For the use of a Registered Medical Practitioner only

1.0 GENERIC NAME
Metronidazole Extended Release Tablets USP 600mg
Flagyl^® ER

2.0 QUALITATIVE AND QUANTITATIVE COMPOSITION:
Each extended release film coated tablet contains:
Metronidazole I.P. ………….600mg
Excipients………………….. q.s.
Colours: Quinoline Yellow Aluminium Lake and Titanium Dioxide I.P.

3.0 DOSAGE FORM AND STRENGTH:
Refer Section 1 & 2

4.0 CLINICAL PARTICULARS
4.1 THERAPEUTIC INDICATION
For the treatment of amoebiasis, urogenital trichomoniasis & Giardiasis.

4.2 POSOLOGY AND METHOD OF ADMINISTRATION
Tablets of Flagyl are to be swallowed and not chewed. Tablets are to be taken after meals
Intestinal amebiasis
Adults: 600 mg four tab once daily for 5 to 10 days
Giardiasis
Adults: 600mg two tab once daily for 7 days
Trichomoniasis
Adults: 600mg two Tab once daily for 5 days

4.3 CONTRAINDICATIONS
• Patients with a prior history of hypersensitivity to metronidazole or other nitroimidazole derivatives.
• Patients with active neurological disorders or a history of blood dyscrasia, hypothyroidism or hypoadrenalism.

4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE
1. Keep out of reach of children
2. Central And Peripheral Nervous System Effects
3. Encephalopathy and peripheral neuropathy: Cases of encephalopathy and peripheral neuropathy (including optic neuropathy) have been reported with metronidazole.
4. Encephalopathy has been reported in association with cerebellar toxicity characterized by ataxia, dizziness, and dysarthria. CNS lesions seen on MRI have been described in reports of encephalopathy. CNS symptoms are generally reversible within days to weeks upon discontinuation of metronidazole. CNS lesions seen on MRI have also been described as reversible.
5. Peripheral neuropathy, mainly of sensory type has been reported and is characterized by numbness or paresthesia of an extremity.
a. Convulsive seizures have been reported in patients treated with metronidazole Aseptic meningitis: Cases of aseptic meningitis have been reported with metronidazole. Symptoms can occur within hours of dose administration and generally resolve after metronidazole therapy is discontinued.
6. The appearance of abnormal neurologic signs and symptoms demands the prompt evaluation of the benefit/risk ratio of the continuation of therapy
7. Alcohol- Alcoholic beverages or drugs containing alcohol, should not be consumed by patients being treated with metronidazole.
8. Candidiasis- Candicidal drug may be required during metronidazole therapy as candida overgrowth in the gastrointestinal or genital tract may occur during the treatment.
9. Long term therapy –If metronidazole is to be administered for more than 10 days then it is recommended that haematological tests, especially total and differential leucocyte count should be carried out regularly.
10. Impaired Renal Function – In patients with renal failure the half-life of metronidazole is unchanged, but those of its major metabolites are prolonged 4-fold or greater. The clinical significance of this is known. Dose has to be re-administered after hemodialysisImpaired Hepatic Function-Patients with hepatic impairment metabolize metronidazole slowly, with resultant accumulation of metronidazole in the plasma. For patients with severe hepatic impairment (Child-Pugh C), a reduced dose of FLAGYL is recommended. For patients with mild to moderate hepatic impairment, no dosage adjustment is needed but these patients should be monitored for metronidazole associated adverse events

Nervous System-Due to the risk of neurological damage metronidazole should be used with caution in patients with active or chronic severe peripheral and central nervous system diseases.

4.5 DRUGS INTERACTIONS

4.6 USE IN SPECIAL POPULATIONS (SUCH AS PREGNANT WOMEN, LACTATING WOMEN, PAEDIATRIC PATIENTS, GERIATRIC PATIENTS ETC.)

• Use In Pregnancy (Category B2) – Metronidazole should not be given in the first trimester of pregnancy as it crosses the placenta and enters foetal circulation rapidly. Short regimens are not recommended too. Avoid unless considered absolutely essential by the physician
• Use In Lactation -Metronidazole is secreted in breast milk.
• Carcinogenicity/Mutagenicity-Metronidazole has been shown to be carcinogenic in the mouse and in the rat.But data from human patients has exemplified the safety of metronidazole.
• Use in Patients with Blood Dyscrasias : Metronidazole is a nitroimidazole and should be used with caution in patients with evidence of or history of blood dyscrasia. A mild leukopenia has been observed during its administration; however, no persistent hematologic abnormalities attributable to metronidazole have been observed in clinical studies. Total and differential leukocyte counts are recommended before and after therapy.
• Use in elderly: Caution is advised in elderly particularly at high diseases as limited data is available on dose modification.

4.7 EFFECTS ON ABILITY TO DRIVE AND USE MACHINES

Metronidazole is unlikely to produce any effects

4.8 UNDESIRABLE EFFECTS
Serious adverse drug reactions occur very rarely with standard dose regimens.
The most common adverse reactions reported have been referable to the gastrointestinal tract, particularly nausea, metallic taste , sometimes accompanied by headache, anorexia, and occasionally vomiting; diarrhea; epigastric distress; and abdominal cramping and constipation.
Other reported adverse reactions include:
Blood and lymphatic system disorders: Neutropenia, transient eosinophilia, very rare cases of agranulocytosis and thrombocytopenia have been reported.
Cardiac disorders: palpitation and chest pain.
Eye disorders: transient vision disorders such as diplopia, myopia, blurred vision, decreased visual acuity, changes in color vision. Optic neuropathy/neuritis has been reported.
Gastrointestinal disorders: Nausea, Diarrhea, vomiting, epigastric distress, epigastric pain, dyspepsia, , coated tongue, tongue discoloration/furry tongue (e.g. due to fungal overgrowth), dry mouth, constipation, taste disorders including metallic taste, oral mucositis.
General disorders and administration site conditions: Thrombophlebitis has occurred with I.V. administration. Fever has been reported.
Hepatobiliary disorders: Increase in liver enzymes (AST, ALT, alkaline phosphatase), cholestatic or mixed hepatitis and hepatocellular liver injury, sometimes with jaundice have been reported. Cases of liver failure requiring liver transplant have been reported in patients treated with metronidazole in combination with other antibiotic drugs.
Immune system disorders: Angioedema, anaphylactic shock. Infections and infestations: rare cases of pseudomembranous colitis have been reported. Moderate leucopenia
Metabolism and nutrition disorders: An antithyroid effect has been reported by some investigators but three different clinical studies failed to confirm this. Anorexia has been reported.
Nervous System disorders: convulsive seizures, peripheral sensory neuropathy, transient ataxia, dizziness, drowsiness, insomnia, headache, aseptic meningitis.
Skin and subcutaneous tissue disorders: Hypersensitivity reactions including flushing, rash, urticaria, and pruritus, very rare pustular eruptions.
Other: Proliferation of Candida albicans in the vagina, vaginal dryness and burning; dysuria; occasional flushing and headaches, especially with concomitant ingestion of alcohol; altered taste of alcoholic beverages.

4.9 OVERDOSE:
There is no specific antidote. Activated charcoal may be administered to aid in the removal of unabsorbed drug. General supportive measures are recommended.

5.0 PHARMACOLOGICAL PROPERTIES

5.1 MECHANISM OF ACTION
Metronidazole exerts antibacterial effects in an anaerobic environment by the following possible mechanism: Once metronidazole enters the organism, the drug is reduced by intracellular electron transport proteins. Because of this alteration to the metronidazole molecule, a concentration gradient is maintained which promotes the drug’s intracellular transport. Presumably, free radicals are formed which, in turn, react with cellular components resulting in death of bacteria

5.2 PHARMACODYNAMIC PROPERTIES
Metronidazole is bactericidal, amoebicidal and trichomonacidal. Metronidazole is reduced by low-redox-potential electron transfer proteins (eg. nitroreductases such as ferredoxin) to unidentified polar product(s) which lack the nitro group. The reduction product(s) appears to be responsible for the cytotoxic and antimicrobial effects of the drug which include disruption of DNA and inhibition of nucleic acid synthesis

5.3 PHARMACOKINETIC PROPERTIES
Metronidazole is widely distributed in body tissues and fluids. It diffuses across the blood-brain barrier and placenta and is found in the breast milk of nursing mothers in concentrations equivalent to those in serum

Metronidazole ER 600mg steady state pharmacokinetics parameter was determined in 12 healthy adult subjects age (range: 18 to 50) The pharmacokinetic parameters of metronidazole after administration of Flagyl ER 600 mg two tablet OD are summarized in the following table.

Steady State Pharmacokinetic Parameters of after Metronidazole 600mg ER 2 tablet Given Once a Day for 5 days

The major route of elimination of metronidazole and its metabolites is via the urine (60% to 80% of the dose), with fecal excretion accounting for 6% to 15% of the dose. The metabolites that appear in the urine result primarily from side-chain oxidation [1-(ß-hydroxyethyl)-2-hydroxymethyl-5-nitroimidazole and 2-methyl-5- nitroimidazole-1-yl-acetic acid] and glucuronide conjugation, with unchanged metronidazole accounting for approximately 20% of the total. Renal clearance of metronidazole is approximately 10 mL/ min/1.73m2.1

6.0 NONCLINICAL PROPERTIES
6.1 ANIMAL TOXICITY DATA
Metronidazole has been shown to be non-mutagenic in mammalian cells in vitro and in vivo. Metronidazole and a metabolite have been shown to be mutagenic is some tests with non- mammalian cells. Although Metronidazole has been shown to be carcinogenic in certain species of mice, it was not carcinogenic in either rats or guinea pigs. There is no suspicion of carcinogenicity in man. Daily peroral metronidazole at 5-times the maximum human daily dose for greater than 4 weeks caused testicular toxicity
and infertility in male rats. Fertility was restored in most subjects by 8 weeks after cessation of treatment, whereas the lower testicular and epididymal weights and sperm counts had improved but were still observed.
Daily peroral metronidazole at approximately 6-times the maximum human daily dose for ≥2 weeks caused testicular toxicity in male mice. Most indices of testicular toxicity were restored within 2 months after cessation of treatment,
whereas the lower testicular and epididymal weights had improved but were still observed. These studies demonstrate that the adverse effects of metronidazole on the male reproductive system are wholly or partially reversible after treatment withdrawal

7.0 DESCRIPTION
FLAGYL ER is supplied for oral administration, as an extended – release tablet of Metronidazole. Each extended – release tablet of FLAGYL ER contains Metronidazole 600 mg.

8.0 PHARMACEUTICAL PARTICULARS
8.1 INCOMPATIBILITIES
No known

8.2 SHELF-LIFE
Refer Pack

8.3 PACKAGING INFORMATION
Refer Pack

8.4 STORAGE AND HANDING INSTRUCTIONS
Refer Pack

9. PATIENT COUNSELLING INFORMATION
• Alcoholic beverages should be avoided while taking metronidazole and for at least three days afterward.
• Patients should be counselled that antibacterial drugs including Flagyl ER should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold).
• When Flagyl ER is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed.
• Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Flagyl ER or other antibacterial drugs in the future.

10. DETAILS OF MANUFACTURER
Refer Pack for manufacturer details.

11. DETAILS OF PERMISSION OR LICENCE NUMBER
Refer Pack for Permission/License details

12. DATE OF REVISION
Version 2.0, dated 07^th Nov 2023

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