Document: spc-doc_PL 00289-1597 change

• spc-doc_PL 00289-1597
• spc-doc_PL 04416-0061
• spc-doc_PL 04556-0011
• spc-doc_PL 17521-0036
• spc-doc_PL 42976-0023

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SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Metronidazole 400mg tablets.

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Metronidazole BP 400mg

For excipients, see section 6.1

3    PHARMACEUTICAL FORM

Tablet

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 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.

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

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

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

Urogenital trichomoniasis in the female (trichomonal vaginitis) and in the male. Non-specific vaginitis.

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

Giardiasis.

Acute ulcerative gingivitis.

Anaerobically-infected leg ulcers and pressure sores.

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

Consideration should be given to official guidance on the appropriate use of anti-bacterial agents.

4.2 Posology and method of administration

For oral use.

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 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 bacteria: Chiefly in the context to abdominal (especially colorectal) and gynaecological surgery.

Adults and children over 12 years:

400 mg 8 hourly during 24 hours immediately preceding operation followed by postoperative intravenous or rectal administration. This dosage regimen for Metronidazole tablets should be followed once the patient is able to take tablets.

Children < 12years: 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

Treatment of established anaerobic infection:

Adults and children over 12 years:

800 mg followed by 400 mg 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 should preferably be monitored after a few days therapy.

For the treatment of various infections refer to the table below for the recommended dosage regimes.

Protozoal and other infection:

	Duration of dosage in days	Adults and children over 10 years	Children aged
			7-10 years	3-7 years	1-3 years
Urogenital Trichomoniasis Where infection is likely in adults the consort should receive similar course of treatment concurrently	1	2000 mg as a single dose	40 mg/kg orally as a single dose; not to exceed 2000mg/dose
	7	200 mg three times daily	15-30 mg/kg/day divided in 2-3 doses; not to exceed 2000mg/day.
	5-7	400 mg twice daily
Bacterial Vaginosis	5-7	400 mg twice daily
	1	2000 mg as a single dose
Amoebiasis (a)    Invasive intestinal disease in susceptible subjects (b)    Intestinal disease in less	5-10	400 mg-800 mg three times daily	200 mg-400 mg three times daily	100 mg-200 mg four times daily	100 mg-200 mg three times daily

	Duration of dosage in days	Adults and children over 10 years	Children aged
			7-10 years	3-7 years	1-3 years
susceptible subjects and chronic amoebic hepatitis (c)    Amoebic liver abscess also forms of extra intestinal amoebiasis (d)    Symptomless cyst passers			Alternatively, doses may be expressed by body weight 35 to 50 mg/kg daily in 3 divided doses, not to exceed 2400 mg/day
Gardiasis	3	2000 mg once daily	1000 mg once daily	600 mg-800 mg once daily	500 mg once daily
			Alternatively, as expressed in mg per kg of body weight: 15-40 mg/kg/day divided in 2-3 doses.
	5	400 mg three times daily
	7-10	500 mg twice daily
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

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.

Use in children an infants weighing <10 kg

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

Use in the Elderly:

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

Hepatic Impairment

In sever liver disease and in the presence of encephalopathy reduce the daily dose to one-third, and give once daily. (See also Section 4.4)

Route of Administration Oral.

4.3 Contraindications

Known hypersensitivity to metronidazole or to any of its excipients.

Pregnancy - metronidazole should not be used in the first trimester in patients with trichomoniasis or bacterial vaginosis (see section 4.6).

Breast feeding should be discontinued for 12-24 hours when single high dose (e.g. 2g) therapy is used (see section 4.6).

4.4 Special warnings and precautions for use

High doses

Caution in patients with epilepsy or those who have had seizures as high doses of Metronidazole can induce seizures. High doses of metronidazole may mask the presence of syphilis.

Use for more than 10 days

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 and/or haematological disorders, such as agranulocytosis, neutropenia, leucopenia and thrombocytopenia (see section 4.8)

Use with caution in the second and third trimester when used to treat trichomoniasis or bacterial vaginosis (see section 4.6.)

Regular clinical and laboratory monitoring are advised if administration of metronidazole for more than 10 days is considered to be necessary.

Anticoagulants

Metronidazole enhances anticoagulant effect (see section 4.5). Prothrombin time should be monitored more frequently and anticoagulant therapy adjusted as necessary.

Use in Sexually Transmitted Disease

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

CNS disorders

Metronidazole tablets should not be used in patients with blood dyscrasias or with active non-infectious disease of the central nervous system.

Hepatic impairment

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.

Renal impairment

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 (IPD) or continuous ambulatory peritoneal dialysis (CAPD).

Discoloration of urine

Patients should be advised that metronidazole may darken urine (due to metronidazole metabolite).

Mutagenicity and carcinogenicity

Metronidazole and a metabolite have been shown to be mutagenic in some tests with non mammalian cells. Carcinogenicity has been shown in mice and rats but not in hamsters (see section 5.3)

Concurrent alcohol

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 reaction. (See section 4.5 ‘Interactions with other medicinal products and other forms of interaction’).

Porphyria

Metronidazole may precipitate an acute attack of porphyria but it may be used with caution if a safer alternative is not available

Lactose intolerance

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

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 (anti-buse) reaction.

Disulfiram: 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. Metronidazole enhances the anticoagulant of coumarins. There is no interaction with heparin. However, anticoagulant activity should be routinely monitored with these products.

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, as this increases the risk of lithium toxicity.

Antiepileptics interact with the metabolism of metronidazole. Patients receiving phenobarbitone metabolise metronidazole at a much greater rate than normally, reducing the half life to approximately 3 hours. Metronidazole inhibits the metabolism of phenytoin, increasing the plasma concentration.

Barbiturates accelerate the metabolism of metronidazole, reducing the plasma concentration.

Metronidazole interacts with the metabolism of cytotoxics - it inhibits the metabolism of fluorouracil, thus causing increased toxicity.

Cimetidine inhibits the metabolism of metronidazole (increases plasma-metronidazole concentration).

Busulfan: Plasma levels of busulfan may be increased by metronidazole.

Broad spectrum antibacterials such as metronidazole can possibly reduce the contraceptive effect of oestrogens. See local/national guidelines or BNF for specific advice.

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

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

4.6 Fertility, pregnancy and lactation

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

Metronidazole is contraindicated in the first trimester (see section 4.3) and should be used with caution in the second and third trimester when used to treat trichomoniasis or bacterial vaginosis (see section 4.4).

For all other indications Metronidazole should only be used if the benefits outweight the risks or no other alternative is available especially in the first trimester.

It is advisable to stop breast feeding until 12 - 24 hours after Metronidazole therapy has been discontinued when single high doses have been used (see section 4.3).

It may give a bitter taste to the milk.

4.7 Effects on ability to drive and use machines

Patients should be warned about the potential of dizziness, drowsiness, 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.

Very rare	agranulocytosis, neutropenia, thrombocytopenia, pancytopenia
Not known	Leucopenia, bone marrow depression disorders such as aplastic anaemia
Immune system class:
Rare	anaphylaxis
Not known	angiodema, urticaria, fever, anaphylactic shocks
Metabolism and nutrition disorders:
Not known	anorexia
Psychiatric disorders:
Very rare	Psychotic disorders, including hallucinations
Nervous system disorders;
Very rare	Encephalopathy (e.g. Confusion, fever, headache, paralysis, light sensitivity, disturbances in sight and movement, stiff neck) and subacute cerebellar syndrome (e.g. Ataxia, dysathria, gait impairment, nystagmus and tremor) which may resolve in discontinuation of the drug Drowsiness, dizziness, convulsions, headaches
Not known	Depression, paraesthesia, 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. Incoordination of movement.
Eye disorders:
Very rare	diplopia, myopia
Gastrointestinal disorders:
Not known	unpleasant taste in the mouth, taste disorders, oral mucositis, furred tongue, nausea, vomiting, gastro-intestinal disturbances, diarrhoea, abdominal pain,

	anorexia, dry mouth
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, flushing
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)

4.9 Overdose

Features:

Singe oral doses of metronidazole, up to 12g have been reported in suicide attempts and accidental overdoses.

Symptoms could be severe gastro-intestinal disturbances, vomiting, ataxia and slight disorientation. Observe for evidence of neuropathy.

Nausea, diarrhoea, anorexia, metallic taste, headache, dizziness and occasionally insomnia and drowsiness. Transiently increased liver enzyme activities have been reported rarely.

Transient epileptiform seizures have been reported following intensive or prolonged therapy. Other adverse effects occurring in these circumstances include peripheral motor neuropathy, blood dyscrasias and liver damage.

The combination of alcohol and metronidazole has been said to cause disulfiram type reactions in about 10% of individuals with sudden onset of excitement, giddiness, flushing, nausea, headache, hypotension and dyspnoea. However the mechanism of this reaction has been questioned.

Treatment:

Unlikely to be required.

There is no specific antidote for metronidazole overdosages. In cases of suspected massive overdosage, a symptomatic and supportive treatment should be instituted.

Disulfiram type reactions should be treated with intravenous fluids and plasma expanders if necessary. Symptomatic and supportive.

In more serious cases:

1.    Single brief convulsions do not require treatment. If frequent or prolonged control with intravenous diazepam (10-20mg in adults; 0.1-0.3mg/kg body weight) or lorazepam (4mg in an adult and 0.05mg/kg in a child). Give oxygen and correct acid base and metabolic disturbances as required.

2.    Other measures as indicated by the patient's clinical condition

Uneventful recovery has followed attempts at suicide with quantities of 30 and 60 x 200 mg tablets. There is no specific treatment for gross overdosage of metronidazole.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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.

The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable especially when treating severe infections.

5.2 Pharmacokinetic properties

Metronidazole is rapidly and almost completely absorbed on administration of Metronidazole Tablets; peak plasma concentrations occur after 20 minutes 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. Metronidazole is excreted in milk but the intake of suckling infant of a mother receiving normal dosage would be considerably less than the therapeutic dosage for the infants.

5.3 Preclinical safety data

Metronidazole has been shown to be carcinogenic in the mouse and rat. However similar studies in the hamster have given negative results and

extensive human epidemiological studies have provided no evidence of increased carcinogenic risk in human. Metronidazole has been shown to be mutagenic in bacteria in vitro. In studies conducted in mammalian cells in vitro as well as in rodent and in rodents and in humans in vivo, there was inadequate evidence of mutagenic effect of metronidazole.

Therefore the use of metronidazole for longer treatment than usually required should be carefully weighed, (see Section 4.4 Special Warning and Precautions for Use).

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose Maize Starch Pregelatinised Starch Polyvidone Purified Water Colloidal Silicon Dioxide Magnesium Stearate

6.2 Incompatibilities

None.

6.3 Shelf life

3 years

6.4 Special precautions for storage

Store in a cool dry place and protect from light. Store in the original package.

6.5 Nature and contents of container

Polypropylene tubular container with an open end equipped to accept a polyethylene closure with a tamper-evident tear strip or tampertainers in pack sizes of 7, 10, 14, 15, 20, 21, 25, 28, 30, 50, 56, 60, 100, 250, 500, and 1000 tablets or PVdC coated PVC/Aluminium blisters (60g/m² PVdC on 250p PVC/20p Al) in pack sizes of 7, 10, 14, 15, 20, 21, 28, 30, 50, 56 and 60 tablets.