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Each capsule contains 50 mg or 100 mg nitrofurantoin in macrocrystal form.
Excipients/Inactive Ingredients: Lactose, maize starch and talc.
Pharmacotherapeutic group: Other Antibacterials - Nitrofuran derivatives. ATC Code: J01XE01.
Pharmacology: Pharmacodynamics: Mode of Action: Nitrofurantoin (Macrodantin) is an in vitro antibacterial agent for most Gram-positive and Gram-negative pathogenic organisms in the urinary tract.
At therapeutic doses, nitrofurantoin in urine exerts bacteriostatic activity. The mechanism of action is different from all currently existing antimicrobial agents. Bacterial flavoproteins reduce nitrofurantoin into highly reactive compounds which inactivate or alter ribosomal proteins and other bacterial macro-molecules. As a result of inactivating these elements, the vital biochemical processes of bacterial proteins synthesis, aerobic metabolism, DNA and RNA synthesis, and bacterial wall synthesis are inhibited. This mechanism of action may explain the lack of bacterial resistance to nitrofurantoin, as well as the multiple mutations of macromolecules that are lethal for the bacteria. Since its launch in 1953, the development of resistance to Nitrofurantoin (Macrodantin) has not been a significant issue. Cross-resistance to other antibiotics and sulfonamides, and the transference of resistance is, at most, a rare phenomenon.
Most of Escherichia coli species are particularly sensitive to nitrofurantoin. It is effective against in vitro Enterococci, as well as against other Gram-positive species, including Staphylococcus, Streptococcus and Corinebacteria. Enterobacteria and Klebsiella spp. are less sensitive and some may develop resistance. Usually, Pseudomonas aeruginosa is resistant and most Proteus spp are moderately resistant. Organisms with a Minimum Inhibitory Concentration (MIC) lower than 32 μg/mL are sensitive, these concentrations are easily found in the urine; while the resistant species have a MIC higher than 128 μg/mL. Generally, nitrofurantoin is an antibacterial agent at concentrations slightly higher than the MIC. It is more active in acid urine. At a pH above 8 the antibacterial activity is lost. The development of resistance is rare during the recommended treatment period, but may be developed during an extended treatment period.
Pharmacokinetics: Nitrofurantoin contained in Nitrofurantoin (Macrodantin) capsules is quickly and completely absorbed through the gastrointestinal tract. The absorption rate depends on the crystals' size. The macrocrystalline form is more slowly absorbed and eliminated, also produces lower serum concentrations compared to the microcrystalline form. After a treatment with 100mg four times a day during 7 days, the mean recovery in the urine in 0-24h on day 1 and day 7 was 37.9% and 35.0%, respectively.
After its absorption, the blood and peripheral tissues concentrations are low due to its rapid elimination, not allowing reaching antibacterial concentrations on them. The quick renal absorption and elimination provides a great therapeutic value as antibacterial agent in the urine. Food presence in gastrointestinal tract may increase the nitrofurantoin bioavailability up to 40% and extend the duration of the therapeutic concentrations in the urine. Nitrofurantoin crosses the placenta and the hematoencephalic barrier; traces have been detected in the mother's milk. It has a 20-minute half-life.
Nitrofurantoin is metabolized in the liver and in most body tissues, while an average of 40% of the dose is quickly eliminated through the urine with no changes. After a 10 mg dose, 50-250 μg/mL concentrations were obtained within 30 minutes in patients with normal renal function, and sustained during approximately 4 to 5 hours.
Because nitrofurantoin is a weak acid; the majority of the drug is reabsorbed from the renal tubules if urine is acid. If urine is alkaline, a small portion of the drug is reabsorbed and the rest is cleared through the urine. The urine has a brown color due to the high solubility of nitrofurantoin in the urine.
A distribution volume of 0.7 liters per kilogram of weight is estimated at extracellular and intracellular compartments. Generally, there are no high concentrations of the drug in the tissues because the drug is susceptible to enzymatic degradation and is quickly excreted.
Toxicology: Nitrofurantoin was not carcinogenic when administered to female Holtzman rats during 44.5 weeks or to Sprague-Dawley rats during 75 weeks. Two biological tests were performed using Swiss mice. A female mouse showed carcinogenic activity with an increased incidence of tubular adenomas, mix benign tumors and ovary granulose cells tumors. An increased incidence of renal tubular cells neoplasms, bone osteosarcomas and subcutaneous tissue neoplasms was observed in a male rat. The administration of high nitrofurantoin doses caused transient sperm decrease which was reversible when stop using the drug substance. Doses higher than 10 mg/kg/day to healthy male humans may produce a slight to moderate decrease in sperm quantity.
Several reproduction studies have been performed with rabbits and rats using nitrofurantoin at doses higher than 6-fold the dose recommended for humans with lack of evidence related to fertility detriment or fetus damage. In a study with mice, nitrofurantoin was administered at doses higher than 25-fold the recommended human dose, malformations were not seen. Nevertheless, the reproduction studies with animals are not always predictive about the human response.
Nitrofurantoin (Macrodantin) capsules are indicated for: Specific prophylaxis and treatment of non-complicated acute urinary tract infections caused by sensitive strains of Gram-positive and Gram-negative pathogenic organisms; Non-complicated urinary tract infections; Non-complicated cystitis and cystourethritis; Asymptomatic bacteriuria treatment; Urinary tract infections treatment in pregnant women; Vesical catheter-associated urinary tract infections treatment; Antibiotic prophylaxis due to anatomical and/or function disorders of urinary tract; Antibiotic prophylaxis for pelvis prolapse surgery and/or urinary incontinence.
(See Table 1.)
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(See Table 2.)
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(See Table 3.)
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Method of Administration: For oral use only.
Must be administered together with food to improve absorption and to increase its gastrointestinal tolerance. It is very important to complete the recommended treatment, and to adhere to dosage and duration because in case of missed doses or an incomplete treatment the treatment efficacy may decrease, and the probability of developing resistance may increase.
Symptoms: Symptoms and signs of overdosage include gastric irritation, nausea and vomiting. Acute overdose cases usually result in vomiting.
Therapy: Emesis induction is recommended or a gastric lavage. There is no specific antidote, but a high intake of liquids is recommended to promote its excretion through the urine. Nitrofurantoin can be haemodialysed in cases of recent ingestion.
Monitoring of full blood count, liver function, and pulmonary function tests are recommended.
Nitrofurantoin (Macrodantin) is contraindicated in: Pregnant patients at term (38-42 weeks' gestation), during labor and delivery, or when the onset of labor is imminent. There is a possibility of hemolytic anemia of the fetus/newborn due to immature erythrocyte enzyme systems (glutathione instability).
Neonates under one month of age, due to the possibility of hemolytic anemia.
Breastfeeding females whose neonates are under one month of age. Also while breast-feeding an infant known or suspected to have an erythrocyte enzyme deficiency.
Anuria, oliguria and worsening of renal function (creatinine clearance below 60 mL per minute or serum creatinine clinically significantly increased) due to the risk of nitrofurantoin toxicity.
Acute porphyria because of G6PD deficiency.
In patients with a previous history of cholestatic jaundice/hepatic dysfunction associated with Nitrofurantoin (Macrodantin).
Patients with known hypersensitivity to nitrofurantoin or to any of the excipients of the product.
Nitrofurantoin (Macrodantin) capsules are contraindicated in children below 12 years of age.
Patients should be advised not to use antacid preparations containing magnesium trisilicate while taking Nitrofurantoin (Macrodantin) (see Interactions).
Patients should be counseled that antibacterial drugs including Nitrofurantoin (Macrodantin) should only be used to treat bacterial infections. Nitrofurantoin (Macrodantin) is not indicated to treat viral infections (e.g., the common cold). When Nitrofurantoin (Macrodantin) is prescribed to treat a bacterial infection, patients should be instructed that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may decrease the effectiveness of the immediate treatment and increase the likelihood that bacteria will develop resistance and will not be treatable by Nitrofurantoin (Macrodantin) or other antibacterial drugs in the future.
Since pre-existing conditions may mask adverse reactions, Nitrofurantoin (Macrodantin) should be used with caution in patients with pulmonary disease, hepatic dysfunction, neurological disorders, and allergic diathesis.
Nitrofurantoin (Macrodantin) should be used with caution in patients with anaemia, diabetes mellitus, electrolyte imbalance, debilitating conditions and vitamin B (particularly folate) deficiency.
Patients should be monitored closely for signs of hepatitis (particularly in long-term use).
Nitrofurantoin (Macrodantin) should be discontinued if otherwise unexplained hepatic syndromes occur.
Urine may be coloured yellow or brown after taking nitrofurantoin. Patients on nitrofurantoin are susceptible to false positive urinary glucose (if tested for reducing substances).
Hemolytic anemia: There are reports of hemolytic anemia due nitrofurantoin hypersensitivity. It seems that hemolysis is secondary to a glucose-6-phosphate dehydrogenase deficiency of the affected patients' erythrocytes; hemolytic anemia, granulocytopenia, agranulocytosis, leukopenia, thrombocytopenia, eosinophilia, and megaloblastic anemia. Nitrofurantoin (Macrodantin) should be discontinued at any sign of haemolysis in those with suspected glucose-6-phosphate dehydrogenase deficiency.
After stopping to use the drug, the values of blood counts return to normal levels.
Hypersensitivity to nitrofurantoin as well as patients with G6PD deficiency are contraindicated (see Contraindications).
Peripheral neuropathy: Peripheral neuropathy and susceptibility to peripheral neuropathy, which may become severe or irreversible, has occurred in patients on nitrofurantoin therapy and may be life threatening. Therefore, treatment should be stopped at the first signs of neural involvement (paresthesia).
Preexisting anemia increases risk of potentially-fatal peripheral neuropathy.
Pulmonary reactions: Acute, subacute and chronic pulmonary reactions have been observed in patients treated with nitrofurantoin. If these reactions occur, nitrofurantoin should be discontinued immediately.
Acute pulmonary reactions usually occur within the first week of treatment and are reversible with cessation of therapy. Acute pulmonary reactions are commonly manifested by fever, chills, cough, chest pain, dyspnoea, pulmonary infiltration with consolidation or pleural effusion on chest x-ray, and eosinophilia. In subacute pulmonary reactions, fever and eosinophilia occur less often than in the acute form.
Chronic pulmonary reactions (including pulmonary fibrosis and diffuse interstitial pneumonitis) occur rarely in patients who have received continuous therapy for six months or longer and are more common in elderly patients. Changes in ECG have occurred, associated with pulmonary reactions. Minor symptoms such as fever, chills, cough and dyspnoea may be significant. Collapse and cyanosis have been reported rarely. The severity of chronic pulmonary reactions and their degree of resolution appear to be related to the duration of therapy after the first clinical signs appear. It is important to recognise symptoms as early as possible and close monitoring of the pulmonary condition of patients receiving long-term therapy is warranted (especially in the elderly). Pulmonary function may be impaired permanently, even after cessation of therapy.
Renal function: There is a linear relationship between the excretion percentage and creatinine clearance, therefore Glomerular filtration rate (GFR) of the patient must be monitored.
Patients with anuria, oliguria or decreased renal function are contraindicated (see Contraindications).
Pseudomembranous colitis: There have been sporadic reports of pseudomembranous colitis with the use of nitrofurantoin. The onset of pseudomembranous colitis symptoms may occur during or after the finalization of the antimicrobial treatment.
Interference with laboratory test: Nitrofurantoin may cause false positive reaction or increased values of bilirubin, blood ureic nitrogen, non-protein nitrogen, creatin and creatinine determination, glucose (Benedict's technique), alkaline phosphatase, cephalin cholesterol, thymol cloudiness, SGOT and SGPT.
Driving and using machines: Patients should be advised that adverse reactions such as confusion, dizziness, somnolence, vertigo, optic neuritis, psychotic reactions have been reported. Therefore, caution should be recommended when driving a car or operating machinery.
Pregnancy: Because of the possibility of hemolytic anemia due to immature erythrocyte enzyme systems (glutathione instability), the drug is contraindicated in pregnant patients at term (38-42 weeks' gestation), during labor and delivery, or when the onset of labor is imminent, because of the possible risk of haemolysis of the infants' immature red cells (see Contraindications).
Lactation: Nitrofurantoin has been detected in human breast milk in trace amounts. Because of the potential for serious adverse reactions from nitrofurantoin the drug is contraindicated in neonates under one month of age. Therefore, nitrofurantoin is contraindicated in breastfeeding females whose neonates are under one month of age but also while breast-feeding an infant known or suspected to have an erythrocyte enzyme deficiency (see Contraindications).
Fertility: No human fertility data are available. Non-clinical data indicate that high doses of nitrofurantoin decrease sperm quantity (see Pharmacology: Toxicology under Actions).
Nausea, Anorexia, Vomiting, Abdominal pain, Diarrhea, Sialodenitis, Pancreatitis, Pseudomembranous colitis.
Hepatitis (including active hepatitis and cholestatic jaundice).
Respiratory, thoracic and mediastinal disorders:
Acute, subacute, and chronic pulmonary reactions with fever, chills, cough, chest pain, dyspnea, pulmonary infiltration (with consolidation or pleural effusion).
Blood and lymphatic system disorders:
Hemolytic anemia, granulocytopenia, agranulocytosis, leukopenia, thrombocytopenia, eosinophilia, megaloblastic anemia and aplastic anemia.
Nervous system disorders:
Confusion, depression, optic neuritis, headache, dizziness, nystagmus, somnolence, vertigo and peripheral neuropathy, benign intracranial pressure increased.
Skin and subcutaneous tissue disorders:
Exfoliative dermatitis, erythema multiforme (including Stevens-Johnson's syndrome), maculopapular rash, rash erythematous or eczema, pruritus, urticaria or angioedema, alopecia and Lupus-like syndrome.
General disorders and administration site conditions:
Asthenia, fever, chills, malaise.
Psychiatric and behavioral symptoms.
Antacids: Absorption is reduced by antacids containing magnesium trisilicate when they are concomitantly administered with Nitrofurantoin (Macrodantin).
Uricosuric drugs: Uricosuric drug substances such as probenecid may inhibit renal tubular secretion of nitrofurantoin and increase the toxicity due to an increase of the serum levels. The decreased urinary levels may affect the treatment efficacy.
Quinolones: Nitrofurantoin antagonizes in vitro antibacterial action of quinolones (nalidixic acid, norfloxacin, oxolinic acid) losing anti-infective effectiveness.
Contraceptives: Nitrofurantoin as other antibacterials will decrease the level or effect of estradiol by altering intestinal flora (applies only to oral forms of hormone). There is a low risk of contraceptive failure.
Live typhoid vaccine: Nitrofurantoin decreases effects of live typhoid vaccine by pharmacodynamic antagonism. The combination has a high likelihood to cause serious or life-threatening interaction. Live bacterial vaccine should be administered after antibiotic therapy is completed.
Nitrofurantoin is not compatible with the following solutions: Ammonium chloride, amphotericin B, codeine phosphate, dextrose in lactated Ringer's solution, dextrose solutions with ascorbic acid and B complex, calcium chloride and tetracycline hydrochloride, B polymixin, meperidine, vancomycin, kanamycin; ethyl alcohol, nalidixic acid.
Store at temperatures not exceeding 30°C.
J01XE01 - nitrofurantoin ; Belongs to the class of nitrofuran derivative antibacterials. Used in the systemic treatment of infections.
Cap 50 mg (hard gelatin capsule size 3 with white body with the Boehringer Ingelheim symbol printed in black, and yellow cap with M01 printed black) x 40's, 100's. 100 mg (hard gelatin capsule size 2 with yellow body with the Boehringer Ingelheim symbol printed in black, and yellow cap with M02 printed black) x 40's , 100's.