INSTRUCTION

for medical use of the preparation

METRONIDAZOLE

Composition:

Active substance: metronidazole;

1 ml of the solution contains metronidazole 5 mg;

Auxiliary substances: sodium chloride, water for infections.

Medicinal form. Solution for infusions.

Pharmacotherapeutical group.

Antibacterial agents. Imidazole derivatives. АТС code J01X D01.

Clinical characteristics.

Indications.

Treatment of septicemia, bacteriemia, peritonitis, brain abscess, necrotizing pneumonia, osteomyelitis, puerperal sepsis, abscess of small pelvis organs, pelvic panniculitis, post-operative intentioned wounds, conditioned by anaerobic bacteria.

Prevention of anaerobic infections during surgical operations in patients belonging to groups of risk.

Contraindications.

Hypersensitivity to metronidazole and other nitroimidazole derivatives. Organic lesions of the central nervous system (including epilepsy), blood diseases; hepatic insufficiency (if indication of high doses of the preparation is necessary).

Way of administration and doses.

The preparation is used only intravenously as infusion with the rate of 5 ml/min. As a rule, parenteral introduction of metronidazole is carried out for 7 days, and after that, if necessary, the patient is indicated metronidazole as tablets, orally.

Anaerobic infections. The course of treatment lasts for 7 days. Due to clinical and bacteriological investigations, the doctor may continue the treatment in order to eliminate the infection from the sites, which cannot be drainaged or liable to repeated infecting with anaerobic bacteria (of oropharyngea, intestine or urinal tracts).

Prevention of anaerobic infections. Mainly of abdominal ones (especially colorectal) and in gynecological surgery.

Adults. Adults are indicated 500 mg before surgery, further - 500 mg every 8 hours. When the patient is able to swallow, he/she is indicated 200 mg or 400 mg every 8 hours orally.

Children. Children are indicated on the basis 7.5 mg/kg (1.5 ml/kg) every 8 hours.

The treatment of established anaerobic infections. If the patient is unable to take the preparation orally, he/she is indicated metronidazole as intravenous infusions.

Adults are indicated once 500 mg every 8 hours. Children – 7.5 mg/kg every 8 hours.

Side effects.

Side effects due to the use of metronidazole infusion are observed seldom. In case of long-term treatment with high doses of the preparation (which may be necessary for treatment of severe infections) the following side effects are described:

From the side of gastrointestinal tract: nausea, vomiting, diarrhea, constipation, loss of appetite, dryness or metal taste in the mouth, furred tongue, epigastria pains, glossitis, stomatitis, pancreatitis, jaundice;

From the side of the central nervous system (in case of long-term administration): headache, dizziness, ataxia, hyperexcitability, depression, disturbed sleep, weakness; in single cases – mental confusion, hallucinations, convulsions, peripheral neuropathy (myalgia, paresthesia), tremor, nystagmus, diplopia, myopia;

From the side of urino-genital system: sensation of burning in urethra, increased possibility of development fungus flora of the vagina (candidiasis), dysuria, cystitis, polyuria, enuresis, reddish-brown coloration of the urine;

From the side of endocrine system: disturbed libido, dysmenorrhea;

Allergic reactions: skin hyperaemia, rash, itch, urticaria, stuffiness in nose, fever, anaphylactic reaction;

From the side of the skeleton: arthralgias;

From the side of hematopoietic system: leucopenia, neutropenia, thrombocytopenia, agranulocytosis, pancytopenia;

Other: pain, hyperaemia or edema at the site of injection, trombophlebitis (locally), changes in the cardiogram (smoothing of Т-wave), sinusitis, pharyngitis.

During the treatment, urine may acquire red-brown color, which is conditioned by the presence of water-soluble pigments, which are the product of metronidazole metabolism.

Overdose.

After the intake of high doses of the preparation, there have been observed desorientation, convulsions and peripheral neuropathy.

Treatment. The therapy is symptomatic. There is no specific antidote. Metronidazole is excreted from the organism with hemodialysis.

Use during pregnancy and lactation.

As the action of metronidazole on fetus development is not studied enough, use of the preparation in the I trimester of pregnancy is not recommended. During II and III trimesters, the preparation should be indicated only by life-saving indication.

Metronidazole is excreted in breast milk in rather significant concentrations, that is why it is contraindicated during lactation. If the indication of the preparation is necessary, breast-feeding should be discontinued.

Children.

Metronidazole, solution for infusions, is indicated in children both for prevention (prevention of the development of post-operative infections), and treatment. In children under 12 years old, a single dose is determined on the basis of 7.5 mg per 1 kg of body weight. Children over 12 years old are indicated the same doses of the preparation as the adults.

Special preventive measures.

During use of the preparation, patients should not take alcohol, as there is a possibility of development of disulfiram-like reaction: abdominal pain of spastic character, nausea, vomiting, headache, hot flashes.

In case of long-term treatment with metronidazole patients should undergo peripheral blood analysis regularly. If leucopenia is established, the decision on therapy discontinuation should depend on the risk degree of infectious process development.

If during therapy with the preparation there is a worsening of neurological status of the patient (ataxia, dizziness, etc.), intravenous infusions should be discontinued.

Use of the preparation may cause Treponema immobilization and thus leas to false-positive Nelson test.

Metronidazole infusions should be indicated with caution to the patients with severe renal insufficiency (creatinine clearance 30 ml/min). Repeated use of this preparation in these patients may lead to metronidazole accumulation in serum.

Peculiarities of the use.

Do not remove the overwrap off the internal container before the use. The overwrap protects the preparation from moisture. Internal container provides sterility of the preparation. After removing the overwrap, press the container to make sure, there is no leak of the preparation. If there is a leak, the vial should be changed.

Immediately before the use, the vial with the preparation should be heated to room temperature or much better – to 37°С.

As soon as possible, it is better to change intravenous infusions of metronidazole by oral use of the preparation (200 - 400 mg three times a day).

Ability to influence the reaction rate when driving or operating other mechanisms.

During therapy with the preparation patients should avoid driving and working with other complicated mechanisms.

Interaction with other medicinal preparations and other forms of interaction.

Metronidazole should be indicated with caution concomitantly with some medicinal praparations.

Warfarin and some indirect anticoagulants. Metronidazole increases the action of indirect anticoagulants, which leads to prolonged time of prothrombin formation and increased risk of bleeding. That is why regular control of coagulogram is necessary.

Disulfiram (esperal). Concomitant use may lead to the development of neurological symptoms, that is why metronidazole should not be indicated to the patients who took disulfiram for two previous weeks.

Cimetidine inhibits metabolism of metronidazole, which may lead to its increased serum concentration and increased risk of side effect development.

Concomitant use of the preparations that stimulate enzymes of microsomal oxidation in the liver (phenobarbital, phenytoin), may accelerate the elimination of metronidazole. As a result, its plasma concentration decreases.

In patients, who received lithium preparations in high doses for a rather long period of time, in case of concomitant use of metronidazole there is a possibility of increased lithium concentration in plasma and development of intoxication symptoms.

Antimicrobial action of metronidazole increases in combination with antibiotics and sulfanilamides.

Alcohol intake during therapy with the preparation may lead to disulfiram-like reaction.

Pharmacological properties.

Pharmacodynamics. Active component of the preparation, metronidazole, is a synthetic (derivative of 5-nitroimidazole), anti-protozoal and antibacterial agent. Mechanism of its action lies in biochemical reduction of metronidazole 5-nitro-group by intracellular transport proteins of anaerobes and protozoans. Reduced metronidazole 5-nitro-group interacts with DNA of microorganisms, inhibiting its synthesis, which leads to the death of microorganisms.

Metronidazole is effective against Trichomonas vaginalis, Giardia intestinalis, Gardnerella vaginalis, Entamoeba histolytica, Balantidium coli, Lamblia spp., as well as obligate anaerobes: Bacteroides spp. (B. fragilis, B. distasonis, B. thetaiotaomicron, B. vulgatus, B. ovatus), Fusobacterium spp, Veillonella spp, Prevotella spp. (P.bivia, P.buccae, P.disins) and some gram-positive microorganisms: Eubacterium spp., Clostridium spp., Peptostreptococcus spp., Peptococcus spp.

In combination with amoxicillin metronidazole is active against Hilobacter pylori, as amoxicillin inhibits the development of metronidazole-resistance.

Aerobes and facultative aerobes are not sensitive to metronidazole

Pharmacokinetics. After metronidazole intravenous infusion in patients with anaerobe infection in the dose of 500 mg (for 20 min), its serum concentration is as follows: in 1 hour – 35.2 µg/ml, in 4 hours – 33.9 µg/ml and in 8 hours – 25.7 µg/ml. Bile concentration of metronidazole in gallbladder after infusion of 500 mg in patients with normal function of biliary tracts is much higher than serum concentration. Metronidazole reaches its bactericidal concentration in most tissues and fluids of human organism, including brain, cerebrospinal fluid, abscess cavities, saliva, bile, genital discharge, amniotic fluid and breast milk.

In human organism 30 - 60% of metronidazole is metabolized by side chain oxidation, hydroxylation and glucuronidation. The main product of its metabolism is 1-(2-oxiethyl)-2-oximethil-5-nitroimidazole, which together with glucuronid is between 40 and 50% of the substance excreted with urine.

In patients with normal hepatic function after introduction of the single dose of the preparation half-decay period of metronidazole is, on average, 8 hours (6 - 12 hours). In case of alcohol-induced liver dysfunction, half-decay period increases to 18 hours (10 - 29 hours).

Metronidazole binding to plasma proteins is insignificant – not more than 10 - 20%. It penetrates into tissues easily; the volume of its distribution is 70 - 95% of body weight.

Between 35 and 65% of all nitro-derivatives of the preparation is excreted with urine within 24 hours. Renal clearance is 10.2 ml/min. In patients with renal dysfunction after repeated introductions of the preparation there is an accumulation of metronidazole in serum. That is why patients with acute renal insufficiency should receive decreased number of introductions.

Pharmaceutical characteristics.

Main physical and chemical properties: transparent, colorless or pale yellow solution without mechanical inclusions.

Incompatibility.

It is not recommended to mix metronidazole for intravenous infusions with other medicinal preparations. Concomitant introduction of metronidazole and mixture of 10% glucose, penicillin G, potassium, lactose and Ringer's solution is contraindicated, as these substances are chemically incompatible.

Shelf life. 2 years.

Storage conditions.

Store in the original package in protected from light place at temperature not exceeding 25°С.

Do not freeze.

Keep out of the reach of children.

Packing. 100 ml in a container, 1 in a package.

Terms of dispensing. On prescription.

Applicant.

Ananta Medicare Ltd.

Location. Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, London, Great Britain.

Manufacturer. Eurolife Healthcare Pvt. Ltd.

Location. Khasra No. 520, Bhagwanpur, Poorkee, Haridwar, India; 69-А Mittal Chambers, Nariman Point, Mumbai-400021, India.