The therapeutic indications of metronidazole are based on its antiparasitic and antibacterial activity and pharmacokinetic properties. They take into account both the clinical studies carried out with the medicinal product, and its position in the range of currently available anti-infectives.

Its use is limited to the treatment of infections caused by microorganisms which have been shown to be susceptible to the drug:

•        amebiasis,

•        urogenital trichomoniasis,

•        nonspecific vaginitis,

•        giardiasis,

•        curative treatment of medical and surgical infections caused by susceptible anaerobes,

•        replacement therapy after curative treatments given by injection of infections caused by susceptible anaerobes.

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

Posology

•        Amebiasi

s

              o     Adults

1.50 g/day as 3 divided doses.

              o     Children

30 to 40 mg/kg/day as 3 divided doses.

In patients with amebic liver abscess, 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), treatment with a single administration of a 2 g 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.

•        Nonspecific 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 g to 1.5 g/day. o    Children:

20 to 30 mg/kg/day.

 Method of administration:

 

Oral use.

• Hypersensitivity to metronidazole or to imidazoles or to any of the excipients listed in Section 6.1. • Wheat allergy (except in patients with celiac disease) (see Section 4.4). • Children under 6 years of age because of the pharmaceutical form (see Section 4.4).

Hypersensitivity / Skin and appendages

 Allergic reactions, including anaphylactic shock, can occur and be life-threatening (see Section 4.8). In this case, treatment with metronidazole must be discontinued and appropriate medical treatment initiated.

 If, at the start of treatment, patients experience generalized erythema with fever and pustules, acute generalized exanthematous pustulosis should be suspected (see Section 4.8). If this occurs, treatment must be discontinued and any further administration of metronidazole alone or in combination with other agents is contraindicated.

 Severe skin reactions have been reported with metronidazole, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, or Lyell syndrome) and acute generalized exanthematous pustulosis. Patients must be informed of the signs and symptoms of these conditions and the skin should be closely monitored.

 If any signs or symptoms of Stevens-Johnson syndrome, toxic epidermal necrolysis (e.g. progressive skin rash often with blisters or mucosal lesions) or acute generalized exanthematous pustulosis (see Section 4.8) occur, treatment must be discontinued and any further administration of metronidazole alone or in combination with other agents is contraindicated.  Central nervous system

 

If symptoms indicative of encephalopathy or cerebellar syndrome appear, patient management should be immediately reassessed and metronidazole treatment discontinued.

 Cases of encephalopathy have been reported as part of post-marketing surveillance of the drug. Cases of MRI changes associated with encephalopathy have also been observed (see Section 4.8). Damage is most often located in the cerebellum (particularly in the dentate nucleus) and in the splenium of the corpus callosum. Most cases of encephalopathy and MRI changes are reversible on treatment discontinuation. Very rare cases of fatal outcome have been reported.

 Patients should be monitored for warning signs of encephalopathy, and exacerbation of symptoms in patients with CNS disorders.

 If aseptic meningitis occurs during treatment, rechallenge with metronidazole is not recommended, and an assessment of the benefit/risk ratio should be done for patients with serious infection.  Peripheral nervous system

 

Patients should be monitored for warning signs of peripheral neuropathy, particularly in long-term treatment or in patients with severe, chronic or progressive peripheral neurological disorders.

 Psychiatric disorders

From administration of the first doses, patients may experience psychotic reactions, including self- endangering behavior, particularly if they have a history of psychiatric disorders (see Section 4.8). If this happens, metronidazole must be discontinued, the physician informed and appropriate therapeutic measures instituted immediately.  Hematological effects

 

In patients who have a history of hematological disorders or who are receiving high-dose and/or long- term treatment, regular blood tests, and particularly leukocyte counts, should be performed.

 In patients with leukopenia, continued treatment will depend on how serious the infection is.

 

Excipient with known effect

 This medicinal product may be administered in patients with celiac disease. Wheat starch can contain gluten, but only in trace amounts, and is therefore considered safe for patients with celiac disease.  Pediatric population

 

Tablets are contraindicated in children under 6 years of age because of the risk of pulmonary aspiration. Other presentations of metronidazole-based medicinal products are available for young children.

 Interaction with other medicinal products

 

Concomitant use of metronidazole and alcohol is not recommended (see Section 4.5).

Concomitant use of metronidazole and busulfan is not recommended (see Section 4.5).

Concomitant use of metronidazole and disulfiram is not recommended (see Section 4.5).

Interactions with laboratory tests

Metronidazole may immobilize treponemes, and thus lead to false positive results for the Nelson test.

 Cases of severe hepatotoxicity/acute liver failure of very rapid onset after treatment initiation, including cases with fatal outcome, have occurred in patients with Cockayne syndrome who were administered medicinal products containing metronidazole intended for systemic use. In this population, metronidazole must therefore be used after thorough evaluation of the benefit/risk ratio and only if no alternative treatment is available. Liver function tests must be performed just before treatment initiation, during treatment and after treatment discontinuation, until liver function values are within the normal range, or until baseline values are reached. If the liver function test values markedly increase during treatment, the medicinal product should be discontinued.

 Patients with Cockayne syndrome must be instructed to immediately report any symptoms of potential liver damage to their doctor and to stop taking metronidazole.

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. Patients should not consume alcoholic beverages or medicinal products containing alcohol. 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 drug combination.

 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 consideration

 

Fluorouracil (and by extrapolation, tegafur and capecitabine) Increased fluorouracil toxicity can occur due to decreased clearance.  Specific issue: 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 seems difficult to determine to what extent the infection itself or its treatment play a role in the INR imbalance. However, certain classes of antibiotics are more involved, particularly fluoroquinolones, macrolides, cyclines, cotrimoxazole and certain cephalosporins.

Pregnancy

 There is no evidence from animal studies that metronidazole is teratogenic. Therefore, no malformative effect is expected in humans. To date, substances causing malformations in humans have been shown to be teratogenic in animals during well-conducted studies in two species.

In man, analysis of a large number of exposed pregnancies did not seem to show any particular teratogenic or fetotoxic effects of metronidazole.

However, only epidemiological studies would make it possible to rule out any risk. Therefore, metronidazole may be prescribed during pregnancy if necessary.  Lactation

Since metronidazole is excreted in breast milk, administration should be avoided in breast-feeding women.

Patients should be warned of the potential risk of dizziness, confusion, hallucinations and seizures or vision disorders, and should be advised not to drive or operate machines if they experience such symptoms.

Blood and lymphatic system disorders

     •     neutropenia, agranulocytosis, thrombocytopenia.

 Psychiatric disorders

•        hallucinations,

•        psychotic reactions with paranoia and/or delirium possibly accompanied by suicidal ideation or suicide attempts in some isolated cases (see Section 4.4),

•        depressed mood.

 Nervous system disorders

 

•        peripheral sensory neuropathy,

•        headache,

•        dizziness,

•        confusion, •         seizures,

•        encephalopathy that may be associated with MRI changes, generally reversible upon treatment discontinuation. Very rare cases of fatal outcome have been reported (see Section 4.4),

•        sub-acute cerebellar syndrome (ataxia, dysarthria, gait disorders, nystagmus, tremor) (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 color vision,

•        neuropathy / optic neuritis.  Gastrointestinal disorders

 

•        minor gastrointestinal disorders (epigastric pain, nausea, vomiting, diarrhea),

•        glossitis with dry mouth, stomatitis, taste disorders, anorexia,

•        pancreatitis, reversible on treatment discontinuation,

•        discoloration or change in the appearance of the tongue (mycosis).  Hepatobiliary disorders

 

•        elevated liver enzyme levels (AST, ALT, alkaline phosphatase), very rare cases of acute cholestatic or mixed hepatitis and hepatocellular liver injury, sometimes with jaundice, have been reported. Isolated cases of hepatocellular insufficiency possibly requiring liver transplantation have been reported.

 Skin and subcutaneous tissue disorders

 

•        hot flushes, pruritus, skin rash occasionally with fever,

•        urticaria, angioedema, anaphylactic shock (see Section 4.4),

•        very rare cases of acute generalized exanthematous pustulosis (see Section 4.4),

•        toxic epidermal necrolysis, •          Stevens-Johnson syndrome, •    fixed drug eruption.

 Other effects

 

•        urine can appear reddish-brown as water-soluble pigments may be found due to metabolism of the drug.

        To report any side effect(s):

•        Saudi Arabia:

 

-           The National Pharmacovigilance and Drug Safety Centre (NPC) o Fax: +966-11-205-7662 o Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340. o Toll free phone: 8002490000 o E-mail: npc.drug@sfda.gov.sa o Website: www.sfda.gov.sa/npc

•        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: antibacterial, antiparasitic antibiotics belonging to the 5-nitroimidazole group, ATC code: J01XD01 — P01AB01 (J: Antiinfectives for systemic use, other antibacterials - imidazole derivatives - P: Antiprotozoals, agents against amebiasis and other protozoal diseases - nitroimidazole derivatives).

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:

Pharmacotherapeutic group: antibacterial, antiparasitic antibiotics belonging to the 5-nitroimidazole group, ATC code: J01XD01 — P01AB01 (J: Antiinfectives for systemic use, other antibacterials - imidazole derivatives - P: Antiprotozoals, agents against amebiasis and other protozoal diseases - nitroimidazole derivatives).

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:

Category	Prevalence of acquired resistance in France (>10%) (range)
Susceptible species
Gram-negative aerobes
Helicobacter pylori	30%
Anaerobes
Bacteroides fragilis
Bifidobacterium	60-70%
Bilophila
Clostridium
Clostridium difficile
Clostridium perfringens
Eubacterium	20-30%
Fusobacterium
Peptostreptococcus
Porphyromonas
Prevotella
Veillonella
Resistant species
Gram-positive aerobes
Actinomyces
Anaerobes
Mobiluncus
Propionibacterium acnes
Antiparasitic activity
Entamoeba histolytica
Giardia intestinalis
Trichomonas vaginalis

 Absorption

 

Following oral administration, metronidazole is rapidly absorbed (at least 80% within one hour). Peak plasma concentrations obtained after oral administration are similar to those obtained after IV administration of equivalent doses.

Oral bioavailability is 100%. It is not significantly affected by concomitant intake of food.  Distribution

 

•        Approximately one hour after a single 500 mg dose, the mean peak plasma concentration is 10 micrograms/mL. After 3 hours, the mean plasma concentration is 13.5 micrograms/mL.

•        The plasma half-life is from 8 to 10 hours.

•        The drug is poorly bound to plasma protein, i.e. below 20%.

•        The apparent volume of distribution is high (approximately 40 L, i.e. 0.65 L/kg).

•        The drug is rapidly and widely distributed, with concentrations close to plasma concentrations, in the lungs, kidneys, liver, skin, bile, CSF, saliva, semen and vaginal secretions. Metronidazole crosses the placental barrier and is excreted in breast milk.  Metabolism

 

Metabolism is mainly hepatic. Two main compounds are formed by oxidation:

•        the 'alcohol' metabolite (major metabolite) with antibacterial activity against anaerobes that is approximately 30% that of metronidazole, and an elimination half-life of approximately 11 hours;

•        the 'acid' metabolite, in small amounts, with a bactericidal activity of approximately 5% that of metronidazole.  Excretion

 

High concentrations of metronidazole can be found in the liver and bile. Low concentrations of the drug are found in the colon. Metronidazole is poorly excreted in the feces. It is mainly eliminated in the urine since metronidazole and its oxidized metabolites, eliminated in the urine, account for approximately 35 to 65% of the administered dose.

Not applicable.

Wheat starch, povidone K30, magnesium stearate, hypromellose, macrogol 20 000.

Not applicable.  

3 years.

Do not store above 30°C. Store the blisters in their outer packaging, protected from light.

14 tablets in (PVC/aluminum) blisters.

No special requirements.