They are based on the antiparasitic and antibacterial activity of metronidazole and its pharmacokinetic characteristics. They take into account the clinical studies on the medicinal product, as well as its place in the range of currently available anti-infective products.
They are limited to infections due to germs defined as sensitive:
• Amoebiasis,
• Urogenital trichomoniasis,
• Non-specific vaginitis,
• Giardiasis,
• Curative treatment of medical-surgical infections with sensitive anaerobic germs,
• Switch from injectable curative treatments to infections with sensitive anaerobic bacteria.
The official recommendations on the proper use of antibacterial agents must be taken into account.

Posology
• Amoebiasis
o Adults
1.50 g daily as 3 divided doses.
o Children
30 to 40 mg/kg/day in 3 divided doses.
In patients with hepatic amoebic liver abscess, stage, abscess drainage should be performed in conjunction with metronidazole therapy.
Treatment duration is 7 consecutive days.
• Trichomoniasis
o In women (urethritis and vaginitis due to Trichomonas), single dose treatment of 2 g in a single dose (4 tablets).
It is important that the partner be treated concomitantly, regardless of whether there are clinical signs of Trichomonas vaginalis infestation, even without a positive laboratory test result.
• Giardiasis
o Adults
0.750 g to 1 g/day for 5 consecutive days.
o Children:
From 10 to 15 years of age: 500 mg/day.
• Non-specific vaginitis
500 mg twice daily for 7 days.
The patient’s partner should be treated at the same time.
• Treatment of infections caused by anaerobes
(as first-line or replacement treatment)
o Adults:
1 to 1.5 g/day.
o Children:
20 to 30 mg/kg/day.
Method of administration
Oral use.

Hypersensitivity/skin and appendages
Allergic reactions, including anaphylactic shock, can occur and may be life-threatening (see section 4.8). In these cases, metronidazole should be discontinued and appropriate medical treatment should be implemented.
The onset of an acute generalised erythema associated with pustules at the beginning of treatment should lead to the suspicion of acute generalised exanthematous pustulosis (see section 4.8); this requires therapy cessation and contraindicates any new administration of metronidazole, alone or combined.
Cases of severe skin reaction including Stevens-Johnson syndrome, Lyell’s Syndrome and Acute Generalised Exanthematous Pustulosis (AGEP) have been reported with metronidazole. Patients must be informed of the signs and symptoms and the skin should be closely monitored.
The occurrence of signs or symptoms of Stevens-Johnson syndrome, Lyell’s Syndrome (e.g., progressive rash often with blisters or mucous membrane injuries) or AGEP (acute generalised exanthematous pustulosis) (see section 4.8) requires therapy cessation and contraindicates any new administration of metronidazole, alone or combined.
Central nervous system
If symptoms suggestive of encephalopathy or cerebellar syndrome occur (for example, ataxia, dysarthria, gait disturbance, nystagmus, tremor, vertigo, confusion, convulsions, peripheral sensory neuropathy, headache (see section 4.8)), the patient’s management must be immediately reassessed, and the metronidazole treatment must be discontinued.
Cases of encephalopathy have been reported during post-marketing monitoring of this medicine. Cases of MRI changes associated with encephalopathy have also been observed (see section 4.8). The observed lesions are localised more frequently in the cerebellum (particularly in the dentate nucleus) and in the splenium of the corpus callosum. Most encephalopathy cases and MRI changes are reversible upon treatment discontinuation. Rare cases with fatal outcomes have been reported.
Signs suggestive of encephalopathy or deterioration in patients with central neurological conditions should be monitored.
In cases of aseptic meningitis being treated with metronidazole, reinitiating treatment is not recommended or must be subject to an assessment of the benefit/risk ratio in the case of a severe infection.
Peripheral nervous system
Signs suggestive of peripheral neuropathy, especially in the case of prolonged treatment or in patients with severe, chronic or progressive peripheral neurological conditions, should be monitored.
Psychiatric disorders
Psychotic reactions with possible risky behaviour for the patient can occur starting from the first doses of the treatment, particularly in patients with psychiatric history (see section 4.8). Metronidazole should therefore be discontinued, the doctor informed and the necessary therapeutic measures taken immediately.
Blood disorders
In the case of history of blood disorders, with a high-dose treatment and/or prolonged treatment, it is recommended to perform regular blood tests, especially differential white blood cell count.
In the case of leukopaenia, treatment continuation depends on the severity of the infection.
Excipient with known effect Wheat starch (containing gluten)
This medicinal product contains only very low levels of gluten (from wheat starch) and is very unlikely to cause problems if you have coeliac disease.
One tablet contains no more than 16.43 micrograms of gluten.
Patients with an allergy to wheat (different from coeliac disease) must not take this medicinal product (see section 4.3).
Paediatric population
The taking of tablets is contraindicated in children under 6 years of age because they may cause choking. Other metronidazole-based presentations exist that are suitable for young children.
Interaction with other medicinal products
The concomitant use of metronidazole and alcohol is not recommended (see section 4.5).
The concomitant use of metronidazole and busulfan is not recommended (see section 4.5).
The concomitant use of metronidazole and disulfiram is not recommended (see section 4.5).
Interference with paraclinical examinations and laboratory tests
Metronidazole may immobilise treponemes and thus lead to false positive Nelson test results.
Metronidazole may interfere with certain types of blood tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], lactate dehydrogenase [LDH], triglycerides, glucose), which may lead to a false negative or an abnormally low result. These analytical methods are based on a decrease in ultraviolet absorbance, which occurs when hydrogenated nicotinamide adenine dinucleotide (NADH) is oxidised to nicotinamide adenine dinucleotide (NAD). This interference is due to the similarity of the absorption peaks of NADH (340 nm) and metronidazole (322 nm) at pH 7.
Hepatotoxicity in patients with Cockayne Syndrome
Cases of severe hepatoxicity/acute hepatic failure, including cases resulting in a fatal outcome with a very fast onset after initiation of the treatment 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 no alternative treatment is available. Hepatic function tests must be performed before the start of treatment, throughout the treatment and after the end of treatment, until the hepatic function is within a normal range or until the initial values are obtained. If the hepatic function tests become significantly increased during the treatment, the medicinal product should be discontinued.
Patients with Cockayne syndrome should be advised to immediately report all symptoms of potential hepatic lesions to their doctor and to stop taking metronidazole (see section 4.8).

Antabuse reaction
Many medicinal products trigger an antabuse effect with alcohol and their concomitant use with alcohol is not advisable.
Inadvisable combinations
+ Alcohol (beverage or excipient)
An antabuse effect (hot flushes, erythema, vomiting, tachycardia) may occur. Consuming alcoholic beverages and other medicinal products containing alcohol should be avoided. Alcoholic beverages or medicinal products containing alcohol should not be ingested again until medicinal products have been completely eliminated from the body. The half-life should be used as a reference.
+ Busulfan
When co-administered with high busulfan doses: metronidazole causes a two-fold increase in plasma busulfan concentrations.
+ Disulfiram
There is a risk of acute psychotic episodes or confusion, reversible on discontinuation of the medicinal product combination.
+ Medicinal products causing QT interval prolongation
Cases of QT interval prolongation have been reported, particularly when metronidazole is administered with medicinal products that may prolong the QT interval.
Combinations requiring precautions for use
+ Enzyme-inducing anticonvulsants
Decreased plasma concentrations of metronidazole can occur due to increased liver metabolism by the inducer.
Clinical monitoring is required and the metronidazole dose may need to be adjusted during and after treatment with the inducer.
+ Rifampicin
Decreased plasma concentrations of metronidazole can occur due to increased liver metabolism by rifampicin.
Clinical monitoring is required and the metronidazole dose may need to be adjusted during and after treatment with rifampicin.
+ Lithium
Increased blood lithium levels can occur, which can reach toxic levels with signs of lithium overdose.
Strict monitoring of blood lithium levels should be performed and the lithium dose adjusted if necessary.
Combinations to be taken into account
Fluorouracil (and by extrapolation, tegafur and capecitabine)
Increased fluorouracil toxicity can occur due to decreased clearance.
Specific issues related to INR imbalance:
Numerous cases of increased oral anticoagulant activity have been reported in patients receiving antibiotics. The severity of the infection or inflammation, age and general health status of the patient appear to be risk factors. Under these circumstances, it is difficult to distinguish between the role of the infectious disease and that of its treatment in the onset of changes in the INR. However, certain classes of antibiotics are more involved, particularly fluoroquinolones, macrolides, cyclins, cotrimoxazole and certain cephalosporins.

Pregnancy
Animal studies do not indicate any teratogenic effect. As there is no teratogenic effect in animals, no malformative effect is expected in humans. To date, substances which cause malformations in humans have been found to be teratogenic in animals during well-conducted studies on two species.
In clinical practice, the analysis of a high number of exposed pregnancies did not clearly reveal any teratogenic or particular foetotoxic effect of metronidazole. However, only epidemiological studies would make it possible to rule out a risk. Therefore, metronidazole can be prescribed during pregnancy if needed.
Breast-feeding
Metronidazole is excreted in human milk and should not be used during breast-feeding.

It is necessary to warn patients about the potential risk of vertigo, confusion, hallucinations, seizures, or vision disorders and advise them not to drive or use machines if this type of disorder occurs.

Blood and lymphatic system disorders
• Neutropenia, agranulocytosis, thrombocytopaenia.
Cardiac disorders
• Not known: Cases of QT interval prolongation have been reported, particularly when metronidazole is administered with medicinal products that may prolong the QT interval.
Psychiatric disorders
• Hallucinations,
• Psychotic reactions with paranoia and/or delirium that, in isolated cases, can be accompanied by suicidal ideation or suicide attempts (see section 4.4),
• Depressed mood.
Nervous system disorders
• Peripheral sensory neuropathy,
• Headaches,
• Dizziness,
• Confusion,
• Seizures,
• Encephalopathy that may be associated with MRI changes are usually reversible upon therapy cessation. Rare cases with fatal outcomes have been reported (see section 4.4),
• Subacute cerebellar syndrome (ataxia, dysarthria, gait disorder, nystagmus, tremors) (see section 4.4),
• Aseptic meningitis (see section 4.4).
Eye disorders
• Transient vision disorders such as blurred vision, diplopia, myopia, reduced visual acuity, impaired colour vision,
• Neuropathy/optic neuritis.
Gastrointestinal disorders
• Mild gastrointestinal disorders (epigastric pain, nausea, vomiting, diarrhoea),
• Glossitis with the feeling of a dry mouth, stomatitis, taste disorders, anorexia,
• Pancreatitis reversible upon treatment discontinuation,
• Discolouration or change in the tongue’s appearance (mycosis).
Hepatobiliary disorders
• Elevated liver enzymes (AST, ALT, alkaline phosphatase), very rare cases of acute hepatic impairment of a cytolytic (sometimes icteric), cholestatic or mixed nature. Isolated cases of hepatocellular insufficiency possibly requiring liver transplant have been reported.
• Cases of severe irreversible hepatotoxicity/acute hepatic failure, including cases resulting in a fatal outcome with a very fast onset after initiation of the systemic use of metronidazole, have been reported in patients with Cockayne syndrome (see section 4.4).
Skin and subcutaneous tissue disorders
• Flushing, pruritus, skin rash, occasionally accompanied with fever,
• Urticaria, angioedema, anaphylactic shock (see section 4.4),
• Very rare cases of acute generalised exanthematous pustulosis (see section 4.4),
• Lyell’s syndrome,
• Stevens-Johnson syndrome,
• Fixed drug eruption.
Other effects
• Reddish-brown coloured urine due to the water-soluble pigments from metabolism of the medicinal product.
Reporting of suspected adverse reactions
• Saudi Arabia:

• Sanofi- Pharmacovigilance: KSA_Pharmacovigilance@sanofi.com

Administration of up to 12 g as a single dose has been reported in cases of attempted suicide and accidental overdose.
The symptoms were limited to vomiting, ataxia and mild disorientation. There is no specific antidote to metronidazole overdose. If massive overdose occurs, symptomatic treatment should be instituted.

Pharmacotherapeutic group: anti-parasitic antibacterial antibiotics of the nitro-5-imidazoles family, ATC code: J01XD01 – P01AB01 (J: Anti-infectives, other antibacterials-imidazole derivatives - P: antiprotozoals, medicines against amoebiasis and other protozoan derivatives of metronidazole)
The MIC breakpoints differentiating susceptible from intermediate strains and intermediate from resistant strains are as follows: S ≤4 mg/l and R >4 mg/l.
The prevalence of acquired resistance in certain species can vary geographically and over time. It is therefore useful to have local information on the prevalence of resistance, especially in treating severe infections. These data are only guidelines indicating the probability of susceptibility of a bacterial strain to this antibiotic.
When the variability of prevalence of resistance of a bacterial species is known in France, it is indicated in the table below:


 

Absorption
After oral administration, metronidazole is rapidly absorbed, at least 80% in one hour. The serum peak levels obtained after oral administration are similar to those obtained after the intravenous administration of equivalent doses.
The bioavailability via oral use is 100%. This is not significantly affected by simultaneous food intake.
Distribution
• Approximately 1 hour after the single dose of 500 mg, the maximum serum concentration reached is 10 micrograms/ml on average. After 3 hours, the average serum concentration is 13.5 micrograms/ml.
• The plasma half-life is 8 to 10 hours.
• The blood protein binding is low: less than 20%.
• The apparent volume of distribution is high, around 40 l (i.e., 0.65 l/kg).
• Metronidazole is rapidly and significantly distributed in the lungs, kidneys, liver, skin, bile, CSF, saliva, semen and vaginal discharge, with concentrations similar to serum levels.
Metronidazole crosses the placental barrier and is excreted in breast milk.
Biotransformation
Metabolism is essentially hepatic. Two key compounds are formed by oxidation:
• The “alcohol” metabolite, major metabolite, with antibacterial activity against anaerobic bacteria that is approximately 30% that of metronidazole and an elimination half-life of approximately 11 hours,
• The “acid” metabolite, in small quantity, with antibacterial activity of approximately 5% that of metronidazole.
Excretion
High concentrations of metronidazole can be found in the liver and bile. Low concentrations of the medicinal product are found in the colon. Metronidazole is poorly excreted in the faeces. Excretion is mainly via the urinary route, as metronidazole and its oxidized metabolites found in urine account for approximately 35% to 65% of the administered dose.

Not applicable.

Wheat starch, povidone K30, magnesium stearate, hypromellose, macrogol 20000.

Not applicable.  

Store the blisters in the outer packaging, protected from light.

4 tablets in thermoformed blisters (PVC/Aluminium).
14 tablets in thermoformed blisters (PVC/Aluminium).

No special requirements.