Document: spc-doc_PL 20416-0106 change

• spc-doc_PL 04416-0061
• spc-doc_PL 20416-0106

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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Metronidazole Tablets 400mg

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Each tablets contains 400mg metronidazole

3    PHARMACEUTICAL FORM

Metronidazole 400mg tablets are presented as yellow, normal convex tablets, with a company logo on one side and ‘A’ breakline ‘321’ on the other.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Metronidazole is indicated in the prophylaxis    and    treatment    of infections in

which anaerobic bacteria have been identified or are suspected to be the cause.

Metronidazole is active against a wide range of pathogenic microorganisms 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.

Metronidazole is indicated in adults and children for the following indications: It is indicated in:

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

2.    The prevention of post-operative infections due to anaerobic bacteria, particularly species of Bacteroides and anaerobic streptococci.

3.    Urogenital trichomoniasis in the female (trichomonal vaginitis) and in the male.

4.    Bacterial vaginosis (also known as non-specific vaginitis, anaerobic vaginosis or gardnerella vaginitis).

5.    All forms of amoebiasis (intestinal and extra-intestinal disease and that of symptomless cyst passers) such as acute amoebic dysentery and amoebic liver abscess and to eradicate cysts from asymptomatic cyst passers.

6.    Giardiasis.

7.    Acute dental infections.

8.    Acute ulcerative gingivitis.

9.    Anaerobically-infected leg ulcers and pressure sores.

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

4.2 Posology and method of administration

Metronidazole tablets should be swallowed with water (not chewed). It is recommended that the tablets be taken during or after a meal.

Anaerobic infections: The duration of a course of Metronidazole tablets treatment is about 7 days but it will depend upon the seriousness of the patient's condition as assessed clinically and bacteriologically.

Prophylaxis against postoperative infections caused by anaerobic infection : Chiefly in the context of abdominal (especially colorectal) and gynaecological surgery.

Adults

400mg 8 hourly during 24 hours immediately preceding operation followed by postoperative intravenous or rectal administration until the patient is able to take tablets.

Children

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.

Treatment of established anaerobic infection:

Adults

800mg followed by 400mg 8 hourly.

Children

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

Protozoal and other infections:

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 re-infection is likely, in adults the consort should receive a similar course of treatment concurrently	7 or	200mg three times daily		40mg/kg orally as a single dose or 15-30mg/kg/day divided in 2-3 doses for 7 days; not to exceed 2000mg/dose
	5-7 or	400mg twice daily
		2.0 g as a single dose
Bacterial Vaginosis	5-7 or	400mg twice daily
	1	2.0g as a single dose
Amoebiasis (a) Invasive Intestinal disease in Susceptible subjects	5	800mg three times daily		400mg three times daily	200mg four times daily	200mg three times daily
(b) Intestinal disease in less susceptible subjects and chronic amoebic hepatitis	5-10	400mg three times daily		200mg three times daily	100mg four times daily	100mg three times daily
(c) Amoebic liver abscess also other forms of extraintestinal amoebiasis	5	400mg three times Daily		200mg three times daily	100 mg four times daily	100mg three times daily
(d) Symptomless cyst passers	5-10	400-800mg 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 50mg/kg daily in 3 divided doses for 5 to 10 days, not to exceed 2400mg/day
Giardiasis	3 or	2.0 g once daily	1.0 g once daily		600 -800 mg 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	100 mg twice daily	50mg three times daily
Acute dental infections	3-7	200mg three times daily
Leg ulcers And pressure sores	7	400mg three times daily
Children and infants weighing less than 10kg should receive proportionally smaller dosages. Elderly: Metronidazole is well tolerated by the elderly but a pharmacokinetic study suggests cautious use of high dosage regimens in this age group.

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.

Route of administration Oral use

4.3 Contraindications

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

Owing to the presence of lactose, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.4 Special warnings and precautions for use

Regular clinical and laboratory monitoring (especially leucocyte count) are advised if administration of Metronidazole 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).

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.

Serum and urine concentrations of metronidazole should be monitored in patients with liver and renal failures. 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 metronidazole 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. Metronidazole 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 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 Metronidazole 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.

Metronidazole does not appear to interact adversely with other antimicrobials at the microbiological level. An additive or, less commonly, a synergistic effect is usually seen with other antibiotics in-vitro against anaerobic bacteria.

4.6 Fertility, pregnancy and lactation

The safety of metronidazole for use in pregnancy has not been evaluated. Since metronidazole diffuses across the placenta and is found in breast milk, it should not be administered during pregnancy and lactation unless the physician considers it essential. In these circumstances, the short, high-dose 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 which may be reversed on drug withdrawal, although fatalities have been reported.

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, dysarthria, 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: diplopia, myopia.

Not known: optic neuropathy/neuritis.

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: abnormal liver function tests, cholestatic hepatitis, jaundice and pancreatitis which is reversible on drug withdrawal.

Skin and subcutaneous tissue disorders:

Very rare: skin rashes, pustular eruptions, pruritis.

Not known: erythema multiforme.

Musculoskeletal, connective tissue and bone disorders:

Very rare: myalgia, arthralgia.

Renal and urinary disorders:

Very rare: darkening of urine (due to Metronidazole metabolite). Brown or reddish-brown discolouration of the urine occurs occasionally, and has been attributed to the formation of azoxy compound secondary to reduction of the nitro group and metronidazole, probably by intestinal microflora possessing nitroreductases.

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

Pharmacotherapeutic group: antimycotics for systemic use - imidazole

derivatives

ATC code: J02A B

Metronidazole has antiprotozoal and antibacterial actions and is effective against Trichomonas vaginalis and other protozoa including Entamoeba histolytica and Giardia lamblia and against anaerobic bacteria. It is used in the treatment of trichomoniasis of the genito-urinary tract in males and females; it does not affect the normal acidophilic flora of the vagina and has no effect on candida species. Resistant strains of T. vaginalis have occasionally been reported. In amoebiasis it is effective at all sites of infection and is used in the treatment of amoebic dysentery and amoebic liver abscess as well as

eradication of E. histolytica from patients passing cysts. Metronidazole is also used in the treatment of giardiasis and of Vincent's infection and in the prevention and treatment of anaerobic infections.

5.2 Pharmacokinetic properties

Metronidazole undergoes biotransformation in humans primarily by oxidative metabolism with the formation of major metabolites, like 2- hydroxy methyl-metronidazole (35 to 40%), 1 acetic acid metronidazole (15 to 20%) and 2-carboxylic acid metronidazole (8 to 20%). The mutagenic activity of urine sample after metronidazole treatment is higher than that expected from urinary metronidazole concentrations alone, suggesting the presence of more active metabolites. 2-hydroxymethyl metronidazole is indeed a 10 times more potent mutagen than metronidazole itself.

Metronidazole is rapidly and almost completely absorbed on administration of Metronidazole tablets; peak plasma concentrations occur after 20 mins to 3 hours.

The half-life of Metronidazole is 8.5±2.9 hours. Metronidazole can be used in chronic renal failure; it is rapidly removed from the plasma by dialysis.

Following 250 mg and 500 mg doses, peak serum concentrations of metronidazole are approximately 5 and 10 micrograms respectively. Time to peak concentrations, as a measure of the rate of absorption of the drug, varies between 0.25 and 4 hours, but average approximately 1 hour. Serum concentrations at 8 hours, a dosing interval often used clinically, are detectable after all dose regimens and are approximately 2, 5 and 8 ng/ml, after 250, 500 and 1000 mg respectively.

Metronidazole diffuses across the placenta, and is found in breast milk of nursing mothers in concentrations equivalent to those in serum, but the intake of a suckling infant of a mother receiving normal dosage 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 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose

Microcrystalline Cellulose Pregelatinised Starch Magnesium Stearate

Quinoline Yellow Aluminium Lake E104 Sunset Yellow Aluminium Lake E110

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

12/01/2004

DATE OF REVISION OF THE TEXT

13/07/2015