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ALVOGEN INC
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47781030801

nitrofurantoin mcr 100 mg cap (generic macrodantin)

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Uses

Urinary Tract Infections

Nitrofurantoin is used in the treatment of initial or recurrent urinary tract infections (UTIs) caused by susceptible gram-positive bacteria including enterococci and Staphylococcus aureus and gram-negative bacteria including Escherichia coli and some strains of Klebsiella, Enterobacter, and Proteus. The manufacturer states that dual-release capsules of nitrofurantoin are indicated for use only in the treatment of acute UTIs (cystitis) caused by susceptible E. coli or S. saprophyticus. The drug is not indicated for the treatment of pyelonephritis or associated renal cortical or perinephric abscesses. Nitrofurantoin is not effective in systemic bacterial infections and has no effect on bacteria in blood or tissues outside the urinary tract. As with other urinary antibacterial agents, the follow-up cure rate with nitrofurantoin in recurrent infections is low.

Prior to and during nitrofurantoin therapy, urine should be cultured and in vitro susceptibility tests performed. As with all urinary tract infections, follow- up cultures should be performed to determine if the infection has been eradicated.

Dosage and Administration

Reconstitution and Administration

Nitrofurantoin is administered orally. The drug should be administered with food (e.g., with breakfast or dinner) to enhance tolerance. Absorption of the dual-release capsules also may be increased when administered with food. The commercially available oral suspension is readily miscible with water, milk, fruit juice, or infant formula.

Dosage

Urinary Tract Infections

The usual dosage of nitrofurantoin (administered as capsules containing macrocrystals or suspension containing microcrystals) for adults is 50-100 mg 4 times daily; for the treatment of uncomplicated urinary tract infections, 50 mg 4 times daily is recommended. The usual dosage of nitrofurantoin (administered as dual-release capsules containing 25 mg of nitrofurantoin as macrocrystals and 75 mg of nitrofurantoin monohydrate) is 100 mg every 12 hours for 7 days. Children and infants older than 1 month of age may receive 5-7 mg/kg daily in 4 divided doses. Nitrofurantoin therapy should be continued for at least 1 week and for at least 3 days after sterility of the urine is attained.

The manufacturers state that if long-term suppression therapy is used, nitrofurantoin dosage should be reduced. In adults, 50-100 mg as a single evening dose, and in children, dosage as low as 1 mg/kg daily given as a single dose or in 2 divided doses, may be adequate. For long-term suppressive therapy, some clinicians have recommended 50-100 mg as a single evening dose in women, 50 mg 4 times daily in men, and 1-2 mg/kg as a single evening dose in children.

Cautions

GI Effects

The most frequent adverse effects of nitrofurantoin are nausea and flatulence, occurring in about 8 and 1.5% of patients receiving the drug as dual- release capsules, respectively. Vomiting, anorexia, diarrhea, dyspepsia, constipation, and abdominal pain occur less frequently. Adverse GI effects appear to be dose related and may be minimized by reducing dosage or by administering the drug with food or milk. Nausea and vomiting appear to occur less frequently in some patients when nitrofurantoin is administered as macrocrystals rather than microcrystals. Sialadenitis and pancreatitis also have been reported in patients receiving nitrofurantoin.

Nervous System Effects

Headache is the most frequent adverse nervous system effect of nitrofurantoin, occurring in about 6% of patients receiving the drug as dual-release capsules. Peripheral polyneuropathy, which may become severe and/or irreversible and is potentially fatal, has been reported in patients receiving nitrofurantoin. Fatalities have occurred. Initial symptoms of peripheral polyneuropathy include paresthesia and dysesthesia, usually of the lower extremities, which may progress to muscle weakness and muscle wasting. Severe neuropathy is characterized by edema of interstitial tissues, demyelination of peripheral nerve fibers, and secondary changes in the spinal cord and striated muscles. The severity of symptoms and the rate of recovery are not related to dosage or the total amount of drug administered. Resolution of the polyneuropathy varies inversely with the severity of muscle weakness. Neuropathy occurs most frequently in patients with impaired renal function (creatinine clearance less than 60 mL/minute) or clinically important increases in serum creatinine concentrations), anemia, diabetes mellitus, electrolyte imbalance, vitamin B deficiency, or a debilitating disease.

Less frequent adverse neurologic effects of nitrofurantoin include dizziness, nystagmus, vertigo, asthenia, drowsiness, reversible intracranial hypertension, cerebellar dysfunction, retrobulbar neuritis, and trigeminal neuralgia.

Pulmonary Effects

Acute, subacute, or chronic pulmonary hypersensitivity reactions occur occasionally with nitrofurantoin. Acute pulmonary reactions are frequently accompanied by eosinophilia and are manifested by sudden, severe dyspnea, chills, chest pain, fever, and cough. Diffuse erythematous, maculopapular, or eczematoid skin eruptions, pruritus, urticaria, angioedema, and myalgia have also been reported with acute pulmonary reactions. Pulmonary infiltration with consolidation or pleural effusion on radiographs also may occur. Acute reactions usually develop within 8 hours following initiation of nitrofurantoin therapy in patients previously sensitized to the drug or within 3 weeks in patients who develop sensitivity during the present course of therapy. Subacute pulmonary reactions, if they occur, usually develop after 1 month of nitrofurantoin therapy and are characterized by dyspnea, tachypnea, fever, persistent and progressive cough, and interstitial pneumonitis and/or fibrosis. Fever and eosinophilia occur less frequently with subacute than acute pulmonary reactions. There may be an associated lupus-like syndrome with arthralgia, pleural effusions, peripheral lymphadenopathy, impaired liver function, elevated erythrocyte sedimentation rate, and polyclonal hypergammaglobulinemia. When chronic reactions occur, they usually develop after 6 months of nitrofurantoin therapy but have been reported after 6 years of continuous therapy. Manifestations of chronic reactions may develop insidiously and include nonproductive cough, dyspnea on exertion, malaise, alterations in pulmonary function, and diffuse interstitial pneumonitis and/or fibrosis. Fever and eosinophilia are rare in chronic reactions.

Although corticosteroids have been used to treat pulmonary reactions to nitrofurantoin, there are no controlled studies to date evaluating the effect of steroid therapy on the rate of resolution of these reactions. Acute and subacute pulmonary reactions usually resolve within 1 week to several months following discontinuance of the drug. The degree of resolution of chronic reactions appears to be related to the duration of nitrofurantoin therapy after the first clinical signs of pulmonary hypersensitivity. Pulmonary function may be permanently impaired, and respiratory failure and death have occurred rarely.

Hepatic Effects

Hepatotoxicity, thought to be an idiosyncratic hypersensitivity reaction, has been reported rarely with nitrofurantoin. Nitrofurantoin-induced hepatotoxicity is usually reversible on discontinuance of the drug; however, fatalities have been reported. This reaction is not dose related. Hepatic reactions may range from acute, self-limiting hepatitis or cholestatic jaundice (usually associated with short-term use) to chronic active hepatitis and severe hepatic necrosis (usually associated with long-term use). Sudden fever, rash, arthralgia, hepatomegaly, eosinophilia, and increased serum concentrations of AST (SGOT), ALT (SGPT), and alkaline phosphatase may occur. (See Cautions: Precautions and Contraindications.) The development of antinuclear antibodies and antismooth muscle antibodies has also been reported.

Hematologic Effects

Hemolytic anemia has been reported rarely in patients receiving nitrofurantoin, especially in those with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency. Nitrofurantoin should be discontinued if there is any indication of hemolysis; hemolysis usually ceases when the drug is discontinued. Agranulocytosis, leukopenia, granulocytopenia, thrombocytopenia, anemia, glucose- 6-phosphate dehydrogenase deficiency anemia, and megaloblastic anemia have also been reported with nitrofurantoin. Adverse hematologic effects usually resolve following discontinuance of the drug.

Dermatologic Effects

Exfoliative dermatitis and erythema multiforme, including Stevens-Johnson syndrome, have been reported rarely with nitrofurantoin. Maculopapular, erythematous, eczematous eruptions; pruritus; urticaria; rash; and transient alopecia also have occurred.

Other Adverse Effects

Nitrofurantoin may impart a dark yellow or brown color to the urine of patients receiving the drug. Other adverse effects reported rarely with the drug include crystalluria, photosensitization, angioedema, anaphylaxis, eosinophilia, increases in serum inorganic phosphorus concentrations, back pain, rhinitis, fever, and asthmatic attacks in patients with a history of asthma. Nitrofurantoin has been associated with parotitis in at least one patient.

Precautions and Contraindications

Early recognition of manifestations of nitrofurantoin-induced pulmonary reactions and discontinuance of the drug are necessary to prevent progression to more severe, potentially irreversible reactions. The insidious onset of chronic pulmonary reactions warrants close monitoring of patients on long-term nitrofurantoin therapy. Long-term nitrofurantoin therapy should be employed only when the potential benefits justify the possible risks to the patient. If a pulmonary reaction occurs, nitrofurantoin should be discontinued and appropriate measures taken.

Nitrofurantoin should be used with caution in patients with renal impairment, anemia, diabetes mellitus, electrolyte abnormalities, vitamin B deficiency, or debilitating disease, since these patients are at increased risk of developing peripheral neuropathy; renal function should be monitored periodically during long-term nitrofurantoin therapy. The drug should also be discontinued at the first sign of numbness or tingling, usually of the extremities, since this may be a symptom of peripheral neuropathy.

Nitrofurantoin should be used with caution in patients with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency, since hemolysis may occur. If hemolysis occurs, nitrofurantoin should be discontinued.

Because the onset of nitrofurantoin-induced hepatotoxicity may be insidious, liver function should be monitored periodically in patients receiving long- term therapy with the drug. If hepatitis occurs, nitrofurantoin should be discontinued immediately and appropriate measures instituted.

Use of nitrofurantoin may result in overgrowth of nonsusceptible organisms, especially Pseudomonas.

Nitrofurantoin is contraindicated in patients who are hypersensitive to the drug. The drug is also contraindicated in patients with anuria, oliguria, or significant renal impairment (creatinine clearance less than 60 mL/minute) because urinary concentrations of the drug will not be effective and there is an increased risk of toxicity in these patients.

Pediatric Precautions

Nitrofurantoin is contraindicated in infants younger than 1 month of age because of the possibility of hemolytic anemia secondary to immature enzyme systems. Safety and efficacy of nitrofurantoin (administered as dual-release capsules) in children younger than 12 years of age have not been established.

Mutagenicity and Carcinogenicity

Evidence of nitrofurantoin-induced mutagenesis was seen in in vitro studies with Salmonella typhimurium and in a mammalian assay using L5178Y mouse lymphoma cells. The drug also was mutagenic in chromosomal aberration studies in Chinese hamster ovary cells and in chromosomal effects assays in which the drug increased the rate of sister chromatid exchange. However, there was no evidence of mutagenicity in the sex-linked recessive lethal assay when nitrofurantoin was administered orally or parenterally to Drosophila; the drug also did not induce heritable mutation in some rodents.

Nitrofurantoin also was not carcinogenic in Swiss or BDF mice. However, the drug was carcinogenic when used in B6C3F female mice as evidenced by an increased incidence of tubular adenomas, benign mixed tumors, and ovarian granulosa cell tumors and in F344/N male rats as evidenced by an increased incidence of uncommon kidney tubular cell neoplasms, bone osteosarcomas, and subcutaneous tissue neoplasms. Following subcutaneous administration of 75 mg/kg of nitrofurantoin to pregnant female mice, lung papillary adenomas of unknown importance were observed in first generation offspring. The drug was not carcinogenic in female Holtzman or Sprague-Dawley rats receiving a diet containing 0.3 or 0.1-0.187% of nitrofurantoin, respectively, for 44.5 or 75 weeks, respectively.

The relevance of these mutagenicity and carcinogenicity studies is not known when nitrofurantoin is administered in usual dosages to humans.

Pregnancy, Fertility, and Lactation

Pregnancy

Reproduction studies in rats and rabbits using nitrofurantoin in doses up to 6 times the usual human dose have not revealed evidence of harm to the fetus. However, growth retardation and a low incidence of minor and common malformations were observed when nitrofurantoin doses 68 times the usual human dose were administered to pregnant mice; fetal malformations were not observed following administration of nitrofurantoin doses 25 times the usual human dose. Lung papillary adenomas of unknown importance were observed in first generation offspring of mice whose mothers received nitrofurantoin doses 19 times the usual human dose. The relevance of these reproduction studies to humans is not known. There are no adequate and controlled studies to date using nitrofurantoin in pregnant women, and the drug should be used during pregnancy only when clearly indicated.

Nitrofurantoin is contraindicated in pregnant women at term (38-42 weeks gestation), including during labor and delivery or when onset of labor is imminent, because of the possibility of hemolytic anemia in the neonate secondary to immature enzyme systems.

Fertility

Administration of high doses of nitrofurantoin in rats has caused transient arrest of spermatogenesis; this effect was reversible following discontinuance of the drug. Dosages of 10 mg/kg or more daily may produce unpredictable, slight to moderate arrest of spermatogenesis in human males as evidenced by decreased sperm counts.

Lactation

Nitrofurantoin is distributed into milk. Because of the potential for adverse effects of nitrofurantoin in nursing infants younger than 1 month old or in infants who are known or suspected to have glucose-6-phosphate dehydrogenase (G-6-PD) deficiency, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

Drug Interactions

Uricosuric Agents

Probenecid or sulfinpyrazone may inhibit renal excretion of nitrofurantoin, thereby increasing plasma concentrations of the anti-infective agent. By blocking renal excretion of nitrofurantoin, these uricosuric agents may reduce the efficacy of the anti-infective in urinary tract infections and may also increase its toxic potential.

Antacids

Concomitant administration of a magnesium trisilicate antacid is reported to decrease the extent and rate of absorption of nitrofurantoin; therefore, concomitant administration of the drugs should be avoided.

Quinolones

In vitro, nitrofurantoin antagonizes the antibacterial activity of quinolone- derivative anti-infectives (e.g., nalidixic acid, norfloxacin, oxolinic acid); however, the clinical importance of this interaction has not been elucidated. Since it is possible that antagonism could occur in vivo, nitrofurantoin should not be used concomitantly with these drugs.

Pharmacokinetics

Absorption

Nitrofurantoin is readily absorbed from the GI tract. Studies in rats indicate that absorption of the drug occurs mainly in the small intestine. When nitrofurantoin is administered orally with food as capsules containing macrocrystals, absorption is slower than when nitrofurantoin is administered as an oral suspension, tablets, or capsules containing microcrystals of the drug. The presence of food in the GI tract or delayed gastric emptying increases the extent of absorption of nitrofurantoin by increasing the dissolution rate of the drug; this effect is most apparent when nitrofurantoin is administered as macrocrystals. When nitrofurantoin is administered with food as dual-release capsules, bioavailability of the drug is increased by 40%. Following oral administration of a single 100-mg dose of nitrofurantoin as macrocrystals or microcrystals to fasting or nonfasting adults, peak plasma nitrofurantoin concentrations are usually less than 2 mcg/mL and antibacterial activity in plasma is negligible. Following oral administration of a single dual-release capsule containing nitrofurantoin as macrocrystals and the monohydrate, peak plasma nitrofurantoin concentrations are usually less than 1 mcg/mL.

Distribution

Nitrofurantoin is 20-60% bound to plasma proteins. Nitrofurantoin crosses the placenta and is distributed into milk and bile.

Elimination

The plasma half-life of nitrofurantoin is approximately 20 minutes in adults with normal renal function. Plasma concentrations of the drug are higher and the half-life is prolonged in patients with impaired renal function.

Nitrofurantoin is partially metabolized, mainly in the liver. A small fraction of the drug is reduced to form aminofurantoin. Within 24 hours, 20-44% of a single oral dose of nitrofurantoin is excreted intact in urine by glomerular filtration and tubular secretion and about 1% is excreted in urine as aminofurantoin. Tubular reabsorption of the drug occurs but is minimal when the urine is alkaline. In adults with normal renal function, peak nitrofurantoin concentrations of 50-150 mcg/mL are usually attained in urine within 30 minutes following a single oral dose of 100 mg of the drug as microcrystals. When nitrofurantoin is administered as macrocrystals, peak urinary concentrations of the drug are attained more slowly but are approximately equivalent to or slightly less than those attained with microcrystals. When nitrofurantoin is administered as dual-release capsules, the extent and rate of urinary excretion are similar to those attained with macrocrystals. Therapeutic concentrations of nitrofurantoin are not attained in the urine of patients with creatinine clearances less than 40 mL/minute. Nitrofurantoin may be eliminated by dialysis.

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