Pronidazole

Pronidazole

Ingredients
Active ingredient: metronidazole
100 ml solution contains 500 mg of metronidazole

Pharmaceutical Form
Solution for infusion

Pharmacotherapeutic group
Antibacterial agents for systemicuse.
Imidazole derivatives.

Clinical characteristics

Indications for use
Treatment and prevention of infections caused by microorganisms that are sensitive to metronidazole (mainly by anaerobic bacteria).
Treatment is effective in the cases below:

• the central nervous system infections (including brain abscess, meningitis);
• the lungs and pleura infections (including necrotizing pneumonia, aspiration pneumonia, lung abscess);
• endocarditis;
• the gastrointestinal tract and abdomen infections, including peritonitis, liver abscess, post-surgical infections in the colon or rectum, purulent lesions of the abdominal or pelvic cavities;
• gynecological infections (including post- hysterectomy and post-cesarean section endometritis, generic fever, septic abortion);
• the upper respiratory tract and oral cavity infections (including preudomembranous tonsillitis);
• bone and joint infections (including osteomyelitis);
• gas gangrene;
• septicemia and septic thrombophlebitis.

In case of mixed aerobic and anaerobic infections, in addition to metronidazole, it is recommended to take appropriate antibiotics for treatment of aerobic infections.
Preventive administration is always prescribed before surgeries assuming high risk of anaerobic infections (before intra-abdominal and gynecological surgeries).
In administering metronidazole, it is necessary to take into account national and international recommendations for the appropriate use of antimicrobial agents.

Contraindications
Hypersensitivity to metronidazole or other nitroimidazole derivatives, or any auxiliary substances contained in the drug.

Administration and Dosage
The dose is adjusted in accordance with individual patient response to the treatment, age and body weight indicators, as well as the disease type and severity.
It is necessary to follow the dosage guidelines below:

Adults and children over 12 years
The usual dose is 500 mg every 8 hours. If there any medical prescriptions at the onset of treatment a loading dose of 15 mg per kg of the body weight can be prescribed.

Children aged 2-12 years
Every 8 hours - 7-10 mg of metronidazole per kg of the body weight that equals the daily dose of 20 - 30 mg of metronidazole per kg of the body weight.

Patients with Renal Failure
There is no need to reduce the dose (see Pharmacological Properties Section).

Patients with Hepatic Insufficiency
Since, in severe hepatic insufficiency the half-life of metronidazole from serum is extended, and clearance is delayed patients suffering from hepatic insufficiency should take lower doses (see Pharmacological Properties Section).

Duration of Treatment
The duration of treatment depends on its effectiveness. In most cases, 7-day treatment course will be sufficient. The treatment duration can be extended, if there any medical prescriptions (also see Pharmacological Properties Section).

Pre-Surgery and Post-Surgery Infection Prevention

Adults and children over 11 years
The dosage is 500 mg, the infusion should be completed 1 hour before the surgery. The dose is administered repeatedly after 8 and 16 hours.

Children aged 2-11 years
The dosage is 15 mg per kg of the body weight, the infusion should be completed 1 hour before the surgery, then – by 7.5 mg per kg of the body weight after 8 and 16 hours.

Method of Administration
Used as an intravenous infusion.
Administration of one vial contents by slow intravenous injection, i.e. maximum 100 ml for at least 20 minutes, but usually within one hour.
Metronidazole can be diluted prior to administration, adding other dilution agents and solutions, such as 0.9% sodium chloride solution for infusions or 5% glucose solution for infusions.
Simultaneously prescribed antibiotics should be administered separately.

Side effects
Side effects are mainly caused by long-term use of high doses. Nausea, taste disturbance and the risk of neuropathy in the case of long-term use are often observed.
The Side Effect Frequency List below contains the following criteria:
very often (≥ 1/10); often (≥ 1/100, <1/10); rarely (≥ 1/1000, <1/100); rarely (≥1/10000, <1/1000); very rarely (<1/10000); unknown (frequency cannot be determined based on the available data).

On the nervous system
Rarely: headache, dizziness, drowsiness or insomnia, convulsions, peripheral neuropathy that manifests in the form of paresthesia.

On the gastrointestinal tract
Rarely: vomiting, nausea, diarrhea, glossitis and stomatitis, regurgitation with a bitter taste, a sensation of heaviness in the epigastric region, loss of appetite, a metallic taste in the mouth, coated tongue.
Unknown: pancreatitis (specific cases).

Hepatobiliary disorders
Rarely: abnormal hepatic enzymes and bilirubin values.
Very rarely: hepatitis, jaundice.

Changes in the skin and subcutaneous tissue
Rarely: Allergic skin reactions, including itching, urticaria, and erythema multiforme.
Very rarely: Stevens-Johnson syndrome (specific reports), toxic epidermal necrolysis (specific reports).
The latter two reactions require immediate therapeutic intervention.

On the musculoskeletal system and connective tissues
Rarely: arthralgia, myalgia.

Kidney and urinary tract disorders
Rarely: dark urine (due to the release of metronidazole metabolite).
Very rarely: dysuria, cystitis and incontinence.

General disorders, disturbances at the injection site
Often: vein irritation (up to thrombophlebitis) after administration, pustular rash.
Rarely: weakness.

Use during pregnancy or breastfeeding

Pregnancy
Safety of metronidazole administration during pregnancy has not been studied sufficiently. In particular, the information on its administration is quite contradictory. Some studies have revealed the increased frequency of malformations. In animal studies no teratogenic effects of metronidazole were observed.
During the first trimester, metronidazole should be used only to treat serious, life-threatening infections, provided that there are no alternative and safer alternatives. During the second and third trimesters metronidazole may also be used for the treatment of other infections, if the expected benefit significantly outweighs the potential risk.

Period of breastfeeding
Since metronidazole is excreted into the breast milk, the breastfeeding process should be stop during the treatment. Lactation should be re-started no earlier than 2-3 days after the treatment, as metronidazole has an extended half-life.

Chlidren
Metronidazole can be administered for children over 2 years as per the prescriptions.

Peculiarities of Administration
In patients with severe liver disease, impaired hematopoiesis (including granulocytopenia), metronidazole should be administered only when the expected benefits outweigh the potential danger.
Due to the risk of deterioration, when using metronidazole for treating patients with active or chronic severe disorders of the peripheral or central nervous system, the expected benefit should significantly exceed the potential risk.
In patients who took metronidazole, convulsive seizures and peripheral neuropathy were observed; the latter was characterized by limb numbness or limb paresthesia. The emergency of neurological disorders requires urgent assessment of benefit/risk ratio for continuing the therapy.
In case of severe hypersensitivity reactions (including anaphylactic shock) the metronidazole treatment should be discontinued immediately and general emergency treatment must be initiated.
Severe persistent diarrhea observed during the treatment or in the following weeks may be the consequence of pseudomembranous colitis that is in many cases, caused by Clostridium difficile (see Side Effects Section). This bowel disease, caused by antibiotics, can be life-threatening and requires immediate treatment. Do not take peristalsis-suppressing drugs.

Interaction with other drugs, other forms of interaction

Alcohol
During metronidazole administration consumption of alcoholic beverages should be avoided due to the risk of adverse reactions, such as dizziness and nausea (disulfiram-related effect).

Barbiturates
Phenobarbital can increase the hepatic metabolism of metronidazole, thus reducing its half-life
Pharmacological Properties.
Pharmacodynamics. Metronidazole is a stable compound that is able to penetrate into microorganisms. Under anaerobic conditions, metronidazole along with microbal pyruvate ferredoxin oxidoreductase forms nitroso radicals by ferredoxin and flavodoxin oxidation. Nitroso radicals create addition compounds with basic DNA pairs, which causes DNA strand breaks and cell death.
The minimum inhibitory concentration (MIC) is established by the European Committee Antimicrobial Susceptibility Testing, breakpoints separating susceptible (S) organisms from resistant (R) organisns, are as follows:
gram-positive anaerobes (S: ≤ 4 mg/ml, R > 4 mg/ml);
gram-negative anaerobes (S: ≤ 4 mg/ml, R > 4 mg/ml).

The list of Sensitive and Resistant Microorganisms
(as per the data provided by the Central Department for Systemic Antibiotic Resistance Analysis, Germany, December 2009):

Normally sensitive strains

Anaerobes

• Bacteroides fragilis
• Clostridium difficile
• Clostridium perfringens
• Fusobacterium spp.
• Peptoniphilus spp.
• Peptostreptococcus spp.
• Porphyromonas spp.
• Prevotella spp.
• Veillonella spp.

Other microorganisms

• Entamoeba histolitica
• Gardnerella vaginalis
• Giardia lamblia
• Trichomonas vaginalis

Strains for which acquired sensitivity can be a problem

Gram-negative anaerobes

• Helicobacter pylori

Naturally resistant microorganisms

• All obligate aerobes

Gram-positive microorganisms

• Enterococcus spp.
• Staphylococcus spp.
• Streptococcus spp.

Gram-negative microorganisms

• Enterobacteriaceae
• Haemophilus spp.