Metronidazole 400 mg film-coated tablets

Film –coated tablet White to off white colored, caplet shaped (17.00 x 6.00 mm) film-coated tablets, debossed “400” on one side and plain on other side.

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 (see sections 4.4 and 5.1). Metronidazole is indicated in adults and children for the following indications:

1. Prevention of post-operative infections due to anaerobic bacteria (gynecological and intra-abdominal operations)
2. Urogenital trichomoniasis in the female and in man.
3. Bacterial vaginosis (also known as non-specific vaginitis)
4. 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.
5. All forms of amoebiasis (intestinal and extra-intestinal disease and asymptomatic cyst passers).
6. Acute ulcerative gingivitis.
7. Giardiasis.
8. Acute dental infections (e.g. acute pericoronitis and acute apical infections)
9. Anaerobically-infected leg ulcers and pressure sores
10. Treatment of Helicobacter pylori infection associated with peptic ulcer as part of triple therapy Consideration should be given to official guidance on the appropriate use of antibacterial agents.4.2 Posology and method of administration **Posology** ****Prophylaxis against anaerobic infection:**** Chiefly in the context of abdominal (especially colorectal) and gynaecological surgery. ***Adults:*** 400 mg 8 hourly during 24 hours immediately preceding operation followed by postoperative intravenous or rectal administration until the patient is able to take tablets. 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 ***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. ***Treatment of established anaerobic infection:*** ***Adults:*** 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 preferable be monitored after a few days therapy. ***Prophylaxis against postoperative infections caused by anaerobic bacteria:*** *Adults:*400 mg 8 hourly during 24 hours immediately preceding operation followed by postoperative intravenous 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 ****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 | 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 | | | | | *Amoebiasis* *(a) Invasive intestinal disease in susceptible subjects* *(b) Intestinal disease in less susceptible subjects and chronic amoebic hepatitis* | 5 5-10 | 800 mg three times daily 400 mg three times a day | 400 mg three times daily 200 mg three times daily | 200 mg four times daily 100 mg four times daily | 200 mg three times daily 100 mg three times daily | | *c) Amoebic liver abscess also other forms of extra- intestinal amoebiasis* | 5 | 400 mg three times daily | 200 mg three times daily | 100 mg four times daily | 100 mg three times daily | | *(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 50mg/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 expressed in mg per kg of body weight: 15-40mg/kg/day divided 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 | | | | | Children and infants weighing less than 10 kg 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, 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 use. Metronidazole Tablets should be taken during or after meals, swallowed with water and NOT CHEWED.4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.4.4 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. 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. 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 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.4.6 Fertility, pregnancy and lactation There is inadequate evidence of the safety of metronidazole in pregnancy but it has been in wide use for many years without apparent ill consequence. Nevertheless Metronidazole, like other medicines, 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 recommended4.7 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 (< 1/10,000), not known (cannot be estimated from the available data). Serious adverse reactions occur rarely with standard recommended regimens. 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 | angiodema, urticaria, fever | | **Metabolism and nutrition disorders:** | | | Not known | anorexia | | **Psychiatric disorders:** | | | Very rare | Psychotic disorders, including hallucinations | | **Nervous system disorders;** | | | Very rare | • Encephalopathy (eg. Confusion, fever, headache, 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 in discontinuation of the drug. • Drowsiness, dizziness, convulsions, headaches | | Not know | 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, StevensJohnson 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 www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.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 group: Antibacterials for systemic use ATC Code: J01X D01 **Mechanism of action** Metronidazole itself is ineffective. It is a stable compound able to penetrate into microorganisms. Under anaerobic conditions nitroso radicals acting on DNA are formed from metronidazole by the microbial pyruvate-ferredoxin-oxidoreductase, with oxidation of ferredoxin and flavodoxin. Nitroso radicals form adducts with base pairs of the DNA, thus leading to breaking of the DNA chain and consecutively to cell death. **PK/PD relationship** Metronidazole acts in a concentration dependent manner. The efficacy of metronidazole mainly depends on the quotient of the maximum serum concentration (cmax) and the minimum inhibitory concentration (MIC) relevant for the microorganism concerned. **Breakpoints** For the testing of metronidazole usual dilution series are applied. The following minimum inhibitory concentration have been established to distinguish susceptible from resistant microorganisms: EUCAST (European Committee on Antimicrobial Susceptibility Testing, Version 7.1, March 2017) breakpoints separating susceptible (S) from resistant organisms (R) are as follows: | | | | | --- | --- | --- | | Organism | Susceptible | Resistant | | *Clostridium difficile1* | ≤ 2 mg/l | > 2 mg/l | | Other Gram-positive anaerobes | ≤ 4 mg | > 4 mg/l | | Gram-negative anaerobes | ≤ 4 mg | > 4 mg/l | 1 The breakpoints are based on epidemiological cut-off values (ECOFFs), which distinguish wild-type isolates from those with reduced susceptibility. List of susceptible and resistant organisms. | | | --- | | **Commonly susceptible species** | | ***Anaerobes*** | | *Clostridium difficile* ° | | *Clostridium perfringens* °∆ | | *Fusobacterium* spp.° | | *Peptoniphilus* spp.° | | *Peptostreptococcus* spp.° | | *Porphyromonas* spp.° | | *Prevotella* spp. | | *Veillonella* spp.° | | *Bacteroides fragilis* | | ***Other micro-organisms*** | | *Entamoeba histolytica* ° | | *Gardnerella vaginalis* ° | | *Giardia lamblia°* | | *Trichomonas vaginalis* ° | | **Species for which acquired resistance may be a problem** | | ***Gram-negative aerobes*** | | *Helicobacter pylori* | | ***Anaerobes*** | | **Inherently resistant organisms** | | All obligate aerobes | | ***Gram-positive micro-organisms*** | | *Enterococcus* spp. | | *Staphylococcus* spp*.* | | *Streptococcus* spp. | | ***Gram-negative micro-organisms*** | | *Enterobacteriaceae* | | *Haemophilus* spp. | ° At the time of publication of these tables, no up-to-date data were available. In primary literature, standard reference books and therapy recommendations susceptibility of the respective strains is assumed. Δ Only to be used in patients with allergy to penicillin **Mechanisms of resistance to metronidazole** The mechanisms of metronidazole resistance are still understood only in part. Strains of Bacteroides being resistant to metronidazole possess genes encoding nitroimidazole reductases converting nitroimidazoles to aminoimidazoles. Therefore, the formation of the antibacterially effective nitroso radicals is inhibited. There is full cross resistance between metronidazole and the other nitroimidazole derivatives (tinidazole, ornidazole, nimorazole). The prevalence of acquired resistance of individual species may vary, depending on region and time. Therefore, especially for the adequate treatment of severe infections specific local information regarding resistance should be available. If there is doubt about the efficacy of metronidazole due to the local resistance situation, expert advice should be sought. Especially in the case of severe infections or failure of treatment, microbiological diagnosis including determination of species of the microorganism and its susceptibility to metronidazole is required.5.2 Pharmacokinetic properties **Absorption:** Metronidazole is readily absorbed from the gastrointestinal tract and the oral bioavailability is > 90%. Consequently, the same mg dose will result in similar exposure (AUC) when switching between intravenous and oral dosing. **Distribution:** Metronidazole is widely distributed in body tissues after injection. It also diffuses across the placenta, and is found in breast milk of nursing mothers in concentrations equivalent to those in serum. Protein binding is less than 20 %, the apparent volume of distribution is 36 litres. Metronidazole appears in most body tissues and fluids including bile, bone, cerebral abscess, cerebrospinal fluid, liver, saliva, seminal fluid, and vaginal secretions, and achieves concentrations similar to those in plasma. **Biotransformation:** Metronidazole is metabolised in the liver by side-chain oxidation and glucuronide formation. Its metabolites include an acid oxidation product, a hydroxy derivative and glucuronide. The major metabolite in the serum is the hydroxylated metabolite, the major metabolite in the urine is the acid metabolite. **Elimination:** Approximately 80% of the substance is excreted in urine with less than 10% in the form of the unchanged drug substance. Small quantities are excreted via the liver. Elimination half-life is 8 (6-10) hours. **Characteristics in special patient groups:** Renal insufficiency delays excretion only to an unimportant degree. The elimination half-life of metronidazole remains unchanged in the presence of renal failure, however such patients retain the metabolites of metronidazole. The clinical significance of this is not known at present. Delayed plasma clearance and prolonged serum half-life (up to 30 h) is to be expected in severe liver disease.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.

6.1 List of excipients **Tablet core:** Anhydrous calcium hydrogen phosphate Maize starch Povidone Crospovidone Microcrystalline cellulose Colloidal anhydrous silica Magnesium stearate Film coat: Hypromellose Polyethylene glycol6.2 Incompatibilities Not applicable.6.3 Shelf life 3 years.6.4 Special precautions for storage This medicinal product does not require any special storage conditions.6.5 Nature and contents of container Alu-PVC/PVDC blisters of 20 and 21 film-coated tablets. Not all pack sizes may be marketed.6.6 Special precautions for disposal and other handling No special requirements for disposal. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.