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NITROFURANTOIN AND RELATED AGENTS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Nitrofurantoin is an antibacterial agent used to prevent or treat urinary tract infections. Nitrofurazone, a nitrofuran derivative, is used as an anti-infective agent for burns and for the preparation of surfaces before skin grafting. This agent is no longer available in the United States.

Specific Substances

    1) F-30
    2) Furadonin
    3) Furadoninum
    4) 1-(5-Nitro-2-furfurylideneamino)-hydantoin
    5) NSC 2107
    6) Nitrofurantoin
    7) Nitrofurazone
    8) CAS 67-20-9 (Nitrofurantoin)
    9) CAS 59-87-0 (Nitrofurazone)
    1.2.1) MOLECULAR FORMULA
    1) C8-H6-N4-O5

Available Forms Sources

    A) FORMS
    1) Macrobid(R) (nitrofurantoin monohydrate/macrocrystals) is available in the US as 100 mg capsules (Prod Info Macrobid(R) oral capsule, 2011). Macrodantin(R) (nitrofurantoin macrocrystals) is available in the US as 25 mg, 50 mg, and 100 mg capsules (Prod Info Macrodantin(R) oral capsule, 2011). Nitrofurantoin generic is available as oral suspension (25 mg/5 mL) and 100 mg tablets (Prod Info nitrofurantoin oral capsules, 2006). Furadantin(R) is available as oral suspension (25 mg/5 mL) (Prod Info FURADANTIN(R) oral suspension, 2008).
    2) Nitrofurazone was available in the US as 0.2% topical ointment (Prod Info Furacin(R), 1994). It is no longer available in the United States.
    B) USES
    1) Nitrofurantoin is used to prevent and treat urinary tract infections due to susceptible strains of Escherichia coli, enterococci, Staphylococcus aureus and some strains of Klebsiella and Enterobacter. It is not indicated for the treatment of pyelonephritis or perinephric abscess (Prod Info Macrodantin(R) oral capsule, 2011; Prod Info Macrobid(R) oral capsule, 2011; Prod Info nitrofurantoin oral capsules, 2006).
    2) Nitrofurazone, a nitrofuran derivative, was used as an anti-infective agent for burns (as adjunctive therapy for second- and third-degree burns) and for the preparation of surfaces before skin grafting (Prod Info Furacin(R), 1994). It is no longer available in the United States.

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Nitrofurantoin is used to prevent and treat urinary tract infections due to susceptible strains of Escherichia coli, enterococci, Staphylococcus aureus and some strains of Klebsiella and Enterobacter. It is not indicated for the treatment of pyelonephritis or perinephric abscess. Nitrofurantoin is also available as nitrofurantoin macrocrystals and nitrofurantoin monohydrate/nitrofurantoin, macrocrystals.
    B) PHARMACOLOGY: Nitrofurantoin is bactericidal at therapeutic doses. Through its reactive intermediates, it inactivates bacterial ribosomal proteins and other large molecules resulting in inhibition of vital biochemical processes such as protein synthesis, aerobic energy metabolism, DNA synthesis, RNA synthesis, and cell wall synthesis.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: Nausea, vomiting, anorexia, headache. OTHER EFFECTS: Diarrhea, abdominal pain, constipation, dyspepsia.
    2) PULMONARY HYPERSENSITIVITY REACTION: Acute, subacute or chronic pulmonary hypersensitivity reactions have rarely occurred; fatalities have been reported. Pulmonary toxicity may include diffuse interstitial pneumonitis, pulmonary fibrosis, or both. Patients receiving long-term treatment for 6 months or longer are at increased risk of developing chronic pulmonary reactions. Acute pulmonary reactions usually occur within the first week of treatment, and can be manifested by eosinophilia, fever, chills, cough, chest pain, dyspnea, or pulmonary infiltration with consolidation or pleural effusion on x-ray. Eosinophilia and fever occur less frequently in subacute pulmonary reactions than in the acute form. Recovery may vary from dramatic resolution to several months. Patients with pulmonary reactions have also developed ECG changes (eg, non-specific ST/T wave changes, bundle branch block).
    3) RARE: Erythema multiforme, Stevens-Johnson syndrome, maculopapular or macular rashes, fixed drug reactions, erythema nodosum, angioedema, bullous eruptions, immune hypersensitivity reactions, nystagmus, papilledema, elevated liver enzymes, cholestatic hepatitis, peripheral neuropathy, neutropenia, leukopenia, granulocytopenia, hemolytic anemia (linked to G6PD deficiency), megaloblastic anemia, agranulocytosis, methemoglobinemia, Lyell's syndrome, and SLE syndromes. Peripheral neuropathy has occurred following nitrofurantoin therapy. Some cases may become severe, irreversible, or fatal. Renal impairment, anemia, diabetes mellitus, electrolyte imbalance, vitamin B deficiency, or debilitating disease may increase the risk for peripheral neuropathy.
    E) WITH POISONING/EXPOSURE
    1) There are very little data available on toxicity of nitrofurantoin after an overdose. Acute overdose has resulted in only vomiting.
    0.2.20) REPRODUCTIVE
    A) Evidence is fairly conclusive that nitrofurantoin is not a human teratogen.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, no studies were found on the possible carcinogenic effects of nitrofurantoin in humans.

Laboratory Monitoring

    A) Laboratory studies are not needed in most patients unless otherwise clinically indicated.
    B) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    C) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    D) Monitor arterial blood gases, pulse oximetry, and pulmonary function tests, and obtain a chest x-ray in any patient with respiratory symptoms.
    E) Monitor CBC with differential with platelet count, renal function, and liver enzymes in symptomatic patients with suspected toxicity from chronic use.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe vomiting.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Significant toxicity is not expected after an acute nitrofurantoin overdose. The most serious chronic effects involve the pulmonary and hematologic systems, as well as various peripheral neuropathies.
    C) DECONTAMINATION
    1) PREHOSPITAL: Gastrointestinal decontamination is not routinely required.
    2) HOSPITAL: Significant toxicity is not expected after an acute nitrofurantoin overdose. Gastrointestinal decontamination is generally not necessary. Consider activated charcoal only if coingestants with significant toxicity are involved.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with severe respiratory symptoms.
    E) ANTIDOTE
    1) None.
    F) ENHANCED ELIMINATION
    1) Severe toxicity has never been reported; enhanced elimination is not necessary.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be monitored for several hours to assess electrolyte and fluid balance. Patients that remain asymptomatic can be discharged.
    3) ADMISSION CRITERIA: Patients should be admitted for severe acute pulmonary reactions. Patients should also be admitted for severe vomiting, diarrhea, severe abdominal pain, dehydration, and electrolyte abnormalities.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    H) PITFALLS
    1) When managing a suspected overdose of nitrofurantoin, the possibility of multidrug involvement should be considered.
    I) PHARMACOKINETICS
    1) Absorption is dependent on crystal size. Macrocrystals have slower absorption and dissolution and lower peak serum concentration. Protein binding: 20% to 60%. Metabolism: liver. Excretion: 40% of nitrofurantoin is excreted rapidly as the parent compound in the urine. Elimination half-life: 20 minutes.
    J) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that cause peripheral neuropathy, pulmonary toxicity, and hepatotoxicity.

Range Of Toxicity

    A) TOXICITY: A toxic dose has not been established.
    B) THERAPEUTIC DOSES: ADULTS: Varies by indication and product; 50 to 100 mg once or 4 times daily or 100 mg twice daily for 5 to 7 days. CHILDREN: Macrobid(R): Nitrofurantoin monohydrate/nitrofurantoin, macrocrystal, uncomplicated UTI: 12 years and older, 100 mg orally every 12 hours for 7 days. Safety and efficacy in children under 12 years of age have not been established. Macrodantin(R): Nitrofurantoin, macrocrystal, urinary tract infection (UTI): (1 month of age and older), 5 to 7 mg/kg/day orally divided 4 times a day for 7 days, maximum 400 mg/day. Generic: Prophylaxis: (1 month of age and older) 1 mg/kg orally as 1 single or 2 divided doses.

Clinical Effects

Summary Of Exposure

    A) USES: Nitrofurantoin is used to prevent and treat urinary tract infections due to susceptible strains of Escherichia coli, enterococci, Staphylococcus aureus and some strains of Klebsiella and Enterobacter. It is not indicated for the treatment of pyelonephritis or perinephric abscess. Nitrofurantoin is also available as nitrofurantoin macrocrystals and nitrofurantoin monohydrate/nitrofurantoin, macrocrystals.
    B) PHARMACOLOGY: Nitrofurantoin is bactericidal at therapeutic doses. Through its reactive intermediates, it inactivates bacterial ribosomal proteins and other large molecules resulting in inhibition of vital biochemical processes such as protein synthesis, aerobic energy metabolism, DNA synthesis, RNA synthesis, and cell wall synthesis.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: Nausea, vomiting, anorexia, headache. OTHER EFFECTS: Diarrhea, abdominal pain, constipation, dyspepsia.
    2) PULMONARY HYPERSENSITIVITY REACTION: Acute, subacute or chronic pulmonary hypersensitivity reactions have rarely occurred; fatalities have been reported. Pulmonary toxicity may include diffuse interstitial pneumonitis, pulmonary fibrosis, or both. Patients receiving long-term treatment for 6 months or longer are at increased risk of developing chronic pulmonary reactions. Acute pulmonary reactions usually occur within the first week of treatment, and can be manifested by eosinophilia, fever, chills, cough, chest pain, dyspnea, or pulmonary infiltration with consolidation or pleural effusion on x-ray. Eosinophilia and fever occur less frequently in subacute pulmonary reactions than in the acute form. Recovery may vary from dramatic resolution to several months. Patients with pulmonary reactions have also developed ECG changes (eg, non-specific ST/T wave changes, bundle branch block).
    3) RARE: Erythema multiforme, Stevens-Johnson syndrome, maculopapular or macular rashes, fixed drug reactions, erythema nodosum, angioedema, bullous eruptions, immune hypersensitivity reactions, nystagmus, papilledema, elevated liver enzymes, cholestatic hepatitis, peripheral neuropathy, neutropenia, leukopenia, granulocytopenia, hemolytic anemia (linked to G6PD deficiency), megaloblastic anemia, agranulocytosis, methemoglobinemia, Lyell's syndrome, and SLE syndromes. Peripheral neuropathy has occurred following nitrofurantoin therapy. Some cases may become severe, irreversible, or fatal. Renal impairment, anemia, diabetes mellitus, electrolyte imbalance, vitamin B deficiency, or debilitating disease may increase the risk for peripheral neuropathy.
    E) WITH POISONING/EXPOSURE
    1) There are very little data available on toxicity of nitrofurantoin after an overdose. Acute overdose has resulted in only vomiting.

Vital Signs

    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) Both fever and chills have been reported with therapy (Prod Info Macrobid(R) oral capsule, 2011).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) PAPILLEDEMA: A 74-year-old man developed sudden loss of central vision in the right eye accompanied by bilateral papilledema 20 days after beginning nitrofurantoin 100 mg per day. Visual defects and papilledema improved with dexamethasone therapy and discontinuation of nitrofurantoin. A diagnosis of nitrofurantoin-induced pseudotumor cerebri was made (Korzets, 1988).
    2) NYSTAGMUS: Nystagmus has occurred following nitrofurantoin monohydrate/macrocrystals therapy in clinical trials (Prod Info Macrobid(R) oral capsule, 2011).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) CONDUCTION DISORDER OF THE HEART
    1) WITH THERAPEUTIC USE
    a) Patients with pulmonary reactions have developed ECG changes (eg, non-specific ST/T wave changes, bundle branch block) (Prod Info Macrobid(R) oral capsule, 2011; Prod Info Macrodantin(R) oral capsule, 2011).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) PULMONARY HYPERSENSITIVITY
    1) WITH THERAPEUTIC USE
    a) SUMMARY: Acute, subacute or chronic pulmonary reactions have rarely occurred following nitrofurantoin monohydrate/macrocrystals therapy in clinical trials; however, fatalities have been reported. Pulmonary toxicity may include diffuse interstitial pneumonitis, pulmonary fibrosis, or both. Patients receiving long-term treatment for 6 months or longer are at increased risk of developing chronic pulmonary reactions. Acute pulmonary reactions usually occur within the first week of treatment, and can be manifested by eosinophilia, fever, chills, cough, chest pain, dyspnea, or pulmonary infiltration with consolidation or pleural effusion on x-ray. Eosinophilia and fever occur less frequently in subacute pulmonary reactions than in the acute form. Recovery may vary from dramatic resolution to several months (Prod Info Macrobid(R) oral capsule, 2011).
    b) Characteristic effects of acute pulmonary toxicity after therapeutic use include: bronchospasm or a hypersensitivity syndrome of dyspnea, nonproductive cough, fever, elevated erythrocyte sedimentation rate, eosinophilia, and chest pain (Chudnofsky & Otten, 1989; Schattner et al, 1999). Symptoms can range from mild dyspnea to noncardiogenic pulmonary edema (Chudnofsky & Otten, 1989).
    c) ONSET: Symptoms have been reported as early as several hours after the start of therapy, and most often occur within the first 3 weeks of administration (Chudnofsky & Otten, 1989; Schattner et al, 1999).
    d) INCIDENCE: Pulmonary effects have been reported to occur in 12.5% to 43% of patients reporting an adverse response to nitrofurantoin; however, the actual incidence is only 1 of 476,190 courses of therapy (Chudnofsky & Otten, 1989).
    e) OUTCOME: In most cases symptoms resolve within 24 hours of drug cessation (Chudnofsky & Otten, 1989).
    f) CHRONIC TOXICITY/SUMMARY: Pulmonary toxicity is a rare (0.0013% of therapeutic courses) occurrence of nitrofurantoin therapy (Schattner et al, 1999).
    1) ONSET: toxicity can develop up to 5 years after exposure with a slow and gradual onset of symptoms (Schattner et al, 1999).
    2) CASE REPORTS: Several elderly patients have developed both pulmonary and hepatic toxicity following chronic exposure to nitrofurantoin (Bialas et al, 1997; Kelly et al, 1998; Schattner et al, 1999).
    g) ALLERGIC REACTION/ELDERLY
    1) There have been a few cases of allergic pneumonitis and interstitial pulmonary fibrosis in elderly patients using nitrofurantoin chronically (Rosenow et al, 1968). The reaction appears to be dose-related (cumulative) despite some hypersensitive factors (Boyd et al, 1979). The reaction may be due to both causes (Shah & Wade, 1989).
    2) There appears to be two main types of reactions:
    3) An acute noncardiogenic pulmonary edema associated with fever, cough, dyspnea, and peripheral eosinophilia which improves within 24 to 48 hours.
    4) A subacute, interstitial pneumonitis which may progress to interstitial fibrosis if the drug is not discontinued (Fleck, 1982; (Jick et al, 1989) Schattner et al, 1999). The average length of treatment before onset of this second type is 30 months (D'Archy, 1985).
    h) ALLERGIC REACTION/PEDIATRIC: Nitrofurantoin pulmonary toxicity has been reported in children aged 7 to 13 years; average duration of therapy was 16 months (Coraggio et al, 1989).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) FREQUENCY: CNS toxicity was the most frequent adverse reaction reported in one study (Coraggio et al, 1989).
    B) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache has occurred in 6% of patients following nitrofurantoin monohydrate/macrocrystals therapy in clinical trials (Prod Info Macrobid(R) oral capsule, 2011).
    C) SECONDARY PERIPHERAL NEUROPATHY
    1) WITH THERAPEUTIC USE
    a) Peripheral neuropathy has occurred following nitrofurantoin monohydrate/macrocrystals therapy. Some cases may become severe, irreversible, or fatal. Renal impairment (creatinine clearance under 60 milliliter/minute or clinically significant elevated serum creatinine), anemia, diabetes mellitus, electrolyte imbalance, vitamin B deficiency, or debilitating disease may increase the risk for peripheral neuropathy (Prod Info Macrobid(R) oral capsule, 2011).
    b) Symptoms are essentially distal, usually affecting primarily the legs, but hands may also be involved. Sensory symptoms of burning, painful feet and distal motor weakness may be noted (Cavanagh, 1973).
    c) PREDISPOSING FACTORS
    1) Peripheral neuropathy has been reported as a complication of treatment with nitrofurantoin, especially in patients with pre-existing renal dysfunction and in doses of 0.3 to 44 grams over 9 to 216 days (White et al, 1984) Toole & Parish, 1973; (Toole et al, 1968).
    2) White et al (1984) also reported a severe case of sensorimotor peripheral neuropathy in a type 2 diabetic with normal renal function who took 50 mg 3 times a day for 4 days.
    d) INCIDENCE: The incidence of neuropathies has been estimated as 0.0007% of courses of therapy (D'Archy, 1985).
    e) PEDIATRIC: Peripheral neuropathy has been associated with nitrofurantoin therapy in children 10 months to 18 years of age. Benign intracranial hypertension was reported in a 10-month-old male, responding to withdrawal of nitrofurantoin and acetazolamide therapy (Coraggio et al, 1989).
    D) CRANIAL NERVE DISORDER
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Cranial nerve palsy developed in a 24-year-old female during her fourth course of nitrofurantoin in less than 6 months which resolved upon discontinuation of the drug (Thomson & James, 1986).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) GASTROINTESTINAL TRACT FINDING
    1) WITH THERAPEUTIC USE
    a) The most common adverse effects are nausea, vomiting, and anorexia. Less common effects include abdominal pain diarrhea, dyspepsia, and constipation (Prod Info Macrodantin(R) oral capsule, 2011; Prod Info Macrobid(R) oral capsule, 2011). The incidence during therapeutic use with microcrystals was approximately 30%, using the macrocrystals it has been reduced approximately 1/2 (D'Archy, 1985).
    b) Nausea has occurred in 8% of patients following nitrofurantoin monohydrate/macrocrystals therapy in clinical trials, possibly or probably related to the drug (Prod Info Macrobid(R) oral capsule, 2011).
    2) WITH POISONING/EXPOSURE
    a) Acute overdose has resulted in only vomiting (Prod Info Macrobid(R) oral capsule, 2011).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) CHOLESTATIC HEPATITIS
    1) WITH THERAPEUTIC USE
    a) Cholestatic jaundice has rarely occurred following nitrofurantoin monohydrate/macrocrystals therapy in clinical trials; however, fatalities have been reported (Prod Info Macrobid(R) oral capsule, 2011).
    b) Cholestatic jaundice and hepatocellular damage have been reported, as well as chronic active hepatitis in a few, generally elderly, patients on 1 to 3 years of continued therapy (Ernaelsteen & Williams, 1961) Zimmerman, 1978; Holmbery et al, 1980; (Gosselin et al, 1984). Several cases of both hepatic and pulmonary toxicity have been described following chronic therapy in elderly patients (Kelly et al, 1998; Schattner et al, 1999).
    c) ONSET: Chronic toxicity usually develops within 6 months of therapy (Stricker et al, 1988), and may have an insidious onset (Stromberg & Wengle, 1976).
    1) Symptoms of hepatotoxicity can begin within 1 to 6 weeks of the start of therapy, presenting with jaundice, abdominal pain, malaise, nausea, eosinophilia, anorexia, and hepatotoxicity (Shah & Wade, 1989; Sharp et al, 1980).
    d) INCIDENCE: Hepatotoxicity is a rare event; incidence has been estimated to be 0.0003% of all therapeutic courses with nitrofurantoin (Schattner et al, 1999).
    e) MECHANISM: Activation of cytotoxic T cells has been suggested in the role of nitrofurantoin-induced liver damage in one patient (Kelly et al, 1998).
    f) CASE REPORT\ADULT: Fulminant liver failure requiring liver transplantation occurred in a 40-year-old female after 1 month of receiving nitrofurantoin 400 mg daily for recurrent urinary-tract infections (Hebert & Roberts, 1993). Although the exact mechanism is unknown, it is suggested that either a hypersensitivity or an idiosyncratic reaction developed.
    g) CASE REPORT\ADULT: A 56-year-old woman developed recurrent symptoms of hepatitis following brief exposure to nitrofurantoin (Bialas et al, 1997). The patient had developed similar symptoms 17 years earlier after receiving nitrofurantoin which was suggestive of a hypersensitivity response.
    h) PEDIATRIC: Hepatic toxicity, including focal nodular hyperplasia, anicteric hepatitis, cholestatic hepatitis, and chronic active hepatitis have been reported in children (Coraggio et al, 1989).
    B) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Elevations of alkaline phosphatase and aspartate transaminase have occurred during therapeutic use of nitrofurantoin (Thomson & James, 1986).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) CRYSTALLURIA
    1) WITH THERAPEUTIC USE
    a) Small irregular purple crystals were found in the urine of 3 elderly patients with urinary catheters following prophylactic nitrofurantoin therapy for 1.5 to 3 months (Macdonald & Macdonald, 1976).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) AGRANULOCYTOSIS
    1) WITH THERAPEUTIC USE
    a) THERAPEUTIC HYPERSENSITIVITY: Leukopenia, granulocytopenia, hemolytic anemia, megaloblastic anemia, and agranulocytosis have been reported with nitrofurantoin use (D'Archy, 1985). These effects occurred following nitrofurantoin monohydrate/macrocrystals therapy in clinical trials, regardless of causality relationship to the drug. In most cases, the hematologic abnormality resolved following discontinuation of therapy (Prod Info Macrobid(R) oral capsule, 2011).
    B) ANEMIA
    1) WITH THERAPEUTIC USE
    a) Anemia has been more frequently seen in patients with either G6PD, enolase, or glutathione peroxidase deficiency (D'Archy, 1985; Steinberg et al, 1970; Carpel, 1970). The hydantoin moiety may rarely cause megaloblastic anemia that would be responsive to folic acid (Shah & Wade, 1989).
    C) METHEMOGLOBINEMIA
    1) WITH THERAPEUTIC USE
    a) Methemoglobinemia has rarely been reported with nitrofurantoin therapy (Coraggio et al, 1989).
    b) Rare cases of cyanosis secondary to methemoglobinemia has been reported (Prod Info Macrobid(R) oral capsule, 2011).
    D) NEUTROPENIA
    1) WITH THERAPEUTIC USE
    a) Neutropenia has rarely been reported with nitrofurantoin therapy (Coraggio et al, 1989).
    E) HEMOLYTIC ANEMIA
    1) WITH THERAPEUTIC USE
    a) Hemolytic anemia of the primaquine-sensitivity type has occurred following nitrofurantoin monohydrate/macrocrystals therapy. Most cases appeared to be linked to a glucose-6-phosphate dehydrogenase (G6PD) deficiency. Hemolysis stopped when the nitrofurantoin was withdrawn (Prod Info Macrobid(R) oral capsule, 2011).
    b) Two cases of hemolytic anemia are reported in children with probable glucose-6-phosphate dehydrogenase deficiency (Coraggio et al, 1989).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERYTHEMA MULTIFORME
    1) WITH THERAPEUTIC USE
    a) CASE REPORT/ADULT: Drug-induced lupus erythematosus with an erythematous skin rash was described in a 66-year-old female following intermittent therapeutic use of nitrofurantoin (Chapman, 1986).
    b) Erythema multiforme has rarely occurred following nitrofurantoin monohydrate/macrocrystals therapy in clinical trials (Prod Info Macrobid(R) oral capsule, 2011).
    B) STEVENS-JOHNSON SYNDROME
    1) WITH THERAPEUTIC USE
    a) Stevens-Johnson syndrome has rarely occurred following nitrofurantoin monohydrate/macrocrystals therapy in clinical trials (Prod Info Macrobid(R) oral capsule, 2011).
    C) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) In postmarketing surveillance worldwide, immune hypersensitivity reactions represent the most frequent spontaneously-reported adverse reactions with the use of nitrofurantoin (Prod Info Macrobid(R) oral capsule, 2011).
    b) Maculopapular or macular rashes, fixed drug reactions, erythema nodosum, angioedema, bullous eruptions, Lyell's syndrome and SLE syndromes have been seen with therapeutic use (Shah & Wade, 1989).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCLE PAIN
    1) WITH THERAPEUTIC USE
    a) CHRONIC TOXICITY: Myalgia as well as arthralgia was reported by Fleck (1981) in a 32-year-old patient who was receiving 100 mg/day chronically (Fleck, 1981).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) In postmarketing surveillance worldwide, immune hypersensitivity reactions represent the most frequent spontaneously-reported adverse reactions with the use of nitrofurantoin (Prod Info Macrobid(R) oral capsule, 2011).
    b) Maculopapular or macular rashes, fixed drug reactions, erythema nodosum, angioedema, bullous eruptions, Lyell's syndrome and SLE syndromes have been seen with therapeutic use (Shah & Wade, 1989).

Reproductive

    3.20.1) SUMMARY
    A) Evidence is fairly conclusive that nitrofurantoin is not a human teratogen.
    3.20.2) TERATOGENICITY
    A) CONGENITAL ANOMALY
    1) Of 590 mothers receiving nitrofurantoin at various stages of pregnancy and 83 mothers receiving nitrofurantoin during lunar months 1-4, 14 and 6 children, respectively, were born with various malformations (Heinonen et al, 1977).
    a) The incidence of malformations in both groups is considered below the established crude relative risks in the populations studied.
    B) LACK OF EFFECT
    1) Nitrofurantoin does not appear to be teratogenic.
    a) The records of 101 pregnant patients receiving nitrofurantoin at a dose of 200 to 400 mg per day by mouth for asymptomatic bacteriuria were compared with those of 101 pregnant patients admitted during the same period who did not have bacteriuria and did not receive chemotherapy (Perry & LeBlanc, 1967).
    1) In the treated cases, no adverse effects in terms of apgar scores, jaundice, or congenital abnormalities were shown.
    b) A Michigan Medicaid surveillance study of 1292 newborns exposed to nitrofurantoin during the first trimester found no increased risk of birth defects for 6 major categories (52 observed versus 55 expected) (Rosa, 1993, cited in Briggs, 1994). Existing data has been subjected to meta-analysis (Ben David et al, 1995). Only 4 of 22 published studies met inclusion criteria. No association between nitrofurantoin use in early pregnancy and the occurrence of malformations was demonstrated, but statistical power to detect an association was limited.
    C) ANIMAL STUDIES
    1) Nitrofurantoin was not teratogenic in rats and rabbits at oral doses as high as 30 mg/kg/day (Prytherch et al, 1984). It was teratogenic at high doses in mice (Nomura et al, 1976).
    2) It increased post-implantation mortality and reduced the newborn viability index and growth statistics in rats when given to both the males and females prior to mating and through the second week of gestation (Prytherch et al, 1984). It also increased pre-implantation mortality in mice when given to the males 5 days prior to mating (RTECS , 1996).
    3.20.3) EFFECTS IN PREGNANCY
    A) HEMOLYSIS
    1) Administration of nitrofurantoin to the mother near term may result in hemolysis in the infant. However, this is not definitively established and more conclusive data are needed (Apgar, 1964). Three other studies failed to find this complication, as well (Monkus, 1969; Gordon, 1972; House, 1969).
    a) Subsequent studies have demonstrated that the use of nitrofurantoin during pregnancy can in fact cause hemolytic anemia, particularly in the black patient population, specifically in patients with G6PD deficiency (Hibbard, 1967; House, 1969).
    2) Nitrofurantoin does not appear to be teratogenic and hemolysis occurring in the fetus has never been documented; however, a potential risk does exist if the fetus is G6PD deficient.
    B) PREGNANCY CATEGORY
    NITROFURANTOINB
    Reference: Briggs et al, 1998
    C) LACK OF EFFECT
    1) No adverse effects were seen in 91 pregnancies when urinary tract infections were treated with nitrofurantoin (Hailey et al, 1983).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Nitrofurantoin is excreted into breast milk in very low concentrations (Briggs et al, 1998). The American Academy of Pediatrics considers nitrofurantoin to be compatible with breast feeding.
    2) There is one case of an infant with G-6-PD deficiency who developed hemolysis from exposure to nitrofurantoin in breast milk (Varsano, 1973). Breast feeding infants with G-6-PD deficiency during maternal nitrofurantoin therapy is therefore not recommended (Pons et al, 1990; WHO, 1988).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) Nitrofurantoin had no effect on fertility in mice of either sex when given at levels up to 0.12 percent in the diet (p 14).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS67-20-9 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) IARC Classification
    a) Listed as: Nitrofurantoin
    b) Carcinogen Rating: 3
    1) The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals. Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans. Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category.
    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, no studies were found on the possible carcinogenic effects of nitrofurantoin in humans.
    3.21.4) ANIMAL STUDIES
    A) CARCINOGENICITY RISK
    1) Nitrofurantoin was not carcinogenic when given to mice at levels up to 0.3 percent in the diet (Ito et al, 1983). It was not carcinogenic in rats at doses up to 116 mg/kg/day (tested as Macrodantin) (Butler et al, 1990a).
    2) Nitrofurantoin was negative in rats fed 0.187 percent in the diet for 2 years, nor did it act as an initiator or promoter for other compounds (Hasegawa et al, 1990). It was judged not to be carcinogenic in mice at doses up to 200 mg/kg/day (tested as Macrodantin); an increase in malignant lymphoma in the males was offset by a decrease in the females, and was probably due to chance (Butler et al, 1990b).
    3) Nitrofurantoin produced clear evidence of carcinogenicity in female mice, inducing tubular adenomas and ovarian tumors (NTP, 1989). There was some evidence in male rats for induction of kidney tubular cell neoplasms in a National Toxicology Program 2-year feeding study (NTP, 1989). It was neoplastic in rats by the oral exposure route, producing tumors of the kidney, ureter and bladder, skin, and appendages. It was carcinogenic in mice for inducing ovarian tumors by the oral exposure route.

Genotoxicity

    A) Nitrofurantoin has shown mixed results of genotoxic activity in short-term tests.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Laboratory studies are not needed in most patients unless otherwise clinically indicated.
    B) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    C) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    D) Monitor arterial blood gases, pulse oximetry, and pulmonary function tests, and obtain a chest x-ray in any patient with respiratory symptoms.
    E) Monitor CBC with differential with platelet count, renal function, and liver enzymes in symptomatic patients with suspected toxicity from chronic use.
    4.1.2) SERUM/BLOOD
    A) TOXICITY
    1) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    4.1.3) URINE
    A) URINARY LEVELS
    1) 50 to 250 mcg/mL would be the normal urine level in patients with normal urine function after taking a therapeutic dose (D'Archy, 1985).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients should be admitted for severe acute pulmonary reactions. Patients should also be admitted for severe vomiting, diarrhea, severe abdominal pain, dehydration, and electrolyte abnormalities.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic, need to be monitored for several hours to assess electrolyte and fluid balance. Patients that remain asymptomatic can be discharged.

Monitoring

    A) Laboratory studies are not needed in most patients unless otherwise clinically indicated.
    B) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    C) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    D) Monitor arterial blood gases, pulse oximetry, and pulmonary function tests, and obtain a chest x-ray in any patient with respiratory symptoms.
    E) Monitor CBC with differential with platelet count, renal function, and liver enzymes in symptomatic patients with suspected toxicity from chronic use.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) PREHOSPITAL: Gastrointestinal decontamination is not routinely required.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY: Significant toxicity is not expected after an acute nitrofurantoin overdose. Gastrointestinal decontamination is generally not necessary. Consider activated charcoal only if coingestants with significant toxicity are involved.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Routine laboratory tests are not necessary after overdose unless otherwise clinically indicated.
    2) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    3) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    4) Monitor arterial blood gases, pulse oximetry, and pulmonary function tests, and obtain a chest x-ray in any patient with respiratory symptoms.
    5) Monitor CBC with differential with platelet count, renal function, and liver enzymes in symptomatic patients with concern for chronic toxicity.

Enhanced Elimination

    A) HEMODIALYSIS
    1) Early hemodialysis would be expected to effectively clear nitrofurantoin (Prod Info Macrodantin(R) oral capsule, 2011), based on its low protein binding.
    2) Severe toxicity has never been reported; enhanced elimination is not necessary.

Range Of Toxicity

Summary

    A) TOXICITY: A toxic dose has not been established.
    B) THERAPEUTIC DOSES: ADULTS: Varies by indication and product; 50 to 100 mg once or 4 times daily or 100 mg twice daily for 5 to 7 days. CHILDREN: Macrobid(R): Nitrofurantoin monohydrate/nitrofurantoin, macrocrystal, uncomplicated UTI: 12 years and older, 100 mg orally every 12 hours for 7 days. Safety and efficacy in children under 12 years of age have not been established. Macrodantin(R): Nitrofurantoin, macrocrystal, urinary tract infection (UTI): (1 month of age and older), 5 to 7 mg/kg/day orally divided 4 times a day for 7 days, maximum 400 mg/day. Generic: Prophylaxis: (1 month of age and older) 1 mg/kg orally as 1 single or 2 divided doses.

Therapeutic Dose

    7.2.1) ADULT
    A) NITROFURANTOIN: Varies by indication and product; 50 to 100 mg once or 4 times daily or 100 mg twice daily for 5 to 7 days (Prod Info Furadantin(R) oral suspension, 2013; Prod Info Macrodantin(R) oral capsule, 2011; Prod Info Macrobid(R) oral capsule, 2011; Prod Info nitrofurantoin oral capsules, 2006).
    7.2.2) PEDIATRIC
    A) MACROBID(R) - NITROFURANTOIN MONOHYDRATE/NITROFURANTOIN, MACROCRYSTAL, UNCOMPLICATED UTI: 12 years and older, 100 mg orally every 12 hours for 7 days (Prod Info Macrobid(R) oral capsule, 2011)
    B) MACROBID(R) - NITROFURANTOIN MONOHYDRATE/NITROFURANTOIN, MACROCYSTAL, UNCOMPLICATED UTI: Safety and efficacy in children under 12 years of age have not been established (Prod Info Macrobid(R) oral capsule, 2011)
    C) FURADANTIN(R) - NITROFURANTOIN AND MACRODANTIN(R) - NITROFURANTOIN, MACROCRYSTAL, URINARY TRACT INFECTION (UTI): (1 month of age and older), 5 to 7 mg/kg/day orally divided 4 times a day for 7 days or at least 3 days after sterile urine is obtained, maximum 400 mg/day (Prod Info Furadantin(R) oral suspension, 2013; Prod Info Macrodantin(R) oral capsule, 2011)
    D) FURADANTIN(R) - NITROFURANTOIN AND GENERIC: NITROFURANTOIN, MACROCRYSTAL, URINARY TRACT INFECTION, PROPHYLAXIS: (1 month of age and older) 1 mg/kg orally as 1 single or 2 divided dose(s) (Prod Info Furadantin(R) oral suspension, 2013; Prod Info nitrofurantoin oral capsules, 2006)

Minimum Lethal Exposure

    A) GENERAL/SUMMARY
    1) Acute overdose has resulted in only vomiting (Prod Info Macrobid(R) oral capsule, 2011). No doses were provided.
    2) ANIMAL STUDIES: In animal tests, mice succumbed to 100 milligrams/kilogram (Gosselin et al, 1984).

Workplace Standards

    A) ACGIH TLV Values for CAS67-20-9 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS67-20-9 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS67-20-9 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): 3 ; Listed as: Nitrofurantoin
    a) 3 : The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals. Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans. Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category.
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS67-20-9 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (INTRAPERITONEAL)MOUSE:
    1) 150 mg/kg
    B) LD50- (ORAL)MOUSE:
    1) 360 mg/kg
    C) LD50- (INTRAPERITONEAL)RAT:
    1) 112 mg/kg
    D) LD50- (ORAL)RAT:
    1) 604 mg/kg

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Nitrofurantoin is an antibacterial which has minimal effect on mammalian cells. Its antibacterial action is pH dependent. The MIC (amount of drug required to kill an organism) increases quickly at a pH over 6 (Brumfitt & Percival, 1967).
    B) The exact mechanism of the hypersensitivity or toxic reactions is yet unknown, but the presence of eosinophilia and fever, recurrence of symptoms with rechallenge, and rapid improvement upon drug discontinuation suggest an immune based response.
    1) A nitrofurantoin metabolite which has not been identified may be involved.

Physicochemical

Physical Characteristics

    A) Nitrofurantoin is odorless with a bitter taste.

Molecular Weight

    A) 238.16 (Budavari, 1996).

References

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