Flagyl 375

— THERAPEUTIC CATEGORIES —
  • Bacterial infections
  • Protozoal infections
  • Vaginal infections
PAGE CONTENTS
  • Jump to Section
  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Flagyl 375 Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Metronidazole 375mg; caps.

    Pharmacological Class

    Nitroimidazole.

    See Also

    How Supplied

    Tabs—50, 100; Caps 375mg—50; IV—contact supplier

    How Supplied

    Flagyl 375 capsules have an iron gray opaque body imprinted with 375 mg and a light green opaque cap imprinted with “FLAGYL”, supplied as a 50-count bottle, and as a carton of 100 unit dose.

    Storage

    Store at controlled room temperature 15–25°C (59–77°F). Dispense in a well-closed container with a child-resistant closure.

    Manufacturer

    Pfizer Inc.

    Mechanism of Action

    Metronidazole exerts antibacterial effects in an anaerobic environment against most obligate anaerobes. Once metronidazole enters the organism by passive diffusion and activated in the cytoplasm of susceptible anaerobic bacteria, it is reduced; this process includes intracellular electron transport proteins such as ferredoxin, transfer of an electron to the nitro group of the metronidazole, and formation of a short-lived nitroso free radical. Because of this alteration of the metronidazole molecule, a concentration gradient is created and maintained which promotes the drug’s intracellular transport. The reduced form of metronidazole and free radicals can interact with DNA leading to inhibition of DNA synthesis and DNA degradation leading to death of the bacteria. The precise mechanism of action of metronidazole is unclear.

    Flagyl 375 Indications

    Indications

    Susceptible anaerobic infections, including intraabdominal, skin and skin structures, gynecologic, bacterial septicemia, bone and joint, CNS, lower respiratory tract, endocarditis.

    Flagyl 375 Dosage and Administration

    Adult

    7.5mg/kg every 6hrs for 7–10 days; max 4g/24hrs. Serious infections: parenteral form usually used first. Bone/joint, lower respiratory tract, endocardium infections: may need to treat longer. Severe hepatic impairment: reduce dose by 50%. Hemodialysis: consider dose supplementation after session.

    Children

    Not established.

    Renal Impairment

    End-stage renal disease (ESRD)

    • Decreased renal function does not change the single-dose pharmacokinetics for metronidazole.

    • Subjects with ESRD had no significant change in pharmacokinetics, but had higher Cmax of metabolites compared with healthy subjects. 

    • Monitor for metronidazole associated adverse events in ESRD patients.

    Effect of Dialysis

    • A hemodialysis session lasting for 4–8 hours removed 40–65% of the administered metronidazole dose. Consider supplementing metronidazole dose after hemodialysis if metronidazole cannot be separated from the dialysis session.

    • A peritoneal dialysis session lasting for 7.5 hours removed ~10% of the administered metronidazole dose. 

    • No dose adjustment is needed in ESRD patients undergoing continuous ambulatory peritoneal dialysis (CAPD).

    Hepatic Impairment

    • Severe hepatic impairment (Child-Pugh C): reduce metronidazole dose by 50%.

    • No dose adjustment needed for mild to moderate hepatic impairment, but monitor for metronidazole associated adverse events.

    Flagyl 375 Contraindications

    Contraindications

    Pregnancy (1st trimester for trichomoniasis). Within 2 weeks of disulfiram (possible psychotic reactions). Concomitant alcohol or propylene glycol containing-products during or at least 3 days after treatment. Cockayne syndrome.

    Flagyl 375 Boxed Warnings

    Not Applicable

    Flagyl 375 Warnings/Precautions

    Warnings/Precautions

    Discontinue if abnormal neurological symptoms occur. Candidiasis. History of blood dyscrasias. Monitor for leukopenia; do CBCs before, during and after therapy. Hepatic or renal impairment; monitor. Elderly: monitor serum levels. Pregnancy. Nursing mothers: not recommended.

    Warnings/Precautions

    Hypersensitivity Reactions

    • Hypersensitivity reactions including toxic epidermal necrolysis (TEN), Stevens-Johnson Syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported. Symptoms can be serious and potentially life-threatening.

    Central and Peripheral Nervous System Effects

    • Cases of encephalopathy and peripheral neuropathy (including optic neuropathy) have been reported.

    • Encephalopathy is associated with cerebellar toxicity which is characterized by ataxia, dizziness, and dysarthria. CNS lesions and symptoms are generally reversible within days to weeks after discontinuing treatment.

    • Peripheral neuropathy is characterized by numbness of paresthesia of an extremity.

    • Cases of aseptic meningitis have been reported, which generally resolves after discontinuing treatment.

    • Evaluate treatment promptly for benefit/risk ratio of continuing if abnormal neurologic signs and symptoms develop.

    Hepatic Impairment

    • Severe hepatic impairment (Child-Pugh C): reduce metronidazole dose by 50%.

    • No dose adjustment needed for mild to moderate hepatic impairment, but monitor for metronidazole associated adverse events.

    Renal Impairment

    • Subjects with ESRD had no significant change in pharmacokinetics, but had higher Cmax of metabolites compared with healthy subjects. 

    • Monitor for metronidazole associated adverse events in ESRD patients.

    Fungal Superinfections

    • Known or previously unrecognized candidiasis may present more prominent symptoms during therapy and requires treatment with a candidacidal agent.

    Use in Patients with Blood Dyscrasias

    • Use caution in patients with evidence of or history of blood dyscrasia.

    • Obtain total and differential leukocyte counts before and after therapy.

    Drug-Resistant Bacteria and Parasites

    • Increased risk of developing drug-resistant bacteria and parasites if Flagyl is prescribed in the absence of a proven or strongly suspected bacterial or parasitic infection or a prophylactic indication.

    Pregnancy Considerations

    • No adequate and well controlled studies in pregnant women.

    • Metronidazole crosses the placental barrier and its effects on the human fetal organogenesis are not known.

    • In animal reproduction studies, there was no evidence of harm to the fetus due to metronidazole.

    Nursing Mother Considerations

    • In mouse and rat studies, metronidazole has shown a risk for tumorigenicity. 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.

    • A nursing mother may choose to pump and discard human milk for the duration of metronidazole therapy, and for 24 hours after therapy ends and feed her infant stored human milk or formula.

    Pediatric Considerations

    • Newborn infants may have a diminished capacity to eliminated metronidazole.

    • Infants whose gestational age were between 28–40 weeks had corresponding elimination half-lives from 109–22.5 hours.

    Geriatric Considerations

    • Monitor for metronidazole associated adverse events.

    Renal Impairment Considerations

    End-stage renal disease (ESRD)

    • Decreased renal function does not change the single-dose pharmacokinetics for metronidazole.

    • Subjects with ESRD had no significant change in pharmacokinetics, but had higher Cmax of metabolites compared with healthy subjects. 

    • Monitor for metronidazole associated adverse events in ESRD patients.

    Effect of Dialysis

    • A hemodialysis session lasting for 4–8 hours removed 40–65% of the administered metronidazole dose. Consider supplementing metronidazole dose after hemodialysis if metronidazole cannot be separated from the dialysis session.

    • A peritoneal dialysis session lasting for 7.5 hours removed ~10% of the administered metronidazole dose. 

    • No dose adjustment is needed in ESRD patients undergoing continuous ambulatory peritoneal dialysis (CAPD).

    Hepatic Impairment Considerations

    • Severe hepatic impairment (Child-Pugh C): reduce metronidazole dose by 50%.

    • No dose adjustment needed for mild to moderate hepatic impairment, but monitor for metronidazole associated adverse events.

    Flagyl 375 Pharmacokinetics

    Absorption

    • Disposition of metronidazole in the body is similar for both oral and intravenous dosage forms.

    • Following oral administration, the peak plasma concentration is reached between 1 to 2 hours.

    • Plasma concentrations of oral metronidazole are proportional to the administered dose.

    • Oral 250mg, 500mg, or 2000mg achieved peak plasma concentrations of 6 mcg/mL, 12 mcg/mL, and 40 mcg/mL, respectively.

    • Oral administration of two 375mg Flagyl capsules under fasting conditions produced a mean peak plasma concentration of 21.4 (±2.8) mcg/mL with a mean Tmax of 1.6 (± 0.7) hours and a mean area under the plasma concentration-time curve of 223 (±44) mcg∙hr/mL.

    Distribution

    • <20% is bound to plasma proteins.

    • Distributed in CSF, saliva, and breast milk at concentrations similar to those found in plasma.

    Metabolism

    • Primarily from side-chain oxidation [1-(ßhydroxyethyl)-2-hydroxymethyl-5-nitroimidazole and 2-methyl-5-nitroimidazole-1-ylacetic acid] and glucuronide conjugation, with unchanged metronidazole accounting for approximately 20% of the total. 

    Elimination

    • Renal (60% to 80% of the dose), fecal (6% to 15%).

    • Half-life: 8 hours.

    Flagyl 375 Interactions

    Interactions

    See Contraindications. May potentiate oral anticoagulants, lithium; monitor. Avoid concomitant busulfan; if needed, adjust busulfan dose and monitor. May be antagonized by phenobarbital, phenytoin, other hepatic enzyme inducers. May impair phenytoin clearance. May be potentiated by cimetidine, other hepatic enzyme inhibitors. IV: may potentiate 5-FU, vecuronium, CYP3A4 substrates (eg, amiodarone, tacrolimus, cyclosporine,carbamazepine, phenytoin, quinidine); monitor. Concomitant drugs with the potential for prolonging the QT interval; caution. May interfere with serum chemistry tests.

    Flagyl 375 Adverse Reactions

    Adverse Reactions

    Nausea, headache, anorexia, vomiting, diarrhea, epigastric distress, abdominal cramping, constipation, metallic taste, dysuria, cystitis; seizures, encephalopathy, optic/peripheral neuropathy, aseptic meningitis.

    Adverse Reactions

    Central Nervous System

    • Most serious adverse reactions have been convulsive seizures, encephalopathy, aseptic meningitis, optic and peripheral neuropathy, the latter characterized mainly by numbness or paresthesia of an extremity. Warn patients about these reactions and advise to discontinue if any neurologic symptoms occur.

    • Also, patients have reported headache, syncope, dizziness, vertigo, incoordination, ataxia, confusion, dysarthria, irritability, depression, weakness, and insomnia.

    Gastrointestinal

    • Most common adverse reactions reported were gastrointestinal tract, particularly nausea, sometimes accompanied by headache, anorexia, and occasionally vomiting; diarrhea; epigastric distress; and abdominal cramping and constipation. 

    Mouth

    • A sharp, unpleasant metallic taste is not unusual. Furry tongue, glossitis, and stomatitis have occurred; these may be associated with a sudden overgrowth of Candida which may occur during therapy.

    Dermatologic

    • Erythematous rash and pruritus.

    Hematopoietic

    • Reversible neutropenia (leukopenia); rarely, reversible thrombocytopenia.

    Cardiovascular

    • QT prolongation has been reported, particularly when metronidazole was administered with drugs with the potential for prolonging the QT interval. Flattening of the T-wave may be seen in electrocardiographic tracings.

    Hypersensitivity

    • Urticaria, erythematous rash, Stevens-Johnson Syndrome, toxic epidermal necrolysis, flushing, nasal congestion, dryness of the mouth (or vagina or vulva), and fever.

    Renal

    • Dysuria, cystitis, polyuria, incontinence, and a sense of pelvic pressure. 

    Hepatic

    • Cases of severe irreversible hepatotoxicity/acute liver failure, including cases with fatal outcomes with very rapid onset after initiation of systemic use of metronidazole, have been reported in patients with Cockayne syndrome.

    Other

    • Proliferation of Candida in the vagina, dyspareunia, decrease of libido, proctitis, and fleeting joint pains sometimes resembling “serum sickness.” Rare cases of pancreatitis, which generally abated on withdrawal of the drug, have been reported.

    • Patients with Crohn’s disease are known to have an increased incidence of gastrointestinal and certain extraintestinal cancers.

    Flagyl 375 Clinical Trials

    See Literature

    Flagyl 375 Note

    Not Applicable

    Flagyl 375 Patient Counseling

    Patient Counseling

    Interaction with Alcohol

    • Discontinue consumption of alcoholic beverages or products containing propylene glycol while taking Flagyl and for at least 3 days after.

    Treatment of Bacterial and Parasitic Infections

    • Inform patients that Flagyl should only be used to treat bacterial and parasitic infections. Not for viral infections.

    • Do not skip doses. Complete full course of therapy.

    Flagyl 375 Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Metronidazole 375mg; caps.

    Pharmacological Class

    Nitroimidazole.

    See Also

    How Supplied

    Tabs—50, 100; Caps 375mg—50

    How Supplied

    Flagyl 250mg Tablets

    • Round, blue, film coated, with “SEARLE” and “1831” debossed on one side, and “FLAGYL” and “250” on the other side; supplied as bottles of 50 and 100.

    Flagyl 500mg Tablets

    • Oblong, blue, film coated, with “FLAGYL” debossed on one side and “500” on the other side; bottles of 50 and 100.

    Storage

    Store below 25°C (77°F) and protect from light.

    Manufacturer

    Pfizer Inc.

    Mechanism of Action

    Metronidazole exerts antibacterial effects in an anaerobic environment against most obligate anaerobes. Once metronidazole enters the organism by passive diffusion and activated in the cytoplasm of susceptible anaerobic bacteria, it is reduced; this process includes intracellular electron transport proteins such as ferredoxin, transfer of an electron to the nitro group of the metronidazole, and formation of a short-lived nitroso free radical. Because of this alteration of the metronidazole molecule, a concentration gradient is created and maintained which promotes the drug’s intracellular transport. The reduced form of metronidazole and free radicals can interact with DNA leading to inhibition of DNA synthesis and DNA degradation leading to death of the bacteria. The precise mechanism of action of metronidazole is unclear.

    Flagyl 375 Indications

    Indications

    Amebic dysentery. Amebic liver abscess.

    Flagyl 375 Dosage and Administration

    Adult

    Give 3 times daily for 5–10 days. Dysentery: 750mg. Abscess: 500mg or 750mg. Severe hepatic impairment: reduce dose by 50%. Hemodialysis: consider dose supplementation after session.

    Children

    35–50mg/kg/24hrs in 3 divided doses for 10 days. Severe hepatic impairment: reduce dose by 50%. Hemodialysis: consider dose supplementation after session.

    Renal Impairment

    End-stage renal disease (ESRD)

    • Decreased renal function does not change the single-dose pharmacokinetics for metronidazole.

    • Subjects with ESRD had no significant change in pharmacokinetics, but had higher Cmax of metabolites compared with healthy subjects. 

    • Monitor for metronidazole associated adverse events in ESRD patients.

    Effect of Dialysis

    • A hemodialysis session lasting for 4–8 hours removed 40–65% of the administered metronidazole dose. Consider supplementing metronidazole dose after hemodialysis if metronidazole cannot be separated from the dialysis session.

    • A peritoneal dialysis session lasting for 7.5 hours removed ~10% of the administered metronidazole dose. 

    • No dose adjustment is needed in ESRD patients undergoing continuous ambulatory peritoneal dialysis (CAPD).

    Hepatic Impairment

    • Severe hepatic impairment (Child-Pugh C): reduce metronidazole dose by 50%.

    • No dose adjustment needed for mild to moderate hepatic impairment, but monitor for metronidazole associated adverse events.

    Flagyl 375 Contraindications

    Contraindications

    Pregnancy (1st trimester for trichomoniasis). Within 2 weeks of disulfiram (possible psychotic reactions). Concomitant alcohol or propylene glycol containing-products during or at least 3 days after treatment. Cockayne syndrome.

    Flagyl 375 Boxed Warnings

    Not Applicable

    Flagyl 375 Warnings/Precautions

    Warnings/Precautions

    Discontinue if abnormal neurological symptoms occur. Candidiasis. History of blood dyscrasias. Monitor for leukopenia; do CBCs before, during and after therapy. Hepatic or renal impairment; monitor. Elderly: monitor serum levels. Pregnancy. Nursing mothers: not recommended.

    Warnings/Precautions

    Hypersensitivity Reactions

    • Hypersensitivity reactions including toxic epidermal necrolysis (TEN), Stevens-Johnson Syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported. Symptoms can be serious and potentially life-threatening.

    Central and Peripheral Nervous System Effects

    • Cases of encephalopathy and peripheral neuropathy (including optic neuropathy) have been reported.

    • Encephalopathy is associated with cerebellar toxicity which is characterized by ataxia, dizziness, and dysarthria. CNS lesions and symptoms are generally reversible within days to weeks after discontinuing treatment.

    • Peripheral neuropathy is characterized by numbness of paresthesia of an extremity.

    • Cases of aseptic meningitis have been reported, which generally resolves after discontinuing treatment.

    • Evaluate treatment promptly for benefit/risk ratio of continuing if abnormal neurologic signs and symptoms develop.

    Hepatic Impairment

    • Severe hepatic impairment (Child-Pugh C): reduce metronidazole dose by 50%.

    • No dose adjustment needed for mild to moderate hepatic impairment, but monitor for metronidazole associated adverse events.

    Renal Impairment

    • Subjects with ESRD had no significant change in pharmacokinetics, but had higher Cmax of metabolites compared with healthy subjects. 

    • Monitor for metronidazole associated adverse events in ESRD patients.

    Fungal Superinfections

    • Known or previously unrecognized candidiasis may present more prominent symptoms during therapy and requires treatment with a candidacidal agent.

    Use in Patients with Blood Dyscrasias

    • Use caution in patients with evidence of or history of blood dyscrasia.

    • Obtain total and differential leukocyte counts before and after therapy.

    Drug-Resistant Bacteria and Parasites

    • Increased risk of developing drug-resistant bacteria and parasites if Flagyl is prescribed in the absence of a proven or strongly suspected bacterial or parasitic infection or a prophylactic indication.

    Pregnancy Considerations

    • No adequate and well controlled studies in pregnant women.

    • Metronidazole crosses the placental barrier and its effects on the human fetal organogenesis are not known.

    • In animal reproduction studies, there was no evidence of harm to the fetus due to metronidazole.

    Nursing Mother Considerations

    • In mouse and rat studies, metronidazole has shown a risk for tumorigenicity. 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.

    • A nursing mother may choose to pump and discard human milk for the duration of metronidazole therapy, and for 24 hours after therapy ends and feed her infant stored human milk or formula.

    Pediatric Considerations

    • Newborn infants may have a diminished capacity to eliminated metronidazole.

    • Infants whose gestational age were between 28–40 weeks had corresponding elimination half-lives from 109–22.5 hours.

    Geriatric Considerations

    • Monitor for metronidazole associated adverse events.

    Renal Impairment Considerations

    End-stage renal disease (ESRD)

    • Decreased renal function does not change the single-dose pharmacokinetics for metronidazole.

    • Subjects with ESRD had no significant change in pharmacokinetics, but had higher Cmax of metabolites compared with healthy subjects. 

    • Monitor for metronidazole associated adverse events in ESRD patients.

    Effect of Dialysis

    • A hemodialysis session lasting for 4–8 hours removed 40–65% of the administered metronidazole dose. Consider supplementing metronidazole dose after hemodialysis if metronidazole cannot be separated from the dialysis session.

    • A peritoneal dialysis session lasting for 7.5 hours removed ~10% of the administered metronidazole dose. 

    • No dose adjustment is needed in ESRD patients undergoing continuous ambulatory peritoneal dialysis (CAPD).

    Hepatic Impairment Considerations

    • Severe hepatic impairment (Child-Pugh C): reduce metronidazole dose by 50%.

    • No dose adjustment needed for mild to moderate hepatic impairment, but monitor for metronidazole associated adverse events.

    Flagyl 375 Pharmacokinetics

    Absorption

    • Disposition of metronidazole in the body is similar for both oral and intravenous dosage forms.

    • Following oral administration, the peak plasma concentration is reached between 1 to 2 hours.

    • Plasma concentrations of oral metronidazole are proportional to the administered dose. Oral 250mg, 500mg, or 2000mg achieved peak plasma concentrations of 6 mcg/mL, 12 mcg/mL, and 40 mcg/mL, respectively.

    Distribution

    • <20% is bound to plasma proteins.

    • Distributed in CSF, saliva, and breast milk at concentrations similar to those found in plasma.

    Metabolism

    • Primarily from side-chain oxidation [1-(ßhydroxyethyl)-2-hydroxymethyl-5-nitroimidazole and 2-methyl-5-nitroimidazole-1-ylacetic acid] and glucuronide conjugation, with unchanged metronidazole accounting for approximately 20% of the total. 

    Elimination

    • Renal (60% to 80% of the dose), fecal (6% to 15%).

    • Half-life: 8 hours.

    Flagyl 375 Interactions

    Interactions

    See Contraindications. May potentiate oral anticoagulants, lithium; monitor. Avoid concomitant busulfan; if needed, adjust busulfan dose and monitor. May be antagonized by phenobarbital, phenytoin, other hepatic enzyme inducers. May impair phenytoin clearance. May be potentiated by cimetidine, other hepatic enzyme inhibitors. IV: may potentiate 5-FU, vecuronium, CYP3A4 substrates (eg, amiodarone, tacrolimus, cyclosporine,carbamazepine, phenytoin, quinidine); monitor. Concomitant drugs with the potential for prolonging the QT interval; caution. May interfere with serum chemistry tests.

    Flagyl 375 Adverse Reactions

    Adverse Reactions

    Nausea, headache, anorexia, vomiting, diarrhea, epigastric distress, abdominal cramping, constipation, metallic taste, dysuria, cystitis; seizures, encephalopathy, optic/peripheral neuropathy, aseptic meningitis.

    Adverse Reactions

    Central Nervous System

    • Most serious adverse reactions have been convulsive seizures, encephalopathy, aseptic meningitis, optic and peripheral neuropathy, the latter characterized mainly by numbness or paresthesia of an extremity. Warn patients about these reactions and advise to discontinue if any neurologic symptoms occur.

    • Also, patients have reported headache, syncope, dizziness, vertigo, incoordination, ataxia, confusion, dysarthria, irritability, depression, weakness, and insomnia.

    Gastrointestinal

    • Most common adverse reactions reported were gastrointestinal tract, particularly nausea, sometimes accompanied by headache, anorexia, and occasionally vomiting; diarrhea; epigastric distress; and abdominal cramping and constipation. 

    Mouth

    • A sharp, unpleasant metallic taste is not unusual. Furry tongue, glossitis, and stomatitis have occurred; these may be associated with a sudden overgrowth of Candida which may occur during therapy.

    Dermatologic

    • Erythematous rash and pruritus.

    Hematopoietic

    • Reversible neutropenia (leukopenia); rarely, reversible thrombocytopenia.

    Cardiovascular

    • QT prolongation has been reported, particularly when metronidazole was administered with drugs with the potential for prolonging the QT interval. Flattening of the T-wave may be seen in electrocardiographic tracings.

    Hypersensitivity

    • Urticaria, erythematous rash, Stevens-Johnson Syndrome, toxic epidermal necrolysis, flushing, nasal congestion, dryness of the mouth (or vagina or vulva), and fever.

    Renal

    • Dysuria, cystitis, polyuria, incontinence, and a sense of pelvic pressure. 

    Hepatic

    • Cases of severe irreversible hepatotoxicity/acute liver failure, including cases with fatal outcomes with very rapid onset after initiation of systemic use of metronidazole, have been reported in patients with Cockayne syndrome.

    Other

    • Proliferation of Candida in the vagina, dyspareunia, decrease of libido, proctitis, and fleeting joint pains sometimes resembling “serum sickness.” Rare cases of pancreatitis, which generally abated on withdrawal of the drug, have been reported.

    • Patients with Crohn’s disease are known to have an increased incidence of gastrointestinal and certain extraintestinal cancers.

    Flagyl 375 Clinical Trials

    See Literature

    Flagyl 375 Note

    Not Applicable

    Flagyl 375 Patient Counseling

    Patient Counseling

    Interaction with Alcohol

    • Discontinue consumption of alcoholic beverages or products containing propylene glycol while taking Flagyl and for at least 3 days after.

    Treatment of Bacterial and Parasitic Infections

    • Inform patients that Flagyl should only be used to treat bacterial and parasitic infections. Not for viral infections.

    • Do not skip doses. Complete full course of therapy.

    Flagyl 375 Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Metronidazole 375mg; caps.

    Pharmacological Class

    Antiprotozoal/antibacterial.

    See Also

    How Supplied

    Tabs—50, 100; ER—30; Caps 375mg—50

    How Supplied

    Flagyl 250mg Tablets

    • Round, blue, film coated, with “SEARLE” and “1831” debossed on one side, and “FLAGYL” and “250” on the other side; supplied as bottles of 50 and 100.

    Flagyl 500mg Tablets

    • Oblong, blue, film coated, with “FLAGYL” debossed on one side and “500” on the other side; bottles of 50 and 100.

    Storage

    Store below 25°C (77°F) and protect from light.

    Manufacturer

    Pfizer Inc.

    Mechanism of Action

    Metronidazole exerts antibacterial effects in an anaerobic environment against most obligate anaerobes. Once metronidazole enters the organism by passive diffusion and activated in the cytoplasm of susceptible anaerobic bacteria, it is reduced; this process includes intracellular electron transport proteins such as ferredoxin, transfer of an electron to the nitro group of the metronidazole, and formation of a short-lived nitroso free radical. Because of this alteration of the metronidazole molecule, a concentration gradient is created and maintained which promotes the drug’s intracellular transport. The reduced form of metronidazole and free radicals can interact with DNA leading to inhibition of DNA synthesis and DNA degradation leading to death of the bacteria. The precise mechanism of action of metronidazole is unclear.

    Flagyl 375 Indications

    Indications

    Trichomoniasis.

    Flagyl 375 Dosage and Administration

    Adult

    375mg twice daily for 7 days. Before repeating course, reconfirm diagnosis and allow 4–6 wks between courses. Treat consorts also. Severe hepatic impairment: reduce dose by 50%. Hemodialysis: consider dose supplementation after session.

    Children

    Not established.

    Renal Impairment

    End-stage renal disease (ESRD)

    • Decreased renal function does not change the single-dose pharmacokinetics for metronidazole.

    • Subjects with ESRD had no significant change in pharmacokinetics, but had higher Cmax of metabolites compared with healthy subjects. 

    • Monitor for metronidazole associated adverse events in ESRD patients.

    Effect of Dialysis

    • A hemodialysis session lasting for 4–8 hours removed 40–65% of the administered metronidazole dose. Consider supplementing metronidazole dose after hemodialysis if metronidazole cannot be separated from the dialysis session.

    • A peritoneal dialysis session lasting for 7.5 hours removed ~10% of the administered metronidazole dose. 

    • No dose adjustment is needed in ESRD patients undergoing continuous ambulatory peritoneal dialysis (CAPD).

    Hepatic Impairment

    • Severe hepatic impairment (Child-Pugh C): reduce metronidazole dose by 50%.

    • No dose adjustment needed for mild to moderate hepatic impairment, but monitor for metronidazole associated adverse events.

    Flagyl 375 Contraindications

    Contraindications

    Pregnancy (1st trimester for trichomoniasis). Within 2 weeks of disulfiram (possible psychotic reactions). Concomitant alcohol or propylene glycol containing-products during or at least 3 days after treatment. Cockayne syndrome.

    Flagyl 375 Boxed Warnings

    Not Applicable

    Flagyl 375 Warnings/Precautions

    Warnings/Precautions

    Discontinue if abnormal neurological symptoms occur. Candidiasis. History of blood dyscrasias. Monitor for leukopenia; do CBCs before, during and after therapy. Hepatic or renal impairment; monitor. Elderly: monitor serum levels. Pregnancy. Nursing mothers: not recommended.

    Warnings/Precautions

    Hypersensitivity Reactions

    • Hypersensitivity reactions including toxic epidermal necrolysis (TEN), Stevens-Johnson Syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported. Symptoms can be serious and potentially life-threatening.

    Central and Peripheral Nervous System Effects

    • Cases of encephalopathy and peripheral neuropathy (including optic neuropathy) have been reported.

    • Encephalopathy is associated with cerebellar toxicity which is characterized by ataxia, dizziness, and dysarthria. CNS lesions and symptoms are generally reversible within days to weeks after discontinuing treatment.

    • Peripheral neuropathy is characterized by numbness of paresthesia of an extremity.

    • Cases of aseptic meningitis have been reported, which generally resolves after discontinuing treatment.

    • Evaluate treatment promptly for benefit/risk ratio of continuing if abnormal neurologic signs and symptoms develop.

    Hepatic Impairment

    • Severe hepatic impairment (Child-Pugh C): reduce metronidazole dose by 50%.

    • No dose adjustment needed for mild to moderate hepatic impairment, but monitor for metronidazole associated adverse events.

    Renal Impairment

    • Subjects with ESRD had no significant change in pharmacokinetics, but had higher Cmax of metabolites compared with healthy subjects. 

    • Monitor for metronidazole associated adverse events in ESRD patients.

    Fungal Superinfections

    • Known or previously unrecognized candidiasis may present more prominent symptoms during therapy and requires treatment with a candidacidal agent.

    Use in Patients with Blood Dyscrasias

    • Use caution in patients with evidence of or history of blood dyscrasia.

    • Obtain total and differential leukocyte counts before and after therapy.

    Drug-Resistant Bacteria and Parasites

    • Increased risk of developing drug-resistant bacteria and parasites if Flagyl is prescribed in the absence of a proven or strongly suspected bacterial or parasitic infection or a prophylactic indication.

    Pregnancy Considerations

    • No adequate and well controlled studies in pregnant women.

    • Metronidazole crosses the placental barrier and its effects on the human fetal organogenesis are not known.

    • In animal reproduction studies, there was no evidence of harm to the fetus due to metronidazole.

    Nursing Mother Considerations

    • In mouse and rat studies, metronidazole has shown a risk for tumorigenicity. 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.

    • A nursing mother may choose to pump and discard human milk for the duration of metronidazole therapy, and for 24 hours after therapy ends and feed her infant stored human milk or formula.

    Pediatric Considerations

    • Newborn infants may have a diminished capacity to eliminated metronidazole.

    • Infants whose gestational age were between 28–40 weeks had corresponding elimination half-lives from 109–22.5 hours.

    Geriatric Considerations

    • Monitor for metronidazole associated adverse events.

    Renal Impairment Considerations

    End-stage renal disease (ESRD)

    • Decreased renal function does not change the single-dose pharmacokinetics for metronidazole.

    • Subjects with ESRD had no significant change in pharmacokinetics, but had higher Cmax of metabolites compared with healthy subjects. 

    • Monitor for metronidazole associated adverse events in ESRD patients.

    Effect of Dialysis

    • A hemodialysis session lasting for 4–8 hours removed 40–65% of the administered metronidazole dose. Consider supplementing metronidazole dose after hemodialysis if metronidazole cannot be separated from the dialysis session.

    • A peritoneal dialysis session lasting for 7.5 hours removed ~10% of the administered metronidazole dose. 

    • No dose adjustment is needed in ESRD patients undergoing continuous ambulatory peritoneal dialysis (CAPD).

    Hepatic Impairment Considerations

    • Severe hepatic impairment (Child-Pugh C): reduce metronidazole dose by 50%.

    • No dose adjustment needed for mild to moderate hepatic impairment, but monitor for metronidazole associated adverse events.

    Flagyl 375 Pharmacokinetics

    Absorption

    • Disposition of metronidazole in the body is similar for both oral and intravenous dosage forms.

    • Following oral administration, the peak plasma concentration is reached between 1 to 2 hours.

    • Plasma concentrations of oral metronidazole are proportional to the administered dose. Oral 250mg, 500mg, or 2000mg achieved peak plasma concentrations of 6 mcg/mL, 12 mcg/mL, and 40 mcg/mL, respectively.

    Distribution

    • <20% is bound to plasma proteins.

    • Distributed in CSF, saliva, and breast milk at concentrations similar to those found in plasma.

    Metabolism

    • Primarily from side-chain oxidation [1-(ßhydroxyethyl)-2-hydroxymethyl-5-nitroimidazole and 2-methyl-5-nitroimidazole-1-ylacetic acid] and glucuronide conjugation, with unchanged metronidazole accounting for approximately 20% of the total. 

    Elimination

    • Renal (60% to 80% of the dose), fecal (6% to 15%).

    • Half-life: 8 hours.

    Flagyl 375 Interactions

    Interactions

    See Contraindications. May potentiate oral anticoagulants, lithium; monitor. Avoid concomitant busulfan; if needed, adjust busulfan dose and monitor. May be antagonized by phenobarbital, phenytoin, other hepatic enzyme inducers. May impair phenytoin clearance. May be potentiated by cimetidine, other hepatic enzyme inhibitors. IV: may potentiate 5-FU, vecuronium, CYP3A4 substrates (eg, amiodarone, tacrolimus, cyclosporine,carbamazepine, phenytoin, quinidine); monitor. Concomitant drugs with the potential for prolonging the QT interval; caution. May interfere with serum chemistry tests.

    Flagyl 375 Adverse Reactions

    Adverse Reactions

    Nausea, headache, anorexia, vomiting, diarrhea, epigastric distress, abdominal cramping, constipation, metallic taste, dysuria, cystitis; seizures, encephalopathy, optic/peripheral neuropathy, aseptic meningitis.

    Adverse Reactions

    Central Nervous System

    • Most serious adverse reactions have been convulsive seizures, encephalopathy, aseptic meningitis, optic and peripheral neuropathy, the latter characterized mainly by numbness or paresthesia of an extremity. Warn patients about these reactions and advise to discontinue if any neurologic symptoms occur.

    • Also, patients have reported headache, syncope, dizziness, vertigo, incoordination, ataxia, confusion, dysarthria, irritability, depression, weakness, and insomnia.

    Gastrointestinal

    • Most common adverse reactions reported were gastrointestinal tract, particularly nausea, sometimes accompanied by headache, anorexia, and occasionally vomiting; diarrhea; epigastric distress; and abdominal cramping and constipation. 

    Mouth

    • A sharp, unpleasant metallic taste is not unusual. Furry tongue, glossitis, and stomatitis have occurred; these may be associated with a sudden overgrowth of Candida which may occur during therapy.

    Dermatologic

    • Erythematous rash and pruritus.

    Hematopoietic

    • Reversible neutropenia (leukopenia); rarely, reversible thrombocytopenia.

    Cardiovascular

    • QT prolongation has been reported, particularly when metronidazole was administered with drugs with the potential for prolonging the QT interval. Flattening of the T-wave may be seen in electrocardiographic tracings.

    Hypersensitivity

    • Urticaria, erythematous rash, Stevens-Johnson Syndrome, toxic epidermal necrolysis, flushing, nasal congestion, dryness of the mouth (or vagina or vulva), and fever.

    Renal

    • Dysuria, cystitis, polyuria, incontinence, and a sense of pelvic pressure. 

    Hepatic

    • Cases of severe irreversible hepatotoxicity/acute liver failure, including cases with fatal outcomes with very rapid onset after initiation of systemic use of metronidazole, have been reported in patients with Cockayne syndrome.

    Other

    • Proliferation of Candida in the vagina, dyspareunia, decrease of libido, proctitis, and fleeting joint pains sometimes resembling “serum sickness.” Rare cases of pancreatitis, which generally abated on withdrawal of the drug, have been reported.

    • Patients with Crohn’s disease are known to have an increased incidence of gastrointestinal and certain extraintestinal cancers.

    Flagyl 375 Clinical Trials

    See Literature

    Flagyl 375 Note

    Not Applicable

    Flagyl 375 Patient Counseling

    Patient Counseling

    Interaction with Alcohol

    • Discontinue consumption of alcoholic beverages or products containing propylene glycol while taking Flagyl and for at least 3 days after.

    Treatment of Bacterial and Parasitic Infections

    • Inform patients that Flagyl should only be used to treat bacterial and parasitic infections. Not for viral infections.

    • Do not skip doses. Complete full course of therapy.

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