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

•  Amebiasis

- Adults: 1.50 g/day as 3 divided doses.

- 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

   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

- Adults: 0.750 g to 1 g/day for 5 consecutive days.

- 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)

- Adults: 1 g to 1.5 g/day.

- Children: 20 to 30 mg/kg/day.

Method of administration:

Oral use.

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.

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.

Healthcare professionals are asked to report any suspected adverse reactions via:

• Saudi Arabia:

The National Pharmacovigilance Centre (NPC):

- Fax: +966-11-205-7662

- SFDA Call Centre: 19999

- E-mail: npc.drug@sfda.gov.sa

- Website: https://ade.sfda.gov.sa

• Other GCC States:

- Please contact the relevant competent authority.

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: Anti infectives 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:

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.

Not applicable.

Store below 30°C, in a dry place, protected from light.

10 tablets in Aluminium-PVC/PVDC blister, 2 blisters packed in a printed carton along with a leaflet.

No special requirements.