Metronidazole 500 mg Film-Coated Tablets

Summary of Product Characteristics Updated 29-Apr-2019 | Creo Pharma Limited

1. Name of the medicinal product

Metronidazole 500 mg Film-Coated Tablets

2. Qualitative and quantitative composition

Each tablet contains metronidazole 500 mg.

Excipients with known effect:

Wheat starch 164.30mg

For the full list of excipients, see section 6.1

3. Pharmaceutical form

Film-Coated Tablets

4. Clinical particulars
4.1 Therapeutic indications

Metronidazole is active against a wide range of pathogenic microorganisms, notably species of Bacteroids, Fusobacteria, Clostridia, Eubacteria, anaerobic cocci and Gardnerella vaginalis.

It is also active against Trichomonas vaginalis, Entamoeba histolytica, Giardia lamblia, Balantidium coli and Helicobacter pylori.

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

1) Prevention of post-operative infections due to anaerobic bacteria, particularly species of

bacteroids and anaerobic streptococci.

2) 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.

3) Urogenital trichomoniasis in the female (Trichomonas vaginalis), and in man.

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

5) All forms of amoebiasis (intestinal and extra-intestinal disease and asymptomatic cyst passers).

6) Treatment of Helicobacter pylori infection associated with peptic ulcer as part of triple therapy.

7) Giardiasis

8) Acute ulcerative gingivitis

9) Anaerobically-infected leg ulcers and pressure sores

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

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

4.2 Posology and method of administration

Posology

Metronidazole Tablets should be taken during or after meals, swallowed with water and not chewed.

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

Hepatic impairment: Caution is advised in patients with hepatic encephalopathy. One third of the daily dose given once a day should be considered (see section 4.4).

1) Anaerobic infections:

Treatment for 7 days should be satisfactory for most patients but, depending upon clinical and bacteriological assessments, the physician may decide to prolong treatment, e.g. for eradication of infection from sites which cannot be drained or are liable to endogenous recontamination by anaerobic pathogens from the gut, oropharynx or genital tract.

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.

Children under 10 years: A more suitable dosage form should be used for this age group.

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

Adults: 1g stat dose 24 hours pre-operatively, followed by 400mg at 8 hourly intervals during the 24 hours preceding operation followed by post-operative iv or rectal administration until the patient is able to take tablets.

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.

Children under 10 years: A more suitable dosage form should be used for this age group.

2) Treatment of established infections:

Adults and children over 10 years: 800mg followed by 400mg 8 hourly.

Children under 10 years: A more suitable dosage form should be used for this age group.

3) Urogenital trichomoniasis:

Where reinfection is likely, sexual partners should be treated concomitantly.

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

Children < 10 years: 40 mg/kg orally as a single dose or 15 – 30 mg/kg/day divided in 2-3 doses for 7 days; not to exceed 2000 mg/dose.

Children under 10 years: A more suitable dosage form should be used for this age group.

4) Bacterial vaginosis

Adults: 400mg twice daily for 7 days, or 2g as a single dose for one day only.

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

5) Amoebiasis

Adults> 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.

Children under 7 years: A more suitable dosage form should be used for this age group.

6) Giardiasis:

Adults > 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.

Children under 7 years: A more suitable dosage form should be used for this age group.

7) Acute ulcerative gingivitis (for 3 day duration):

Adults and children over 10 years: 200mg three times daily.

Children under 10 years: A more suitable dosage form should be used for this age.

8) Acute dental infections (for 3-7 day duration):

Adults and children over 10 years: 200mg three times daily.

9) Leg ulcers and pressure sores (for 7 day duration):

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

10) Treatment of Helicobacter pylori in infected 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.

Method of Administration For oral administration.

4.3 Contraindications

• Known hypersensitivity to metronidazole or any of the ingredients in the tablets.

• 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

Contains wheat starch. Suitable for people with coeliac disease. Patients with wheat allergy (different from coeliac disease) should not take this medicine.

• Patients should abstain from alcohol for at least 48 hours following discontinuation of therapy with metronidazole. A disulfiram-like reaction with hypotension and flushing has occurred (see section 4.5).

• Caution is advised in patients with porphyria.

• Metronidazole tablets should not be used in patients with blood dyscrasias or with active non-infectious disease of the central nervous system. High doses of metronidazole may mask the presence of syphilis.

• Caution in patients with epilepsy or those who have had seizures as high doses of Metronidazole can induce seizures.

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

• Regular clinical and laboratory surveillance are advised if treatment continues for more than 10 days.

• Consideration of the therapeutic benefit against the risk of peripheral neuropathy is advised with continuous therapy for chronic conditions.

• 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 readministered 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).

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

Cases of severe hepatotoxicity/acute hepatic failure, including cases with a fatal outcome with very rapid onset after treatment initiation in patients with Cockayne syndrome have been reported with products containing metronidazole for systemic use. In this population, metronidazole should therefore be used after careful benefit-risk assessment and only if no alternative treatment is available. Liver function tests must be performed just prior to the start of therapy, throughout and after end of treatment until liver function is within normal ranges, or until the baseline values are reached. If the liver function tests become markedly elevated during treatment, the drug should be discontinued.

Patients with Cockayne syndrome should be advised to immediately report any symptoms of potential liver injury to their physician and stop taking metronidazole.

4.5 Interaction with other medicinal products and other forms of interaction

Combinations to be used with caution:

Lithium: 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.

Anticoagulants: 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. No interactions have been reported with anticoagulants of the heparin type. However, anticoagulant activity should be routinely monitored with these products.

Alcohol: Patients should be advised not to take alcohol during metronidazole therapy and for at least 48 hours after because of the possibility of a disulfiram-like reaction.

Disulfiram: Psychotic reactions have been reported.

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

Pharmacokinetic interactions:

Antiepileptics: Patients receiving phenobarbital metabolise metronidazole at a much greater rate than normally, reducing the half-life to approximately 3 hours. Metronidazole inhibits metabolism of phenytoin (increases plasma-phenytoin concentration). Primidone accelerates the metabolism of Metronidazole causing reduced plasma concentrations.

Cytotoxics: Metronidazole inhibits metabolism of fluorouracil. Therefore, increased toxicity of fluorouracil can result.

Ulcer-healing drugs: Cimetidine inhibits the metabolism of metronidazole (increases plasma-metronidazole concentration).

Oestrogens: broad spectrum antibiotics possibly reduce the contraceptive effect.

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

As with all medicines, metronidazole should not be given during pregnancy or during lactation unless it is considered essential, and in these circumstances the short, high- dosage regimens are not recommended.

Pregnancy

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 trichomoniais or bacterial vaginosis (see section 4.4).

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

Breast-feeding

It is advisable to stop breast feeding until 12 – 24 hours after Metronidazole therapy has been discontinued (see section 4.3).

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

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

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 (<10,000); not known (cannot be estimated from the available data.

Serious adverse reactions occur rarely with standard recommended regime. Frequency, type and severity of adverse reactions in children are the same as in adults.

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, bone marrow depression disorders such as aplastic anaemia

Immune system class:

Rare

anaphylaxis

Not known

angioedema, urticaria, fever

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, dysarthria, gait impairment, nystagmus and tremor) which may resolve on 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

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, pruritus, 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)

No

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, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Features:

Nausea, vomiting, 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.

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

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Nitroimidazole derivatives

ATC Code: P01A B01

Mechanism of action

Metronidazole has antiprotozoan and antibacterial effects. It is effects against Trichomonas vaginalis, Gardnerella vaginalis and other protazoa including Entamoeba histolytica, Gardia lamblia and anaerobic bacteria.

5.2 Pharmacokinetic properties

Absorption

Metronidazole is readily absorbed following administration by mouth and bioavailability is 90-100%. Peak plasma concentrations of approximately 5µg/ml and 10µg/ml are achieved an average of 1-2 hours after single doses of 250mg and 500mg respectively. Some accumulation and consequently higher concentrations occur when multiple doses are given. Absorption may be delayed, but is not reduced overall, by administration with food.

Distribution

Metronidazole is widely distributed. It appears in most body tissues and fluids. It also crosses the placenta and rapidly enters foetal circulation. No more than 20% is bound to plasma proteins.

Biotransformation

Metronidazole is metabolised in the liver by side-chain oxidation and glucuronide formation.

The plasma elimination half-life of metronidazole is about 6-9 hours; that of the hydroxy metabolite is slightly longer. The half-life of metronidazole is reported to be longer in neonates and in patients with severe liver disease.

Elimination

The majority of a dose of metronidazole is excreted in the urine, mainly as metabolites; a small amount appears in the faeces.

5.3 Preclinical safety data

None.

6. Pharmaceutical particulars
6.1 List of excipients

Tablet core

Wheat starch

Povidone (K30)

Magnesium stearate

Film coating

Hypromellose

Macrogol (type 20000)

6.2 Incompatibilities

None.

6.3 Shelf life

36 months

6.4 Special precautions for storage

Keep blister in the outer carton, protected from light

6.5 Nature and contents of container

Blister pack (aluminium (25 µm)/PVC (250 µm)), pack sizes of 21 tablets. Not all pack sizes may be marketed

6.6 Special precautions for disposal and other handling

Not applicable.

7. Marketing authorisation holder

Creo Pharma Limited

Felsted Business Centre

Felsted

Essex

CM6 3LY

8. Marketing authorisation number(s)

PL 31862/0015

9. Date of first authorisation/renewal of the authorisation

11/10/2018

10. Date of revision of the text

11/10/2018

Company Contact Details
Creo Pharma Limited
Address

Felsted Business Centre, Felsted, Essex, CM6 3LY

Telephone

+44 (0)1371 822 022

Medical Information Direct Line

+44 (0)1371 823 933

Customer Care direct line

+44 (0)1371 822 022

Stock Availability

+44 (0) 8448 793188

WWW

http://www.creopharma.com

Fax

+44 (0)1371 822 044

Medical Information e-mail
Medical Information Fax

+44 (0)1371 822 044