobiologyRifampin, isoniazid, and pyrazinamide at therapeutic levels have demonstrated bactericidal activity against both intracellular andextracellular Mycobacterium tuberculosis organisms.

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

Isoniazid kills actively growing tubercle bacilli by inhibiting the biosynthesis of mycolic acids which are major components of the cell wall of Mycobacterium tuberculosis.

The exact mechanism of action by which pyrazinamide inhibits the growth of Mycobacterium tuberculosis organisms is unknown. In vitro and in vivo studies have demonstrated that pyrazinamide is only active at a slightly acidic pH (pH 5.5).

RIFATER ADVERSE REACTIONS

RIFATER CONTRAINDICATIONS

CONTRAINDICATIONS
RIFATER is contraindicated in patients with a history of hypersensitivity to rifampin, isoniazid, pyrazinamide, or any of the
components. Other contraindications include patients with severe hepatic damage; severe adverse reactions to isoniazid, such as drug
fever, chills, and arthritis; patients with acute liver disease of any etiology; and patients with acute gout.

ABUSE

abusers)should be followed closely.Because it contains pyrazinamide, RIFATER should be discontinued and not be resumed if signs of hepatocellular damage orhyperuricemia accompanied by an acute gouty arthritis appear. If hyperuricemia accompanied by an acute gouty arthritis occurswithout liver dysfunction, the patient should be transferred to a regimen not containing pyrazinamide.

PRECAUTIONS

RIFATER should be used with caution in patients with a history of diabetes mellitus, as diabetes management may be more difficult.

For treatment of tuberculosis, rifampin is usually administered on a daily basis. Doses of rifampin ( 600 mg) given once or twice weekly have resulted in a higher incidence of adverse reactions, including the "flu syndrome" (fever, chills and malaise); hematopoietic reactions (leukopenia, thrombocytopenia, or acute hemolytic anemia); cutaneous, gastrointestinal, and hepatic reactions; shortness of breath; shock and renal failure.

The patient should be advised that the reliability of oral contraceptives may be affected; consideration should be given to using alternative contraceptive measures.

All drugs should be stopped and an evaluation of the patient should be made at the first sign of a hypersensitivity reaction.

Use of RIFATER, because it contains isoniazid, should be carefully monitored in the following:

• Patients who are receiving phenytoin (diphenylhydantoin) concurrently. Isoniazid may decrease the excretion of phenytoin or may enhance its effects. To avoid phenytoin intoxication, appropriate adjustment of the anticonvulsant dose should be made.
• Daily users of alcohol. Daily ingestion of alcohol may be associated with a higher incidence of isoniazid hepatitis.

Pyrazinamide inhibits renal excretion of urates, frequently resulting in hyperuricemia which is usually asymptomatic. If hyperuricemia is accompanied by acute gouty arthritis, RIFATER, because it contains pyrazinamide, should be discontinued.

INFORMATION FOR PATIENTS

Because isoniazid has some monoamine oxidase inhibiting activity, an interaction with tyramine-containing foods (cheese, red wine) may occur. Diamine oxidase may also be inhibited, causing exaggerated response (eg, headache, sweating, palpitations, flushing, hypotension) to foods containing histamine (eg, skipjack, tuna, other tropical fish). Tyramine- and histamine-containing foods should be avoided in patients receiving RIFATER.

RIFATER, because it contains rifampin, may produce a reddish coloration of the urine, sweat, sputum, and tears, and the patient should be forewarned of this. Soft contact lenses may be permanently stained.

Patients should be instructed to take RIFATER either 1 hour before or 2 hours after a meal.

Patients should be instructed to notify their physicians promptly if they experience any of the following: fever, loss of appetite, malaise, nausea and vomiting, darkened urine, yellowish discoloration of the skin and eyes, pain or swelling of the joints.

Compliance with the full course of therapy must be emphasized, and the importance of not missing any doses must be stressed.

LABORATORY TESTS

Laboratory TestsA complete blood count (CBC), liver function tests, and blood uric acid determinations should be obtained prior to instituting therapyand periodically throughout the course of therapy. Because of a possible transient rise in transaminase and bilirubin values, blood forbaseline clinical chemistries should be obtained before RIFATER dosing.

DRUG INTERACTIONS

Enzyme Induction: Rifampin is known to induce certain cytochrome P-450 enzymes. Coadministration of RIFATER, because it contains rifampin, with drugs that undergo biotransformation through these metabolic pathways may accelerate elimination. To maintain optimum therapeutic blood levels, dosages of drugs metabolized by these enzymes may require adjustment when starting or stopping concomitantly administered rifampin.

Concomitant antacid administration may reduce the absorption of rifampin. Daily doses of RIFATER, because it contains rifampin, should be given at least 1 hour before the ingestion of antacids.

Probenecid and cotrimoxazole have been reported to increase the blood level of rifampin.

When rifampin is given concomitantly with either halothane or isoniazid the potential for hepatotoxicity is increased. The concomitant use of RIFATER, because it contains both rifampin and isoniazid, and halothane should be avoided. Patients receiving both rifampin and isoniazid as in RIFATER should be monitored closely for hepatotoxicity. See the boxed WARNING.

Plasma concentrations of sulfapyridine may be reduced following the concomitant administration of sulfasalazine and RIFATER, because it contains rifampin. This finding may be the result of alteration in the colonic bacteria responsible for the reduction of sulfasalazine to sulfapyridine and mesalamine.

Isoniazid

Enzyme Inhibition: Isoniazid is known to inhibit certain cytochrome P-450 enzymes. Coadministration of isoniazid with drugs that undergo biotransformation through these metabolic pathways may decrease elimination. Consequently, dosages of drugs metabolized by these enzymes may require adjustment when starting or stopping concomitantly administered RIFATER, because it contains isoniazid, to maintain optimum therapeutic blood levels.
Isoniazid has been reported to inhibit the metabolism of the following drugs: anticonvulsants (eg, carbamazepine, phenytoin, primidone, valproic acid), benzodiazepines (eg, diazepam), haloperidol, ketoconazole, theophylline, and warfarin. It may be necessary to adjust the dosages of these drugs if they are given concurrently with RIFATER because it contains isoniazid. The impact of the competing effects of rifampin and isoniazid on the metabolism of these drugs is unknown.

Concomitant antacid administration may reduce the absorption of isoniazid. Ingestion with food may also reduce the absorption of isoniazid. Daily doses of RIFATER, because it contains isoniazid, should be given on an empty stomach at least 1 hour before the ingestion of antacids or food.

Corticosteroids (eg, prednisolone) may decrease the serum concentration of isoniazid by increasing acetylation rate and/or renal clearance. Para-aminosalicylic acid may increase the plasma concentration and elimination half-life of isoniazid by competition of acetylating enzymes.

Daily ingestion of alcohol may be associated with a higher incidence of isoniazid hepatitis. Isoniazid, when given concomitantly with rifampin, has been reported to increase the hepatotoxicity of both drugs. Patients receiving both rifampin and isoniazid as in RIFATER should be monitored closely for hepatotoxicity.

The CNS effects of meperidine (drowsiness), cycloserine (dizziness, drowsiness), and disulfiram (acute behavioral and coordination changes) may be exaggerated when concomitant RIFATER, because it contains isoniazid, is given. Concurrent RIFATER, because it contains isoniazid, and levodopa administration may produce symptoms of excess catecholamine stimulation (agitation, flushing, palpitations) or lack of levodopa effect.

Isoniazid may produce hyperglycemia and lead to loss of glucose control in patients on oral hypoglycemics.

Fast acetylation of isoniazid may produce high concentrations of hydrazine that facilitate deflorination of enflurane. Renal function should be monitored in patients receiving both RIFATER and enflurane.

Because isoniazid has some monoamine oxidase inhibiting activity, an interaction with tyramine-containing foods (cheese, red wine) may occur. Diamine oxidase may also be inhibited, causing exaggerated response (eg, headache, sweating, palpitations, flushing, hypotension) to foods containing histamine (eg, skipjack, tuna, other tropical fish). Tyramine- and histamine-containing foods should be avoided by patients receiving RIFATER.

PREGNANCY

Category C. Animal reproduction studies have not been conducted with RIFATER. It is also not known whether RIFATER can cause fetal harm when administered to a pregnant woman. RIFATER should be given to a pregnant woman only if clearly needed.

Although rifampin has been reported to cross the placental barrier and appear in cord blood, the effect of rifampin, alone or in combination with other antituberculosis drugs, on the human fetus is not known. An increase in congenital malformations, primarily spina bifida and cleft palate, has been reported in the offspring of rodents given oral doses of 150 to 250 mg/kg/day of rifampin during pregnancy. The possible teratogenic potential in women capable of bearing children should be carefully weighed against the benefits of RIFATER therapy.

It has been reported that in both rats and rabbits, isoniazid may exert an embryocidal effect when administered orally during pregnancy, although no isoniazid-related congenital anomalies have been found in reproduction studies in mammalian species (mice, rats, and rabbits). RIFATER, because it contains isoniazid, should be prescribed during pregnancy only when therapeutically necessary. The benefit of preventive therapy should be weighed against a possible risk to the fetus. Preventive treatment generally should be started after delivery because of the increased risk of tuberculosis for new mothers.

Animal reproductive studies have not been conducted with pyrazinamide. It is also not known whether pyrazinamide can cause fetal harm when administered to a pregnant woman. RIFATER, because it contains pyrazinamide, should be given to a pregnant woman only if clearly needed.

It is not known whether RIFATER can affect reproduction capacity

When administered during the last few weeks of pregnancy, rifampin can cause postnatal hemorrhages in the mother and infant. In this case, treatment with vitamin K may be indicated for postnatal hemorrhage.

TERATOGENIC EFFECTS

Category C. Animal reproduction studies have not been conducted with RIFATER. It is also not known whether RIFATER can cause fetal harm when administered to a pregnant woman. RIFATER should be given to a pregnant woman only if clearly needed.

Although rifampin has been reported to cross the placental barrier and appear in cord blood, the effect of rifampin, alone or in combination with other antituberculosis drugs, on the human fetus is not known. An increase in congenital malformations, primarily spina bifida and cleft palate, has been reported in the offspring of rodents given oral doses of 150 to 250 mg/kg/day of rifampin during pregnancy. The possible teratogenic potential in women capable of bearing children should be carefully weighed against the benefits of RIFATER therapy.

It has been reported that in both rats and rabbits, isoniazid may exert an embryocidal effect when administered orally during pregnancy, although no isoniazid-related congenital anomalies have been found in reproduction studies in mammalian species (mice, rats, and rabbits). RIFATER, because it contains isoniazid, should be prescribed during pregnancy only when therapeutically necessary. The benefit of preventive therapy should be weighed against a possible risk to the fetus. Preventive treatment generally should be started after delivery because of the increased risk of tuberculosis for new mothers.

Animal reproductive studies have not been conducted with pyrazinamide. It is also not known whether pyrazinamide can cause fetal harm when administered to a pregnant woman. RIFATER, because it contains pyrazinamide, should be given to a pregnant woman only if clearly needed.

It is not known whether RIFATER can affect reproduction capacity

When administered during the last few weeks of pregnancy, rifampin can cause postnatal hemorrhages in the mother and infant. In this case, treatment with vitamin K may be indicated for postnatal hemorrhage

NURSING MOTHERS

Nursing MothersSince rifampin, isoniazid, and pyrazinamide are known to pass into maternal breast milk, a decision should be made whether todiscontinue nursing or to discontinue RIFATER, taking into account the importance of the drug to the mother.

PEDIATRIC USE

Pediatric UseSafety and effectiveness in pediatric patients under the age of 15 have not been established.

GERIATRIC USE

Clinical studies of RIFATER 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. (See WARNINGS)

CLINICAL STUDIES

OVERDOSAGE

Non-fatal overdoses with as high as 12 g of rifampin have been reported.
One case of fatal overdose is known: A 26-year-old man died after self-administering 60 g of rifampin.

Untreated or inadequately treated cases of gross isoniazid overdosage can be fatal, but good response has been reported in most patients treated within the first few hours after drug ingestion.

Ingested acutely, as little as 1.5 g isoniazid may cause toxicity in adults. Doses of 35 to 40 mg/kg have resulted in seizures. Ingestion of 80 to 150 mg/kg isoniazid has been associated with severe toxicity and, if untreated, significant mortality.

The following signs and symptoms have been seen with each individual component in an overdosage situation.

Rifampin

Nausea, vomiting, and increasing lethargy will probably occur within a short time after rifampin overdosage; unconsciousness may occur when there is severe hepatic disease. 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.

Isoniazid overdosage produces signs and symptoms within 30 minutes to 3 hours. Nausea, vomiting, dizziness, slurring of speech, blurring of vision, and visual hallucinations (including bright colors and strange designs) 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.

In one case of pyrazinamide overdosage, abnormal liver function tests developed. These spontaneously reverted to normal when the drug was stopped.

The airway should be secured and adequate respiratory exchange should be established in cases of overdosage with RIFATER.

Obtain blood samples for immediate determination of gases, electrolytes, BUN, glucose, etc; type and cross-match blood in preparation for possible hemodialysis.

Gastric lavage within the first 2 to 3 hours after ingestion is advised, but it should not be attempted until convulsions are under control. To treat convulsions, administer IV diazepam or short-acting barbiturates, and IV pyridoxine (usually 1 mg/1 mg isoniazid ingested). Following evacuation of gastric contents, the instillation of activated charcoal slurry into the stomach may help absorb any remaining drug from the gastrointestinal tract. Antiemetic medication may be required to control severe nausea and vomiting.

RAPID CONTROL OF METABOLIC ACIDOSIS IS FUNDAMENTAL TO MANAGEMENT. Give IV sodium bicarbonate at once and repeat as needed, adjusting subsequent dosage on the basis of laboratory findings (ie, serum sodium, pH, etc).

Forced osmotic diuresis must be started early and should be continued for some hours after clinical improvement to hasten renal clearance of drug and help prevent relapse; monitor fluid intake and output.

Hemodialysis is advised for severe cases; if this is not available, 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, utilize meticulous respiratory and other intensive care to protect against hypoxia, hypotension, aspiration pneumonitis, etc.

HOW SUPPLIED

RIFATER tablets are light beige, smooth, round, and shiny sugar-coated tablets imprinted with "RIFATER" in black ink and contain 120 mg rifampin, 50 mg isoniazid, and 300 mg pyrazinamide, and are supplied as:

Bottles of 60 tablets (NDC 0088-0576-41).

Store at controlled room temperature 59–86°F (15–30°C). Protect from excessive humidity.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL