Exicipients/Inactive Ingredients: Sodium chloride, disodium hydrogen phosphate (anhydrous), citric acid monohydrate, water for injection.
Pharmacotherapeutic Group: Antimicrobial - antiprotozoal. ATC Code: J01K.
Pharmacology: Pharmacodynamics: Mechanism of Action: The mechanism of action of metronidazole is thought to involve reduction by bacterial nitroreductase to an unstable intermediate, which interact with DNA and effectively preventing further replication.
Pharmacokinetics: Absorption: Plasma concentration of metronidazole are proportional to the administered dose. An 8-hour intravenous infusion of 100 to 400 mg of metronidazole in healthy subjects showed a linear relationship between dose and peak plasma concentration.
Distribution: Metronidazole is widely distributed after absorption. It appears in most body tissues and fluids including bile, bone, breast milk, cerebral abscesses, CSF, liver and liver abscesses, saliva, seminal fluid, and vaginal secretions. It is less than 20% bound to plasma proteins in humans.
Metabolism: Metronidazole is metabolized in the liver by side-chain oxidation and glucuronide formation. The principal oxidative metabolites are the hydroxy metabolite which has an antibacterial activity and is detected in plasma and urine, and the acid metabolite which has virtually no antibacterial activity and is often not detected in plasma, but is excreted in urine.
Excretion: The elimination half-life of metronidazole is about 8 hours. The major route of elimination of metronidazole and its metabolites is via urine (60-80% of the dose), with fecal excretion accounting for 6-15% of the dose. The metabolites that appear in the urine result primarily from side-chain oxidation [1-(β-hydroxyethyl)-2-hydroxymethyl-5-nitromidazole and 2-methyl-5-nitroimidazole-1-yl-acetic acid] and glucuronide conjugation, with unchanged metronidazole accounting for approximately 20% of the total. Renal clearance of metronidazole is approximately 10 mL/min/1.73 m2.
Toxicology: Preclinical Safety Data: Metronidazole has shown evidence of carcinogenic activity in studies involving chronic, oral administration in mice and rats, but similar studies in the hamster gave negative results. Also, metronidazole has shown mutagenic activity in a number of in vitro assay system, but studies in mammals (in vivo) failed to demonstrate a potential for genetic damage.
Reproduction studies have been performed in pregnant mice at doses up to 1.5 times the human dose and have revealed no evidence of fetotoxicity due to metronidazole. Metronidazole administered intraperitoneally to pregnant mice at approximately the human dose caused fetotoxicity.
Microbiology: Metonidazole has been shown to have in vitro and clinical activity against the following organisms: Anaerobic gram-negative bacilli, including Bacteroides species, including Bacteroides fragilis group (B. ovatus, B. thetaiotaomicon, B. vulgatus) and Fusobacterium species.
Anaerobic gram-positive cocci, including Clostridium species and susceptible strains of Eubacterium, Peptococcus and Peptostreptococcus.
Nirmet is used in the treatment of serious infections such as intra-abdominal infections, gynecologic infections, skin and skin structure infections, bone and joints infections, lower respiratory infections, CNS infections, septicemia, and endocarditis caused by susceptible anaerobic bacteria.
Nirmet is used for perioperative prophylaxis to reduce the incidence of postoperative anaerobic bacterial infections in patients undergoing contaminated or potentially contaminated colorectal surgery.
Treatment of Anaerobic Infections: The recommended dosage schedule for adults is: Loading Dose: 15 mg/kg infused over one hour (approximately 1 g for a 70-kg adult).
Maintenance Dose: 7.5 mg/kg infused over one hour every six hours (approximately 500 mg for a 70-kg adult). The first maintenance dose should be instituted six hours following the initiation of the loading dose.
IV to oral conversion: Parenteral therapy may be changed to oral metronidazole when conditions warrant, based upon the severity of the disease and the response of the patient to Nirmet treatment. The usual adult oral dosage is 7.5 mg/kg every six hours.
A maximum adult IV or oral dose recommended is 4 g during a 24-hour period.
Hepatic function impairment: Patients with severe hepatic disease metabolize metronidazole slowly, with resultant accumulation of metronidazole and its metabolites in the plasma. Accordingly, for such patients, doses and/or frequency of administration of metronidazole should be modified in response to the degree of hepatic impairment. Close monitoring of plasma metronidazole levels and toxicity is recommended.
Perioperative Prophylaxis: For surgical prophylactic use, to prevent postoperative infection in contaminated or potentially contaminated colorectal surgery, the recommended dosage schedule for adults is 15 mg/kg infused over 30 to 60 minutes and completed approximately one hour before surgery followed by 7.5 mg/kg infused over 30-60 minutes at 6 and 12 hours after initial dose.
It is important that administration of the initial preoperative dose be completed approximately one hour before surgery so that adequate drug levels are present in the serum and tissues at the time of initial incision. Nirmet is administered, if necessary, at 6-hour intervals to maintain effective drug levels. Prophylactic use of Nirmet should be limited to the day of surgery only, following the previous guidelines.
Nirmet is to be administered by slow intravenous drip infusion only, either as a continuous or intermittent infusion. Additives should not be introduced into Nirmet. If used with a primary intravenous fluid system, the primary solution should be discontinued during metronidazole infusion. Do not use equipment containing aluminum (e.g. needles, cannulae) that would come in contact with the drug solution.
Use of dosages of intravenous metronidazole higher than those recommended has been reported. These include the use of 27 mg/kg three times a day for 20 days, and the use of 75 mg/kg as single loading dose followed by 7.5 mg/kg maintenance doses. No adverse reactions were reported in either of the two cases.
Single oral dose of metronidazole, up to 15 g have been reported in suicide attempts and accidental overdoses. Symptoms reported included nausea, vomiting and ataxia.
Treatment: There is no specific antidote for overdose; therefore, management of the patient should consist of symptomatic and supportive therapy.
Nirmet is contraindicated in patients with a prior history of hypersensitivity to metronidazole or other nitromidazole derivatives, or any component of the formulation.
Metronidazole was carcinogenic in mice and rats in chronic studies, so unnecessary use of metronidazole should be avoided.
Metronidazole may cause convulsive seizures and peripheral neuropathy characterized mainly by numbness, tingling, or parasthesia of an extremity, have been reported rarely in patients treated with Nirmet. Peripheral neuropathy is usually reversible if metronidazole is discontinued but may persist in patients who receive prolonged therapy or higher than recommended dosage of the drug.
Metronidazole intravenous infusion should be used with caution in patients receiving corticosteroids and in patients with renal disease cardiovascular disease and predisposed to edema because the infusion contains sodium 0.326%.
Metronidazole intravenous infusion may result in oral, vaginal, or intestinal candidiasis. If superinfection or suprainfection occurs, appropriate therapy should be instituted.
Metronidazole intravenous infusion may cause leucopenia, so metronidazole should be used with care in patients with evidence of or history of blood dyscrasia. Total and differential leucocyte count are recommended before and after therapy.
Patients with severe hepatic disease metabolized metronidazole slowly, with resultant accumulation of metronidazole and its metabolites in the plasma. Accordingly, for such patients, doses below those usually recommended should be administered cautiously.
Effects on the Ability to Drive or Operate Machinery: 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 during therapy of Metronidazole Injection.
Pregnancy: Pregnancy Category: B.
Metronidazole crosses the placental barrier and enters the fetal circulation rapidly. There are no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, and because metronidazole is a carcinogen in rodents, these drugs should be used during pregnancy only if clearly needed.
Lactation: 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. Metronidazole is secreted in breastmilk in concentrations similar to those found in plasma.
The 2 most serious adverse reactions reported in patients treated with Nirmet have been convulsive seizures and peripheral neuropathy.
The following reactions have also been reported during treatment with Nirmet: Gastrointestinal:
Nausea, vomiting, abdominal discomfort, diarrhea and an unpleasant metallic taste.
Erythematous rash and pruritus.
Central Nervous System:
Headache, dizziness, syncope, ataxia, and confusion.
Thrombophlebitis after intravenous infusion. This reaction can be minimized or avoided by avoiding prolonged use of indwelling intravenous catheters.
Miscellaneous: Fever. Instances of darkened urine have also been reported. A furred tongue, glossitis and stomatitis have occurred; these may be associated with an overgrowth of Candida.
Nirmet potentiates the anticoagulant effect of warfarin and other oral coumarin anticoagulants resulting in a prolongation of prothrombin time, and concurrent administration should avoided if possible.
The simultaneous administration of drugs that induce microsomal liver enzyme activity, such as phenobarbital may accelerate the elimination of metronidazole, resulting in reduced plasma levels and efficacy of metronidazole.
In contrast, the simultaneous administration of drugs that decrease microsomal liver enzyme activity, such as cimetidine, may increase plasma half-life and plasma level of metronidazole.
Alcoholic beverages should not be consumed during metronidazole therapy. A disulfiram-like reaction including symptoms of flushing, palpitation, tachycardia, nausea, vomiting, etc, may occur with concurrent use. Do not consume alcohol during or for at least 1-3 days following completion of metronidazole therapy.
Acute psychosis or confusion has been associated with the use of metronidazole and disulfiram concurrently. Metronidazole should not be given to patients who have taken disulfiram within the last two weeks.
Metronidazole may decrease the elimination of anticonvulsants, hydantoin and lithium, so it may increase hydantoin and lithium concentration, resulting in toxicity in some cases.
Metronidazole may interfere with certain types of determinations of serum chemistry values, such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), triglycerides and hexokinase glucose.
Incompatibilities: Nirmet should not be mixed with other drugs, and other IV infusion should be discontinued while Metronidazole is being infused.
Store below 30°C. Do not freeze, protect from light.
Shelf-Life: 36 months.
J01XD01 - metronidazole ; Belongs to the class of imidazole derivative antibacterials. Used in the systemic treatment of infections.
Infusion 500 mg/100 mL (almost white to pale yellow clear, colourless solution) x 1's.