Flagyl

Metronidazole.

Tablet: Each tablet contains: Metronidazole 500 mg.
Oral Suspension: Each 5 mL (1 teaspoonful) contains: Metronidazole (as benzoate) 125 mg (equiv. to 201 mg Metronidazole).
Flagyl is metronidazole 2-methyl-5-nitroimidazole; 1-ethanol;(2-hydroxyethyl)-2-methyl)-5-nitroimidazole; 1-(bethylol)-2methyl-5-nitro-3azapyrole or C₆H₉N₃O₃ with molecular weight of 171.16.

Pharmacology: Pharmacodynamics: Tablet: Metronidazole is an anti-infective agent belonging to the 5-nitroimidazole group. The antibacterial spectrum of metronidazole concerns exclusively anaerobic microorganisms.
Susceptible species: More than 90% of the species are susceptible: 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: Propionibacterium, Actinomyces, Mobilincus.
The antiparasitic activity concerns: Trichomonas vaginalis, Giardia intestinalis, Entamoeba histolytica.
Oral suspension: Specific bactericidal activity against important obligate anaerobes.
Pharmacokinetics: Tablet: Absorption: Metronidazole is rapidly absorbed following oral administration, at least 80% in less than one hour. The peak serum concentration achieved following oral administration is similar to those obtained following intravenous administration of equivalent doses.
The oral bioavailability is 100% and is not modified by simultaneous ingestion of food.
Distribution: Approximately one hour after a single dose administration of 500 mg of metronidazole, the peak serum concentration is, on average, 10 μg/mL.
The plasma half-life is between 8 to 10 hours.
The protein binding is low: <20%.
The volume of distribution is large, on average 40 L (i.e. 0.65 L/kg).
Diffusion of the drug is rapid and extensive with concentrations close to serum levels in the lungs, kidneys, liver, skin, bile, CSF, saliva, seminal fluid and vaginal secretions.
Metronidazole crosses the placental barrier and is excreted in breast milk.
Metabolism: Metronidazole is primarily metabolized in the liver. Oxidation yields two main metabolites: The alcoholic metabolite, the primary metabolite, with a bactericidal activity against anaerobic bacteria equal to approximately 30% of that of metronidazole, and with an elimination half-life of 11 hours.
The acid metabolite, in small amounts, and with a bactericidal activity approximately equal to 5% of that of metronidazole.
Elimination: High liver and biliary concentration. Low concentration in the colon.
Little fecal elimination.
Excretion is primarily urinary, shown by the fact that the metronidazole and its oxidation metabolites excreted in the urine account for approximately 35 to 65% of the administered dose.
Oral suspension: Metronidazole is readily and almost absorbed after oral doses. Peak plasma conc of about 6 and 12 micrograms/mL are achieved, usually within 1 to 2 hours, after single doses of 250 and 500 mg respectively. Some accumulation occurs and consequently there are higher conc when multiple doses are given. Absorption may be delayed, but is not reduced overall by food. Metronidazole benzoate given by mouth is hydrolysed in the gastrointestinal tract to release metronidazole, which in turn is then absorbed.
Metronidazole is widely distributed. It appears in most body tissues, and fluids including bile, bone, breast milk, cerebral abscesses, CSF, liver and liver abscess, saliva, seminal fluid, and vaginal secretions, and achieves concentrations similar to those in plasma. It also crosses the placenta rapidly and enters fetal circulation. Not more than 20% is bound to plasma proteins.
The elimination half-life of metronidazole is about 8 hr that of hydroxy metabolite is slightly longer. The half-life of metronidazole is reported to be longer in neonates and in patients with severe hepatic impairment, that of the hydroxy metabolite is prolonged in patients with substantial renal impairment.
Toxicology: Tablet: Non-Clinical Safety Data: 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 epidemiological studies in humans have provided no evidence of an increased carcinogenic risk in humans.
Therefore, the use of metronidazole for prolonged treatment duration should be carefully weighed (see Warnings and Precautions under Precautions).
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 metronidazole for prolonged treatment duration should be carefully weighed (see Warnings and Precautions under Precautions).

Tablet: The indications are based on the anti-parasitic and antibacterial activity, and on the pharmacokinetic characteristics of metronidazole.
They are restricted to infections caused by the microorganisms defined previously as susceptible to metronidazole: Amebiasis; Urogenital trichomoniasis; Non-specific vaginitis; Giardiasis; Curative treatment of medico-surgical infections due to susceptible anaerobic pathogens. Prophylaxis against infections caused by susceptible anaerobic pathogens in high risk surgical contexts. Conversion from prophylactic or curative injectable treatment of infections due to susceptible anaerobic pathogens.
Oral Suspension: For the treatment of anaerobic protozoal infections such as amoebiasis (intestinal and extraintestinal), giardiasis, trichomoniasis, balantidiasis, blastocystiasis, dientamoebiasis; for the treatment of bacterial infections, including Bacteroides fragilis and Clostridium tetanus.

Tablet: Amebiasis: The duration of treatment is 7 consecutive days.
Adults: 1.50 g daily, in 3 divided doses.
Children: 30 to 40 mg/kg/day, in 3 divided doses.
In hepatic amebiasis, at the abscess stage, the abscess must be evacuated concomitantly with metronidazole treatment.
Giardiasis: The duration of treatment is 5 consecutive days.
Adults: 0.750 to 1 g daily.
Children: From 2 to 5 years: 250 mg/day.
From 5 to 10 years: 375 mg/day.
From 10 to 15 years: 500 mg/day.
Trichomoniasis: In women (urethritis and vaginitis due to Trichomonas): single dose of 2 g or 500 mg/day by oral route in two divided doses for 10 days.
Whether or not the partner presents clinical signs of infection with Trichomonas vaginalis, he must be treated concurrently, even in the absence of positive laboratory tests.
In men (urethritis due to Trichomonas): 2 g in a single dose or 500 mg by oral route in 2 divided doses for 10 days.
Non-specific vaginitis: 500 mg, twice daily for 7 days.
The partner must be treated simultaneously.
Treatment of anaerobic infections: As first line treatment or substitute treatment: Adults: 1 to 1.5 g/day.
Children: 20 to 30 mg/kg/day.
Surgical chemoprophylaxis: The studies published in the literature do not make it possible to define the ideal protocol for surgical chemoprophylaxis Metronidazole must be combined with a product active against Enterobacteria.
One 500 mg dose every 8 hours, the treatment being begun approximately 48 hours before surgery, appears to be effective.
The last dose must be administered at the latest 12 hours before surgery.
The goal of chemoprophylaxis is to reduce the bacterial inoculum in the gastro-intestinal tract at the time of surgery; it is therefore useless to continue the antibiotic in the post-operative period, at least by the oral route.
Children: same protocol at a dosage of 20 mg to 30 mg/kg/day.
Oral Suspension: Trichomoniasis: Adults: Given orally either as a single 2 g dose, as a 2-day course of 800 mg in the morning and 1.2 g in the evening, or as a 7-day course of 600 mg to 1 g daily in two or three divided doses.
Anaerobic infections: Given orally in an initial dose of 800 mg followed by 400 mg every 8 hours, usually for about 7 days.
Amoebiasis: Adults: Given in oral doses of 400 to 800 mg three times daily for 5 days to 10 days. An alternative adult dose is 1.5 to 2.5 g as a single daily dose for 2 or 3 days.
Children: Aged 1 to 3 years may be given one-quarter, those aged 3 to 7 years one-third, and those aged 7 to 10 years one-half the total adult daily dose, alternatively 35 to 50 mg/kg daily in divided doses.
Giardiasis: Adults: Usually oral dose is 2 g once daily for 3 successive days, or 400 mg three times daily for 5 days, or 500 mg twice daily for 7 to 10 days.
Children: Alternative schedule for children is 15 mg/kg daily in divided doses. Or as prescribed by the physician.

Tablet: Single oral doses of metronidazole, up to 12 g have been reported in suicide attempts and accidental overdoses.
Signs and Symptoms: Symptoms were limited to vomiting, ataxia and slight disorientation.
Management: There is no specific antidote for metronidazole overdosages. In case of suspected massive overdosages, a symptomatic and supportive treatment should be instituted.
Oral Suspension: Single oral doses of metronidazole, up to 12 g, have been reported in suicide attempts and accidental overdoses. Symptoms reported including nausea, vomiting, and ataxia. Oral metronidazole has been studied as a radiation sensitizer in the treatment of malignant tumors. Neurotoxic effects, including seizures and peripheral neuropathy, have been reported after 5 to 7 days of doses of 6 to 10.4g every other day.
Treatment: There is no specific antidote for metronidazole overdose; therefore, management of the patient should consist of symptomatic and supportive therapy.

Tablet: Hypersensitivity to imidazoles.
Oral Suspension: Patients with a prior history of hypersensitivity to metronidazole or other nitroimidazole derivatives. Patients with history or evidence of blood dyscrasia. In patients with trichomoniasis, metronidazole is contraindicated during the first trimester of pregnancy.

Tablet: Metronidazole, like any other imidazole derivative, has been shown to be carcinogenic in rodents. Unnecessary use of the drug should therefore be avoided.
Oral Suspension: Metronidazole should not be given in the first trimester of pregnancy as it crosses the placenta and enters fetal circulation rapidly.

Tablet: Warnings: 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.
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.
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, metronidazole should therefore be used after careful benefit-risk assessment, and only if no alternative treatment is available. Liver functions 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 metronidazole.
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). If symptoms or signs of SJS, TEN or AGEP are present, Metronidazole (Flagyl/Flagyl Forte) treatment must be immediately discontinued.
Precautions: The use of Metronidazole (Flagyl/Flagyl Forte) for prolonged treatment duration should be carefully weighed (see Pharmacology: Toxicology: Non-clinical safety data under Actions).
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).
Metronidazole (Flagyl/Flagyl Forte) should be administered with caution to patients with hepatic encephalopathy. Patients should be warned that metronidazole may darken urine (due to metronidazole metabolite).
Driving a Vehicle or Performing Other Hazardous Tasks: Patients should be warned about the potential for confusion, dizziness, hallucinations, or transient visual disorders, and advised not to drive or operate machinery if these symptoms occur.
Oral Suspension: Patients should be monitored for neurological signs. Candida overgrowth may occur, interacts with alcohol and warfarin. As much as possible, its use should be avoided during pregnancy.

Tablet: 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.
Oral Suspension: Metronidazole is secreted in breast milk. In view of its tumorigenic and mutagenic potential, breastfeeding is not recommended.

Tablet: Gastrointestinal effects: 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 on 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.
Ear and labyrinth disorders: Hearing impaired/hearing loss (including sensorineural); tinnitus.
Blood and lymphatic system disorders: Cases of agranulocytosis, neutropenia and thrombocytopenia have 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, urticarial pustular eruptions, acute generalized exanthematous pustulosis; fixed drug eruption; Stevens-Johnson syndrome, toxic epidermal necrolysis.
General disorders and administration site conditions: Fever.
Oral Suspension: The adverse drug reactions of metronidazole are generally dose-related. The most common are gastrointestinal disturbances, especially nausea and unpleasant metallic taste. Vomiting and diarrhea or constipation may also occur. A furred tongue, glossitis and stomatitis may be associated with an overgrowth of Candida. There have been rare report of antibiotic-associated colitis with metronidazole, although it also used in the treatment of this condition.
Weakness, dizziness, ataxia, headache, drowsiness, insomnia and changes in mood or mental state such as depression or confusion have also been reported. Peripheral neuropathy, usually presenting as numbness or tingling in the extremities, and epileptiform seizures have been associated with high doses of metronidazole or prolonged treatment.
Temporary moderate leucopenia and thrombocytopenia may occur in some patients receiving metronidazole. Skin rashes, urticaria and pruritus occur occasionally and multiforme, angioedema and anaphylaxis have been reported rarely. Other adverse effects include urethral discomfort and darkening of the urine. Raised liver enzymes values, cholestatic hepatitis, and jaundice have occasionally been reported. Thrombophlebitis may follow the intravenous administration of metronidazole.
Studies have shown metronidazole to be mutagenic in bacteria and carcinogenic in some animals.

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 metronidazole therapy and for at least one day afterwards because of the possibility of disulfiram-like antabuse effect reaction (flushing, vomiting, tachycardia).
Oral anticoagulant therapy (warfarin type): Potentiation 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.
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.
Cyclosporin: Risk of elevation of the cyclosporin serum levels. Serum cyclosporin and serum creatinine 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.
Oral Suspension: When given with alcohol, metronidazole may provoke a disulfiram-like reaction in some patients. Acute psychoses or confusion have been associated with the use of metronidazole and disulfiram together.
Metronidazole is reported to impair the metabolism or excretion of several drugs including warfarin and phenytoin, lithium, ciclosporin, and fluorouracil, with the consequent potential for an increased incidence of adverse effects. There is some evidence that phenytoin might accelerate metabolism of metronidazole. Plasma concentrations of metronidazole are decreased by Phenobarbitals, with a consequent reduction in the effectiveness of metronidazole. Cimetidine increases plasma concentration of metronidazole and might increase risk of neurological adverse effects.

Store at temperatures not exceeding 30°C.

Other Antibiotics / Preparations for Vaginal Conditions

P01AB01 - metronidazole ; Belongs to the class of nitroimidazole derivatives antiprotozoals. Used in the treatment amoebiasis and other protozoal diseases.

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