SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Metronidazole MacoPharma 0.5%w/v Solution for Infusion

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Metronidazole 500mg/100ml

Excipients: contains sodium (as sodium chloride and disodium phosphate anhydrous), 15mmol (340mg) per 100ml dose.

For a full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Solution for infusion.

Clear pale yellow infusion solution without visible particles.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Metronidazole is indicated in adults and children for the treatment of severe infections due to anaerobic bacteria, and for prophylaxis against such infections in patients for whom oral medication is not practical.

Consideration should be given to official guidance on the appropriate use of antibacterial agents

4.2    Posology and method of administration

Metronidazole MacoPharma 0.5%w/v Solution for Infusion should be infused intravenously at a rate of approximately 5ml per minute, and should be substituted with oral medication as soon as possible.

Metronidazole MacoPharma 0.5%w/v Solution for Infusion may be administered concurrently (but separately) with other appropriate antimicrobial agents in parenteral dosage forms.

Treatment of established anaerobic infections:

Intravenous medication can be used in patients with severe anaerobic infections for whom oral medication is precluded. Treatment for 7 days should suffice in most cases but this period may be extended depending on clinical and microbiological assessments and the site of infection. Regular clinical and laboratory monitoring is advised if administration continues for more than 10 days (see section 4.4 Warnings and Precautions for Use).

Adults: Infuse 500mg (100ml) 8 hourly.

Children > 8 weeks to 12 years of age: The usual daily dose is 20-30 mg/kg/day as a single dose or divided into 7.5 mg/kg every 8 hours. The daily dose may be increased to 40 mg/kg, depending on the severity of the infection. Duration of treatment is usually 7 days.

Children < 8 weeks of age: 15 mg/kg as a single dose daily or divided into 7.5 mg/kg every 12 hours.

In newborns with a gestation age <40 weeks, accumulation of metronidazole can occur during the first week of life, therefore the concentrations of metronidazole in serum preferably should be monitored after a few days treatment.

Use with caution in the elderly.

Prophylaxis against postoperative infections caused by anaerobic bacteria :

Metronidazole MacoPharma 0.5%w/v Solution for Infusion is indicated predominantly in abdominal (especially colorectal) and gynaecological surgery.

Adults: the usual dose is 500mg (100ml) immediately before, during or after surgery, then 500mg 8 hourly.

Children < 12 years: 20-30 mg/kg as a single dose given 1-2 hours before surgery

Newborns with a gestation age <40 weeks: 10 mg/kg body weight as a single dose before operation

Use with caution in the elderly although limited information is available on how dose should be altered.

Bacterial vaginosis:

Adolescents: 400 mg twice daily for 5-7 days or 2000 mg as a single dose

Urogenital trichomoniasis

Adults and adolescents: 2000 mg as a single dose or 200 mg 3 times daily for 7 days or 400mg twice daily for 5-7 days

Children < 10 years: 15 - 30 mg/kg/day divided in 2-3 doses for 7 days; not to exceed 2000 mg/dose

Giardiasis:

>    10 years: 2000 mg once daily for 3 days, or 400 mg three times daily for 5 days, or 500 mg

twice daily for 7 to 10 days

Children 7 to 10 years: 1000 mg once daily for 3 days Children 3 to 7 years: 600 to 800 mg once daily for 3 days

Children 1 to 3 years: 500 mg once daily for 3 days

Alternatively, as expressed in mg per kg of body weight:

15-40 mg/kg/day divided in 2-3 doses.

Amoebiasis:

>    10 years: 400 to 800 mg 3 times daily for 5-10 days Children 7 to 10 years: 200 to 400 mg 3 times daily for 5-10 days Children 3 to 7 years: 100 to 200 mg 4 times daily for 5-10 days Children 1 to 3 years: 100 to 200 mg 3 times daily for 5-10 days

Alternatively, doses may be expressed by body weight

35 to 50 mg/kg daily in 3 divided doses for 5 to 10 days, not to exceed 2400

mg/day

Eradication of Helicobacter pylori in paediatric patients:

As a part of a combination therapy, 20 mg/kg/day not to exceed 500 mg twice daily for 7-14

days. Official guidelines should be consulted before initiating therapy

Posology adjustments:

-    The elimination half-life of metronidazole is unchanged in renal failure and dosage needs no reduction. Patients with renal failure retain the metabolites of metronidazole but the clinical significance of this is currently unknown. No routine adjustment in the dosage of Metronidazole MacoPharma 0.5%w/v Solution for Infusion need be made in patients with renal failure undergoing intermittent peritoneal dialysis (IPD) or continuous ambulatory peritoneal dialysis (CAPD).

-    In patients undergoing haemodialysis metronidazole and its metabolites are efficiently removed during an 8 hour period. Metronidazole should therefore be administered immediately after haemodialysis.

-    Metronidazole MacoPharma 0.5%w/v Solution for Infusion should be administered with caution to patients with hepatic encephalopathy as it is metabolised mainly by hepatic oxidation. Substantial impairment of metronidazole clearance may occur with advanced hepatic insufficiency. Significant accumulation may occur in patients with hepatic encephalopathy and the resulting high plasma concentrations of metronidazole may contribute to the symptoms. The daily dosage should be reduced to one-third and may be administered once daily.

4.3 Contraindications

Known hypersensitivity to metronidazole.

4.4 Special warnings and precautions for use

Intensive or prolonged metronidazole therapy should be conducted only under conditions of close surveillance for clinical and biological effects and under specialist direction.

Reversible peripheral neuropathy has been reported with intensive or prolonged therapy with metronidazole.

If prolonged therapy is required the physician should bear in mind the possibility of peripheral neuropathy or leucopenia. Both effects are usually reversible.

High dose regimens have been associated with transient epileptiform seizures.

Metronidazole should be administered with caution to patients with hepatic encephalopathy.

Metronidazole should be used with great care in patients with active disease of the central nervous system other than brain abscess.

Other imidazoles should be administered with caution to patients who have previously developed pancreatitis as an adverse reaction to metronidazole.

All patients receiving metronidazole for more than 10 days should be monitored, and treatment discontinued if signs of peripheral neuropathy or CNS toxicity develop

This solution contains sodium (as sodium chloride and disodium phosphate anhydrous), 15mmol (340mg) per 100ml dose, which needs to be taken into consideration by patients on a sodium-controlled diet.

4.5 Interaction with other medicinal products and other forms of interaction

Patients should not consume alcohol during and for at least 48 hours after metronidazole treatment because of a possible disulfiram-like (antabuse effect) reaction.

Metronidazole has been reported to enhance the anticoagulant effect of the warfarin and coumarin type anticoagulants, the dosage of which may therefore require reducing. Prothrombin times should be monitored. No interactions have been reported with the heparin-type anticoagulants.

Simultaneous treatment with lithium and metronidazole may impair clearance of lithium, accompanied by evidence of possible renal damage. Lithium treatment should be withdrawn or gradually reduced before administering metronidazole. Plasma concentrations of lithium, creatinine and electrolytes should be monitored in patients treated with both lithium and metronidazole.

The rate of metabolism of metronidazole is increased in patients treated with pheno-barbitone, reducing metronidazole half-life to approximately 3 hours.

Metronidazole may impair the clearance of phenytoin.

Aspartate amino-transferase assays may give spuriously low values in patients treated with metronidazole, depending on the test method use.

Metronidazole has anti-treponemal activity and may mask the immunological response seen in untreated early syphilis; contacts of syphilis receiving metronidazole should probably be screened for an additional 4 - 8 weeks.

Metronidazole increases the toxicity of 5-fluorouracil by decreasing its renal clearance.

Metronidazole potentiates the activity of vecuronium.

Metronidazole may interact with disulfiram causing psychotic effects

4.6 Pregnancy and lactation

Metronidazole, like other medicines, should not be given during pregnancy or lactation unless the physician considers it essential; in these circumstances short high-dosage regimens are not recommended. Metronidazole is excreted in milk but the intake of a suckling infant of a mother receiving normal dosage would be considerably less than the therapeutic dosage for infants.

4.7 Effects on ability to drive and use machines

Patients should not drive or operate machinery if they become dizzy or drowsy.

4.8 Undesirable effects

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).

Serious adverse reactions occur rarely with the recommended dosage regimens. Clinicians who contemplate continuous therapy for the relief of chronic conditions, for periods longer than those recommended, are advised to consider the possible therapeutic benefit against the risk of peripheral neuropathy.

The frequency, type and severity of adverse reactions in children are the same as in adults

Thrombophlebitis may occur following intravenous administration of metronidazole.

Blood and lymphatic system disorders:

Very rare: agranulocytosis, neutropenia, thrombocytopenia and pancytopenia, often reversible on drug withdrawal, fatalities have occurred.

Not known: temporary moderate leucopenia

Immune system disorders:

Rare: anaphylaxis

Very rare: Steven-Johnson syndrome Not known: angioedema, urticaria

Metabolism and nutrition disorders Not known: anorexia.

Psychiatric disorders:

Very rare: psychotic disorders, including hallucinations.

Not known: insomnia and changes in mood or mental state such as depression or confusion

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, headache

Not known: during high-dosage or prolonged metronidazole treatment, a few instances of peripheral neuropathy or transient epileptiform seizures have been reported. In most cases neuropathy disappeared after treatment was stopped or when dosage was reduced.

Eye disorders:

Very rare: transient visual disorders such as diplopia and myopia Gastrointestinal disorders:

Not known: taste disorders, oral mucositis, furred tongue, nausea, vomiting, gastro-intestinal disturbance, antibiotic-associated pseudomembranous colitis

Hepatobiliary disorders:

Very rare: abnormal liver function tests, cholestatic hepatitis, jaundice, and pancreatitis reversible on drug withdrawal

Skin and subcutaneous tissue disorders:

Very rare: skin rashes, pruritis, pustular eruptions

Not known: Erythema multiforme which may be reversed on drug removal.

Musculoskeletal, connective tissue and bone disorders:

Very rare: myalgia, arthralgia

Renal and urinary disorders:

Very rare: darkening of the urine (due to metronidazole metabolite).

4.9 Overdose

There is no specific treatment for gross overdose of metronidazole. Metronidazole and its metabolites are efficiently removed during an 8 hour period of haemodialysis.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Metronidazole is an antimicrobial agent of the nitro-5-imidazole family. It is active against a wide range of pathogenic micro-organisms in particular species of Bacteroides, Clostridia, Eubacteria, Fusobacteria, Gardnerella vaginalis,and anaerobic cocci. It is also active against Balantidium coli, Entamoeba histolytica, Giardia lamlia and Trichomonas. Metronidazole enters target cells of bacteria or protozoa probably by passive diffusion and is activated by reduction of the nitro group by pyruvate-ferredoxin oxidoreductase; the resultant unstable intermediate interacts with DNA effectively preventing replication.

5.2 Pharmacokinetic properties

After injection, metronidazole is widely distributed in most body tissues and fluids reaching concentrations similar to those in plasma; it crosses the placenta and rapidly enters the foetal circulation. No more than 20% metronidazole is bound to plasma proteins. Peak steady state plasma concentrations of approximately 25gg/ml with a trough concentration of 18gg/ml have been reported in patients given an intravenous loading dose of 15mg/kg body weight followed by 7.5mg/kg every 6 hours.

Metronidazole is metabolised mainly by hepatic oxidation and glucuronide formation. At least half of the infused dose is recovered in urine after approximately 8 hours, as metronidazole but mainly as its principal metabolites: metabolite I (hydroxy form) present in plasma and urine and with 30 - 65% activity of metronidazole, and metabolite II (acid form) not detected in plasma but representing 40 - 50% of the substances in urine, with 5% activity of metronidazole. Metronidazole crosses the placenta and rapidly enters the foetal circulation. It is excreted in milk but the intake of a breastfed infant of a mother receiving the recommended dose would be considerably less than the therapeutic dose for infants.

The half-life of metronidazole is reported to be longer in neonates and in patients with liver disease; that of the hydroxy metabolite is prolonged in patients with renal failure.

Metronidazole may impair the clearance of phenytoin.

Cimetidine has increased plasma concentrations of metronidazole and might increase the risk of neurological side-effects.

5.3 Preclinical safety data

There are no preclinical data of relevance to the prescriber not already included in other sections of the SPC.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium chloride Disodium phosphate anhydrous Citric acid monohydrate Water for Injections in bulk

6.2 Incompatibilities

Metronidazole solution must not be mixed with cefamandole nafate, cefoxitin sodium, 10%w/v dextrose infusion, compound sodium lactate infusion, penicillin G potassium.

Cefuroxime sodium is physically and chemically compatible with Metronidazole MacoPharma 0.5%w/v Solution for Infusion. The following drugs are physically compatible in terms of pH and appearance over the recommended period of administration, although chemical stability has not been demonstrated : amikacin sulphate, ampicillin sodium, carbenicillin sodium, cephazolin sodium, cefotaxime sodium, cephalothin sodium, chloramphenicol sodium succinate, clindamycin phosphate, gentamicin sulphate, hydrocortisone sodium succinate, latamoxef disodium, netilmicin sulphate and tobramycin sulphate.

In patients maintained on intravenous fluids, Metronidazole MacoPharma 0.5%w/v Solution for Infusion may be diluted with appropriate volumes of 0.9%w/v sodium chloride solution, isotonic dextrose and sodium chloride solution, 5%w/v dextrose, or 20 or 40mmol/litre potassium chloride solution.

6.3    Shelf life

2 years.

Use immediately on removal from overwrap.

6.4    Special precautions for storage

Do not store above 25°C. Do not freeze. Store in the original outer container to protect from light.

6.5    Nature and contents of container

Macoflex flexible l00ml PVC bag, individually wrapped in transparent polypropylene laminate.

The closed infusion system Macoperf flexible 100ml container incorporates an integral infusion set for direct connection to a luer (eg catheter) in the patient. The bag is individually overwrapped in transparent polypropylene laminate.

6.6    Special precautions for disposal

Metronidazole MacoPharma 0.5%w/v Solution for Infusion is for single use. Do not use unless the solution is clear and free from visible particles and the container undamaged. Discard any unused solution. Do not reconnect partially used bags.

Macoflex bags

Remove the bag from the plastic overwrap. Remove the twist-off protector and connect by to an administration set.

Macoperf bags:

Remove the closed infusion system from the plastic peelable overwrap.

Move the roller clamp down 1 cm before clamping the tubing.

Prime the line:

Break the in-line cannula by flexing the tubing in one direction then the other Fill the drip chamber with solution by squeezing the bag Gradually open the flow regulator and prime the line fully Clamp the tubing and connect to a luer as appropriate The flow rate must be checked regularly during infusion

7    MARKETING AUTHORISATION HOLDER

Macopharma (UK) Ltd,

8^th floor -Regal House 70 London Road Twickenham Middlesex TW1 3QS

8    MARKETING AUTHORISATION NUMBER(S)

PL 12580/0010

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

21/05/2010

10    DATE OF REVISION OF THE TEXT

15/07/2011