SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Norzol 200mg/5ml Oral Suspension Metronidazole 200mg/5ml Oral Suspension

2.    QUALITATIVE AND QUANTITATIVE COMPOSITION

Metronidazole Benzoate Ph Eur 320mg/5ml

3.    PHARMACEUTICAL FORM

Oral Suspension

4    CLINICAL PARTICULARS

4.1 Therapeutic indications

Norzol is indicated in the prophylaxis and treatment of infections in which anaerobic bacteria have been identified or are suspected as the pathogen.

Norzol is active against a wide range of pathogenic micro-organisms, notably Trichomonas vaginalis, Entamoeba histolytica, Giardia lamblia, Balantidium coli and other species of bacteroides, fusobacteria, eubacteria, clostridia and anaerobic cocci.

It is indicated in

Adults, Children and Newborns with a gestation age of over 40 weeks for:

•    The treatment of septicaemia, bacteraemia, brain abscess, necrotising pneumonia, osteomyelitis, puerperal sepsis, pelvic abscess, pelvic cellulitis, peritonitis and post-operative wound infections from which one or more pathogenic anaerobes have been isolated.

•    The prevention of post-operative infections caused by anaerobic bacteria particularly species of bacteroides and anaerobic streptococci.

Adults and Children over 10 years only for:

•    Bacterial vaginosis (also known as non-specific vaginitis, anaerobic vaginitis or Gardnerella vaginitis).

•    Acute dental infections (e.g. acute pericoronitis and acute apical infections).

•    Anaerobically infected leg ulcers and pressure sores.

Adults and Children for:

•    The treatment of urogenital trichomoniasis in the female (trichomonal vaginitis) and in the male.

•    All forms of amoebiasis (intestinal and extra-intestinal disease and that of symptomless cyst passers)

•    Giardiasis

•    Acute ulcerative gingivitis.

Children for

•    Eradication of Helicobacter pylori

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

4.2 Posology and method of administration

For oral administration only.

A: Prophylaxis: against anaerobic infection- chiefly in the context of abdominal (especially colorectal) and gynaecological surgery.

Dosage: 400mg at 8 hourly intervals during the 24 hours preceding the operation followed by postoperative intravenous or rectal administration until the patient is able to take Norzol by mouth.

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

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

Elderly: Caution is advised in the elderly, particularly at high doses, although there is limited information available on modification of drug.

B: Treatment of established anaerobic infection:

800mg followed by 400mg at 8 hourly intervals.

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, which is why the concentrations of metronidazole in serum should preferably be monitored after a few days therapy.

C: Treatment of Protozoal and Other Infections:

(See Table).

	Duration of dosage in days	Adults and children over 10 years**	Children*
			7-10 years	3-7 years	1-3 years
Urogenital Trichomoniasis Where re-infection is likely, in adults the consort should receive a similar course of treatment concurrently	7 or	200mg three times daily	40mg/kg oral or 15 - 30mg/k| not to exceec	ly as a single dose g/day divided in 2 - 3 doses 2000mg/dose
	5 - 7 or	400mg twice daily
	1	2000mg as a single dose
Bacterial Vaginosis	5 - 7 or	400mg twice daily
	1	2000mg as a single dose

Amoebiasis	5-10	400 - 800mg three times daily	200 -400mg three times daily	100 - 200mg four times daily		100 - 200mg three times daily
			Alternatively, doses may be expressed by body weight 35 to 50mg/kg daily in 3 divided doses for 5 to 10 days, not to exceed 2400mg/day
Giardiasis	3 or	2000mg once daily	1000mg once daily	600-800mg once daily		500mg once daily
	5 or	400mg three times daily
	7 - 10	500mg twice daily
			Alternatively, as expressed in mg per kg of body weight: 15 - 40mg/kg/day divided in 2 - 3 doses.
Acute Ulcerative Gingivitis	3	200mg three times daily	100mg three times daily	100mg twice daily	50mg three times
Acute Dental Infections	3-7	200mg three times daily
Leg Ulcers and Pressure Sores	7	400mg three times daily

Dosage is given in terms of metronidazole or metronidazole equivalent.

* Children and babies weighing less than 10Kg should receive proportionally smaller doses.

** Norzol is well tolerated by the elderly, but a pharmacokinetic study suggests cautious use of high dosage regimen in this age group.

Eradication of Helicobacter pylori in paediatric patients:

As a part of 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 Metronidazole and/or hydroxybenzoates.

4.4 Special warnings and precautions for use

Regular clinical and laboratory monitoring (especially leucocyte count) are advised if administration of Norzol 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 paraesthesia, ataxia, dizziness, convulsive seizures).

There is the 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 Norzol need be made in patients with renal failure undergoing intermittent peritoneal dialysis (IPD) 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 encephalopathy.

Norzol should be administered with caution to patients with hepatic encephalopathy. The daily dosage may be reduced to one third and may be administered once daily.

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.

Norzol contains glucose, sucrose and sorbitol. Each 5ml contains 1.1g glucose, 0.6g sucrose and 0.6g sorbitol. Patients with hereditary fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine. The glucose and sucrose content should be taken into account in patients with diabetes mellitus. It may also be harmful to teeth.

Methyl, ethyl and propyl hydroxybenzoates are contained in this product which may cause allergic reactions (possibly delayed).

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 Norzol 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 anti-coagulants. Dosage of the anticoagulant may require reducing. Prothrombin time should be monitored. No interactions have been reported of the heparin type.

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 concentration of lithium, creatinine and electrolytes should be monitored in patients under treatment with lithium while they receive metronidazole.

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

Increased serum carbamazepine levels and toxicity have been seen in patients given concomitant metronidazole.

Aspartate amino transferase assays may give spuriously low values in patients taking metronidazole, depending on the method used.

Clinicians who contemplate continuous therapy for the relief of chronic conditions, for periods no longer than those recommended, are advised to consider the possible therapeutic benefit against the risk of peripheral neuropathy.

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

Patients receiving ciclosporin or tacrolimus with metronidazole are at risk of elevated ciclosporin / tacrolimus serum levels. Serum ciclosporin / tacrolimus 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. Norzol should not therefore be given during pregnancy or during lactation unless the physician considers it essential, in these circumstances short, high dosage regimes are not recommended.

A significant amount of metronidazole is found in breast milk and breast feeding should be avoided after a large dose. This could give a bitter taste to the milk.

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).

Frequency, type and severity of adverse reactions in children are the same as in adults.

Serious adverse reactions occur very rarely with standard recommended regimens. However, 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 and

pancytopenia, often reversible on drug withdrawal, although fatalities have occurred.

Not known: A moderate leucopenia has been reported in some patients but the white cell count has always returned to normal before or after treatment has been completed.

Immune system disorders:

Rare:    Anaphylaxis

Not known: urticaria, angioedema and 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) have been reported very rarely which may resolve on discontinuation of the drug

•    Drowsiness, dizziness, convulsions, headache, ataxia, inco-ordination of movement

Not known:

•    During intensive and/or prolonged metronidazole therapy 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.

•    Aseptic meningitis has been reported

Eye disorders:

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

been reported

Not known: Optic neuropathy/neuritis has been reported Gastrointestinal disorders:

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

Hepatobiliary disorders:

Very rare:

•    Abnormal liver function tests, increase in liver enzymes (AST, ALT, alkaline phosphatase), cholestatic or mixed hepatitis, and hepatocellular liver injury, jaundice and pancreatitis, reversible on drug withdrawal have been reported.

•    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, pruritus, flushing

Not known: Erythema multiforme may occur, which may be reversed on

drug withdrawal. Stevens-Johnson syndrome or toxic epidermal necrolysis.

Musculoskeletal, connective tissue and bone disorders:

Very rare:    myalgia, arthralgia

Renal and urinary disorders:

darkening of the urine (due to metronidazole metabolite)

Norzol contains glycerol, which can cause headache, gastro-intestinal disturbance and diarrhoea.

The parahydroxybenzoates used in Norzol may cause immediate or delayed hypersensitivity reactions.

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.    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

The selective action of this compound against anaerobes and anoxic and hypoxic cells is due to the mode of action. The nitro group of metronidazole acts as electron acceptor and is thus reduced to a chemically reactive drug form. This produces biochemical lesions in the cells, thus causing death. The major site of action is believed to be DNA, where it causes loss of the helical structure and inhibits synthesis.

5.2. Pharmacokinetic Properties

It is readily absorbed from the gastro-intestinal tract and widely distributed in body tissues. Half life in plasma is about 8-10 hours. About 10% is bound to plasma proteins.

It penetrates well into body tissues and fluids, including vaginal secretions, seminal fluid, saliva and breast milk. Therapeutic concentrations are also achieved in cerebrospinal fluid.

Unchanged metronidazole and several metabolites are excreted in the urine, the liver is the main site of metabolism and the major metabolites are as a result of side chain oxidation, forming glucuronides.

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 others studies were negative.

6.    PHARMACEUTICAL    PARTICULARS

6.1    List of excipients

Dispersible cellulose, colloidal silicon dioxide, sucrose, glucose, sorbitol solution, glycerine, polysorbate 80, methyl hydroxybenzoate, ethyl hydroxybenzoate, propyl hydroxybenzoate, propylene glycol, lemon flavour, orange flavour and purified water.

6.2. Incompatibilities

None known

6.3. Shelf-Life

24 months

6.4. Special Precautions for Storage

Store below 25°C and protect from light.

6.5.    Nature and Contents of Container

Bottle:    Amber (Type III) glass

Closures:    HDPE, EPE wadded, tamper evident, child resistant.

Pack Sizes:    100ml.

6.6.    Instruction for Use, Handling and Disposal

Keep out of the reach of children.

Shake the bottle well before use.

If a dose of under 5ml is required, the suspension should be administered using an oral dosing device.

7. MARKETING AUTHORIZATION HOLDER

Rosemont Pharmaceuticals Limited

Rosemont House

Yorkdale Industrial Park

Braithwaite Street

Leeds

LS11 9XE

8. MARKETING AUTHORISATION NUMBER

PL 00427/0068

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

18/11/1982.

10 DATE OF REVISION OF THE TEXT

09/04/2015