APPROVED

Order of the Ministry of Health of Ukraine

dated 03.09.2015 No. 562

Marketing Authorization

           No. UA/10714/01/01 _    

 

INSTRUCTION

for medical use of the drug product

METRESSA

 

Composition:

active substance: metronidazole;

100 ml of solution contain 500 mg of metronidazole;

excipients: sodium chloride, water for injection.

Pharmaceutical form. Solution for infusion.

Basic physic-chemical properties: clear, colourless or slightly yellowish solution.

Pharmacotherapeutic group.

Antibacterial agents for systemic use. Imidazole derivatives.

ATC code J01X D01.

Pharmacological properties.

Pharmacodynamics.

Product active component − metronidazole – is a synthetic (5-nitroimidazole derivative), antiprotozoal and antibacterial agent. Its mechanism of action involves the biochemical reduction of 5-nitrogroup of metronidazole by intracellular transport proteins of anaerobic microorganisms and protozoa. Reduced 5-nitrogroup of metronidazole 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 spas 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, since amoxicillin inhibits the development of resistance to metronidazole.

Aerobic microorganisms and facultative anaerobes are non-susceptible to metronidazole.

Pharmacokinetics.

After intravenous infusion of 500 mg of metronidazole (during 20 min) to patients with anaerobic infections the drug product serum concentration was 35.2 μg/ml after 1 h; 33.9 μg/ml after 4 h and 25.7 μg/ml after 8 h. Metronidazole bile concentration after intravenous infusion of 500 mg to patients with normal function of biliary tract is significantly higher than that in blood serum. Metronidazole reaches bactericidal concentration in most body tissues and fluids, including the brain, spinal fluid, abscess cavities, saliva, bile, genital secretions, amniotic fluid and breast milk.

In human body 30-60 % of metronidazole is metabolized by oxidation of the side chain, hydroxylation and glucuronidation. The main metabolite is 1-(2-oxyethyl)-2-oxymethylл-5-nitromidazole that together with glucuronide constitutes from 40 % to 50 % of the substance that is excreted in the urine.

In patients with normal hepatic function after a single dose administration the half-life period averages 8 h (6-12 h). In case of alcohol-induced hepatic function impairment the half-life period increases to 18 h (10-29 h).

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

Within 24 h from 35 % of 65 % of all drug product nitro-derivatives are excreted in the urine. Renal clearance is 10.2 ml/min. In patients with renal function impairment after repeated administrations of the drug product the accumulation of metronidazole in blood serum occurs. Therefore it is recommended to reduce the number of infusions in patients with acute renal failure.

Clinical particulars.

Therapeutic indications.

Treatment and prophylaxis of infections caused by microorganisms susceptible to metronidazole (mainly anaerobic bacteria).

Treatment is effective in case of:

– infections of the central nervous system (including brain abscess, meningitis);

– infections of the lungs and pleura (including necrotising pneumonia, aspiration pneumonia, lung abscess);

– endocarditis;

– infections of the gastrointestinal tract and abdominal cavity, including peritonitis, hepatic abscess, post-operative infections of colon or rectum, purulent lesions of abdominal or pelvic cavity;

– gynaecological infections (including endometritis after caesarean section or hysterectomy, puerperal fever, septic abortion);

– infections of ENT organs and oral cavity (including angina Vincenti-Plaut);

– infections of bones and joints (including osteomyelitis);

– gaseous gangrene;

– septicaemia with thrombophlebitis.

In mixed aerobic and anaerobic infections, the relevant antibiotics for treatment of aerobic infections should be used additionally to Metressa.

Prophylactic use is always indicated before surgeries involving a high risk of anaerobic infections (before gynaecological and intra-abdominal surgeries).

When using metronidazole, national and international recommendations for proper use of antimicrobial drug products should be considered.

Contraindications.

Hypersensitivity to metronidazole or to other nitroimidazole derivatives. Organic lesions of the central nervous system (including epilepsy); blood disorders; hepatic failure (if high doses of the drug product are required).

Interactions with other medicinal products and other forms of interaction.

Metressa should be prescribed with caution in case of treatment with some drug products.

Alcohol.

Alcohol intake during treatment can lead to undesirable effects, such as flushing, tachycardia, dizziness and nausea (disulfiram-like effect).

Amiodarone.

QT interval prolongation and torsade de pointes have been reported with the coadministration of metronidazole and amiodarone. It may be appropriate to monitor QT interval on the ECG if amiodarone is used in combination with metronidazole. Patients treated on an outpatient basis should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, palpitations, or syncope.

Antibiotics and sulfanilamides.

Antimicrobial effect of Metressa is enhanced in combination with antibiotics and sulfanilamides.

Barbiturates.

Phenobarbital can increase the hepatic metabolism of metronidazole, reducing its plasma half-life to 3 hours.

Busulfan.

Coadministration with metronidazole can significantly increase the plasma concentrations of busulfan. The mechanism of interaction has not been described. Due to the potential risk for severe toxicity and mortality associated with elevated busulfan plasma levels, concomitant use with metronidazole should be avoided.

Disulfiram (esperal).

Coadministration can cause confusion or even psychotic reaction. Combinations of these drug products should be avoided.

Carbamazepine.

Metronidazole may inhibit the metabolism of carbamazepine and raise the plasma concentrations as a consequence.

Contraceptive drug products.

Some antibiotics can, in some exceptional cases, decrease the effect of contraceptive pills by interfering with the bacterial hydrolysis of steroid conjugates in the intestine and hereby reduce the re-absorption of unconjugated steroid. Therefore the plasma levels of the active steroid decrease. This unusual interaction can occur in women with a high excretion of steroid conjugates through the bile. There are case reports of oral contraceptive failure in association with different antibiotics, e.g. ampicillin, amoxicillin, tetracyclines and also metronidazole.

Lithium.

In patients receiving prolonged treatment with lithium drugs at high doses, coadministration with metronidazole can increase lithium plasma concentration and cause the symptoms of intoxication.

Mycophenolat mofetil.

Substances that alter the gastrointestinal flora (e.g., antibiotics) may reduce the oral bioavailability of mycophenolic acid products. Close clinical and laboratory monitoring for evidence of diminished immunosuppressive effect of mycophenolic acid is recommended during concomitant therapy with anti-infective agents.

Coumarin derivatives.

Metronidazole potentiates the anticoagulant effect of coumarin derivatives that leads to increased prothrombin time and increases the risk for bleeding as a consequence of decreased hepatic degradation. Dose adjustment of the anticoagulant can be necessary.

Oral anticoagulant therapy: increased oral anticoagulants effects and an increased risk of haemorrhagic complications due to a slowsown in their hepatic metabolism. More often supervision of INR (international normalized ratio) is required. During metronidazole administration and within 8 days upon its discontinuation the oral anticoagulant dose adjustment is recommended.

Specific problems regarding INR (international normalized ratio).

Many cases of oral anticoagulants increased activity have been observed in patients treated with antibiotics. Risk factors can include infectious, inflammatory diseases and general health state. It is difficult to define the role of infectious disease and its treatment in the frequency of INR. However, certain types of antibacterial agents require special attention. This applies to fluoroquinolones, macrolides, cyclins, clotrimazole and some cephalosporins.

Phenytoin. Metronidazole inhibits the metabolism of concurrently administered phenytoin, i.e. plasma concentrations of phenytoin are increased. On the other hand, the efficacy of metronidazole is reduced when phenytoin is administered concurrently.

Fluorouracil. Metronidazole inhibits the metabolism of fluorouracil in their coadministration, i.e. plasma concentrations of phenytoin are increased.

Cyclosporine. In concomitant treatment with cyclosporine and metronidazole there is a risk of increased serum concentrations of cyclosporine. Frequent monitoring of cyclosporine and creatinine levels is required.

Cimetidine. Cimetidine inhibits the metabolism of metronidazole that can lead to an increased serum concentration of metronidazole and an increased risk of undesirable effects.

Tacrolimus. Coadministration with metronidazole may increase blood concentrations of tacrolimus. The proposed mechanism is inhibition of hepatic tacrolimus metabolism via CYP 3A4. Tacrolimus blood levels and renal function should be checked frequently and the dose adjusted accordingly, particularly following the initiation or discontinuation of metronidazole therapy in patients who are stabilized on their tacrolimus regimen.

Impact on paraclinical tests.

It sgould be remembered that metronidazole is able to immobilize treponema that can lead to the false-positive Melson test result.

Special warnings and precautions for use.

Do not remove the primary container from the wrapper before use. The outer wrapper protects the drug product from moisture. The primary container provides the drug product sterility. After removing the outer wrapper, press on the container in order to check for partial leakage of the drug product. If a leakage occurs, the vial should be replaced.

The vial containing the drug product should be warmed to ambient temperature or better to 37 °С immediately before use. This drug product is intended for single use only. Discard any unused portions of the drug product.

Use only if the solution is clear, and the container or package is intact.

A patient should switch from intravenous infusions of Metressa to oral administration (200-400 mg 3 times a day) as soon as possible.

Patients should be advised not to take alcohol during the therapy because of a disulfram-like reaction: spastic abdominal pain, nausea, vomiting, headache, flushing.

In patients with severe hepatic damage, compromised haemopoesis (including granulocytopenia) metronidazole should only be used if its expected benefits clearly outweigh potential hazards.

Since metronidazole is metabolized mainly in the liver, metronidazole clearance can reduce in patients with hepatic function impairment. Significant accumulation of metronidazole can occur in patients with hepatic encephalopathy and the resulting increased plasma concentrations of metronidazole may contribute to the enhanced symptoms of the encephalopathy. If required, the daily dose may be reduced to ¹/₃ and administered once daily.

In renal function impairment the half-life of metronidazole remains unchanged; therefore the dose adjustment is not required. Metronidazole metabolites, however, delay in such patients. Clinical significance of this fact is unknown.

Metronidazole should be administered with caution to patients with bone marrow or central nervous system diseases, as well as to elderly patients.

In the presence of medical history of haematological disorders, or in case of treatment with high doses of metronidazole and/or prolonged use it is recommended regularly to monitor the number of white blood cells.

If leucopenia develops, it is important to carefully compare the expected benefits of continued treatment and possible risks. In case of prolonged treatment the appearance of undesirable effects should be controlled, such as central and peripheral neuropathy (paresthesia, ataxia, dizziness or convulsive crisis).

Metronidazole should not be administered to patients with porphyria.

Treatment should be discontinued if ataxia, dizziness or confusion occurs.

It is important to consider the risk of deterioration of neurological status in patients with severe, chronic or active peripheral and central nervous system diseases.

Metronidazole is ineffective against aerobic and facultative anaerobic microorganisms.

In prolonged treatment (exceeding 10 days) blood analysis and hepatic function tests should be conducted.

After treatment of Trichomonas vaginalis possibility of gonococcal infection still remains.

Metronidazole and its metabolites are eliminated by dialysis within 8 h. Therefore in patients after haemodialysis c should be re-administered immediately.

Metronidazole can lead to false-negative results of aspartate aminotransferase serum level tests.

During metronidazole treatment and not less than 3 days after its discontinuation patients should be advised not to take alcohol beverages due to the possible occurrence of reactions similar to Antabuse syndrome (dizziness, vomiting).

Prolonged use is not recommended, since carcinogenicity of the drug product has been reported.

Special precautions regarding specific drug product components.

Patients on a diet with controlled sodium intake should consider that one drug product dose contains 790 mg of sodium.

In the case of severe hypersensitivity reactions (including anaphylactic shock) treatment with metronidazole must be discontinued immediately and general emergency treatment must be initiated.

Severe persistent diarrhoea occurring during treatment or during the subsequent weeks may be due to pseudomembranous colitis (in most cases caused by Сlostridium difficile), see section “Undesirable effects”. This intestinal disease, precipitated by the antibiotic treatment, may be life-threatening and requires immediate appropriate treatment. Anti-peristaltic drug products must not be taken.

Duration of treatment with metronidazole or drugs containing other nitroimidazoles should not exceed 10 days. Only in specific elective cases and if definitely needed, the treatment period may be extended, accompanied by the appropriate clinical and laboratory monitoring. Repeated therapy should be maximally restricted to specific elective cases only. These restrictions must be observed strictly because the possibility of metronidazole developing mutagenic activity cannot be safely excluded and because in animal experiments an increase of the incidence of certain tumours has been noted.

Interference with laboratory tests

Metronidazole interferes with the enzymatic-spectrophotometric determination of aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), triglycerides and glucose hexokinase resulting in decreased values (possibly down to zero).

Metronidazole has a high absorbance at the wavelength at which nicotinamide-adenine dinucleotide (NADH) is determined. Therefore elevated hepatic enzyme concentrations may be masked by metronidazole when measured by continuous-flow methods based on endpoint decrease in reduced NADH. Unusually low liver enzyme concentrations, including zero values, have been reported.

Use during pregnancy and breastfeeding.

The drug product is contraindicated during pregnancy.

Breastfeeding should be discontinued for the period of drug product treatment.

Effects on ability to drive and use machines.

Metressa can have a minor or moderate effect on the reaction rate when driving and using other machines, especially in case of alcohol intake during treatment. Patients should be warned about the potential for drowsiness, dizziness, confusion, hallucinations, convulsions or transient visual disorders, and are advised not to drive or operate machinery if these symptoms occur.

Posology and method of administration.

The dosage is adjusted according to the patient’s individual response to therapy, her/his age and body weight and according to nature and severity of the disease.

The following dosage guidelines should be followed:

Adults and children aged above 12 years

The usual dose is 500 mg every 8 h. In case of medical indications at the initiation of treatment the loading dose of 15 mg/kg body weight may be prescribed.

Children aged from 2 to 12 years

7-10 mg of metronidazole/kg body weight every 8 h that corresponds to the daily dose of 20-30 mg metronidazole/kg body weight.

Patients with renal insufficiency

No need for dose reduction (see section “Pharmacological properties”).

Patients with hepatic insufficiency

As serum half-life is prolonged and plasma clearance is delayed in severe hepatic insufficiency, patients with severe liver disease will require lower doses (see section “Pharmacological properties”).

Treatment duration

Treatment duration depends on its efficacy. In most cases the seven day course may be sufficient. In case of clinical indications treatment may be prolonged (see also section “   Special warnings and precautions for use”).

Pre- and post-operative prophylaxis of infections

Adults and children aged above 11 years

500 mg, administration should be stopped approximately 1 hour before surgery. The dose should be repeated after 8 and 16 h.

Children aged from 2 to 11 years

15 mg/kg body weight, administration should be stopped approximately 1 hour before surgery, further 7.5 mg/kg body weight after 8 and 16 h.

 

Administration route

The drug product should be used only intravenously in the form of infusion at a rate of 5 ml/min. Generally parenteral Metressa administration is conducted during 7 days, and then, if required, Metressa is prescribed orally in the form of tablets.

Metressa, solution for infusion may be diluted in a suitable drug product or solutions for infusion, such as 0.9 % sodium chloride solution for infusion or 5 % glucose solution for infusion.

Concurrent antibiotics are administered separately.

Paediatric population.

The drug product may be used in children aged above 2 years according to therapeutic indications.

Overdose.

Undesirable effects can occur at the administration of the drug product (see section “Undesirable effects”).

Treatment. Therapy is symptomatic. There is no known specific antidote. Metronidazole is eliminated by dialysis.

Undesirable effects.

Undesirable effects are rare in case of treatment with Metressa solution for infusion. In prolonged treatment with high doses (which may be required for treatment of severe infections) the following undesirable effects have been described:

Infections and infestations: genital superinfections caused by Сandida, pseudomembranous colitis that can occur during or after therapy and manifests in the form of severe persistent diarrhoea. Detailed description of emergency treatment is described in section “Special warnings and precautions for use”.

Blood and lymphatic system disorders: (leucopenia, granulocytopenia, and thrombocytopenia), neutropenia, pancytopenia, agranulocytosis, aplastic anaemia.

During prolonged treatment the regular control of haematic picture is mandatory.

Immune system disorders: mild to moderate hypersensitivity reactions, including skin reactions (see “Skin and subcutaneous tissue disorders”), angioedema and drug fever, severe systemic hypersensitivity reactions: anaphylaxis, up to anaphylactic shock, severe skin reactions (see “Skin and subcutaneous tissue disorders”).

Severe reactions require immediate therapeutic intervention.

Psychiatric disorders: irritability, depression, anxiety, asthenia, depressed mood, psychotic disorders, including confusion, hallucination.

Nervous system disorders: headache, dizziness, sleep disturbances, seizures, peripheral neuropathy (myalgia, paresthesia), heavy and tingling sensations in the extremities, encephalopathy, development of subacute cerebellar syndrome (ataxia, dysarthria, coordination disturbances, nystagmus, tremor), diplopia, myopia, febrile manifestations, optic neuropathy/neuritis.

In case of seizures of signs of peripheral neuropathy a patient must seek medical attention immediately.

Eye disorders: vision disturbances, including blurred vision, reduction in visual acuity, changes in colour vision, double vision, myopia, oculogyric crisis (isolated cases).

Cardiac disorders: ECG changes (flattening of T-wave).

Gastrointestinal disorders: vomiting, nausea, diarrhoea, glossitis and stomatitis, eructation with bitter taste, epigastric pressure, loss of appetite, dry mouth or metallic taste in the mouth, pancreatitis, discolouration of the tongue, furred tongue (e.g. due to the excessive development of fungal flora).

Endocrine system disorders: libido disturbances, dysmenorrhoea.

Hepatobiliary disorders: abnormal values of hepatic enzymes and bilirubin, hepatitis, jaundice, destruction of hepatic cells, cases of hepatic failure requiring liver transplantation in patients treated with metronidazole in combination with other antibiotics.

Skin and subcutaneous tissue disorders: allergic skin reactions, including pruritus, urticaria, erythema multiforme, rash; urticaria, skin hyperaemia, Stevens-Johnson syndrome (isolated reports), toxic epidermal necrolysis (isolated reports).

The last two reactions require immediate therapeutic intervention.

Musculoskeletal system and connective tissue disorders: arthralgia, myalgia.

Renal and urinary disorders: red-brown coloured urine (due to water-soluble pigments which are metronidazole metabolites), dysuria, cystitis, enuresis, burning sensation in the urethra, increasing the probability of development of fungal vaginal flora (candidiasis).

General disorders and administration site conditions: pain, prolonged hyperaemia, hyperaemia or oedema in the injection site, thrombophlebitis (local), pustular rash.

Others: sinusitis, pharyngitis, aseptic meningitis.

Shelf life. 3 years.

Storage conditions.

Store in the original container at a temperature below 25 °С.

Keep away from children.

Discard any unused portions of the drug product.

Incompatibility.

Metressa for infusion should not be mixed with other drug products, excluding those specified in section “Posology and method of administration”. Coadministration of 10% dextrose, penicillin G, potassium, lactose and Ringer solution with Metressa is contraindicated, as these substances are chemically incompatible.

Package. 100 ml of the drug product in containers. 1 container in polyvinyl chloride film together with the instruction for medical use in a box.

Dispensing category. Available upon prescription.

Manufacturer. Eurolife Healthcare Pvt.Ltd.

Manufacturer’s address.

Khasra No. 520, Bhagwanpur, Roorkee, Haridwar, India

Applicant. Ananta Medicare Ltd.

Applicant’s address.

Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, London, United Kingdom.

Date of the last revision. September 3, 2015.