Nitrofurantoin (nitrofurantoin macrocrystal)

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Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Antibiotics/Fecal Microbiota

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Fecal microbiota is a suspension of live bacteria, which may be compromised by concurrent use of antibiotics.(1)

CLINICAL EFFECTS: Antibiotics may decrease the effectiveness of fecal microbiota.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Antibiotics should not be used concurrently with fecal microbiota. Antibacterial treatment should be completed for 24 to 72 hours before initiating treatment with fecal microbiota. Do not use antibiotics for up to 8 weeks after fecal microbiota.(1)

DISCUSSION: Antibiotics may compromise the effectiveness of fecal microbiota.

Antibiotics/Fecal Microbiota Spores

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Fecal microbiota spores is a suspension of live bacterial spores, which may be compromised by concurrent use of antibiotics.(1)

CLINICAL EFFECTS: Antibiotics may decrease the effectiveness of fecal microbiota spores.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Antibiotics should not be used concurrently with fecal microbiota spores. Antibacterial treatment should be completed for 2 to 4 days before initiating treatment with fecal microbiota spores.(1)

DISCUSSION: Antibiotics may compromise the effectiveness of fecal microbiota spores.

Antimicrobials/Live Typhoid Vaccine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The antimicrobial may be active against the organism in the live-vaccine. Antimicrobial therapy may prevent the vaccine organism from replicating enough to trigger an immune response.(1)

CLINICAL EFFECTS: Vaccination may be ineffective.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Do not give oral typhoid vaccine until 72 hours after the last dose of antimicrobial. If possible, to optimize vaccine effectiveness, do not start antibacterial drugs for 72 hours after the last dose of oral typhoid vaccine. A longer interval should be considered for long-acting antimicrobials, such as azithromycin.(3)

DISCUSSION: Because antimicrobial therapy may prevent sufficient vaccine-organism replication to generate an immune response, the manufacturer of live-attenuated typhoid vaccine and the Centers for Disease Control (CDC) state that the vaccine should not be administered to patients receiving antimicrobial therapy.(1-3)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Nitrofurantoin/Magnesium Trisilicate

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Magnesium trisilicate may bind to nitrofurantoin in the gastrointestinal tract, preventing its absorption.(1,2)

CLINICAL EFFECTS: The concurrent administration of nitrofurantoin and magnesium trisilicate may result in decreased levels and effectiveness of nitrofurantoin.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of nitrofurantoin states that patients receiving nitrofurantoin should be instructed not to use magnesium trisilicate.(1,2) If concurrent therapy cannot be avoided, the doses of nitrofurantoin and magnesium trisilicate should be separated by as much time as possible.

DISCUSSION: In a study in 6 subjects, the concurrent administration of a single dose of nitrofurantoin (100 mg) with a single dose of magnesium trisilicate (5 G) resulted in a decrease in both the rate and extent of absorption of nitrofurantoin. The time that nitrofurantoin was above its minimum effective concentration in the urine was also decreased. In vitro studies confirmed magnesium trisilicate bound nitrofurantoin. In vitro studies found that bismuth oxycarbonate, talc, kaolin, and magnesium oxide had intermediate absorptive powers when compared to magnesium trisilicate. Aluminum hydroxide and calcium carbonate had low to no absorptive powers.(3)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Nitrofurantoin/Methotrexate

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Nitrofurantoin may inhibit the renal elimination of methotrexate.(1-5)

CLINICAL EFFECTS: Concurrent use of nitrofurantoin may result in an increase in both the therapeutic and toxic effects of methotrexate, leading to increased risk of severe neurotoxicity, stomatitis, and myelosuppression, including neutropenia.

PREDISPOSING FACTORS: Risk factors for methotrexate toxicity include: - High-dose oncology regimens - Impaired renal function, ascites, or pleural effusions

PATIENT MANAGEMENT: If concurrent use cannot be avoided, monitor methotrexate blood levels closely and adjust the dose accordingly.

DISCUSSION: Concomitant administration of methotrexate and nitrofurantoin has been shown to increase methotrexate plasma levels.(2-5) Case reports of methotrexate toxicity have been described with concurrent use of nitrofurantoin.(2-4) Nitrofurantoin may inhibit organic anion transporter 3 (OAT3), resulting in decreased renal clearance of methotrexate.(5)

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• Acute intermittent porphyria
• Anuria
• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Glucose-6-phosphate dehydrogenase (g6Pd) deficiency
• Hemoglobin H disease
• Hemolytic anemia from pyruvate kinase and g6PD deficiencies
• Oliguria

• Cholestasis
• Clostridioides difficile infection
• Disease of liver
• Interstitial pneumonitis
• Kidney disease with likely reduction in glomerular filtration rate (GFr)
• Optic neuritis
• Peripheral neuropathy
• Pulmonary fibrosis
• Vitamin B deficiency

• Diabetes mellitus

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More Frequent

• Interstitial pneumonitis

Less Frequent

• Granulocytopenic disorder
• Leukopenia
• Megaloblastic anemia
• Polyneuropathy

Rare or Very Rare

• Agranulocytosis
• Allergic dermatitis
• Anaphylaxis
• Clostridioides difficile infection
• Erythema multiforme
• Exfoliative dermatitis
• Glucose-6-phosphate dehydrogenase (g6Pd) deficiency anemia
• Hemolytic anemia
• Hepatic necrosis
• Hepatitis
• Idiopathic intracranial hypertension
• Increased alanine transaminase
• Increased aspartate transaminase
• Lupus-like syndrome
• Methemoglobinemia
• Obstructive hyperbilirubinemia
• Optic neuritis
• Pancreatitis
• Peripheral neuropathy
• Pruritus of skin
• Pulmonary fibrosis
• Sialoadenitis
• Skin rash
• Stevens-johnson syndrome
• Thrombocytopenic disorder
• Urticaria
• Vasculitis

More Frequent

• Anorexia
• Headache disorder
• Nausea
• Urine discoloration
• Vomiting

Less Frequent

• Acute abdominal pain
• Diarrhea
• Flatulence

Rare or Very Rare

• Alopecia
• Chills
• Constipation
• Dizziness
• Drowsy
• Dyspepsia
• Fever
• General weakness
• Malaise
• Nystagmus
• Toxic amblyopia
• Vertigo

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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.

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.

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