Rifater Side Effects, and Drug Interactions - Rifampin, Isoniazid and Pyrazinamide

Rifater Side Effects, and Drug Interactions - Rifampin, Isoniazid and Pyrazinamide

SIDE EFFECTS

Adverse Experiences During the Clinical Trial

Adverse event data reported for the RIFATER and the separate drug treatment groups during the first 2 months of the trial are shown in the table below.

No serious adverse events were reported in the patients receiving RIFATER tablets. Three serious adverse events were reported in the patients given isoniazid, rifampin, and pyrazinamide as separate tablets and capsules. The three serious adverse events were two general hypersensitivity reactions and one jaundice reaction.

There were no significant differences between the two treatment groups in standard liver function, renal function and hematological laboratory test values measured at baseline and after 8 weeks of treatment. As would be expected for these drugs, there were alterations in liver enzymes (SGOT, SGPT) and serum uric acid levels. The adverse reactions reported during therapy with RIFATER are consistent with those described below for the individual components.

Adverse Reactions Reported for Individual Components

Rifampin, Gastrointestinal: Heartburn, epigastric distress, anorexia, nausea, vomiting, jaundice, flatulence, cramps, and diarrhea have been noted in some patients. Although Clostridium difficile has been shown in vitro to be sensitive to rifampin, pseudomembranous colitis has been reported with the use of rifampin (and other broad spectrum antibiotics). Therefore, it is important to consider this diagnosis in patients who develop diarrhea in association with antibiotic use. Rarely, hepatitis or a shocklike syndrome with hepatic involvement and abnormal liver function tests has been reported.

Hematologic: Thrombocytopenia has occurred primarily with high dose intermittent therapy, but has also been noted after resumption of interrupted treatment. It rarely occurs during well-supervised daily therapy. This effect is reversible if the drug is discontinued as soon as purpura occurs. Cerebral hemorrhage and fatalities have been reported when rifampin administration has been continued or resumed after the appearance of purpura.

Transient leukopenia, hemolytic anemia, and decreased hemoglobin have been observed.

Central Nervous System: Headache, fever, drowsiness, fatigue, ataxia, dizziness, inability to concentrate, mental confusion, behavioral changes, muscular weakness, pains in extremities, and generalized numbness have been observed.

Rare reports of myopathy have also been observed.

Ocular: Visual disturbances have been observed.

Endocrine: Menstrual disturbances have been observed.

Renal: Elevations in BUN and serum uric acid have been reported. Rarely, hemolysis, hemoglobinuria, hematuria, interstitial nephritis, renal insufficiency, and acute renal failure have been noted. These are generally considered to be hypersensitivity reactions. They usually occur during intermittent therapy or when treatment is resumed following intentional or accidental interruption of a daily dosage regimen, and are reversible when rifampin is discontinued and appropriate therapy instituted.

Dermatologic: Cutaneous reactions are mild and self-limiting and do not appear to be hypersensitivity reactions. Typically, they consist of flushing and itching with or without a rash. More serious cutaneous reactions which may be due to hypersensitivity occur but are uncommon.

Hypersensitivity Reactions: Occasionally pruritus, urticaria, rash, pemphigoid reaction, eosinophilia, sore mouth, sore tongue and conjunctivitis have been observed.

Miscellaneous: Edema of the face and extremities have been reported. Other reactions which have occurred with intermittent dosage regimens include "flu" syndrome (such as episodes of fever, chills, headache, dizziness, and bone pain), shortness of breath, wheezing, decrease in blood pressure and shock. The "flu" syndrome may also appear if rifampin is taken irregularly by the patient or if daily administration is resumed after a drug free interval.

Isoniazid. The most frequent reactions are those affecting the nervous system and the liver. See the boxed WARNING .

Nervous System: Peripheral neuropathy is the most common toxic effect. It is dose-related, occurs most often in the malnourished and in those predisposed to neuritis (eg, alcoholics and diabetics), and is usually preceded by paresthesias of the feet and hands. The incidence is higher in "slow inactivators."

Other neurotoxic effects, which are uncommon with conventional doses, are convulsions, toxic encephalopathy, optic neuritis and atrophy, memory impairment, and toxic psychosis.

Gastrointestinal: Nausea, vomiting, and epigastric distress.

Hepatic: Elevated serum transaminases (SGOT, SGPT), bilirubinemia, bilirubinuria, jaundice, and occasionally severe and sometimes fatal hepatitis. The common prodromal symptoms are anorexia, nausea, vomiting, fatigue, malaise, and weakness. Mild and transient elevation of serum transaminase levels occurs in 10 to 20% of persons taking isoniazid. The abnormality usually occurs in the first 4 to 6 months of treatment but can occur at any time during therapy. In most instances, enzyme levels return to normal with no necessity to discontinue medication. In occasional instances, progressive liver damage occurs, with accompanying symptoms. In these cases, the drug should be discontinued immediately. The frequency of progressive liver damage increases with age. It is rare in persons under 20, but occurs in up to 2.3% of those over 50 years of age.

Hematologic: Agranulocytosis; hemolytic, sideroblastic, or aplastic anemia; thrombocytopenia; and eosinophilia.

Hypersensitivity Reactions: Fever, skin eruptions (morbilliform, maculopapular, purpuric, or exfoliative), lymphadenopathy, and vasculitis.

Metabolic and Endocrine: Pyridoxine deficiency, pellagra, hyperglycemia, metabolic acidosis, and gynecomastia.

Miscellaneous: Rheumatic syndrome and systemic lupus erythematosus-like syndrome.

Pyrazinamide. The principal adverse effect is a hepatic reaction (see WARNINGS ). Hepatotoxicity appears to be dose related and may appear at any time during therapy. Pyrazinamide can cause hyperuricemia and gout (see PRECAUTIONS ).

Gastrointestinal: GI disturbances including nausea, vomiting, and anorexia have also been reported.

Hematologic and Lymphatic: Thrombocytopenia and sideroblastic anemia with erythroid hyperplasia, vacuolation of erythrocytes and increased serum concentration have occurred rarely with this drug. Adverse effects on blood clotting mechanisms have also been rarely reported.

Other: Mild arthralgia and myalgia have been reported frequently. Hypersensitivity reactions including rashes, urticaria, and pruritus have been reported. Fever, acne, photosensitivity, porphyria, dysuria, and interstitial nephritis have been reported rarely.

Rifampin. 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.

Rifampin has been reported to accelerate the metabolism of the following drugs: anticonvulsants (eg, phenytoin), antiar-rythmics (eg, disopyramide, mexiletine, quinidine, tocainide), anticoagulants, antifungals (eg, fluconazole, itraconazole, ketoconazole), barbiturates, beta-blockers, calcium channel blockers (eg, diltiazem, nifedipine, verapamil), chloramphenicol, ciprofloxacin, corticosteroids, cyclosporine, cardiac glycoside preparations, clofibrate, oral contraceptives, dapsone, diazepam, haloperidol, oral hypoglycemic agents (sulfonylureas), methadone, narcotic analgesics, nortriptyline, progestins, and theophylline. It may be necessary to adjust dosages of these drugs if they are given concurrently with RIFATER since it contains rifampin.

Rifampin has been observed to increase the requirements for anticoagulant drugs of the coumarin type. In patients receiving anticoagulants and RIFATER concurrently, it is recommended that the prothrombin time be performed daily or as frequently as necessary to establish and maintain the required dose of anticoagulant.

Concurrent use of ketoconazole and rifampin has resulted in decreased serum concentration of both drugs. Concurrent use of rifampin and enalapril has resulted in decreased concentrations of enalaprilat, the active metabolite of enalapril. Since RIFATER contains rifampin, dosage adjustments should be made if RIFATER is concurrently administered with ketoconazole or enalapril if indicated by the patient's clinical condition.

Other Interactions: 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.

Other Interactions: 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.

Pharmacodynamic Interactions: 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 which facilitate deflorination of enflurane. Renal function should be monitored in patients receiving both RIFATER and enflurane.

Food Interactions: 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.