Mavrodantin (Nitrofurantoin Macrocrystals)

MACRODANTIN®

Procter & Gamble Pharmaceuticals

Nitrofurantoin Macrocrystals

Urinary Tract Antibacterial

Action And Clinical Pharmacology: Nitrofurantoin is reduced by bacterial flavoproteins to reactive intermediates which inactivate or alter bacterial ribosomal proteins and other macromolecules. As a result of such inactivations, the vital biochemical processes of protein synthesis, aerobic energy metabolism, DNA synthesis, RNA synthesis and cell wall synthesis are inhibited. The broad-based nature of this mode of action may explain the lack of acquired bacterial resistance to nitrofurantoin, as the necessary multiple and simultaneous mutations of the target macromolecules would likely be lethal to the bacteria.

Macrodantin is a larger crystal form of nitrofurantoin. The absorption of Macrodantin is slower and its urinary excretion somewhat less when compared to nitrofurantoin tablets. At therapeutic doses, low drug concentrations are observed in blood, with therapeutic concentrations achieved only in the urine. A number of patients who cannot tolerate nitrofurantoin tablets can take Macrodantin without nausea.

Nitrofurantoin taken orally is rapidly absorbed from the gastrointestinal tract and appears to be widely distributed. Based upon urine recovery levels its bioavailability may be increased by as much as 40% when administered with food. In one study in which healthy male adults were provided a single 100 mg capsule of Macrodantin with food the Cmax, tmax, and elimination t1/2 were respectively 100 µg/mL, 3.6 hrs, and 1.13 hours in urine. Plasma levels do not normally exceed 1 µg/mL following therapeutic administration of Macrodantin to subjects with normal kidney function. Levels far exceeding those in plasma have been reported for human bile, seminal fluid and kidney. About 20 to 25% of a single dose of Macrodantin is recovered in the urine and about 1.5% of urine contents are metabolized. Little is known about nitrofurantoin metabolism and the rate or extent of its excretion by other routes in humans.

Indications And Clinical Uses: The treatment of urinary tract infections, e.g., cystitis, when due to susceptible strains of E. coli, enterococci, S. aureus and certain susceptible strains of Klebsiella species, Enterobacter species and Proteus species.

It is not indicated for treatment of associated renal cortical or perinephric abscesses.

Nitrofurantoin is not indicated for therapy of any systemic infections or for use in prostatitis.

Contra-Indications: Anuria, oliguria or significant impairment of renal function (creatinine clearance under 60 mL/min or clinically significant elevated serum creatinine) are contraindications to therapy with this drug. Treatment of this type of patient carries an increased risk of toxicity because of impaired excretion of the drug. For the same reason, the drug is much less effective under these circumstances.

Nitrofurantoin is contraindicated in pregnant patients during labor and delivery, or when the onset of labor is imminent, and in infants under 1 month of age, because of the possibility of hemolytic anemia in the fetus or the newborn infant due to their immature erythrocyte enzyme systems (glutathione instability).

Macrodantin capsule therapy is also contraindicated in those patients with known hypersensitivity to nitrofurantoin.

Manufacturers’ Warnings In Clinical States: Acute, subacute and chronic pulmonary reactions have been observed in patients treated with nitrofurantoin products (see Adverse Effects). If these reactions occur, the drug should be withdrawn and appropriate measures taken. Reports have cited pulmonary reactions as a contributing cause of death.

Chronic pulmonary reactions (diffuse interstitial pneumonitis or pulmonary fibrosis, or both) can develop insidiously. These reactions occur rarely and generally in patients receiving therapy for 6 months or longer. Close monitoring of the pulmonary condition of patients receiving long-term therapy is warranted and requires that the benefits of therapy be weighed against potential risks (see Adverse Effects).

Hepatic reactions, including hepatitis, hepatic necrosis, cholestatic jaundice and chronic active hepatitis, occur rarely. Fatalities have been reported. The onset of chronic active hepatitis may be insidious, and patients should be monitored periodically for changes in liver function. If hepatitis occurs the drug should be withdrawn immediately and appropriate measures taken.

Peripheral neuropathy (including optic neuritis) may occur with nitrofurantoin therapy; this may become severe or irreversible. Fatalities have been reported. Predisposing conditions such as renal impairment (creatinine clearance under 60 mL/min or clinically significant elevated serum creatinine), anemia, diabetes mellitus, electrolyte imbalance, vitamin B deficiency and debilitating disease may enhance such occurrence. Patients receiving long-term therapy should be monitored periodically for changes in renal function. If numbness or tingling occurs, discontinue use.

Cases of hemolytic anemia of the primaquine sensitivity type have been induced by nitrofurantoin. The hemolysis appears to be linked to a glucose-6-phosphate dehydrogenase deficiency in the red blood cells of the affected patients. This deficiency is found in 10% of blacks and a small percentage of ethnic groups of Mediterranean and Near-Eastern origin. Any sign of hemolysis is an indication to discontinue the drug. Hemolysis ceases when the drug is withdrawn.

Pseudomonas is the organism most commonly implicated in superinfections in patients with nitrofurantoin preparations.

Carcinogenesis, Mutagenesis and Impairment of Fertility: Nitrofurantoin presented evidence of carcinogenic activity in female B6C3F1 mice as shown by increased incidences of tubular adenomas, benign mixed tumor and granulosa cell tumor of the ovary. In male F344/N rats, there were increased incidences of uncommon kidney tubular cell neoplasms, osteosarcomas of the bone and neoplasms of the s.c. tissue. In one study involving three s.c. injections of 75 mg/kg nitrofurantoin to pregnant female mice, lung papillary adenomas were observed in the F1 generation.

Nitrofurantoin was not carcinogenic when fed to female Holtzman rats for 44.5 weeks or to female Sprague-Dawley rats for 75 weeks. Two chronic rodent bioassays utilizing male and female Sprague-Dawley rats and 2 chronic bioassays in Swiss mice and BDF1 mice revealed no evidence of carcinogenicity.

Nitrofurantoin has demonstrated mutagenic potential in a variety of laboratory assays conducted in vitro with mammalian and nonmammalian cells exposed to therapeutically attainable and higher concentrations. Point and possibly other types of mutations were observed in bacteria, yeast and fungi. Damage to DNA or inhibition of DNA synthesis was produced in human fibroblasts and lymphocytes, and Chinese hamster ovaries and lung fibroblasts.

In vivo tests on rodents utilizing a wide range of doses demonstrated similar potential. DNA damage to liver, lung, spleen and kidney were observed in rat (alkaline elution test), immature red blood cells (rat micronucleus test) and sperm (H-test in mouse). Some test results were negative such as the sex-linked recessive lethal assay in Drosophila where nitrofurantoin was administered by feeding or injection.

The significance of the carcinogenicity and mutagenicity findings relative to the therapeutic use of nitrofurantoin in humans is unknown. Because of the potential toxicity of nitrofurantoin when used for long-term therapy, the benefits of long-term therapy should be weighed against potential risks (see Dosage).

The administration of high doses of nitrofurantoin to rats causes temporary spermatogenic arrest, which is reversible on discontinuing the drug. Doses of 10 mg/kg/day or greater in healthy human males may, in certain unpredictable instances, produce slight to moderate spermatogenic arrest with a decrease in sperm count.

Precautions: Drug Interactions : Antacids containing magnesium trisilicate, when administered concomitantly with nitrofurantoin, reduce both the rate and extent of absorption. The mechanism for this interaction probably is adsorption of drug onto the surface of magnesium trisilicate. Nitrofurantoin should not be given along with drugs which may produce impaired renal function. Uricosuric drugs, such as probenecid and sulfinpyrazone, may inhibit renal tubular secretion of nitrofurantoin. The resulting increase in serum levels may increase toxicity and the decreased urinary levels could lessen its efficacy as a urinary tract antibacterial.

Drug/Laboratory Test Interactions : As a result of administration of nitrofurantoin, a false-positive reaction for glucose in the urine may occur. This has been observed with Benedict’s and Fehling’s solution but not with the glucose enzymatic test.

Pregnancy: Several reproduction studies performed in rabbits and rats with low multiples of human doses and plasma levels revealed no evidence of general reproductive effects, impaired fertility or harm to the fetus. However, in one published study in which pregnant mice were administered 250 mg/kg s.c. on 3 days, growth retardation and a low incidence of malformations were observed. These effects were not observed at 100 mg/kg. In another controlled study in which cultured rat embryos were exposed for 26 hours to concentrations of 48 µg/mL all were malformed. None of those exposed to 60 µg/mL of nitrofurantoin survived.

The relevance of these findings to humans is uncertain. There are, however, no adequate well-controlled studies in pregnant women. Though animal reproduction studies are not always predictive of human response, this drug should not be used during pregnancy unless clearly needed.

Labor and Delivery: Nitrofurantoin should not be given to women during labor and delivery, or when the onset of labor is imminent (see Contraindications).

Lactation: Nitrofurantoin has been detected in trace amounts in breast milk. Caution should be exercised when the nitrofurantoin is administered to a nursing woman, especially if the infant is known or suspected to have a glucose-6-phosphate dehydrogenase deficiency.

Children: Nitrofurantoin is contraindicated in infants under 1 month of age (see Contraindications and Dosage).

Adverse Reactions: The following clinical adverse events have been reported with the use of nitrofurantoin: Respiratory: Chronic, subacute or acute pulmonary hypersensitivity reactions may occur with the use of nitrofurantoin (see Warnings). Chronic pulmonary reactions generally occur in patients who have received continuous treatment for 6 months or longer. Malaise, dyspnea on exertion, cough and altered pulmonary function are common manifestations which can occur insidiously. Radiologic and histologic findings of diffuse interstitial pneumonitis or fibrosis, or both, are also common manifestations of the chronic pulmonary reaction. Fever is rarely prominent. The severity of chronic pulmonary reactions and the degree of their resolution appear to be related to the duration of therapy after the first clinical signs appear. Pulmonary function may be impaired permanently even after cessation of nitrofurantoin therapy. The risk is greater when pulmonary reactions are not recognized early.

In subacute pulmonary reactions, fever and eosinophilia occur less than in the acute form. Upon cessation of therapy, recovery may require several months. If the symptoms are not recognized as being drug related and nitrofurantoin is not stopped, the symptoms may become more severe.

Acute reactions are commonly manifested by fever, chills, cough, chest pain, dyspnea, pulmonary infiltration with consolidation or pleural effusion on x-ray, and eosinophilia. Acute reactions usually occur within the first week of treatment and are reversible with cessation of therapy. Resolution often is dramatic.

Changes in ECG may occur associated with pulmonary reactions.

Collapse and cyanosis have seldom been reported.

Gastrointestinal: Diarrhea, dyspepsia, abdominal pain, constipation, emesis, sialadenitis, pancreatitis.

Hepatic: Hepatic reactions, including hepatitis, cholestatic jaundice, chronic active hepatitis and hepatic necrosis occur rarely (see Warnings).

Neurologic: Peripheral neuropathy, including optic neuritis (see Warnings).

Dizziness, drowsiness, amblyopia, asthenia, vertigo and nystagmus also have been reported with the use of nitrofurantoin.

Benign intracranial hypertension has seldom been reported.

Confusion, depression, euphoria and psychotic reactions have been reported rarely.

Dermatologic: Alopecia. Exfoliative dermatitis and erythema multiforme (including Stevens-Johnson syndrome) have been reported rarely.

Allergic Reactions: Lupus-like syndrome associated with pulmonary reaction to nitrofurantoin has been reported. Also, angioedema; maculopapular, erythematous or eczematous eruptions; pruritus; urticaria; anaphylaxis; arthralgia; myalgia; drug fever; chills; and malaise have been reported.

Hematologic: Glucose-6-phosphate dehydrogenase deficiency anemia (see Warnings), agranulocytosis, leukopenia, granulocytopenia, hemolytic anemia, thrombocytopenia, megaloblastic anemia and eosinophilia have occurred. In most cases, these hematologic abnormalities resolved following cessation of therapy. Aplastic anemia has been reported rarely.

Miscellaneous: As with other antimicrobial agents, superinfections with resistant organisms, e.g., Pseudomonas species or Candida species, may occur with the use of nitrofurantoin. Superinfections have been limited to the genitourinary tract.

Increased AST, increased ALT, decreased hemoglobin and increased serum phosphorus.

Nitrofurantoin may cause a rust-yellow to brown discoloration of the urine.

Symptoms And Treatment Of Overdose: Symptoms: Occasional incidents of acute overdosage of nitrofurantoin have not resulted in any specific symptomatology other than vomiting.

Treatment: In case vomiting does not occur soon after an excessive dose, induction of emesis is recommended. There is no specific antidote for nitrofurantoin but a high fluid intake should be maintained to promote urinary excretion of the drug. It is dialyzable.

Dosage And Administration: Adults: 50 to 100 mg 4 times a day. Children: Dosage should be calculated on the basis of 5 to 7 mg/kg of body weight/24 hours given in divided doses 4 times a day (contraindicated in infants under 1 month).

Macrodantin may be given with food or milk to further minimize gastric upset.

Therapy should be continued for at least 1 week or for at least 3 days after sterility of the urine is obtained. Continued infection indicates the need for re-evaluation.

For long-term suppressive therapy in adults, a reduction of dosage to 50 to 100 mg once daily at bedtime may be adequate. See Warnings section regarding risks associated with long-term therapy. For long-term suppressive therapy in children, doses as low as 1 mg/kg/24 hours, given in a single or in 2 divided doses, may be adequate.

Availability And Storage: 50 mg: Each opaque, yellow and white capsule, coded with 2 black bars and Macrodantin, 50 mg, 0149, 0008, contains: nitrofurantoin macrocrystals 50 mg. Nonmedicinal ingredients: edible black ink, carnauba wax, gelatin, lactose, starch, talc and titanium dioxide, and may contain FD&C Yellow #6 and D&C Yellow #10. Bisulfite-, gluten-, paraben-, sodium- and tartrazine-free. Bottles of 100 and 500.

100 mg: Each opaque, yellow capsule, coded with 3 black bars and Macrodantin, 100 mg, 0149, 0009, contains: nitrofurantoin macrocrystals 100 mg. Nonmedicinal ingredients: edible black ink, carnauba wax, gelatin, lactose, starch, talc and titanium dioxide, and may contain FD&C Yellow #6 and D&C Yellow #10. Bisulfite-, gluten-, paraben-, sodium- and tartrazine-free. Bottles of 100 and 500.

Avoid excessive heat (over 40°C).

MACRODANTIN® Procter & Gamble Pharmaceuticals Nitrofurantoin Macrocrystals Urinary Tract Antibacterial

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