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  • CLASSES

    Nitrofuran Derivative Antibiotics
    Other Urinary Antiseptics

    DEA CLASS

    Rx

    DESCRIPTION

    Oral nitrofuran antibacterial agent specifically used to treat urinary tract infections caused by many gram-negative and some gram-positive bacteria.

    COMMON BRAND NAMES

    Furadantin, Macrobid, Macrodantin

    HOW SUPPLIED

    Furadantin/Nitrofurantoin Oral Susp: 5mL, 25mg
    Macrobid/Macrodantin/Nitrofurantoin/Nitrofurantoin, Macrocrystalline/Nitrofurantoin, Nitrofurantoin, Macrocrystalline Oral Cap: 25mg, 50mg, 100mg, 75-25mg

    DOSAGE & INDICATIONS

    For the treatment of uncomplicated urinary tract infection (UTI) including acute cystitis.
    Oral dosage (all products except oral suspension and Macrobid)
    Adults

    50 to 100 mg PO every 6 hours. Give for 7 days or for at least 3 days after the urine is sterile.

    Infants, Children, and Adolescents

    5 to 7 mg/kg/day PO given in 4 divided doses. Give for 7 days or for at least 3 days after the urine is sterile.

    Oral dosage (oral suspension containing 25 mg/5mL of nitrofurantoin)
    Adults

    50 to 100 mg PO every 6 hours. Give for 7 days or for at least 3 days after the urine is sterile.

    Children and Adolescents weighing 42 kg or more

    50 to 100 mg PO every 6 hours. Give for 7 days or for at least 3 days after the urine is sterile.

    Infants, Children, and Adolescents weighing less than 42 kg

    5 to 7 mg/kg/day PO given in 4 divided doses. Give for 7 days or for at least 3 days after the urine is sterile.

    Oral dosage (Macrobid)
    Adults

    100 mg PO every 12 hours for 7 days. For uncomplicated cystitis, the Infectious Diseases Society of America (IDSA) suggests 5 days of treatment.

    Adolescents

    100 mg PO every 12 hours for 7 days. For uncomplicated cystitis, the Infectious Diseases Society of America (IDSA) suggests 5 days of treatment.

    For long-term suppressive therapy for urinary tract infection (UTI) prophylaxis in patients predisposed to urinary tract infection.
    Oral dosage (all products except Macrobid)
    Adults

    50 to 100 mg PO as a single dose at bedtime.

    Infants, Children, and Adolescents

    1 mg/kg/day PO as a single dose at bedtime, or divided every 12 hours.

    MAXIMUM DOSAGE

    Adults

    7 mg/kg/day PO.

    Geriatric

    7 mg/kg/day PO.

    Adolescents

    7 mg/kg/day PO.

    Children

    7 mg/kg/day PO.

    Infants

    7 mg/kg/day PO.

    Neonates

    Contraindicated.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Nitrofurantoin is associated with hepatotoxicity and should be used cautiously in patients with hepatic impairment. However, no specific dosage adjustment guidelines are available.

    Renal Impairment

    CrCl less than 60 mL/minute: Although the FDA-approved labeling states that use is contraindicated in patients with a CrCl less than 60 mL/minute, data are lacking to support this recommendation. Retrospective studies have shown that short-term nitrofurantoin use is effective and generally well tolerated in patients with a CrCl of 30 mL/minute or more, although higher adverse events have been noted in patients with renal impairment. The Beers Criteria recommends avoiding nitrofurantoin in geriatric patients 65 years and older with a CrCl less than 30 mL/minute.

    ADMINISTRATION

     
    NOTE: If treatment with nitrofurantoin has ever been discontinued due to pulmonary complications, it is recommended that a re-challenge not be attempted.

    Oral Administration

    May be given without regard to meals, but administration with food, water, or milk may enhance tolerance.

    Oral Liquid Formulations

    Suspension can be mixed with water, milk, fruit juice, or infant formula.

    STORAGE

    Generic:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Furadantin:
    - Discard opened bottle after 30 days
    - Protect from freezing
    - Protect from light
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Macrobid:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Macrodantin:
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Patients receiving nitrofurantoin may present with a false-positive reaction for glucose in the urine. Benedict's and Fehling's solutions are affected but not the glucose enzymatic test.

    Viral infection

    Nitrofurantoin will not treat a viral infection (e.g., common cold). Prescribing nitrofurantoin in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. Patients should be told to complete the full course of treatment, even if they feel better earlier.

    Anuria, oliguria, renal disease, renal impairment

    The success of nitrofurantoin therapy depends on achieving adequate urinary concentrations of the drug. Although data are lacking, the FDA-approved labeling states that nitrofurantoin is contraindicated in patients with anuria, oliguria, or severe renal impairment where CrCl is less than 60 mL/minute and should be used with extreme caution in patients with renal disease. Retrospective studies have shown that short-term nitrofurantoin use is effective and generally well tolerated in patients with a CrCl of 30 mL/minute or more, although higher adverse events have been noted in patients with renal impairment. The Beers Criteria recommends avoiding nitrofurantoin in geriatric patients 65 years and older with a CrCl less than 30 mL/minute.

    Anemia, G6PD deficiency, hemolytic anemia

    Patients with G6PD deficiency should not use nitrofurantoin because of the risk of developing hemolytic anemia. Patients with anemia also have a propensity to develop hemolytic anemia and nitrofurantoin should be used with caution.

    Children, infants, neonates

    All forms of nitrofurantoin are contraindicated in neonates < 1 month old. Nitrofurantoin can induce hemolytic anemia in G6PD-deficient patients and in patients whose RBCs lack sufficient quantities of reduced glutathione, including neonates. The safety and efficacy the nitrofurantoin and nitrofurantoin monohydrate macrocrystalline capsules have not been established in neonates, infants, and children less than 12 years of age.

    Labor, obstetric delivery, pregnancy

    Nitrofurantoin is contraindicated in pregnancy at term (38—42 weeks gestation) and during labor or obstetric delivery. Although it is classified as a pregnancy category B drug for use during pregnancy, nitrofurantoin can induce hemolytic anemia in G6PD-deficient patients and in patients whose RBCs lack sufficient quantities of reduced glutathione. Because neonates exhibit this latter condition, generally it is wise to avoid the use of this drug during late pregnancy; however, hemolytic anemia in the newborn as a result of in utero exposure to nitrofurantoin has not been reported.

    Breast-feeding

    Nitrofurantoin is distributed into breast milk and should be used with caution in breast-feeding women. The drug is especially problematic for infants with G6PD deficiency, because of the risk of hemolytic anemia. Because of the potential for serious adverse reactions from nitrofurantoin in nursing infants < 1 month old, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Nitrofurantoin is contraindicated in neonates < 1 month old. Nitrofurantoin is considered to be usually compatible with breast-feeding by the American Academy of Pediatrics (AAP). Cephalexin, trimethoprim, or sulfamethoxazole; trimethoprim may be potential alternatives to consider during breast-feeding. However, site of infection, patient factors, local susceptibility patterns, and specific microbial susceptibility should be assessed before choosing an alternative agent. Trimethoprim (in combination with sulfamethoxazole) is considered to be usually compatible with breast-feeding by the AAP. Cephalosporins, such as cephalexin, are generally considered to be compatible with breast-feeding.Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Diabetes mellitus, electrolyte imbalance, optic neuritis, peripheral neuropathy, vitamin B12 deficiency

    Patients most likely to develop peripheral neuropathy, including optic neuritis, when receiving nitrofurantoin are those with preexisting peripheral neuropathy, anemia, diabetes mellitus, electrolyte imbalance, vitamin B12 deficiency, or otherwise debilitated patients. These populations should be treated with caution.

    Hepatic disease, jaundice

    Nitrofurantoin is contraindicated in patients with a history of cholestatic jaundice or hepatic dysfunction associated with previous nitrofurantoin therapy. In general, nitrofurantoin should be used with caution in patients with hepatic disease due to the possibility of developing drug-induced hepatotoxicity. Liver-function tests should be performed periodically during long-term therapy.

    Pulmonary disease

    Nitrofurantoin use is associated with acute and chronic pulmonary reactions (see Adverse Reactions). While acute reactions (i.e., those occurring within several days after beginning therapy) are usually reversible, pulmonary reactions occurring after prolonged therapy (i.e., those occurring after many months of continuous therapy) may not resolve. Patients receiving chronic therapy should be monitored carefully because delayed pulmonary reactions can be insidious. Nitrofurantoin should be used with caution in patients with any preexisting pulmonary disease.

    Geriatric

    Use nitrofurantoin with caution in geriatric patients. Spontaneous reports suggest a higher proportion of pulmonary reactions, including fatalities, in geriatric patients; these differences appear to be related to the higher proportion of older patients receiving long-term nitrofurantoin therapy. As in younger patients, chronic pulmonary reactions generally are observed in patients receiving therapy for 6 months or longer. Spontaneous reports also suggest an increased proportion of severe hepatic reactions, including fatalities, in geriatric patients. In general, the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in elderly patients should be considered when prescribing nitrofurantoin. Nitrofurantoin is known to be substantially excreted by the kidney. Anuria, oliguria, or significant impairment of renal function, defined as a creatinine clearance (CrCl) less than 60 mL/minute or clinically significant elevated serum creatinine, are contraindications to nitrofurantoin use per the package labels. The concentration of the drug in the urine is inadequate for therapeutic effectiveness in patients with renal impairment (i.e., CrCl less than 60 mL/minute) and the risk for adverse reactions is greater in those with substantial renal impairment. According to the Beers Criteria, nitrofurantoin is considered a potentially inappropriate medication (PIM) for use in geriatric patients due to the possibility of pulmonary toxicity, hepatotoxicity, and peripheral neuropathy, especially with long-term use, lack of efficacy in patients with renal impairment, and the availability of safer alternatives. The Beers expert panel recommends avoiding nitrofurantoin as a long-term bacterial suppressant and avoiding use in geriatric patients with a creatinine clearance less than 30 mL/minute. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to OBRA, nitrofurantoin is not the anti-infective of choice for the treatment of acute urinary tract infections or as prophylaxis in patients with impaired renal function (CrCl less than 60 mL/minute) because of ineffectiveness and the high risk of serious adverse effects. The drug may cause pulmonary fibrosis and peripheral neuropathy.

    Colitis, diarrhea, GI disease, inflammatory bowel disease, pseudomembranous colitis, ulcerative colitis

    Almost all antibacterial agents have been associated with pseudomembranous colitis (antibiotic-associated colitis) which may range in severity from mild to life-threatening. In the colon, overgrowth of Clostridia may exist when normal flora is altered subsequent to antibacterial administration. The toxin produced by Clostridium difficile is a primary cause of pseudomembranous colitis. It is known that systemic use of antibiotics predisposes patients to development of pseudomembranous colitis. Consideration should be given to the diagnosis of pseudomembranous colitis in patients presenting with diarrhea following nitrofurantoin administration. Systemic antibiotics should be prescribed with caution to patients with inflammatory bowel disease such as ulcerative colitis or other GI disease. If diarrhea develops during therapy, the drug should be discontinued. Following diagnosis of pseudomembranous colitis, therapeutic measures should be instituted. In milder cases, the colitis may respond to discontinuation of the offending agent. In moderate to severe cases, fluids and electrolytes, protein supplementation, and treatment with an antibacterial effective against Clostridium difficile may be warranted. Products inhibiting peristalsis are contraindicated in this clinical situation. Practitioners should be aware that antibiotic-associated colitis has been observed to occur over two months or more following discontinuation of systemic antibiotic therapy; a careful medical history should be taken.

    ADVERSE REACTIONS

    Severe

    agranulocytosis / Delayed / 1.0-5.0
    hemolytic anemia / Delayed / 1.0-5.0
    megaloblastic anemia / Delayed / 1.0-5.0
    anaphylactoid reactions / Rapid / 0-1.0
    erythema multiforme / Delayed / 0-1.0
    Stevens-Johnson syndrome / Delayed / 0-1.0
    angioedema / Rapid / 0-1.0
    pulmonary fibrosis / Delayed / 0-1.0
    exfoliative dermatitis / Delayed / 0-1.0
    cyanosis / Early / 0-1.0
    aplastic anemia / Delayed / 0-1.0
    hepatic necrosis / Delayed / 0-1.0
    optic neuritis / Delayed / 0-1.0
    pleural effusion / Delayed / Incidence not known
    vasculitis / Delayed / Incidence not known
    lupus-like symptoms / Delayed / Incidence not known
    methemoglobinemia / Early / Incidence not known
    pancreatitis / Delayed / Incidence not known

    Moderate

    thrombocytopenia / Delayed / 1.0-5.0
    leukopenia / Delayed / 1.0-5.0
    elevated hepatic enzymes / Delayed / 1.0-5.0
    pneumonitis / Delayed / 0-1.0
    hepatitis / Delayed / 0-1.0
    cholestasis / Delayed / 0-1.0
    jaundice / Delayed / 0-1.0
    confusion / Early / 0-1.0
    psychosis / Early / 0-1.0
    pseudotumor cerebri / Delayed / 0-1.0
    depression / Delayed / 0-1.0
    tachypnea / Early / Incidence not known
    dyspnea / Early / Incidence not known
    angina / Early / Incidence not known
    bundle-branch block / Early / Incidence not known
    chest pain (unspecified) / Early / Incidence not known
    eosinophilia / Delayed / Incidence not known
    amblyopia / Delayed / Incidence not known
    nystagmus / Delayed / Incidence not known
    peripheral neuropathy / Delayed / Incidence not known
    hemolysis / Early / Incidence not known
    constipation / Delayed / Incidence not known
    sialadenitis / Delayed / Incidence not known
    candidiasis / Delayed / Incidence not known
    superinfection / Delayed / Incidence not known
    pseudomembranous colitis / Delayed / Incidence not known

    Mild

    arthralgia / Delayed / Incidence not known
    malaise / Early / Incidence not known
    alopecia / Delayed / Incidence not known
    pruritus / Rapid / Incidence not known
    maculopapular rash / Early / Incidence not known
    urticaria / Rapid / Incidence not known
    chills / Rapid / Incidence not known
    fever / Early / Incidence not known
    myalgia / Early / Incidence not known
    cough / Delayed / Incidence not known
    drowsiness / Early / Incidence not known
    asthenia / Delayed / Incidence not known
    vertigo / Early / Incidence not known
    headache / Early / Incidence not known
    dizziness / Early / Incidence not known
    anorexia / Delayed / Incidence not known
    vomiting / Early / Incidence not known
    abdominal pain / Early / Incidence not known
    dyspepsia / Early / Incidence not known
    diarrhea / Early / Incidence not known
    nausea / Early / Incidence not known
    urine discoloration / Early / Incidence not known

    DRUG INTERACTIONS

    Antacids: (Major) Antacids can delay both the rate and the extent of GI absorption of nitrofurantoin. This interaction may be due to surface absorption of the antibacterial onto the antacid. Separate administration by at least 1 hour.
    Anticholinergics: (Moderate) Antimuscarinics can delay gastric emptying, possibly increasing the bioavailability of nitrofurantoin.
    Atropine: (Moderate) Antimuscarinics can delay gastric emptying, possibly increasing the bioavailability of nitrofurantoin.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Antimuscarinics can delay gastric emptying, possibly increasing the bioavailability of nitrofurantoin.
    Atropine; Difenoxin: (Moderate) Antimuscarinics can delay gastric emptying, possibly increasing the bioavailability of nitrofurantoin.
    Atropine; Diphenoxylate: (Moderate) Antimuscarinics can delay gastric emptying, possibly increasing the bioavailability of nitrofurantoin.
    Atropine; Edrophonium: (Moderate) Antimuscarinics can delay gastric emptying, possibly increasing the bioavailability of nitrofurantoin.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Moderate) Antimuscarinics can delay gastric emptying, possibly increasing the bioavailability of nitrofurantoin.
    Azelaic Acid; Copper; Folic Acid; Nicotinamide; Pyridoxine; Zinc: (Moderate) L-methylfolate and nitrofurantoin should be used together cautiously. Nitrofurantoin is a folate antagonist. Plasma concentrations of both medications may be reduced when used concomitantly. (Moderate) Nitrofurantoin is a folate antagonist. Patients taking nitrofurantoin may develop folate deficiency. Further study is needed to confirm these interactions.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Moderate) Antimuscarinics can delay gastric emptying, possibly increasing the bioavailability of nitrofurantoin.
    Belladonna; Opium: (Moderate) Antimuscarinics can delay gastric emptying, possibly increasing the bioavailability of nitrofurantoin.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Antimuscarinics can delay gastric emptying, possibly increasing the bioavailability of nitrofurantoin.
    Benztropine: (Moderate) Antimuscarinics can delay gastric emptying, possibly increasing the bioavailability of nitrofurantoin.
    Bortezomib: (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like nitrofurantoin; the risk of peripheral neuropathy may be additive.
    Calcium Carbonate: (Major) Antacids can delay both the rate and the extent of GI absorption of nitrofurantoin. This interaction may be due to surface absorption of the antibacterial onto the antacid. Separate administration by at least 1 hour.
    Calcium Carbonate; Magnesium Hydroxide: (Major) Antacids can delay both the rate and the extent of GI absorption of nitrofurantoin. This interaction may be due to surface absorption of the antibacterial onto the antacid. Separate administration by at least 1 hour.
    Calcium Carbonate; Risedronate: (Major) Antacids can delay both the rate and the extent of GI absorption of nitrofurantoin. This interaction may be due to surface absorption of the antibacterial onto the antacid. Separate administration by at least 1 hour.
    Calcium; Vitamin D: (Major) Antacids can delay both the rate and the extent of GI absorption of nitrofurantoin. This interaction may be due to surface absorption of the antibacterial onto the antacid. Separate administration by at least 1 hour.
    Chlordiazepoxide; Clidinium: (Moderate) Antimuscarinics can delay gastric emptying, possibly increasing the bioavailability of nitrofurantoin.
    Darifenacin: (Moderate) Antimuscarinics can delay gastric emptying, possibly increasing the bioavailability of nitrofurantoin.
    Dicyclomine: (Moderate) Antimuscarinics can delay gastric emptying, possibly increasing the bioavailability of nitrofurantoin.
    Dienogest; Estradiol valerate: (Moderate) Anti-infectives that disrupt the normal GI flora may potentially decrease the effectiveness of estrogen-containing oral contraceptives. (Moderate) It was previously thought that antibiotics may decrease the effectiveness of oral contraceptives containing estrogens due to stimulation of estrogen metabolism or a reduction in estrogen enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with oral contraceptives (OCs) and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma levels of oral contraceptives. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review of the subject concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Drospirenone; Estradiol: (Moderate) It was previously thought that antibiotics may decrease the effectiveness of oral contraceptives containing estrogens due to stimulation of estrogen metabolism or a reduction in estrogen enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with oral contraceptives (OCs) and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma levels of oral contraceptives. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review of the subject concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Drospirenone; Ethinyl Estradiol: (Moderate) It was previously thought that antibiotics may decrease the effectiveness of oral contraceptives containing estrogens due to stimulation of estrogen metabolism or a reduction in estrogen enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with oral contraceptives (OCs) and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma levels of oral contraceptives. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review of the subject concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) It was previously thought that antibiotics may decrease the effectiveness of oral contraceptives containing estrogens due to stimulation of estrogen metabolism or a reduction in estrogen enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with oral contraceptives (OCs) and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma levels of oral contraceptives. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review of the subject concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. (Moderate) L-methylfolate and nitrofurantoin should be used together cautiously. Nitrofurantoin is a folate antagonist. Plasma concentrations of both medications may be reduced when used concomitantly.
    Estradiol: (Moderate) Anti-infectives that disrupt the normal GI flora may potentially decrease the effectiveness of estrogen-containing oral contraceptives.
    Estradiol; Levonorgestrel: (Moderate) It was previously thought that antibiotics may decrease the effectiveness of oral contraceptives containing estrogens due to stimulation of estrogen metabolism or a reduction in estrogen enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with oral contraceptives (OCs) and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma levels of oral contraceptives. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review of the subject concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Estradiol; Norethindrone: (Moderate) It was previously thought that antibiotics may decrease the effectiveness of oral contraceptives containing estrogens due to stimulation of estrogen metabolism or a reduction in estrogen enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with oral contraceptives (OCs) and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma levels of oral contraceptives. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review of the subject concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Estradiol; Norgestimate: (Moderate) It was previously thought that antibiotics may decrease the effectiveness of oral contraceptives containing estrogens due to stimulation of estrogen metabolism or a reduction in estrogen enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with oral contraceptives (OCs) and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma levels of oral contraceptives. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review of the subject concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Ethinyl Estradiol: (Moderate) It was previously thought that antibiotics may decrease the effectiveness of oral contraceptives containing estrogens due to stimulation of estrogen metabolism or a reduction in estrogen enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with oral contraceptives (OCs) and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma levels of oral contraceptives. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review of the subject concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Ethinyl Estradiol; Desogestrel: (Moderate) It was previously thought that antibiotics may decrease the effectiveness of oral contraceptives containing estrogens due to stimulation of estrogen metabolism or a reduction in estrogen enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with oral contraceptives (OCs) and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma levels of oral contraceptives. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review of the subject concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Moderate) It was previously thought that antibiotics may decrease the effectiveness of oral contraceptives containing estrogens due to stimulation of estrogen metabolism or a reduction in estrogen enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with oral contraceptives (OCs) and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma levels of oral contraceptives. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review of the subject concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Ethinyl Estradiol; Etonogestrel: (Moderate) It was previously thought that antibiotics may decrease the effectiveness of oral contraceptives containing estrogens due to stimulation of estrogen metabolism or a reduction in estrogen enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with oral contraceptives (OCs) and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma levels of oral contraceptives. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review of the subject concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Ethinyl Estradiol; Levonorgestrel: (Moderate) It was previously thought that antibiotics may decrease the effectiveness of oral contraceptives containing estrogens due to stimulation of estrogen metabolism or a reduction in estrogen enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with oral contraceptives (OCs) and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma levels of oral contraceptives. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review of the subject concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Moderate) It was previously thought that antibiotics may decrease the effectiveness of oral contraceptives containing estrogens due to stimulation of estrogen metabolism or a reduction in estrogen enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with oral contraceptives (OCs) and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma levels of oral contraceptives. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review of the subject concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. (Moderate) L-methylfolate and nitrofurantoin should be used together cautiously. Nitrofurantoin is a folate antagonist. Plasma concentrations of both medications may be reduced when used concomitantly. (Moderate) Nitrofurantoin is a folate antagonist. Patients taking nitrofurantoin may develop folate deficiency. Further study is needed to confirm these interactions.
    Ethinyl Estradiol; Norelgestromin: (Moderate) It was previously thought that antibiotics may decrease the effectiveness of oral contraceptives containing estrogens due to stimulation of estrogen metabolism or a reduction in estrogen enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with oral contraceptives (OCs) and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma levels of oral contraceptives. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review of the subject concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Ethinyl Estradiol; Norethindrone Acetate: (Moderate) It was previously thought that antibiotics may decrease the effectiveness of oral contraceptives containing estrogens due to stimulation of estrogen metabolism or a reduction in estrogen enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with oral contraceptives (OCs) and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma levels of oral contraceptives. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review of the subject concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Moderate) It was previously thought that antibiotics may decrease the effectiveness of oral contraceptives containing estrogens due to stimulation of estrogen metabolism or a reduction in estrogen enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with oral contraceptives (OCs) and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma levels of oral contraceptives. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review of the subject concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Ethinyl Estradiol; Norethindrone: (Moderate) It was previously thought that antibiotics may decrease the effectiveness of oral contraceptives containing estrogens due to stimulation of estrogen metabolism or a reduction in estrogen enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with oral contraceptives (OCs) and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma levels of oral contraceptives. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review of the subject concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Moderate) It was previously thought that antibiotics may decrease the effectiveness of oral contraceptives containing estrogens due to stimulation of estrogen metabolism or a reduction in estrogen enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with oral contraceptives (OCs) and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma levels of oral contraceptives. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review of the subject concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Ethinyl Estradiol; Norgestimate: (Moderate) It was previously thought that antibiotics may decrease the effectiveness of oral contraceptives containing estrogens due to stimulation of estrogen metabolism or a reduction in estrogen enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with oral contraceptives (OCs) and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma levels of oral contraceptives. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review of the subject concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Ethinyl Estradiol; Norgestrel: (Moderate) It was previously thought that antibiotics may decrease the effectiveness of oral contraceptives containing estrogens due to stimulation of estrogen metabolism or a reduction in estrogen enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with oral contraceptives (OCs) and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma levels of oral contraceptives. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review of the subject concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Fesoterodine: (Moderate) Antimuscarinics can delay gastric emptying, possibly increasing the bioavailability of nitrofurantoin.
    Flavoxate: (Moderate) Antimuscarinics can delay gastric emptying, possibly increasing the bioavailability of nitrofurantoin.
    Folic Acid, Vitamin B9: (Moderate) L-methylfolate and nitrofurantoin should be used together cautiously. Nitrofurantoin is a folate antagonist. Plasma concentrations of both medications may be reduced when used concomitantly. (Moderate) Nitrofurantoin is a folate antagonist. Patients taking nitrofurantoin may develop folate deficiency. Further study is needed to confirm these interactions.
    Glycopyrrolate: (Moderate) Antimuscarinics can delay gastric emptying, possibly increasing the bioavailability of nitrofurantoin.
    Glycopyrrolate; Formoterol: (Moderate) Antimuscarinics can delay gastric emptying, possibly increasing the bioavailability of nitrofurantoin.
    Homatropine; Hydrocodone: (Moderate) Antimuscarinics can delay gastric emptying, possibly increasing the bioavailability of nitrofurantoin.
    Hyoscyamine: (Moderate) Antimuscarinics can delay gastric emptying, possibly increasing the bioavailability of nitrofurantoin.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Moderate) Antimuscarinics can delay gastric emptying, possibly increasing the bioavailability of nitrofurantoin.
    Indacaterol; Glycopyrrolate: (Moderate) Antimuscarinics can delay gastric emptying, possibly increasing the bioavailability of nitrofurantoin.
    Indocyanine Green: (Moderate) Nitrofurantoin may increase the clearance of indocyanine green. The half-life of indocyanine green was lower in patients taking the drugs concomitantly compared to patients with normal and abnormal liver function taking no concomitant medications. The mechanism of interaction is unclear; those proposed in the medical literature include increased indocyanine green uptake by the liver cell, enhanced binding by specific hepatic carrier proteins, or more rapid excretion into bile.
    Iron Salts: (Moderate) Nitrofurantoin is a folate antagonist. Patients taking nitrofurantoin may develop folate deficiency. Further study is needed to confirm these interactions.
    Lanthanum Carbonate: (Major) Oral compounds known to interact with antacids, like nitrofurantoin, should not be taken within 2 hours of dosing with lanthanum carbonate. If these agents are used concomitantly, space the dosing intervals appropriately. Monitor serum concentrations and clinical condition.
    Leuprolide; Norethindrone: (Moderate) It was previously thought that antibiotics may decrease the effectiveness of oral contraceptives containing estrogens due to stimulation of estrogen metabolism or a reduction in estrogen enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with oral contraceptives (OCs) and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma levels of oral contraceptives. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review of the subject concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Levomefolate: (Moderate) L-methylfolate and nitrofurantoin should be used together cautiously. Nitrofurantoin is a folate antagonist. Plasma concentrations of both medications may be reduced when used concomitantly.
    Levomefolate; Mecobalamin; Pyridoxal-5-phosphate: (Moderate) L-methylfolate and nitrofurantoin should be used together cautiously. Nitrofurantoin is a folate antagonist. Plasma concentrations of both medications may be reduced when used concomitantly.
    Levonorgestrel: (Moderate) It was previously thought that antibiotics may decrease the effectiveness of oral contraceptives containing estrogens due to stimulation of estrogen metabolism or a reduction in estrogen enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with oral contraceptives (OCs) and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma levels of oral contraceptives. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review of the subject concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Mepenzolate: (Moderate) Antimuscarinics can delay gastric emptying, possibly increasing the bioavailability of nitrofurantoin.
    Mestranol; Norethindrone: (Moderate) It was previously thought that antibiotics may decrease the effectiveness of oral contraceptives containing estrogens due to stimulation of estrogen metabolism or a reduction in estrogen enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with oral contraceptives (OCs) and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma levels of oral contraceptives. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review of the subject concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Moderate) Antimuscarinics can delay gastric emptying, possibly increasing the bioavailability of nitrofurantoin.
    Methscopolamine: (Moderate) Antimuscarinics can delay gastric emptying, possibly increasing the bioavailability of nitrofurantoin.
    Norethindrone: (Moderate) It was previously thought that antibiotics may decrease the effectiveness of oral contraceptives containing estrogens due to stimulation of estrogen metabolism or a reduction in estrogen enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with oral contraceptives (OCs) and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma levels of oral contraceptives. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review of the subject concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Norgestrel: (Moderate) It was previously thought that antibiotics may decrease the effectiveness of oral contraceptives containing estrogens due to stimulation of estrogen metabolism or a reduction in estrogen enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with oral contraceptives (OCs) and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma levels of oral contraceptives. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review of the subject concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Omeprazole; Sodium Bicarbonate: (Major) Antacids can delay both the rate and the extent of GI absorption of nitrofurantoin. This interaction may be due to surface absorption of the antibacterial onto the antacid. Separate administration by at least 1 hour.
    Oral Contraceptives: (Moderate) It was previously thought that antibiotics may decrease the effectiveness of oral contraceptives containing estrogens due to stimulation of estrogen metabolism or a reduction in estrogen enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with oral contraceptives (OCs) and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma levels of oral contraceptives. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review of the subject concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available.
    Oxybutynin: (Moderate) Antimuscarinics can delay gastric emptying, possibly increasing the bioavailability of nitrofurantoin.
    Prilocaine: (Minor) Patients treated with prilocaine who are receiving other drugs that can cause methemoglobin formation, such as nitrofurantoin, are at greater risk for developing methemoglobinemia.
    Prilocaine; Epinephrine: (Minor) Patients treated with prilocaine who are receiving other drugs that can cause methemoglobin formation, such as nitrofurantoin, are at greater risk for developing methemoglobinemia.
    Probenecid: (Moderate) High doses of probenecid can inhibit the renal tubular secretion of nitrofurantoin, leading to a decrease in renal clearance. Nitrofurantoin serum concentrations can increase, elevating the risk of toxicity. Lower doses of nitrofurantoin should be used when probenecid is used.
    Propantheline: (Moderate) Antimuscarinics can delay gastric emptying, possibly increasing the bioavailability of nitrofurantoin.
    Scopolamine: (Moderate) Antimuscarinics can delay gastric emptying, possibly increasing the bioavailability of nitrofurantoin.
    Sodium Bicarbonate: (Major) Antacids can delay both the rate and the extent of GI absorption of nitrofurantoin. This interaction may be due to surface absorption of the antibacterial onto the antacid. Separate administration by at least 1 hour.
    Sulfinpyrazone: (Moderate) High doses of sulfinpyrazone can inhibit the renal tubular secretion of nitrofurantoin, leading to a decrease in renal clearance. Nitrofurantoin serum concentrations can increase, elevating the risk of toxicity. Lower doses of nitrofurantoin should be used when sulfinpyrazone is used.
    Trihexyphenidyl: (Moderate) Antimuscarinics can delay gastric emptying, possibly increasing the bioavailability of nitrofurantoin.
    Warfarin: (Moderate) The concomitant use of warfarin with many classes of antibiotics, including nitrofurantoin, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
    Zalcitabine, ddC: (Major) Coadministration of zalcitabine, ddC with drugs associated with peripheral neuropathy, such as nitrofurantoin, should be avoided when possible.

    PREGNANCY AND LACTATION

    Pregnancy

    Nitrofurantoin is distributed into breast milk and should be used with caution in breast-feeding women. The drug is especially problematic for infants with G6PD deficiency, because of the risk of hemolytic anemia. Because of the potential for serious adverse reactions from nitrofurantoin in nursing infants < 1 month old, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Nitrofurantoin is contraindicated in neonates < 1 month old. Nitrofurantoin is considered to be usually compatible with breast-feeding by the American Academy of Pediatrics (AAP). Cephalexin, trimethoprim, or sulfamethoxazole; trimethoprim may be potential alternatives to consider during breast-feeding. However, site of infection, patient factors, local susceptibility patterns, and specific microbial susceptibility should be assessed before choosing an alternative agent. Trimethoprim (in combination with sulfamethoxazole) is considered to be usually compatible with breast-feeding by the AAP. Cephalosporins, such as cephalexin, are generally considered to be compatible with breast-feeding.Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Nitrofurantoin inhibits bacterial acetyl-coenzyme A, interfering with the organism's carbohydrate metabolism. The drug also can disrupt bacterial cell wall formation. The antibacterial activity of nitrofurantoin is dependent on urine acidity. Nitrofurantoin is generally bacteriostatic, but it can be bactericidal in high doses and against certain organisms.

    PHARMACOKINETICS

    Nitrofurantoin is administered orally. Protein binding of nitrofurantoin is approximately 20—60%. Nitrofurantoin crosses the placenta and is distributed into breast milk. High concentrations of nitrofurantoin are found in urine. Urinary concentrations in patients with normal renal function range from 50—250 mcg/ml. Although there is some hepatic metabolism, about 30—50% of the drug is excreted unchanged in the urine within 24 hours of dosage. Nitrofurantoin is eliminated by glomerular filtration and tubular secretion, with some reabsorption. In patients with normal renal function, the plasma half-life is roughly 20 minutes; minimal antibacterial activity occurs in the plasma.

    Oral Route

    Nitrofurantoin is readily absorbed following oral administration. The macrocrystalline form is more slowly absorbed due to a slower rate of dissolution. This form can produce fewer adverse GI effects. Bioavailability, especially of the macrocrystals, can be increased by the presence of any substance that delays gastric emptying such as food. Peak urinary concentrations occur within about 30 minutes after administration of microcrystals, while dosage with macrocrystals takes slightly longer.