Rifater Side Effects

Generic Name: isoniazid/pyrazinamide/rifampin

Please note - some side effects for Rifater may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Side Effects of Rifater - for the Consumer

Rifater

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Rifater:

Diarrhea; dizziness; drowsiness; gas; headache; heartburn; mild joint or muscle aches; mild stomach upset or cramps; nausea; trouble sleeping.

Seek medical attention right away if any of these SEVERE side effects occur when using Rifater:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue; unusual hoarseness); bloody or dark urine, change in the amount of urine produced; changes in vision; chest pain; coughing up blood; dark, tarry, or bloody stools; fever, chills, or sore throat; general feeling of discomfort; increased thirst or urination; irregular heartbeat; joint pain or swelling; loss of appetite; memory problems; menstrual changes; mental or mood changes; red, swollen, blistered, or peeling skin; ringing in the ears; seizures; severe diarrhea, nausea, or stomach cramps; severe or persistent muscle pain or weakness; severe pain or tenderness in the big toe; shortness of breath; stomach pain or tenderness; swelling of the hands or legs; swollen lymph nodes; symptoms of low B₆ levels (eg, confusion, cracks in the corners of the mouth, irritability, mouth redness or soreness, scaly rash); tingling or numbness in the hands or feet; unusual bruising or bleeding; unusual tiredness or weakness; vomiting; yellowing of the skin or eyes.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

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Rifater Side Effects - for the Professional

Rifater

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.

Adverse Events Reported During the Clinical Study

	Number of Patients With Adverse Events*
Adverse Events by Body Systems During First 2 Months of Trial	Rifater n = 122†	Separate‡ n = 123†
* A given patient may have experienced ≥1 adverse event. † A total of 250 patients (124 Rifater; 126 separate) were originally enrolled in the study. Five patients (2 Rifater; 3 separate) were excluded due to admission errors. ‡ Isoniazid, rifampin and pyrazinamide dosed as separate tablets and capsules.
Cutaneous (rash, erythroderma, erythema, exfoliative dermatitis, Lyell syndrome, urticaria, localized skin rash, diffuse skin rash, pruritus, generalized hypersensitivity)	8 (7%)	21 (17%)
Gastrointestinal (nausea, vomiting, digestive pain, diarrhea)	8 (7%)	14 (11%)
Musculoskeletal (arthralgia, long bones pain, phlebitis, localized joint pain, diffuse joint pain, edema of the legs)	5 (4%)	8 (7%)
Hearing and Vestibular (tinnitus, vertigo, vertigo with loss of equilibrium)	3 (2%)	6 (5%)
Liver and Biliary (hepatitis with conjunctival jaundice, hepatitis with deep jaundice)	0 (0%)	2 (2%)
Central and Peripheral Nervous System (sweating, headache, insomnia, diffuse paresthesia of the legs, anxiety, diabetic coma)	5 (4%)	4 (3%)
Total Body (spiking fever, persistent fever)	2 (2%)	4 (3%)
Cardiorespiratory (tightness in chest, coughing, diffuse chest pain, hemoptysis, angina, palpitation, total pneumothorax)	8 (7%)	3 (2%)
Total number of patients with one or more adverse events	29	43

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.

Hepatic

Transient abnormalities in liver function tests (e.g., elevations in serum bilirubin, BSP, alkaline phosphatase, serum transaminases) have been observed. 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.

Rare reports of disseminated intravascular coagulation have been observed.

Leukopenia, hemolytic anemia, and decreased hemoglobin have been observed.

Agranulocytosis has been reported rarely.

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.

Psychoses have been rarely reported.

Rare reports of myopathy have also been observed.

Ocular

Visual disturbances have been observed.

Endocrine

Menstrual disturbances have been observed.

Rare reports of adrenal insufficiency in patients with compromised adrenal function have been observed.

Renal

Elevations in BUN and serum uric acid have been reported. Rarely, hemolysis, hemoglobinuria, hematuria, interstitial nephritis, acute tubular necrosis, 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, erythema multiforme including Stevens-Johnson Syndrome, toxic epidermal necrolysis, vasculitis, eosinophilia, sore mouth, sore tongue and conjunctivitis have been observed.

Anaphylaxis has been reported rarely.

Although rifampin has been reported to have an immunosuppressive effect in some animal experiments, available human data indicate that this has no clinical significance.

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.

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 paresthesia 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

Pancreatitis, 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, anaphylactic reactions, Stevens-Johnson syndrome, 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. Hepatotoxicity appears to be dose related and may appear at any time during therapy. Pyrazinamide can cause hyperuricemia and gout.

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, pruritus, and erythema have been reported. Angioedema has been reported rarely. Fever, acne, photosensitivity, porphyria, dysuria, and interstitial nephritis have been reported rarely.

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Side Effects by Body System - for Healthcare Professionals

General

The adverse effects observed during treatment with isoniazid/pyrazinamide/rifampin were consistent with those reported with the individual components. The most common side effects reported with isoniazid were those affecting the nervous system and the liver. The primary side effect associated with pyrazinamide was a hepatic reaction.

Hepatic

Hepatic side effects have included hepatitis with jaundice (conjunctival and deep) and at least 1 serious jaundice reaction in patients taking isoniazid, pyrazinamide, and rifampin as separate tablets and capsules during clinical trials. Alterations in liver enzymes (SGOT, SGPT) have been reported in patients taking isoniazid, pyrazinamide, and rifampin as the combination tablet and as separate tablets and capsules during clinical trials. Hepatic side effects have been reported frequently with isoniazid and have included elevated serum transaminases (SGOT, SGPT), bilirubinemia, bilirubinuria, jaundice, and occasionally severe and sometimes fatal hepatitis. Hepatotoxicity has been reported with pyrazinamide use. Jaundice, transient abnormalities in liver function tests (e.g., elevations in serum bilirubin, BSP, alkaline phosphatase, serum transaminases), and, rarely, hepatitis or a shocklike syndrome (with liver involvement and abnormal liver function tests) have been reported with rifampin use.

Prodromal symptoms are often observed with isoniazid-associated liver reactions and usually include anorexia, nausea, vomiting, fatigue, malaise, and weakness. Mild and transient elevation of serum transaminase levels occurs in 10% to 20% of patients taking isoniazid. The abnormality usually occurs in the first 4 to 6 months of treatment but can occur at any time during therapy. Enzyme levels usually return to normal even with treatment continuation; however, progressive liver damage occurs in some cases. Isoniazid should be discontinued at once if signs or symptoms indicative of liver damage are detected. The frequency of progressive liver damage increases with age. It is rare in patients under 20, but occurs in up to 2.3% of patients over 50 years of age.

Hepatotoxicity associated with pyrazinamide appears to be dose related and may occur at any time during therapy.

Nervous system

Nervous system side effects have included headache, insomnia, and diffuse paresthesia of the legs in patients taking isoniazid/pyrazinamide/rifampin during clinical trials. Nervous system side effects have been reported frequently with isoniazid and have included peripheral neuropathy and paresthesias. Convulsions and toxic encephalopathy have rarely been reported with standard isoniazid doses. Headache, fever, drowsiness, fatigue, ataxia, dizziness, pains in extremities, and generalized numbness have been reported with rifampin use.

Peripheral neuropathy associated with isoniazid is dose-dependent, most often occurs in malnourished patients and in patients predisposed to neuritis (such as alcoholics and diabetics), and generally follows paresthesias of the hands and feet. The rate is higher in slow acetylators.

Dermatologic

Dermatologic side effects have included rash, erythroderma, erythema, exfoliative dermatitis, Lyell syndrome, urticaria, skin rash (localized and diffuse), pruritus, and sweating in patients taking isoniazid/pyrazinamide/rifampin during clinical trials. Rarely, acne and photosensitivity have been reported with pyrazinamide use. Mild and self-limiting cutaneous reactions associated with rifampin consist of flushing and itching (with or without rash). More serious cutaneous reactions associated with rifampin may be due to hypersensitivity and are uncommon.

Gastrointestinal

Gastrointestinal side effects have included nausea, vomiting, digestive pain, and diarrhea in patients taking isoniazid/pyrazinamide/rifampin during clinical trials. Nausea, vomiting, pancreatitis, and epigastric distress have been reported with isoniazid use. Gastrointestinal disturbances including nausea, vomiting, and anorexia have been reported with pyrazinamide use. Heartburn, epigastric distress, anorexia, nausea, vomiting, flatulence, cramps, diarrhea, pseudomembranous colitis, and a brownish-red or orange discoloration of feces, saliva, and sputum have been reported with rifampin use.

Cardiovascular

Cardiovascular side effects have included phlebitis, chest tightness, diffuse chest pain, angina, and palpitation in patients taking isoniazid/pyrazinamide/rifampin during clinical trials. Decrease in blood pressure has been reported with intermittent rifampin use.

Respiratory

Respiratory side effects have included coughing, hemoptysis, and total pneumothorax in patients taking isoniazid/pyrazinamide/rifampin during clinical trials. Shortness of breath and wheezing have been reported with intermittent rifampin use.

Hematologic

Thrombocytopenia has been associated with rifampin therapy. It has typically occurred with high dose intermittent treatment, but has also been observed following resumption of interrupted therapy. Thrombocytopenia rarely occurs during supervised daily therapy and is usually reversible when rifampin is discontinued as soon as purpura occurs. However, cerebral hemorrhage and fatalities have occurred when treatment was continued or resumed after the appearance of purpura.

Hematologic side effects associated with isoniazid have included agranulocytosis, anemia (hemolytic, sideroblastic, or aplastic), thrombocytopenia, and eosinophilia. Rarely, thrombocytopenia, sideroblastic anemia (with erythroid hyperplasia, vacuolation of erythrocytes, and increased serum concentration), and adverse effects on blood clotting mechanisms have been reported with pyrazinamide use. Thrombocytopenia, leukopenia, hemolytic anemia, decreased hemoglobin, disseminated intravascular coagulation (rare), and agranulocytosis (rare) have been reported with rifampin use.

Musculoskeletal

Musculoskeletal side effects have included arthralgia, long bones pain, and joint pain (localized and diffuse) in patients taking isoniazid/pyrazinamide/rifampin during clinical trials. Rheumatic syndrome has been reported with isoniazid use. Mild arthralgia and myalgia have frequently been reported with pyrazinamide use. Muscular weakness and myopathy (rare) have been reported with rifampin use.

Endocrine

Endocrine side effects have included diabetic coma in patients taking isoniazid/pyrazinamide/rifampin during clinical trials. Gynecomastia has been reported with isoniazid use. Rare reports of adrenal insufficiency in patients with compromised adrenal function have been reported with rifampin use.

Metabolic

Metabolic side effects have included alterations in serum uric acid levels in patients taking isoniazid, pyrazinamide, and rifampin as the combination tablet and as separate tablets and capsules during clinical trials. Pyridoxine deficiency, pellagra, hyperglycemia, and metabolic acidosis have been reported with isoniazid use. Hyperuricemia, gout, and porphyria (rare) have been reported with pyrazinamide use. Elevated serum uric acid has also been reported with rifampin.

Other

Other side effects have included fever (spiking and persistent), tinnitus, vertigo (including with loss of equilibrium), and leg edema in patients taking isoniazid/pyrazinamide/rifampin during clinical trials. Systemic lupus erythematosus-like syndrome has been reported with isoniazid use. Rarely, fever has been reported with pyrazinamide use. Edema (face and extremities), "flu" syndrome (fever, chills, headache, dizziness, and bone pain), shock, and a brownish-red or orange discoloration of sweat have been reported with rifampin use.

The "flu" syndrome and shock associated with rifampin have occurred with intermittent dosage regimens. The "flu" syndrome has also been reported with irregular use of rifampin or resumption of daily administration following a drug free interval.

Hypersensitivity

Hypersensitivity side effects have included generalized hypersensitivity in patients taking isoniazid/pyrazinamide/rifampin during clinical trials. General hypersensitivity reactions have been reported as serious in patients taking isoniazid, pyrazinamide, and rifampin as separate tablets and capsules during clinical trials. Hypersensitivity reactions including anaphylactic reactions, Stevens-Johnson syndrome, fever, skin eruptions (morbilliform, maculopapular, purpuric, or exfoliative), lymphadenopathy, and vasculitis have been reported with isoniazid use. Hypersensitivity reactions including rashes, urticaria, pruritus, and erythema and angioedema (rare) have been reported with pyrazinamide use. Anaphylaxis (rare) and occasionally pruritus, urticaria, rash, pemphigoid reaction, erythema multiforme including Stevens-Johnson syndrome, toxic epidermal necrolysis, vasculitis, eosinophilia, sore mouth, sore tongue, and conjunctivitis have been reported with rifampin use.

Renal

Renal side effects associated with pyrazinamide have rarely included interstitial nephritis. Elevations in blood urea nitrogen and serum uric acid have been reported with rifampin use. Hemolysis, hemoglobinuria, hematuria, interstitial nephritis, acute tubular necrosis, renal insufficiency, and acute renal failure have rarely been reported with rifampin and are usually considered hypersensitivity reactions.

Renal hypersensitivity reactions usually occur during intermittent treatment or in patients resuming treatment following intentional or accidental interruption of the daily regimen. These reactions are reversible when rifampin is discontinued and appropriate therapy started.

Psychiatric

Psychiatric side effects have included anxiety in patients taking isoniazid/pyrazinamide/rifampin during clinical trials. Psychiatric side effects associated with isoniazid are infrequent with standard doses and have included memory impairment and toxic psychosis. Inability to concentrate, mental confusion, psychoses, and behavioral changes have been reported with rifampin use.

Ocular

Ocular side effects associated with isoniazid are infrequent with standard doses and have included optic neuritis and atrophy. Visual disturbances and a brownish-red or orange discoloration of tears have been reported with rifampin use.

Genitourinary

Genitourinary side effects associated with pyrazinamide have rarely included dysuria. Menstrual disturbances and a brownish-red or orange discoloration of urine have been reported with rifampin use.

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