Flagyl/Flagyl Forte

Flagyl susupension: Each 5 ml contains benzoyl metronidazole equivalent to 125 mg metronidazole and 0.89% (V/V) ethanol.
Flagyl 0.5 g suppository: each contains 500 mg metronidazole.
Flagyl 1 g suppository: each contains 1 g metronidazole.
Flagyl Forte 500 mg film coated tablets: each contains 500 mg metronidazole.

Trichomoniacide, anaerobicide.
Pharmacology: Pharmacodynamics: Flagyl Suspension: Metronidazole is an anti-infectious agent belonging 5-nitroimidazole group. Antibacterial spectrum of metronidazole concerns exclusively anaerobic pathogens. Susceptible species: more than 90% of the species are susceptible (S): Peptostreptococcus, C. perfringens, C. difficile, Bacteroides fragilis, Bacteroides sp., Fusobacterium, Clostridium sp., Prevotella, Veillonella.
Species with inconstant susceptibility: The susceptibility of the pathogens should be tested by an antibiogram: Bifidobacterium, Eubacterium.
Normally resistant species: More than 50 % of the species are resistant (R): Propionibacterium, Actinomyces, Mobilincus.
Antiparasitic activity: Trichomonas vaginalis, Giardia intestinalis, Entamoeba histolytica.
Flagyl Forte: Disposition of Metronidazole given orally or by intravenous injection remains constant, with average elimination time of 8 hours in healthy man. Metronidazole was detected in cerebrospinal fluid, saliva and breast milk in same concentration as in plasma. Metronidazole was also detected in the pus of hepatic abscess.
Pharmacokinetics: Absorption: Metronidazole is rapidly absorbed following oral administration, at least 80% in less than one hour.
The serum peak concentrations achieved following oral administration are similar to those obtained following intravenous administration of equivalent doses.
The oral bioavailability is 100% and not modified by ingestion of food.
Distribution: After a single dose administration of 500 mg metronidazole the average peak serum level is of 10 mg/ml one hour after the ingestion.
The plasma half-life is between 8 to 10 hours.
The protein binding is low: <20%.
The volume of distribution is high, on average of 40 L (i.e. 0.65 L/kg).
Diffusion is rapid and tissue concentrations are similar to the serum concentrations in: lungs, kidneys, liver, skin, bile, CSF, saliva, seminal fluid and vaginal secretions.
Metronidazole crosses the placenta barrier and is excreted in breast milk.
Metabolism: Metronidazole is metabolized by oxidation in the liver in two metabolites: The alcoholic metabolite which has a bactericidal activity on the anaerobic pathogens on average 30% in comparison with the metronidazole, and an elimination half-life of 11 hours.
The acid metabolite is low with a bactericidal activity of 5%.
Elimination: Hepatic and biliary concentrations are high. Colon and fecal concentrations are low.
Excretion is mainly urinary, metronidazole and its metabolites represent 35 to 65% of the ingested dose.

Flagyl Suspension: Urethritis and vaginitis due to Trichomonas vaginalis; intestinal and hepatic amoebiasis; anaerobic infection (especially postoperation); Giardia lambliasis.
Flagyl Suppository: Treatment of infections in which anaerobic bacteria have been identified: septicaemia, bacteremia, peritonitis, brain abscess, necrotizing pneumonia, osteomyelitis, puerperal sepsis, pelvic cellulitis; Prevention of postoperative infections due to anaerobic bacteria, particularly species of bacteroides and anerobic streptococci.
Flagyl Forte: Urethritis and vaginitis due to Trichomonas vaginalis; Amoebiasis (intestinal and hepatic amoebiasis); Prevention of post-operative anaerobic infection; Giardiasis due to Giardia lamblia.

Flagyl Suspension: Suspension should be taken 1 hour before meals.
Amoebiasis: Adults, intestinal amoebiasis: 750 mg, three times daily for 5 to 10 days; Adults, hepatic amoebiasis: 500-750 mg, three times daily for 5 to 10 days; Children: 35-50 mg/kg/24 hours, divided into three doses, for 10 days.
Trichomoniasis: Treatment for men is as same as for women. The dosage regimen should be individualized, to reduce the reinfection. Adults: 2 gram, given either as a single dose or in two divided doses or 250 mg, three times daily for 7 consecutive days; Children: 15 mg/kg bodyweight daily, divided into three doses, for 7 to 10 days.
Giardia lambliasis: Adults: 250 mg to 500 mg, three times daily for 5 to 7 days or 2 gram daily as a single dose for 3 days; Children: 5 mg/kg bodyweight three times daily for 5 to 7 days.
Anaerobic bacterial infections: Adults : 7.5 mg/kg every 6 hours (approximately 500 mg for a 70 kg adult). A maximum of 4 gram should not be exceeded during a 24-hour period. The usual duration of therapy is 7 to 10 days.
Flagyl Suppository: A. Treatment of infections in which anaerobic bacteria have been identified.
Adults: 1 gram suppository at 8 hourly intervals until oral medication becomes possible. If the suppository administration is more than 3 days, reduced the further doses into 1 gram
at 12 hourly intervals.
Children: 7.5 mg/kg body-weight at 8 hourly intervals.
B. Prevention of post operative infections due to anaerobic bacteria.
Adults: 1 gram suppository 2-4 hours before surgery, then at 8 hourly intervals until oral medication becomes possible.
Children: ½ or ¼ of 500 mg suppository at 8 hourly intervals.
Flagyl Forte: It is recommended to take tablet during or after meal. Suspension should be taken 1 hour before meal.
Amoebiasis: Adults, intestinal amoebiasis: 750 mg, three times daily for 5 to 10 days; Adults, hepatic amoebiasis: 750 mg, three times daily for 5 to 10 days; Children: 35-50 mg/kg/24 hours, divided into three doses, for 10 days.
Trichomoniasis: To prevent reinfection, spouse of a patients should be given the same dosage regimen; Adults: 2 gram, given either as a single dose in one day or 500 mg, two
times daily or 250 mg, three times daily for 7 consecutive days; Children: 15 mg/kg bodyweight daily, divided into three doses, for 7 to 10 days.
Giardiasis: Adults: 250 mg to 500 mg, three times daily for 5 to 7 days or 2 gram daily as a single dose for 3 days; Children: 5 mg/kg bodyweight three times daily for 5 to 7 days.
Anaerobic bacterial infections: In serious infection, metronidazole intravenous has to be given as an initial treatment.Adults : 7.5 mg/kg every 6 hours (approximately 500 mg for a 70 kg adult), maximum 4 gram daily for 7 to 10 days.

Single oral doses of metronidazole, up to 12 g have been reported in suicide attempts and accidental overdoses. Symptoms were limited to vomiting, ataxia and slight disorientation. There is no specific antidote for metronidazole overdosage. In cases of suspected massive overdose, symptomatic and supportive treatment should be instituted.

Hypersensitivity to metronidazole or to other nitroimidazoles.
Flagyl Suspension, Suppository and Forte: During the first trimester of pregnancy.
Flagyl Suspension and Suppository: Metronidazole should not be used in patients with an established history of bone marrow depression.

Flagyl Suspension: Treatment should be discontinued in case of ataxia, vertigo, hallucinations mental confusion.
Metronidazole potentiates the action of vecuronium (non-depolarising neuromuscular blocking agent).
Care must be taken for patients with hepatic insufficiency, doses below those usually recommended should be administered caustiously.
Safety in children has not been established, except in amoebiasis.
Care must be taken for second and third trimesters of pregnancy.
Flagyl Forte/Flagyl Suspension: Metronidazole 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. Disturbances of central nervous system has been reported in some cases but disappeared if therapy is discontinued or dose decreased (Flagyl Forte only.)
Patients should be advised not to take alcohol during metronidazole therapy and for at least one day afterwards because of the possibility of a disulfiram­ like (Antabuse effect) reaction.

Flagyl Forte/Flagyl Suspension: The use of Flagyl for prolonged treatment duration should be carefully weighed.
If for compelling reasons, metronidazole must be administered longer than the usually recommended duration, it is recommended that hematological tests, especially leucocyte count should be carried out regularly and that patients should be monitored for adverse reactions such as peripheral or central neuropathy (such as paresthesia, ataxia, dizziness, convulsive seizures).
Flagyl should be administered with caution to patients with hepatic encephalopathy.
Patients should be warned that metronidazole may darken urine (due to metronidazole metabolite).
Flagyl Suspension: There is no suspicion in carcinogenicity in human although the product has proved carcinogenic in a certain strain of mouse but not in rats and hamsters.
Flagyl Suppository: Care must be taken for: Lactating woman as metronidazole is secreted in breast milk.
Second and third trimesters of pregnancy as metronidazole can pass the placenta barrier.
FLAGYL should be administered with caution to patients with CNS diseases. The CNS interference has been reported in some cases, but will disappear on the withdrawn or on the reduced doses of metronidazole.
When taken together with alcohol, metronidazole can provoke a dilsufiram-like reaction.
Count the blood examination is recommended for a long term treatment.
For patients with hepatic insufficiency, doses below those usually recommended should be administered caustiously.
Safety in children has not been established, except in amoebiasis.
Flagyl Forte: Used with caution in nursing mothers as metronidazole is excreted in breast milk, during first and second trimesters of pregnancy as metronidazole crosses the placental barrier.
Doses should be reduced and administered with caution to patients with hepatic diseases.
Safety and effectiveness in pediatric patients have not been established, except in the treatment of amoebiasis.
Effects on ability to drive and use machines: Patients should be warned about the potential for drowsiness, dizziness, confusion, hallucinations, convulsions or transient visual disorders, and advised not to drive or operate machinery if these symptoms occur.
Carcinogenicity: Metronidazole has been shown to be carcinogenic in the mouse and in the rat. However similar studies in the hamster have given negative results and extensive human epidemiological studies in humans have provided no evidence of an increased carcinogenic risk in humans. Therefore, the use of Flagyl for longer treatment than usually required prolonged treatment duration should be carefully weighed.
Mutagenicity: Metronidazole has been shown to be mutagenic in bacteria in vitro. In studies conducted in mammalian cells in vitro as well as in rodent or humans in vivo, there was inadequate evidence of a mutagenic effect of metronidazole, with some studies reporting mutagenic effects, while other studies were negative. Therefore, the use of Flagyl for longer treatment than usually required prolonged treatment duration should be carefully weighed.

Pregnancy: As metronidazole crosses the placental barrier and as its effects on human fetal organogenesis are not known, its use in pregnancy should be carefully evaluated.
Lactation: As metronidazole is excreted in human milk, unnecessary exposure to the drug should be avoided.

Flagyl Suspension: Gastrointestinal disorders: Epigastric pain, nausea, vomiting, diarrhea.
Oral mucositis, taste disorders, anorexia.
Reversible cases of pancreatitis.
Tongue discoloration/ furry tongue (e.g. due to fungal overgrowth).
Immune system disorders: Angioedema, anaphylactic shock.
Nervous system disorders: Peripheral sensory neuropathy.
Headache, convulsions, dizziness.
Reports of encephalopathy (e.g. confusion) and subacute cerebellar syndrome (e.g. ataxia, dysarthria, gait impairment, nystagmus, and tremor ), which may resolve with discontinuation of the drug.
Aseptic meningitis.
Psychiatric disorders: Psychotic disorders including confusion, hallucinations.
Depressed mood.
Eye disorders: Transient vision disorders such as diplopia, myopia, blurred vision, decreased visual acuity, changes in color vision.
Optic neuropathy/neuritis.
Blood and lymphatic system disorders: Cases of agranulocytosis, neutropenia and thrombocytopenia have been reported.
Mild reversible leucopenia in some patients has been reported.
Hepatobiliary disorders: 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 antibiotics.
Skin and subcutaneous tissue disorders: Rash, pruritus, flushing, urticaria.
Pustular eruptions.
General disorders and administration site conditions: Fever.
Flagyl Suppository: The frequency of adverse events listed below is defined using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).
Blood and lymphatic system disorders: Very rare: Agranulocytosis, neutropenia, thrombocytopenia, pancytopenia.
Not known: Leucopenia.
Immune system disorders: Rare: Anaphylaxis.
Not known: Angioedema, urticaria, fever.
Metabolism and nutrition disorders: Not known: Anorexia.
Psychiatric disorders: Very rare: Psychotic disorders, including confusion and hallucinations.
Not known: Depressed mood.
Nervous system disorders: Very rare: Encephalopathy (eg. confusion, fever, headache, hallucinations, paralysis, light sensitivity, disturbances in sight and movement, stiff neck) and subacute cerebellar syndrome (eg. ataxia, dysathria, gait impairment, nystagmus and tremor) which may resolve on discontinuation of the drug.
Drowsiness, dizziness, convulsions, headaches.
Not known: During intensive and/or prolonged metronidazole therapy, peripheral sensory neuropathy or transient epileptiform seizures have been reported. In most cases neuropathy disappeared after treatment was stopped or when dosage was reduced.
Aseptic menigitis.
Eye disorders: Very rare: Vision disorders such as diplopia and myopia, which, in most cases, is transient.
Not known: Optic neuropathy/neuritis.
Gastrointestinal disorders: Not known: Taste disorders, oral mucositis, furred tongue, nausea, vomiting, gastrointestinal disturbances such as epigastric pain and diarrhoea.
Hepatobiliary disorders: Very rare: Increase in liver enzymes (AST, ALT, alkaline phosphatase), cholestatic or mixed hepatitis and hepatocellular liver injury, jaundice and pancreatitis which is reversible on drug withdrawal.
Cases of liver failure requiring liver transplant have been reported in patients treated with metronidazole in combination with other anitibiotic drugs.
Skin and subcutaneous tissue disorders: Very rare: Skin rashes, pustular eruptions, pruritis, flushing.
Not known: Erythema multiforme, Stevens-Johnson syndrome or toxic epidermal necrolysis.
Musculoskeletal, connective tissue and bone disorders: Very rare: Myalgia, arthralgia.
Renal and Urinary disorders: Very rare: Darkening of urine (due to metronidazole metabolite).
Flagyl Forte: Gastrointestinal disorders: Epigastric pain, nausea, vomiting, diarrhea.
Oral mucositis, taste disorders, anorexia.
Reversible cases of pancreatitis.
Tongue discoloration/furry tongue (e.g. due to fungal overgrowth).
Immune system disorders: Angioedema, anaphylactic shock.
Nervous system disorders: Peripheral sensory neuropathy.
Headache, convulsions, dizziness.
Reports of encephalopathy (e.g. confusion ) and subacute cerebellar syndrome (e.g. ataxia, dysarthria, gait impairment, nystagmus, and tremor which may resolve with discontinuation of the drug.
Aspetic meningitis.
Psychiatric disorders: psychiatric disorders including confuison, hallucinations.
Depressed mood.
Eye disorders: Transient vision disorders such as diplopia, myopia, blurred vision, decreased visual acuity, changes in colored vision.
Optic neuropathy/neuritis.
Blood and lympathic system disorders: Cases of agranulocytosis, neutropenia and thrombocytopenia have been reported.
Mild reversible leucopenia in some patients has been reported.
Hepatobiliary disorders: 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.
Skin and subcutaneous tissue disorders: Rash, pruritus, flushing, urticaria.
Pustular eruptions.
General disorders and administration site conditions: Fever.

Flagyl Suspension/Flagyl Forte: Disulfiram: Psychotic reactions have been reported in patients who were using metronidazole and disulfiram concurrently.
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).
Oral anticoagulant therapy (warfarin type): Potention of the anticoagulant effect and increased hemorrhagic risk caused by decreased hepatic catabolism. In case of coadministration, prothrombin time should be more frequently monitored and anticoagulant therapy adjusted during treatment with metronidazole.
Vecuronium (non-depolarising neuromuscular blocking agent) potentiates the action of vecuronium.
Flagyl may be given alone. In combination with other antibiotic given in full normal therapeutic doses. metronidazole both should be.
Cimetidine prolongs the plasma clearance of metronidazole, presumably by inhibiting metabolic enzymes, toxic concentrations of metronidazole may be produced.
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.
Ciclosporin: Risk of elevation of ciclosporin serum levels. Serum ciclosporin and serum creatine should be closely monitored when coadministration is necessary.
Phenytoin or Phenobarbital: Increased elimination of metronidazole resulting in reduced plasma levels.
5 Fluorouracil: Reduced clearance of 5 fluorouracil resulting in increased toxicity of 5 fluorouracil.
Busulfan: Plasma levels of busulfan may be increased by metronidazole, which may lead to severe busulfan toxicity.
Flagyl Suspension: Metronidazole may immobilize treponema and hence result in a falsely positive treponema pallidum immobilization test.
In order to prevent possible interactions you must inform physician or pharmacist about the current treatment.
Flagyl Suppository: FLAGYL may be given alone. In combination with other antibiotic: both should be given in full normal therapeutic doses.
Prior to simultaneous administration with warfarin, the anticoagulant should be checked and if possible to be suitably reduced.
Cimetidine prolongs the plasma clearance of metronidazole, presumably by inhibiting metabolic enzymes, toxic concentrations of metronidazole may be produced.
Metronidazole reduces the clearance of 5-fluorouracil and can therefore result in increased toxicity of 5-fluorouracil.
Plasma levels of busulfan may be increased by metronidazole which may lead to severe busulfan toxicity.
Flagyl Forte: It is recommended to use metronidazole as single drug. In combination with other antibiotic, both should be given in a full dose for normal therapy Cimetidine might prolonged metronidazole plasma clearance which lead to toxic concentration of metronidazole.
Psychotic reaction has been reported when concomitant metronidazole, disulfiram and alcohol was taken simultaneously.

Flagyl Suspension: Store below 25°C.
Flagyl Suppository: Store below 25°C. Protect from light.
Flagyl Forte: Store between 25°C-30°C. Protected from light.
Shelf life: 3 years.

Other Antibiotics / Antiamoebics / Preparations for Vaginal Conditions

G01AF01 - metronidazole ; Belongs to the class of imidazole derivative antiinfectives. Used in the treatment of gynecological infections.
P01AB01 - metronidazole ; Belongs to the class of nitroimidazole derivatives antiprotozoals. Used in the treatment amoebiasis and other protozoal diseases.

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