SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Flagyl S 200mg/5ml Oral Suspension

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 5ml of suspension contains 200mg metronidazole (as the benzoate)

Excipients

This medicinal product contains small amounts of ethanol (alcohol), less than 100mg per 5ml.

For a full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Oral suspension

Flagyl S suspension is a white to cream suspension with a slight yellow tinge and an odour of orange and lemon.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Flagyl is indicated in adults and children for the following indications:

1.    The prevention of post-operative infections due to anaerobic bacteria,

particularly species of    Bacteroides,    and anaerobic streptococci.

2.    Treatment of urogenital trichomonas in the female (trichomonal vaginitis) and in the male.

3.    Treatment of all forms of amoebiasis (intestinal and extra-intestinal disease and that of symptomless cyst passers).

Treatment of giardiasis.

5.    Treatment of acute ulcerative gingivitis (Vincent’s).

6.    Treatment of anaerobically-infected leg ulcers and pressure sores.

7.    Treatment of acute dental infections (e.g. acute pericoronitis and acute apical infections).

8.    Treatment of septicaemia, bacteraemia, brain abscess, necrotising pneumonia, osteomyelitis, puerperal sepsis, pelvic abscess, pelvic cellulitis, peritonitis, and post-operative wound infections from which pathogenic anaerobes have been isolated.

9.    Non specific vaginitis.

Considerations should be given to official guidance on the appropriate use of

antibacterial agents.

4.2 Posology and method of administration

For oral administration.

Suspension can be diluted with syrup BP.

Dosage is given in terms of metronidazole or metronidazole equivalent.

Treatment of anaerobic infections:

Treatment for seven days should be satisfactory for most patients but, depending on the clinical and bacteriological assessments, the physician might decide to prolong treatment. The tablets or suspension may be given alone or concurrently with other appropriate antibacterial agents.

Adults and children over 10 years - 400 mg orally three times daily.

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

Children < 8 weeks of age: 15mg/kg as a single dose daily or divided into 7.5mg/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 should preferable be monitored after a few days therapy.

Prophylaxis against postoperative infections caused by anaerobic bacteria:

Children < 12 years of age: 20-30 mg/kg as a single dose given 2-3 hours before surgery

Newborns with a gestation age <40 weeks: 10mg/kg body weight as a single dose 2-3 hours before surgery

Dosage is given in terms of metronidazole or metronidazole equivalent

	Duration of dosage in days	Adults and children over 10 years	Children
			7 to 10 years	3 to 7 years	1 to 3 years
Urogenital trichomoniasis Where reinfection is likely, in adults the consort should receive a similar course of treatment concurrently	7 or	2000mg as a single dose or 200 mg three times daily or	40mg/kg orally as a single dose or 15-30 mg/kg/day divided in 2-3 doses; not to exceed 2000mg/dose
	5-7	400mg twice daily
Bacterial vaginosis	5-7 or	400 mg twice daily
	1	2000mg as a single dose

Dosage is given in terms of metronidazole or metronidazole equivalent

	Duration of dosage in days	Adults and children over 10 years	Children
			7 to 10 years	3 to 7 years	1 to 3 years
Amoebiasis (a) Invasive intestinal disease in susceptible subjects	5	800 mg three times daily	400 mg three times daily	200 mg four times daily	200 mg three times daily
(b) Intestinal disease in less susceptible subjects and chronic amoebic hepatitis	5-10	400 mg three times daily	200 mg three times daily	100 mg four times daily	100 mg three times daily
(c) Amoebic liver abscess also other forms of extra-intestinal amoebiasis	5

(d) Symptomless cyst passers	5-10	400-800 mg three times daily	200-400 mg three times daily	100-200 mg four times daily	100-200 mg three times daily
	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 2400mg/day
Giardiasis	3	2000mg once daily or	1000mg once daily	600-800 mg once daily	500 mg once daily
	5	400mg three times daily or
	7-10	500mg twice daily
	Alternatively, as expre 15-40 mg/kg/day divic		ssed in mg per kg of body weight: ed in 2-3 doses.
Acute ulcerative gingivitis	3	200 mg three times daily	100 mg three times daily	100 mg twice daily	50 mg three times daily
Acute dental infections	3-7	200 mg three times daily
Leg ulcers and pressure sores	7	400 mg three times daily

Immature children and infants weighing less than 10 kg should receive proportionally smaller dosages.

Eradication of Helicobacter pylori in paediatric patients:

As a part of a combination therapy, 20mg/kg/day not to exceed 500mg twice daily for 7-14 days. Official guidelines should be consulted before initiating therapy.

4.3 Contraindications

Known hypersensitivity to nitroimidazoles, metronidazole or any of the excipients.

4.4 Special warnings and precautions for use

Flagyl suspension contains methylhydroxybenzoate and propylhydroxybenzoate which may cause allergic reactions (possibly delayed).

Flagyl suspension contains small amounts of ethanol (alcohol), less than 100mg per 5ml.

Regular clinical and laboratory monitoring (especially leucocyte count) are advised if administration of Flagyl for more than 10 days is considered to be necessary and patients should be monitored for adverse reactions such as peripheral or central neuropathy (such as paresthesia, ataxia, dizziness, convulsive seizures).

Metronidazole should be used with caution in patients with active or chronic severe peripheral and central nervous system disease due to the risk of neurological aggravation.

There is a possibility that after Trichomonas vaginalis has been eliminated a gonococcal infection might persist.

The elimination half-life of metronidazole remains unchanged in the presence of renal failure. The dosage of metronidazole therefore needs no reduction. Such patients however retain the metabolites of metronidazole. The clinical significance of this is not known at present.

In patients undergoing haemodialysis metronidazole and metabolites are efficiently removed during an eight hour period of dialysis. Metronidazole should therefore be re-administered immediately after haemodialysis.

No routine adjustment in the dosage of Flagyl need be made in patients with renal failure undergoing intermittent peritoneal dialysis (IDP) or continuous ambulatory peritoneal dialysis (CAPD).

Metronidazole is mainly metabolised by hepatic oxidation. Substantial impairment of metronidazole clearance may occur in the presence of advanced hepatic insufficiency. Significant cumulation may occur in patients with hepatic encephalopathy and the resulting high plasma concentrations of metronidazole may contribute to the symptoms of the encephalopathy. Flagyl should therefore, be administered with caution to patients with hepatic encephalopathy. The daily dosage should be reduced to one third and may be administered once daily.

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

Patients should be warned that metronidazole may darken urine.

Due to inadequate evidence on the mutagenicity risk in humans (see section 5.3), the use of flagyl for longer treatment than usually required should be carefully considered.

4.5 Interaction with other medicinal products and other forms of interaction

Patients should be advised not to take alcohol during metronidazole therapy and for at least 48 hours afterwards because of the possibility of a disulfiram-like (antabuse effect) reaction. Psychotic reactions have been reported in patients who were using metronidazole and disulfiram concurrently.

Some potentiation of anticoagulant therapy has been reported when metronidazole has been used with the warfarin type oral anticoagulants. Dosage of the latter may require reducing. Prothrombin times should be monitored. There is no interaction with heparin.

Lithium retention accompanied by evidence of possible renal damage has been reported in patients treated simultaneously with lithium and metronidazole. Lithium treatment should be tapered or withdrawn before administering metronidazole. Plasma concentrations of lithium, creatinine and electrolytes should be monitored in patients under treatment with lithium while they receive metronidazole.

Patients receiving phenobarbital or phenytoin metabolise metronidazole at a much greater rate than normally, reducing the half-life to approximately 3 hours.

Metronidazole reduces the clearance of 5 fluorouracil and can therefore result in increased toxicity of 5 fluorouracil.

Patients receiving ciclosporin are at risk of elevated ciclosporin serum levels. Serum ciclosporin and serum creatinine should be closely monitored when coadministration is necessary.

Plasma levels of busulfan may be increased by metronidazole which may lead to severe busulfan toxicity.

4.6 Pregnancy and lactation

There is inadequate evidence of the safety of metronidazole in pregnancy. Flagyl should not be given during pregnancy or during lactation unless the physician considers it essential; in these circumstances the short, high-dosage regimens are not recommended.

4.7 Effects on ability to drive and use machines

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.

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 standard recommended 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.

Blood and lymphatic system disorders:

Very rare: agranulocytosis, neutropenia, thrombocytopenia, pancytopenia

Not known: leucopenia.

Immune system disorders:

Rare: anaphylaxis

Not known: angiodema, urticaria, fever.

Metabolism and nutrition disorders:

Not known: anorexia.

Psychiatric disorders:

Very rare: psychotic disorders, including confusion and hallucinations.

Not known: depressed mood 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, headaches Not known:

•    during intensive and/or prolonged metronidazole therapy, peripheral sensory neuropathy or transient epileptiform seizures have been reported. In most cases neuropathy disappeared after treatment was stopped or when dosage was reduced.

•    aseptic meningitis

Eye disorders:

Very rare: vision disorders such as diplopia and myopia, which, in most cases, is transient.

Not Known: optic neuropathy/neuritis Ear and labyrinth disorders

Not known: hearing impaired/hearing loss (including sensorineural), tinnitus Gastrointestinal disorders:

Not known: taste disorders, oral mucositis, furred tongue, nausea, vomiting, gastro-intestinal disturbances such as epigastric pain and diarrhoea.

Hepatobiliary disorders:

Very rare:

•    increase in liver enzymes (AST, ALT, alkaline phosphatase), cholestatic or mixed hepatitis and hepatocellular liver injury, jaundice and pancreatitis which is reversible on drug withdrawal.

•    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:

Very rare: skin rashes, pustular eruptions, pruritis, flushing

Not known: erythema multiforme, Stevens-Johnson syndrome or toxic epidermal necrolysis, fixed drug eruption

Musculoskeletal, connective tissue and bone disorders:

Very rare: myalgia, arthralgia.

Renal and urinary disorders:

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

Reporting of suspected adverse reactions:

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Single oral doses of metronidazole, up to 12g have been reported in suicide attempts and accidental overdoses. Symptoms were limited to vomiting, ataxia and slight disorientation. There is no specific antidote for metronidazole overdosage. In cases of suspected massive overdose, symptomatic and supportive treatment should be instituted.

5.1 Pharmacodynamic properties

Pharmacotherapeutic code: Antibacterials for systemic us, ATC code: J01X D01

Metronidazole is active against a wide range of pathogenic micro-organisms notably species of Bacteroides, Fusobacteria, Clostridia, Eubacteria, anaerobic cocci and Gardnerella vaginalis. It is also active against Trichomonas, Entamoeba histolytica, Giardia lamblia and Balantidium coli.

5.2 Pharmacokinetic properties

After a 400mg metronidazole (or equivalent) single oral dose, given either as metronidazole benzoate 6.4% suspension or metronidazole tablet, t_max is delayed by approximately 2 hours (3h versus 50 minutes), C_max decreased by 45% and AUC by 20% corresponding to a decrease in relative bioavailability of 20% of the oral suspension compared to the tablet. No change in elimination half-life is reported. These slight differences in the rate and extent of metronidazole absorption are due to the transformation of metronidazole benzoate to the active compound metronidazole by hydrolysation in the gastrointestinal tract.

Metronidazole is excreted in milk but the intake of a suckling infant of a mother receiving normal dose would be considerably less than the therapeutic dosage for infants.

5.3 Preclinical safety data

Metronidazole has been shown to be carcinogenic in the mouse and in the rat following chronic oral administration however similar studies in the hamster have given negative results. Epidemiological studies have provided no clear evidence of an increased carcinogenic risk in humans.

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.

6.1    List of excipients

Sucrose

Sodium dihydrogen phosphate LC or sodium acid phosphate crystalline Veegum HV

Methyl hydroxybenzoate (E218)

Propyl hydroxybenzoate (E216)

Ethanol 96% v/v Lemon No. 1 NA Oil orange terpenless Purified water

6.2    Incompatibilities

This medicinal product must not be mixed with other medicinal products except syrup BP for dilution.

6.3    Shelf life

3 years

After dilution with syrup BP the shelf life is 14 days

6.4    Special precautions for storage

Store below 25°C. Protect from light.

Store in the original package in order to protect from light.

6.5 Nature and contents of container

Flagyl S suspension is available in amber glass bottles containing 50, 100 or 125 ml with either a rolled on pilfer proof aluminium cap and a PVDC emulsion coated wad or a HDPE/polypropylene child resistant cap with a tamper evident band.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements

7 MARKETING AUTHORISATION HOLDER

Winthrop Pharmaceuticals UK Limited

One Onslow Street

Guildford

Surrey

GU1 4YS

United Kingdom

Trading as: Winthrop Pharmaceuticals, PO Box 611, Guildford, Surrey, GU1 4YS Or

Trading as: Zentiva, One Onslow Street, Guildford, Surrey, GU1 4YS, UK

8    MARKETING AUTHORISATION NUMBER(S)

PL 17780/0275

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

01/09/1998

10 DATE OF REVISION OF THE TEXT

13/11/2016