BIOGYL Oral suspension Ref.[115632] Active ingredients: Methronidazole

The use of Biogyl for prolonged treatment duration should be carefully weighed. If prolonged therapy is required, the physician should bear in mind the possibility of peripheral neuropathy or leucopenia. Both effects are usually reversible. It is recommended that haematological tests be carried out regularly and that patients should be monitored for adverse reactions such as peripheral or central neuropathy (such as paraesthesia, ataxia, dizziness, vertigo, convulsive seizures). High dosage regimens have been associated with transient epileptiform seizures. Caution is required in patients with active disease of the central nervous system except for brain abscess.

Metronidazole and a metabolite have been shown to be mutagenic in some tests with non-mammalian cells. Intensive or prolonged metronidazole therapy should be conducted only under conditions of close surveillance for clinical and biological effects and under specialist direction.

Metronidazole is removed during haemodialysis and should be administered after the procedure is finished. Metronidazole is mainly metabolised by hepatic oxidation. Substantial impairment of metronidazole clearance may occur in the presence of advanced hepatic insufficiency. The risk/benefit using metronidazole to treat trichomoniasis in such patients should be carefully considered.

Flagyl should be administered with caution to patients with hepatic encephalopathy. Cases of severe bullous skin reactions, sometimes fatal, such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) or acute generalised exanthematous pustulosis (AGEP) have been reported with metronidazole. The majority of cases of SJS reported occurred within 7 weeks of starting treatment with metronidazole. Patients should be advised of the signs and symptoms and monitored closely for skin reactions. If symptoms of SJS, TEN or AGEP (e.g. flu-like symptoms, progressive skin rash often with blisters or mucosal lesions) are present, treatment must be immediately discontinued. Patients should be warned that metronidazole may darken urine (due to metronidazole metabolite).

Patients should be advised not to take alcohol during metronidazole therapy and for at least 48 hour s afterwards. Hepatotoxicity in patients with Cockayne Syndrome 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 not be used unless the benefit is considered to outweigh the risk and 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.

This medicinal product contains 31.4 mg of ethanol in each 5 ml of suspension which is equivalent to 6.28 mg per ml (0.628% w/v). The amount in each 5 ml of this medicinal product is equivalent to less than 1 ml beer or 1 ml wine. The small amount of ethanol in this medicinal product will not have any noticeable effects.

This medicinal product contains less than 1mmol sodium (23 mg) per 5ml, that is to say essentially 'sodium free'. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

Metronidazole may interfere with certain types of blood test determinations in blood (aminotransferase [ALT], aspartate aminotransferase [AST], lactate dehydrogenase [LDH], triglycerides, glucose), which may lead to false negative or an abnormally low result. These analytical determinations are based on a decrease in ultraviolet absorbance, a fact that occurs when nicotinamide adenine dinucleotide hydrogen (NADH) is oxidized to nicotinamide adenine dinucleotide (NAD). The interference is due to the similarity in the absorption peaks of NADH (340 nm) and metronidazole (322 nm) at pH 7.

Potentiation of the anticoagulant effect and increased hemorrhagic risk caused by decreased hepatic catabolism. In case of co-administration, prothrombin time should be more frequently monitored and anticoagulant therapy adjusted during treatment with metronidazole. Lithium retention observed by increased plasma lithium levels, accompanied by evidence of possible renal damage has been reported in patients treated simultaneously with lithium and metronidazole. Plasma levels of lithium may be increased by 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.

Phenytoin or Phenobarbital: increased elimination of metronidazole resulting in reduced plasma levels. A similar effect may occur with other drugs which induces hepatic microsomal enzymes. Patients should be advised not to take alcohol, (or drugs containing alcohol) during metronidazole therapy and for at least 48 hours afterwards because of a disulfiram-like (antabuse effect) reaction (flushing, vomiting, tachycardia).

Disulfiram: psychotic reactions have been reported in patients who were using metronidazole and disulfiram concurrently.

Cyclosporin: risk of elevation of the cyclosporin serum levels. Serum cyclosporin and serum creatinine should be closely monitored when coadministration is necessary.

5-Fluorouracil: reduced clearance of 5-fluorouracil resulting in increased toxicity of 5-fluorouracil.

Busulfan: Plasma levels of busulfan may be increased by metronidazole, which may lead to severe busulfan toxicity.

Drugs that prolong QT interval: QT prolongation has been reported, particularly when metronidazole was administered with drugs with the potential for prolonging the QT interval.

Metronidazole should only be used during pregnancy or lactation following careful evaluation and only if considered essential by the physician. Its effects on foetal organogenesis are not known. If used, high dosage regimens should be avoided. The drug crosses the placenta and is excreted in breast milk in which concentrations equal those in serum. Unnecessary exposure to the drug should be avoided.

Patients should be warned about the potential for confusion, dizziness, vertigo, hallucinations, convulsions or eye disorders and advised not to drive or operate machinery if these symptoms occur.

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

Gastrointestinal disorders:

• epigastric pain, nausea, vomiting, malaise, diarrhea.
• oral mucositis, taste disorders, dry mouth, anorexia.
• reversible cases of pancreatitis.
• tongue discolouration/furry tongue.

Immune system disorders:

• angioedema anaphylactic shock.

Nervous system disorders:

• peripheral sensory neuropathy, paraesthesia
• headache, convulsions, dizziness.
• reports of encephalopathy (e.g. confusion) and subacute cerebellar syndrome (e.g. ataxia, dysathria, gait impairment, nystagmus and tremor) which may resolve with discontinuation of the drug.
• aseptic meningitis, vertigo

Psychiatric disorders:

• psychotic disorders including confusion, hallucinations
• depressed mood

Eye disorders:

• transient vision disorders such as diplopia, myopia, blurred vision, decreased visual acuity, changes in color vision.
• Optic neuropathy/neuritis.

Ear and labyrinth disorders:

• hearing impaired/hearing loss (including sensorineural)
• tinnitus Blood and lymphatic system disorders
• cases of agranulocytosis, neutropenia and thrombocytopenia have 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 mostly when used in combination with other antibiotic drugs. Cases of severe irreversible hepatotoxicity/acute liver failure, including cases with fatal outcomes with very rapid onset after initiation of systemic use of metronidazole, have been reported in patients with Cockayne Syndrome.

Skin and subcutaneous tissue disorders:

• rash, pruritus, flushing, urticaria
• pustular eruptions, acute generalised exanthematous pustulosis
• fixed drug eruption
• Stevens-Johnson syndrome, toxic epidermal necrolysis.

General disorders and administration site conditions:

• fever

Cardiac disorders:

• Frequency not known: QT prolongation has been reported, particularly when metronidazole was administered with drugs with the potential for prolonging the QT interval.

None.