Flagyl 375 Capsules

Central and Peripheral Nervous System Effects

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

Encephalopathy has been reported in association with cerebellar toxicity characterized by ataxia, dizziness, and dysarthria. CNS lesions seen on MRI have been described in reports of encephalopathy. CNS symptoms are generally reversible within days to weeks upon discontinuation of metronidazole. CNS lesions seen on MRI have also been described as reversible.

Peripheral neuropathy, mainly of sensory type has been reported and is characterized by numbness or paresthesia of an extremity.

Convulsive seizures have been reported in patients treated with metronidazole.

Cases of aseptic meningitis have been reported with metronidazole. Symptoms can occur within hours of dose administration and generally resolve after metronidazole therapy is discontinued.

The appearance of abnormal neurologic signs and symptoms demands the prompt evaluation of the benefit/risk ratio of the continuation of therapy (see ADVERSE REACTIONS).

General

Patients with hepatic impairment metabolize metronidazole slowly, with resultant accumulation of metronidazole in the plasma. The Flagyl 375 Capsules dosage or the frequency of administration should be reduced in patients with severe (Child-Pugh C) hepatic impairment. For patients with mild to moderate hepatic impairment, no dosage adjustment is needed. Patients with hepatic impairment should be monitored for metronidazole associated adverse events (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

Patients with end-stage renal disease may excrete metronidazole and metabolites slowly in the urine, resulting in significant accumulation of metronidazole metabolites. Monitoring for metronidazole associated adverse events is recommended (see CLINICAL PHARMACOLOGY).

Known or previously unrecognized candidiasis may present more prominent symptoms during therapy with Flagyl 375 Capsules and requires treatment with a candidacidal agent.

Metronidazole is a nitroimidazole and should be used with caution in patients with evidence of or history of blood dyscrasia. A mild leucopenia has been observed during its administration; however, no persistent hematologic abnormalities attributable to metronidazole have been observed in clinical studies. Total and differential leukocyte counts are recommended before and after therapy.

Prescribing Flagyl 375 Capsules in the absence of a proven or strongly suspected bacterial or parasitic infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria and parasites.

Information for patients

Discontinue consumption of alcoholic beverages or products containing propylene glycol while taking Flagyl 375 Capsules and for at least three days afterward because abdominal cramps, nausea, vomiting, headaches, and flushing may occur (see CONTRAINDICATIONS and PRECAUTIONS, Drug Interactions).

Patients should be counseled that FLAGYL 375 should only be used to treat bacterial and parasitic infections. They do not treat viral infections (e.g., the common cold). When FLAGYL 375 is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by FLAGYL 375 in the future.

Drug interactions

Psychotic reactions have been reported in alcoholic patients who are using metronidazole and disulfiram concurrently. Metronidazole should not be given to patients who have taken disulfiram within the last 2 weeks (see CONTRAINDICATIONS).

Abdominal cramps, nausea, vomiting, headaches, and flushing may occur if alcoholic beverages or products containing propylene glycol are consumed during or following metronidazole therapy (see CONTRAINDICATIONS).

Metronidazole has been reported to potentiate the anticoagulant effect of warfarin and other oral coumarin anticoagulants, resulting in a prolongation of prothrombin time. When Flagyl 375 Capsules is prescribed for patients on this type of anticoagulant therapy prothrombin time and INR should be carefully monitored.

In patients stabilized on relatively high doses of lithium, short-term metronidazole therapy has been associated with elevation of serum lithium and, in a few cases, signs of lithium toxicity. Serum lithium and serum creatinine levels should be obtained several days after beginning metronidazole to detect any increase that may precede clinical symptoms of lithium intoxication.

Metronidazole has been reported to increase plasma concentrations of busulfan, which can result in an increased risk for serious busulfan toxicity. Metronidazole should not be administered concomitantly with busulfan unless the benefit outweighs the risk. If no therapeutic alternatives to metronidazole are available, and concomitant administration with busulfan is medically needed, frequent monitoring of busulfan plasma concentration should be performed and the busulfan dose should be adjusted accordingly.

The simultaneous administration of drugs that decrease microsomal liver enzyme activity, such as cimetidine, may prolong the half-life and decrease plasma clearance of metronidazole.

The simultaneous administration of drugs that induce microsomal liver enzymes, such as phenytoin or phenobarbital, may accelerate the elimination of metronidazole, resulting in reduced plasma levels; impaired clearance of phenytoin has also been reported.

Drug/Laboratory Test Interactions

Metronidazole may interfere with certain types of determinations of serum chemistry values, such as aspartate aminotransferase (AST, SGOT), alanine aminotransferase (ALT, SGPT), lactate dehydrogenase (LDH), triglycerides, and glucose hexokinase. Values of zero may be observed. All of the assays in which interference has been reported involve enzymatic coupling of the assay to oxidation-reduction of nicotinamide adenine dinucleotide (NAD+ ⇆ NADH). Interference is due to the similarity in absorbance peaks of NADH (340 nm) and metronidazole (322 nm) at pH 7.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Tumors affecting the liver, lung, mammary and lymphatic tissues have been detected in several studies of metronidazole in rats and mice, but not hamsters.

Pulmonary tumors have been observed in all six reported studies in the mouse, including one study in which the animals were dosed on an intermittent schedule (administration during every fourth week only). Malignant liver tumors were increased in male mice treated at approximately 1500 mg/m2 (similar to the maximum recommended daily dose, based on body surface area comparisons). Malignant lymphomas and pulmonary neoplasms were also increased with lifetime feeding of the drug to mice. Mammary and hepatic tumors were increased among female rats administered oral metronidazole compared to concurrent controls. Two lifetime tumorigenicity studies in hamsters have been performed and reported to be negative.

Metronidazole has shown mutagenic activity in in vitro assay systems including the Ames test. Studies in mammals in vivo have failed to demonstrate a potential for genetic damage.

Metronidazole failed to produce any adverse effects on fertility or testicular function in male rats at doses up to 400 mg/kg/day (similar to the maximum recommended clinical dose based on body surface area comparisons) for 28 days. However, rats treated at the same dose for 6 weeks or longer were infertile and showed severe degeneration of the seminiferous epithelium in the testes as well as marked decreases in testicular spermatid counts and epididymal sperm counts. Fertility was restored in most rats after an eight week, drug-free recovery period.

Pregnancy

There are no adequate and well-controlled studies of Flagyl 375 Capsules in pregnant women. There are published data from case-control studies, cohort studies, and 2-meta-analyses that include more than 5000 pregnant women who used metronidazole during pregnancy. Many studies included first trimester exposures. One study showed an increased risk of cleft lip, with or without cleft palate, in infants exposed to metronidazole in-utero; however, these finding were not confirmed. In addition, more than ten randomized placebo-controlled clinical trials enrolled more than 5000 pregnant women to assess the use of antibiotic treatment (including metronidazole) for bacterial vaginosis on the incidence of preterm delivery. Most studies did not show an increased risk for congenital abnormalities or other adverse fetal outcomes following metronidazole exposure during pregnancy. Three studies conducted to assess the risk of infant cancer following metronidazole exposure during pregnancy did not show an increased risk; however, the ability of these studies to detect such a signal was limited.

Metronidazole crosses the placental barrier and its effects on the human fetal organogenesis are not known. Reproduction studies have been performed in rats, rabbits, and mice at doses similar to the maximum recommended human dose based on body surface area comparisons. There was no evidence of harm to the fetus due to metronidazole.

Nursing mothers

Metronidazole is present in human milk at concentrations similar to maternal serum levels, and infant serum levels can be close to or comparable to infant therapeutic levels. Because of the potential for tumorigenicity shown for metronidazole in mouse and rat studies, 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. Alternatively, 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.

Geriatric use

In geriatric patients, monitoring for metronidazole associated adverse events is recommended (see CLINICAL PHARMACOLOGY and PRECAUTIONS). Decreased liver function in geriatric patients can result in increased concentrations of metronidazole that may necessitate adjustment of metronidazole dosage (see DOSAGE AND ADMINISTRATION).

Pediatric use

Safety and effectiveness in pediatric patients have not been established, except in the treatment of amebiasis.

You should not use metronidazole if you are allergic to it, or if you have taken disulfiram (Antabuse) within the past 2 weeks.

Do not drink alcohol or consume foods or medicines that contain propylene glycol while you are taking metronidazole and for at least 3 days after you stop taking it.

In animal studies, metronidazole caused certain types of cancers or tumors. It is not known whether these effects would occur in people using this medicine. Ask your doctor about your risk.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include nausea, vomiting, dizziness, loss of balance or coordination, numbness and tingling, or seizures (convulsions).

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• vision problems, pain behind your eyes;

• weakness, confusion, slurred speech, problems with coordination;

• trouble sleeping, depression, feeling irritable;

• a light-headed feeling, like you might pass out;

• a seizure;

• fever, neck stiffness, increased sensitivity to light, purple spots on the skin;

• numbness, tingling, or burning pain in your hands or feet;

• severe stomach pain, diarrhea that is watery or bloody; or

• blisters or ulcers in your mouth, red or swollen gums, trouble swallowing.

Side effects may be more likely in older adults.

Common side effects may include:

• nausea, vomiting, loss of appetite, stomach pain;

• diarrhea, constipation;

• unpleasant metallic taste;

• rash, itching;

• vaginal itching or discharge;

• mouth sores; or

• swollen, red, or "hairy" tongue.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Sometimes it is not safe to use certain medications at the same time. Some drugs can affect your blood levels of other drugs you take, which may increase side effects or make the medications less effective.

Tell your doctor about all your current medicines and any you start or stop using, especially:

• busulfan;

• lithium; or

• a blood thinner--warfarin, Coumadin, Jantoven.

This list is not complete. Other drugs may interact with metronidazole, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

Applies to metronidazole: compounding powder, intravenous powder for injection, intravenous solution, oral capsule, oral suspension, oral tablet, oral tablet extended release

General

The most serious side effects reported were convulsive seizures, encephalopathy, aseptic meningitis, and optic and peripheral neuropathy (characterized by numbness or paresthesia of an extremity).[Ref]

Nervous system

Very common (10% or more): Headache (up to 18%)
Common (1% to 10%): Taste metallic, dizziness
Rare (0.01% to 0.1%): Drowsiness, ataxia, peripheral neuropathy, transient epileptiform seizure, encephalopathy
Very rare (less than 0.01%): Acute cerebellar syndrome, paralysis, dysarthria, gait impaired, nystagmus, tremor, convulsion, incoordination
Frequency not reported: Convulsive seizure, headache, syncope, paresthesia, optic neuritis, peripheral sensory neuropathy[Ref]

Gastrointestinal

Very common (10% or more): Nausea (up to 10%)
Common (1% to 10%): Abdominal pain, diarrhea, dry mouth, vomiting, stomatitis, glossitis
Rare (less than 0.1%): Pancreatitis, mucositis, epigastralgia
Frequency not reported: Epigastric pain/distress, abdominal cramping, constipation, furry tongue, glossitis, stomatitis, oral mucositis, taste disorder, dyspepsia, pseudomembranous colitis, tongue discolored[Ref]

Genitourinary

Very common (10% or more): Vaginitis (15%)
Common (1% to 10%): Pruritus genital, urine abnormal, dysmenorrhea, moniliasis, urinary tract infection
Rare (less than 0.1%): Darkened urine
Frequency not reported: Vaginal dryness, vulva dryness, dysuria, polyuria, incontinence, pelvic pressure, cystitis, candida infection proliferated, dyspareunia, procitiits, pyuria[Ref]

Other

Common (1% to 10%): Bacterial infection, influenza-like symptoms, weakness
Rare (less than 0.1%): Fever, aseptic meningitis
Frequency not reported: Vertigo, tinnitus, hearing impaired, hearing loss, sensorineural hearing loss, overgrowth of Candida, disulfiram-like reaction[Ref]

Respiratory

Common (1% to 10%): Upper respiratory tract infection, rhinitis, sinusitis, pharyngitis
Frequency not reported: Nasal congestion, hiccup[Ref]

Hematologic

Uncommon (0.1% to 1%): Leukopenia
Rare (less than 0.1%): Neutropenia, neutropenia reversible, thrombocytopenia, pancytopenia, agranulocytosis, blood dyscrasia
Frequency not reported: Bone marrow aplasia, bone marrow depression[Ref]

Cardiovascular

Frequency not reported: Flat T-wave, flushing, QT interval prolonged[Ref]

Dermatologic

Common (1% to 10%): Pruritus
Rare (0.01% to 0.1%): Stevens-Johnson Syndrome, toxic epidermal necrolysis, skin rash, erythema multiforme, pustulosis, Quincke edema
Very rare (less than 0.01%): Fixed drug eruption
Frequency not reported: Erythematosus rash, pruritus, urticaria, mild erythematous eruption, pustular eruption, angioedema[Ref]

Local

Frequency not reported: Thrombophlebitis[Ref]

Psychiatric

Very rare (less than 0.01%): Confusion, hallucination, psychotic disorder
Frequency not reported: Irritability, depression, insomnia, libido decreased, psychosis, disorientation, psychotic reaction, depressed mood[Ref]

Ocular

Rare (0.01% to 0.1%): Optic neuropathy, diplopia, myopia
Very rare (less than 0.01%): Light sensitivity, vision disorder
Frequency not reported: Vision blurred, visual acuity decreased, color vision change[Ref]

Metabolic

Rare (less than 0.1%): Anorexia[Ref]

Musculoskeletal

Common (1% to 10%): Myalgia
Very rare (less than 0.01%): Stiff neck, arthralgia
Frequency not reported: Fleeting joint pain[Ref]

Oncologic

Frequency not reported: Breast cancer, colon cancer[Ref]

Hepatic

Rare (0.01% to 0.1%): Cholestatic hepatitis, liver function test abnormal
Very rare (less than 0.01%): Mixed hepatitis, hepatocellular injury, jaundice, liver failure, liver transplant
Frequency not reported: Drug-induced hepatitis, liver enzymes increased[Ref]

Immunologic

Rare (less than 0.1%): Anaphylaxis, anaphylactic shock, Herxheimer reaction
Frequency not reported: Reaction serum sickness-like, hypersensitivity reaction[Ref]

Some side effects of Flagyl 375 may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.