Nitrofurantoin

Nitrofurantoin belongs to the pharmacological class of Nitrofurantoin derivatives.

Nitrofurantoin has been approved to relieve symptoms and also for the treatment and maintenance of Asymptomatic bacteriuria in pregnancy, Cystitis, acute uncomplicated or acute simple cystitis, treatment, Cystitis, prophylaxis for recurrent infection.

Nitrofurantoin exhibits a peak concentration (Cmax) ranging from 0.875 to 0.963 mg/L and an area under the concentration-time curve (AUC) of 2.21 to 2.42 mg*h/L, indicating its absorption characteristics. The bioavailability of nitrofurantoin is estimated to be around 38.8% to 44.3%. When taken with food, the absorption of nitrofurantoin is enhanced, leading to increased concentrations in the urine and prolonged therapeutic effects. Although limited information is available on the volume of distribution in humans, it has been reported as 0.46 L/kg in dogs. In plasma, nitrofurantoin can bind to proteins up to 90%. The metabolism of nitrofurantoin involves the conversion of approximately 0.8% to 1.8% of the dose to aminofurantoin, while other metabolites account for less than 0.9% of the dose. Following oral administration, approximately 27% to 50% of the dose is excreted unchanged in the urine, representing 90% of the total elimination of nitrofurantoin.

The common side effects involved in using Nitrofurantoin are Intense abdominal pain, Watery or bloody diarrhea, Impaired vision, Elevated body temperature (fever), Cold shivers or chills, Persistent cough, Sharp chest discomfort, Difficulty breathing, Abnormal sensations like numbness, tingling, or burning in the hands or feet, Excruciating pain located behind the eyes, Pale skin, Weakness or fatigue.

Nitrofurantoin is available in the form of Capsules, Oral suspension.

Nitrofurantoin is approved in Germany, Japan, Malaysia, India, the U.K., the U.S., and China.

Nitrofurantoin belongs to the pharmacological class of Nitrofurantoin derivatives.

Bacterial nitro reductases convert nitrofurantoin into reactive intermediates that inhibit various cellular processes, including the citric acid cycle, as well as the synthesis of DNA, RNA, and proteins.

Nitrofurantoin has been approved to relieve symptoms and also for the treatment and maintenance of Asymptomatic bacteriuria in pregnancy, Cystitis, acute uncomplicated or acute simple cystitis, treatment, Cystitis, prophylaxis for recurrent infection.

Nitrofurantoin achieves a maximum concentration (Cmax) in the range of 0.875-0.963 mg/L and an area under the concentration-time curve (AUC) in the range of 2.21-2.42 mg*h/L.

The onset of action of Nitrofurantoin is three to five days.

Nitrofurantoin is found to be available in the form of Capsules, Oral suspension.

Nitrofurantoin can be used in the following treatment:

• Asymptomatic bacteriuria in pregnancy
• Cystitis, acute uncomplicated or acute simple cystitis, treatment
• Cystitis, prophylaxis for recurrent infection

Nitrofurantoin can help to relieve symptoms and also for the treatment and maintenance of Asymptomatic bacteriuria in pregnancy, Cystitis, acute uncomplicated or acute simple cystitis, treatment, Cystitis, prophylaxis for recurrent infection.

Nitrofurantoin is approved for use in the following clinical indications:

• Asymptomatic bacteriuria in pregnancy
• Cystitis, acute uncomplicated or acute simple cystitis, treatment
• Cystitis, prophylaxis for recurrent infection

• Asymptomatic bacteriuria in pregnancy:

Note: The use of nitrofurantoin is contraindicated in pregnant patients at term (38 to 42 weeks gestation), during labor and delivery, or when the onset of labor is imminent due to the potential risk of hemolytic anemia in the newborn, as stated in the manufacturer's labeling. The available information from studies evaluating the risk of congenital anomalies after first-trimester exposure is inconclusive.

For the treatment of asymptomatic bacteriuria (≥105 CFU per mL) in pregnancy, oral nitrofurantoin monohydrate/microcrystals (Macrobid) is recommended: 100 mg twice daily for 4 to 7 days.

• Cystitis, acute uncomplicated or acute simple cystitis, treatment:

Note: In patients with suspected pyelonephritis, recent nitrofurantoin use within the last 3 months, or documented nitrofurantoin resistance in the last 3 months, consider using a different empiric agent.

For the treatment of acute uncomplicated cystitis limited to the bladder without signs/symptoms of upper tract, prostate, or systemic infection, the following oral nitrofurantoin regimens are recommended:

Nitrofurantoin monohydrate/microcrystals (Macrobid): 100 mg twice daily; treat females for 5 days and males for 7 days.

Nitrofurantoin microcrystals (Furadantin, Macrodantin): 50 to 100 mg every 6 hours; treat females for 5 days and males for 7 days. Note: The duration of therapy with this formulation is based on the recommendation for the nitrofurantoin monohydrate/macrocrystal formulation and expert opinion.

• Cystitis, prophylaxis for recurrent infection:

Note: Nitrofurantoin may be considered in nonpregnant women with bothersome, frequently recurrent cystitis despite non-antimicrobial preventive measures. The duration of prophylaxis ranges from 3 to 12 months, with periodic reassessment. Prolonged use (>6 months) of nitrofurantoin has been associated with potential adverse effects such as diffuse interstitial pneumonitis and/or pulmonary fibrosis, chronic hepatitis, and neuropathy.

For continuous prophylaxis:

Nitrofurantoin monohydrate/macrocrystals (off-label use): 100 mg once daily at bedtime.

Nitrofurantoin microcrystals: 50 to 100 mg once daily at bedtime.

For postcoital prophylaxis in females with cystitis temporally related to sexual intercourse:

Nitrofurantoin monohydrate/macrocrystals (off-label use): 100 mg as a single dose taken within 2 hours of sexual intercourse.

Nitrofurantoin microcrystals: 50 to 100 mg as a single dose taken within 2 hours of sexual intercourse.

Capsules : 25mg, 50mg, 100mg

Oral suspension : 25mg/ml

Capsules, Oral suspension.

Dosage Adjustments in Kidney Patients:

For patients with a creatinine clearance (CrCl) of ≥60 mL/minute, no adjustment in dosage is necessary.

For patients with a CrCl of 30 to <60 mL/minute, although nitrofurantoin is contraindicated according to the manufacturer's labeling, limited data suggest its safety and effectiveness for short-term treatment of uncomplicated acute cystitis in these patients. Please refer to the appropriate reference for more information. Additionally, one retrospective cohort study found an increased risk of pulmonary adverse events in patients with an estimated glomerular filtration rate (eGFR) <50 mL/minute.

For patients with a CrCl <30 mL/minute, the use of nitrofurantoin should be avoided.

Dosage Adjustments in Pediatric Patients:

Treatment for Urinary Tract Infection (UTI):

• Furadantin and Macrodantin: For infants, children, and adolescents, the recommended oral dosage is 5 to 7 mg/kg/day, divided into four doses every 6 hours for a duration of 7 days or at least 3 days after obtaining sterile urine. The maximum dose per administration is 100 mg.

Fixed dosing for Furadantin oral suspension:

• 7 to <12 kg: 12.5 mg every 6 hours.
• 12 to <22 kg: 25 mg every 6 hours.
• 22 to <31 kg: 37.5 mg every 6 hours.
• 31 to <42 kg: 50 mg every 6 hours.
• ≥42 kg: 50 to 100 mg every 6 hours.

Macrobid (macrocrystal/monohydrate): For adolescents, the recommended oral dosage is 100 mg every 12 hours for a duration of 7 days.

Prophylaxis for Urinary Tract Infection:

• Furadantin and Macrodantin: For infants, children, and adolescents, the recommended oral dosage is 1 to 2 mg/kg/day, either as a single bedtime dose or divided into two doses throughout the day. The maximum daily dose is 100 mg/day. It is important to note that prophylaxis should be considered in infants and children under 24 months only for those with grade III-V reflux or recurrent febrile UTIs. There is limited evidence supporting the routine use of continuous antimicrobial prophylaxis.

• Nitrofurantoin may be taken with food to enhance tolerance and improve drug absorption. It is recommended to take it with a meal or a snack.
• Avoid Antacids:
• Avoid taking antacids containing magnesium trisilicate concurrently with nitrofurantoin, as they can reduce the rate and extent of drug absorption. This interaction occurs due to the adsorption of the drug onto the surface of magnesium trisilicate.
• Fluid Intake:
• Maintain a high fluid intake while taking nitrofurantoin to promote urinary excretion of the drug. Adequate hydration helps in the elimination of the medication from the body.

Nitrofurantoin may be contraindicated under the following conditions:

• Contraindicated in pregnant patients during labor and delivery or when labor onset is imminent
• Contraindicated in infants under one month of age
• Potential risk of hemolytic anemia in the fetus or newborn due to immature erythrocyte enzyme systems (glutathione instability)
• Contraindicated in patients with known hypersensitivity to nitrofurantoin

Pulmonary Reactions

• Acute, subacute, or chronic pulmonary reactions observed
• Withdrawal of the drug and appropriate measures required
• Pulmonary reactions cited as contributing cause of death
• Close monitoring during long-term therapy

• Hepatic Reactions
• Hepatitis, hepatic necrosis, cholestatic jaundice, and chronic active hepatitis
• A rare occurrence with reported fatalities
• Insidious onset of chronic active hepatitis
• Periodic monitoring of liver function
• Immediate withdrawal of the drug if hepatitis occurs

• Peripheral Neuropathy
• Occurrence with nitrofurantoin therapy, including optic neuritis
• Severity or irreversibility possible
• Predisposing conditions enhancing occurrence
• Periodic monitoring of renal function
• Discontinue use if numbness or tingling occurs

• Hemolytic Anemia
• Cases induced by nitrofurantoin
• Linked to glucose-6-phosphate dehydrogenase deficiency
• Indication to discontinue the drug with any sign of hemolysis
• Hemolysis ceases upon drug withdrawal

• Superinfections
• Pseudomonas commonly implicated in superinfections

• Carcinogenesis, Mutagenesis, and Impairment of Fertility
• Carcinogenic activity observed in mice and rats
• Mutagenic potential demonstrated in laboratory assays
• In vivo tests on rodents showing DNA damage
• Significance relative to therapeutic use in humans is unknown
• Consider potential risks in long-term therapy

• Spermatogenic Arrest
• Temporary spermatogenic arrest in rats with high doses
• Reversible upon discontinuing the drug
• Slight to moderate spermatogenic arrest possible in certain instances in humans

• Susceptibility/Resistance
• Development of drug-resistant bacteria
• Avoid prescribing without proven or strongly suspected bacterial infection
• Risks outweigh potential benefits

There is no specific alcohol warning related to the use of Nitrofurantoin. However, it is generally advisable to avoid or limit alcohol consumption while undergoing any medical treatment. Alcohol can interact with medications and may potentially worsen side effects or interfere with the effectiveness of the medication. Additionally, Nitrofurantoin is primarily used in the treatment of serious fungal infections, and alcohol can weaken the immune system, making it less effective in fighting off infections.

Trace amounts of nitrofurantoin have been found in breast milk. It is important to exercise caution when administering nitrofurantoin to a nursing woman, particularly if the infant has a known or suspected glucose-6-phosphate dehydrogenase deficiency.

Pregnancy:

Teratogenic Effects - Category B

Reproduction studies conducted on rabbits and rats using low doses and plasma levels comparable to human doses showed no evidence of adverse effects on reproduction, fertility, or fetal harm. However, one study on pregnant mice revealed growth retardation and a low incidence of malformations when administered a subcutaneous dose of 250 mg/kg for three days. These effects were not observed at a dose of 100 mg/kg. Additionally, in a controlled study on cultured rat embryos exposed to concentrations of 48 mcg/mL for 26 hours, all embryos exhibited malformations, while none of those exposed to 60 mcg/mL of nitrofurantoin survived.

The relevance of these findings to humans is uncertain, and there are no well-controlled studies in pregnant women. Although animal studies do not always accurately predict human response, the use of this drug during pregnancy should be avoided unless absolutely necessary.

• Take nitrofurantoin with food: It is recommended to take nitrofurantoin with food or milk. This can help enhance its tolerance and improve drug absorption. Taking it on an empty stomach may increase the risk of gastrointestinal side effects.
• Avoid antacids containing magnesium trisilicate: Antacids that contain magnesium trisilicate should be avoided or taken separately from nitrofurantoin. When taken together, magnesium trisilicate can reduce the absorption of nitrofurantoin. It is best to consult with your healthcare provider regarding the timing of nitrofurantoin and antacid administration.
• Maintain high fluid intake: It is important to maintain a high fluid intake while taking nitrofurantoin. Adequate hydration can help promote urinary excretion of the drug and reduce the risk of certain side effects.

The adverse reactions related to Nitrofurantoin can be categorized as follows:

Common:

• Nausea
• Vomiting
• Loss of appetite
• Diarrhea
• Abdominal pain
• Headache
• Dizziness
• Fatigue
• Skin rash or itching
• Brownish discoloration of urine

Less common:

• Fever
• Chills
• Chest pain
• Difficulty breathing
• Swollen or tender joints
• Muscle pain or weakness
• Numbness or tingling in the hands or feet
• Pale skin
• Swollen glands

Rare:

• Severe stomach pain
• Watery or bloody diarrhea
• Vision problems
• Severe pain behind the eyes
• Ringing in the ears
• Yellowing of the skin or eyes (jaundice)
• Dark urine

• Severe headache

  • Pain, redness, or swelling in the lower jaw

When taken together, antacids containing magnesium trisilicate can decrease the absorption of nitrofurantoin by both slowing down its rate and reducing its extent. This interaction is likely caused by the drug being adsorbed onto the surface of magnesium trisilicate. It is important to avoid administering nitrofurantoin with medications that may impair renal function. Uricosuric drugs like probenecid and sulfinpyrazone can inhibit the renal tubular secretion of nitrofurantoin. As a result, serum levels of nitrofurantoin may increase, leading to a higher risk of toxicity, while urinary levels may decrease, potentially reducing its effectiveness as a urinary tract antibacterial agent.

The following are the side effects involving Nitrofurantoin:

• Intense abdominal pain
• Watery or bloody diarrhea
• Impaired vision
• Elevated body temperature (fever)
• Cold shivers or chills
• Persistent cough
• Sharp chest discomfort
• Difficulty breathing
• Abnormal sensations like numbness, tingling, or burning in the hands or feet
• Excruciating pain located behind the eyes
• Pale skin
• Weakness or fatigue
• Joint pain or swelling accompanied by fever
• Enlarged lymph nodes
• Muscle soreness
• Intense pain, redness, or swelling in the lower jaw
• Severe headaches
• Ringing sound in the ears
• Dizziness
• Nausea
• Severe upper abdominal pain that may radiate to the back
• Vomiting
• Dark-colored urine
• Yellowing of the skin or eyes (jaundice)

Pregnancy:

Teratogenic Effects - Category B

Reproduction studies conducted on rabbits and rats using low doses and plasma levels comparable to human doses showed no evidence of adverse effects on reproduction, fertility, or fetal harm. However, one study on pregnant mice revealed growth retardation and a low incidence of malformations when administered a subcutaneous dose of 250 mg/kg for three days. These effects were not observed at a dose of 100 mg/kg. Additionally, in a controlled study on cultured rat embryos exposed to concentrations of 48 mcg/mL for 26 hours, all embryos exhibited malformations, while none of those exposed to 60 mcg/mL of nitrofurantoin survived.

The relevance of these findings to humans is uncertain, and there are no well-controlled studies in pregnant women. Although animal studies do not always accurately predict human response, the use of this drug during pregnancy should be avoided unless absolutely necessary.

Lactation:

Trace amounts of nitrofurantoin have been found in breast milk. It is important to exercise caution when administering nitrofurantoin to a nursing woman, particularly if the infant has a known or suspected glucose-6-phosphate dehydrogenase deficiency.

Pediatric:

The use of nitrofurantoin is not recommended for infants younger than one-month-old.

Geriatric Use:

Clinical trials evaluating nitrofurantoin macrocrystal formulations did not include a sufficient number of participants aged 65 and over, making it unclear if they respond differently from younger individuals. However, available clinical experience suggests no significant differences in treatment outcomes between elderly and younger patients. Reports indicate that pulmonary reactions, including fatalities, may be more common in elderly patients receiving long-term nitrofurantoin therapy. Similarly, severe hepatic reactions, including fatalities, appear to be more prevalent in elderly patients. It is important to consider age-related factors such as decreased hepatic, renal, or cardiac function, as well as concomitant diseases or medications when prescribing TNitrofurantoin. Since the drug is primarily eliminated through the kidneys, impaired renal function can increase the risk of adverse reactions. Anuria, oliguria, or significant renal impairment are contraindications for this medication. Dose selection should be cautious in elderly patients, and renal function monitoring may be beneficial. Patients should be advised to take nitrofurantoin with food for improved tolerance and absorption. It is crucial for patients to complete the full course of therapy and promptly inform their physician of any unusual symptoms. While some patients who experience nausea with microcrystalline nitrofurantoin can tolerate TNitrofurantoin without such side effects.

Physicians should be knowledgeable as well as vigilant about the treatment and identification of overdosage of Nitrofurantoin.

Rare instances of acute overdose with nitrofurantoin have generally been associated with vomiting as the main symptom. If vomiting does not occur promptly after an excessive dose, it is advised to induce vomiting. While there is no specific antidote available for nitrofurantoin, maintaining a high fluid intake is recommended to enhance the elimination of the drug through urine. Additionally, it is important to note that nitrofurantoin is dialyzable, meaning it can be removed from the body through dialysis.

Pharmacodynamics

Nitrofurantoin exerts its bactericidal effects by disrupting essential bacterial processes, ultimately resulting in bacterial death. It quickly achieves therapeutic concentrations in the urine and is rapidly eliminated from the body.

Pharmacokinetics

Nitrofurantoin, when taken orally, is quickly absorbed from the gastrointestinal tract and demonstrates wide distribution in the body. Administration of nitrofurantoin with food may increase its bioavailability by approximately 40%, as observed through urine recovery levels. In a study involving healthy adult males who received a single 100 mg capsule of nitrofurantoin with food, the maximum concentration (Cmax) in urine was 100 mcg/mL, with a time to reach maximum concentration (Tmax) of 3.6 hours and an area under the curve (AUC) of 1.13 hours. Plasma levels of nitrofurantoin following therapeutic administration in individuals with normal kidney function typically do not exceed 1 mcg/mL. However, higher concentrations have been reported in human bile, seminal fluid, and kidney. Approximately 20-25% of a single dose of nitrofurantoin is excreted in the urine, while about 1.5% undergoes metabolism within the urine. The metabolism of nitrofurantoin and its excretion through other routes in humans is not well understood.

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