Source: Health Products and Food Branch (CA) Revision Year: 2018
Hypersensitivity to FLAGYSTATIN (metronidazole and nystatin); or any of its constituents, or to imidazoles.
Combined treatment with oral metronidazole should be avoided in cases of active neurological disorders or a history of blood dyscrasia, hypothyroidism or hypoadrenalism unless, in the opinion of the physician, the benefits outweigh the possible hazard to the patient.
Metronidazole has been shown to be carcinogenic in mice and rats (see TOXICOLOGY section). Unnecessary use of the drug should be avoided and prolonged treatment duration should be carefully weighed. Its use should be reserved for the conditions described in the INDICATIONS section.
Nystatin possesses little or no antibacterial activity while metronidazole is selective against certain anaerobic bacteria; therefore, FLAGYSTATIN may not be effective in bacterial vaginal infections.
Primary resistance to nystatin is rare; cross-resistance with other polyene antibiotics has been reported.
Nystatin is not absorbed from mucous membranes; therefore, no systemic effect is expected (see PHARMACOLOGY section). Local irritation or sensitizations have occasionally been reported after local application. If this occurs, it is recommended to stop the treatment (see ADVERSE REACTIONS section).
FLAGYSTATIN should not be prescribed unless there is direct evidence of trichomonal infestation or candidiasis.
Once candidiasis has been confirmed, care must be taken to investigate the possible factors that could promote fungal growth. To avoid recurrences, it is essential to eradicate or offset these promoting factors.
It is recommended to treat all sites associated with Candida concomitantly (e.g. intestinal and vaginal or other infections).
FLAGYSTATIN, a metronidazole containing preparation, should be used with great caution in patients with a history of hepatic enzyme increase or liver injury associated with previous administration of metronidazole (see ADVERSE REACTIONS section).
Cases of severe hepatotoxicity/acute hepatic failure, including cases with a fatal outcome, with very rapid onset after treatment initiation, in patients with Cockayne syndrome have been reported with products containing metronidazole for systemic use. In this population, FLAGYSTATIN should therefore only be used after careful benefit-risk assessment and only if no alternative treatment is available. Liver function tests must be performed just prior to the start of therapy, throughout and after end of treatment until liver function is within normal ranges, or until the baseline values are reached. If the liver function tests become markedly elevated during treatment, the drug should be discontinued. Patients with Cockayne syndrome should be advised to immediately report any symptoms of potential liver injury to their physician and stop taking FLAGYSTATIN.
Cases of severe bullous skin reactions such as Stevens Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN) or acute generalized exanthematous pustulosis (AGEP) have been reported with metronidazole (see ADVERSE REACTIONS section). If symptoms or signs of SJS, TEN or AGEP are present, FLAGYSTATIN treatment must be immediately discontinued.
Prescribing FLAGYSTATIN in the absence of a proven or strongly suspected mixed vaginal infection is unlikely to provide benefit to the patient and risks the development of resistant organisms.
Prolonged use of FLAGYSTATIN may result in overgrowth of non-susceptible bacteria and fungi. If the infection is not improved following 2 treatment courses of 10 days, cultures should be obtained to guide further treatment. If such infections occur, discontinue use and institute alternate therapy.
Where there is evidence of trichomonal infestation in the sexual partner, he should be treated concomitantly with oral metronidazole to avoid reinfestation.
The effectiveness of condoms or diaphragms could be impaired by some of the fatty constituents contained in nystatin and metronidazole gynaecological ovule, therefore their use during FLAGYSTATIN treatment is not recommended.
Treatment should not be stopped during menstruation.
Vaginal injection, menstrual tampons and soaps with an acid pH (for personal hygiene use) should not be used during treatment because they may promote fungal replication.
It is possible that adverse effects normally associated with oral administration of metronidazole or nystatin may occur following the vaginal administration of FLAGYSTATIN.
Patients should be warned against consuming alcohol, during FLAGYSTATIN therapy and for at least one day afterward, because of a possible disulfiram-like reaction related to the metronidazole.
Although no persistent hematologic abnormalities have been observed in clinical studies, total and differential leukocyte counts should be made before and after treatment, especially if a second course of metronidazole therapy is needed.
Patients should be monitored for adverse reactions such as peripheral or central neuropathy (such as paresthesia, ataxia, dizziness, and convulsive seizures) related to metronidazole.
FLAGYSTATIN should be used with caution in patients with active or chronic severe peripheral and central nervous system diseases due to the risk of neurological aggravation related to metronidazole.
Treatment with metronidazole should be discontinued if ataxia or any other symptom of CNS involvement occurs.
FLAGYSTATIN should be administered with caution to patients with hepatic encephalopathy. Patients with severe hepatic disease metabolize metronidazole slowly with resultant accumulation of metronidazole and its metabolites in the plasma. Accordingly, for such patients, doses of FLAGYSTATIN below those usually recommended should be administered and with caution.
Patients should be warned that FLAGYSTATIN may darken urine (due to metronidazole metabolite).
Metronidazole: Metronidazole passes the placental barrier. Although it has been given to pregnant women without apparent complication, its effects on human fetal organogenesis are not known; it is advisable that its use be avoided in pregnant patients and the drug be withheld during the first trimester of pregnancy.
Nystatin: No reliable teratogenicity data related to nystatin administration from animal studies is available. Use of nystatin should be avoided unless the benefits to the mother outweigh the potential risks to the fetus or baby.
The applicator should not be used after the 7th month of pregnancy.
Metronidazole: As metronidazole is excreted in human milk, exposure to the drug should be avoided.
Nystatin: No data is available whether nystatin enters the breast milk.
Patients should be warned about the potential for confusion, dizziness, hallucinations, convulsions or eye disorders when treated with metronidazole, and advised not to drive or operate machinery if these symptoms occur.
They are infrequent and minor: vaginal burning and granular sensation. Bitter taste, nausea and vomiting, already known to occur with metronidazole, were mainly seen when oral metronidazole was administered concomitantly with FLAGYSTATIN local treatment.
In the course of clinical trials with FLAGYSTATIN, reactions, not necessarily related to the product, were observed: spots on the skin around the knees, welts all over the body, aching and swelling of wrists and ankles, pruritis, headache, coated tongue and fatigue.
Other adverse events related to metronidazole, usually observed after oral or I.V. administration of metronidazole, and to nystatin include:
Metronidazole: Transient eosinophilia, neutropenia, cases of agranulocytosis and thrombocytopenia have been reported.
Metronidazole: Palpitation and chest pain
Metronidazole: Transient vision disorders such as diplopia, myopia, blurred vision, decreased visual acuity, changes in color vision. Optic neuropathy/neuritis has been reported.
Metronidazole: Diarrhea, nausea, vomiting, epigastric distress, epigastric pain, dyspepsia, constipation, tongue discoloration/coated tongue, dry mouth, taste disorders including metallic taste, oral mucositis. Reversible cases of pancreatitis have been reported.
Metronidazole: Thrombophlebitis has occurred with I.V. administration. Fever has been reported.
Metronidazole: Increase in liver enzymes (AST, ALT, alkaline phosphatase), cholestatic or mixed hepatitis and hepatocellular liver injury, sometimes with jaundice have been reported.
Cases of liver failure requiring liver transplant have been reported in patients treated with metronidazole in combination with other antibiotic drugs.
Cases of severe hepatotoxicity/acute hepatic failure, including cases with a fatal outcome, in patients with Cockayne syndrome have been reported with products containing metronidazole.
Metronidazole: Angioedema, anaphylactic shock.
Nystatin: Hypersensitivity reactions may occur. Local irritation or sensitizations have been reported after local application. Skin reactions may occur; particularly, Stevens-Johnson Syndrome has been reported.
Metronidazole: Cases of pseudomembranous colitis have been reported.
Metronidazole: Anorexia has been reported.
Metronidazole: Convulsive seizures, peripheral sensory neuropathy, transient ataxia, dizziness, drowsiness, insomnia, headache, and aseptic meningitis.
Reports of encephalopathy (e.g. confusion) and subacute cerebellar syndrome (e.g. ataxia, dysarthria, gait impairment, nystagmus, and tremor) have been reported, which may resolve with discontinuation of the drug.
Metronidazole: Psychotic disorders including confusion, hallucinations. Depressed mood.
Vaginal burning sensation.
Metronidazole: Hypersensitivity reactions including flushing, urticaria and pustular eruptions, acute generalized exanthematous pustulosis (AGEP). Rash and pruritus, fixed drug eruption. Cases of Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported. Many of these case reports revealed the use of concomitant medications known to be associated with SJS or TEN.
Nystatin: Local irritation or sensitizations have been reported after local application, treatment should be stopped if such reaction occurs. Skin reactions may occur; particularly Stevens-Johnson Syndrome has been reported.
Metronidazole: Proliferation of Candida albicans in the vagina, vaginal dryness and burning; dysuria; and headaches. Reversible lowering of serum lipids has been reported. A case of gynecomastia has been reported which resolved on discontinuing metronidazole administration.
Nystatin: Nystatin is not absorbed from mucous membranes; therefore, no systemic manifestations are observed after local application of the product (see PHARMACOLOGY section).
Precautions must be borne in mind, as it is possible that drug interactions usually associated with oral administration of metronidazole or nystatin may occur following the vaginal administration of FLAGYSTATIN.
Alcohol: alcoholic beverages and drugs containing alcohol should not be consumed during therapy and for at least one day afterwards because of the possibility of a disulfiram-like (antabuse effect) reaction (flushing, vomiting, tachycardia).
Busulfan: plasma levels of busulfan may be increased by metronidazole, which may lead to severe busulfan toxicity.
Cyclosporin: risk of elevation of cyclosporin serum levels. Serum cyclosporin and serum creatinine should be closely monitored when coadministration with metronidazole is necessary.
Disulfiram: psychotic reactions have been reported in patients who were using metronidazole and disulfiram concurrently.
5 Fluorouracil: reduced clearance of 5 fluorouracil resulting in increased toxicity of 5 fluorouracil (coadministration with metronidazole)
Lithium: plasma levels of lithium may be increased by metronidazole. Plasma concentration of lithium, creatinine and electrolytes should be monitored in patients under treatment with lithium while they receive metronidazole.
Oral anticoagulant therapy (warfarin type): potentiation of the anticoagulant effect and increased hemorrhagic risk caused by decreased hepatic catabolism. In case of coadministration with metronidazole, prothrombin time should be more frequently monitored and anticoagulant therapy adjusted during treatment with metronidazole.
Phenytoin or phenobarbital: increased elimination of metronidazole resulting in reduced plasma levels. Patients maintained on phenytoin were found to have toxic blood levels after oral metronidazole administration. Phenytoin concentration returned to therapeutic blood level after discontinuance of metronidazole.
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