Ornidazole-darnitsa

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ORNIDAZOLE-DARNITSA (ORNIDAZOLE-DARNITSA)

Composition:

Active substance: ornidazole;

1 ml of solution contains 5 mg of ornidazole;

Excipients: sodium chloride, hydrochloric acid, water for injections.

Pharmaceutical form. Infusion solution.

Main physicochemical properties: clear colorless or slightly yellowish liquid.

Pharmacotherapeutic group. Antibacterial agents for systemic use. Imidazole derivatives. Ornidazole. ATC code J01X D03.

Pharmacological properties.

Pharmacodynamics.

Ornidazole is an antiprotozoal and antibacterial agent, a derivative of 5-nitroimidazole. It readily penetrates microbial cells and, by binding to DNA, disrupts the replication process.

Ornidazole is active against Trichomonas vaginalis, Entamoeba histolytica, Giardia lamblia (Giardia intestinalis), as well as certain anaerobic bacteria such as Bacteroides (B. fragilis, Prevotella melaninogenica, Porphyromonas spp.), Fusobacterium spp., anaerobic bacteria: Clostridium spp., sensitive strains of Eubacterium spp.; anaerobic cocci: Peptococcus spp., Peptostreptococcus spp.

The mechanism of action of ornidazole is associated with disruption of DNA structure, with selective activity against microorganisms possessing enzymatic systems capable of reducing the nitro group and catalyzing the interaction of ferredoxin-group proteins with nitro compounds. After penetration into the microbial cell, the mechanism of ornidazole’s action involves reduction of the nitro group under the influence of microbial nitroreductases and the activity of the already reduced nitroimidazole. The reduction products form complexes with DNA, causing its degradation and disrupting DNA replication and transcription processes. In addition, ornidazole metabolites exhibit cytotoxic properties and interfere with cellular respiration.

Pharmacokinetics.

Distribution. One and 24 hours after intravenous bolus administration of 1 g, plasma concentrations of ornidazole are 17.7 and 4.9 µg/mL, respectively. After slow intravenous infusion of a single 20 mg/kg dose, the maximum plasma concentration (Cmax) is 18.7 µg/mL, decreasing to 7.32 µg/mL after 24 hours.

The area under the pharmacokinetic curve (AUC) is approximately 185 mg·h/L following a single 500 mg intravenous dose and 375 mg·h/L for a 1 g dose.

The volume of distribution after intravenous administration is 0.7–0.9 L/kg. Protein binding of ornidazole to plasma proteins is less than 15%. The active substance penetrates into cerebrospinal fluid, other body fluids, and tissues.

The optimal plasma concentration of ornidazole ranges between 6–36 mg/L, which corresponds to levels considered optimal for the drug's indications.

Metabolism. Over 90% of ornidazole is metabolized. Two major metabolites exhibit approximately the same activity against anaerobic bacteria as ornidazole itself.

Elimination. The elimination half-life is 13 hours. After a single dose, 85% of the administered dose is excreted within the first 5 days, primarily via urine (63% as metabolites) and feces (22%). Approximately 4% of the administered dose is excreted unchanged by the kidneys. The accumulation factor after repeated administration of 500 mg or 1000 mg doses every 12 hours in healthy volunteers ranged from 1.5 to 2.5.

Special patient groups.

Patients with hepatic impairment. The elimination half-life of ornidazole is prolonged to 22 hours in patients with liver cirrhosis, and clearance is reduced (35 mL/min compared to 51 mL/min in healthy individuals).

Patients with renal impairment. Pharmacokinetics of ornidazole are not altered in patients with impaired renal function. Ornidazole is removed by hemodialysis.

Children. The pharmacokinetics of ornidazole in children (including neonates) are similar to those in adults.

Clinical characteristics.

Indications.

Parenteral administration of the medicinal product is indicated in cases of acute and severe infection or when oral administration is not possible, for the following diseases and conditions:

• Anaerobic systemic infections caused by microorganisms sensitive to ornidazole: sepsis, meningitis, peritonitis, postoperative wound infections, postpartum sepsis, septic abortion, and endometritis;
• Prophylaxis of infections caused by anaerobic bacteria during surgical procedures (especially operations on the colon and rectum), and gynecological surgeries;
• Severe course of amoebic dysentery, all extraintestinal forms of amoebiasis, giardiasis, liver abscess.

Contraindications.

• Hypersensitivity to the components of the medicinal product or to other nitroimidazole derivatives.
• Central nervous system disorders.
• Epilepsy.
• Multiple sclerosis.
• Chronic alcoholism.
• Circulatory disorders, pathological blood disorders or other hematological abnormalities.
• First trimester of pregnancy.
• Children with body weight less than 6 kg.

Interaction with other medicinal products and other types of interactions.

Effect of ornidazole on the pharmacodynamics and/or pharmacokinetics of other medicinal products

Concomitant use not recommended

Alcohol: alcohol should not be consumed during the course of treatment and for at least 3 days after discontinuation of the medicinal product, as there is a possibility of developing a disulfiram-like reaction (feeling of warmth, flushing, vomiting, tachycardia).

Concomitant use requiring caution

Oral anticoagulants: ornidazole enhances the effect of oral anticoagulants of the coumarin group (warfarin), requiring appropriate adjustment of their dosage.

Cyclosporine: concomitant use of ornidazole with cyclosporines may increase cyclosporine levels in blood serum; therefore, monitoring of cyclosporine and creatinine levels in blood serum is recommended in patients receiving this combination.

Imbalance of international normalized ratio (INR): increased activity of oral anticoagulants (e.g., warfarin) may occur in patients simultaneously treated with antibiotics. Risk factors may include infectious and inflammatory diseases, advanced age, and poor general health. It is difficult to determine whether the imbalance is caused by the infectious pathology itself or by its treatment.

Vecuronium bromide: ornidazole prolongs the muscle relaxant effect of vecuronium bromide.

5-fluorouracil: ornidazole reduces the clearance of 5-fluorouracil when administered concomitantly with nitroimidazoles, resulting in increased toxicity of 5-fluorouracil.

Effect of other medicinal products on the pharmacokinetics of ornidazole

Enzyme inducers: concomitant use of enzyme-inducing drugs (e.g., phenobarbital) and other enzyme inducers reduces the circulation period of ornidazole in blood serum.

Enzyme inhibitors: enzyme inhibitors (e.g., cimetidine) increase the elimination half-life of ornidazole from blood serum.

Lithium: during lithium therapy, it is necessary to monitor concentrations of lithium salts, creatinine, and electrolytes.

Special precautions for use.

There is a certain risk of developing adverse effects in children, patients with liver disease, and patients who abuse alcohol when recommended doses are exceeded. Clinical and laboratory monitoring is recommended when high doses of ornidazole are used or when treatment lasts longer than 10 days.

In patients with a history of blood disorders, monitoring of leukocytes is recommended, especially during repeated courses of treatment.

Exacerbation of central or peripheral nervous system disorders may occur during ornidazole therapy. If peripheral neuropathy, impaired motor coordination (ataxia), dizziness, or impaired consciousness occurs, treatment should be discontinued.

Exacerbation of candidiasis may occur, which requires appropriate treatment.

In patients undergoing hemodialysis, the reduced elimination half-life should be taken into account, and additional doses of the drug should be administered before or after hemodialysis.

The effect of other medicinal products may be increased or decreased during treatment with ornidazole.

This medicinal product contains less than 1 mmol (23 mg) of sodium per dose, i.e., it is practically sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy.

Ornidazole is contraindicated during the first trimester of pregnancy. During the second and third trimesters of pregnancy, the drug should be prescribed only if clearly indicated.

Breastfeeding period.

Ornidazole passes into breast milk; therefore, if ornidazole must be used, breastfeeding should be discontinued.

Ability to affect reaction speed when driving or operating machinery.

During ornidazole therapy, adverse effects such as drowsiness, muscle rigidity, dizziness, tremor, seizures, impaired coordination, and transient loss of consciousness may occur. Patients who drive or operate machinery should be aware of these potential effects. If any of these adverse effects occur, patients should refrain from driving or operating machinery.

Administration and Dosage

The dosage and duration of treatment are determined by a physician depending on the nature of the disease and treatment regimen.

The medicinal product should be administered intravenously over 15–30 minutes.

For anaerobic systemic infections: in adults and children aged 12 years and older, the initial dose is 500–1000 mg, followed by 500 mg every 12 hours or 1000 mg every 24 hours for 5–10 days (step-down dosing). Once the patient's condition has stabilized, switch to oral administration of ornidazole (e.g., 500 mg tablets, one tablet every 12 hours).

For children under 12 years of age with body weight above 6 kg, the daily dose should be calculated at 20 mg/kg body weight, divided into two doses, administered over 5–10 days.

For prophylaxis of anaerobic infections during surgical procedures: in adults and children aged 12 years and older, ornidazole should be administered at a dose of 500–1000 mg 30 minutes prior to surgery.

For prophylaxis of mixed infections, ornidazole should be used in combination with aminoglycosides, penicillin, or cephalosporins. Medicinal products should be administered separately.

Severe amoebic dysentery, all extraintestinal forms of amoebiasis, giardiasis, hepatic abscess: for adults and children aged 12 years and older, the first dose is 500–1000 mg, followed by 500 mg every 12 hours for 3–6 days.

For children under 12 years of age with body weight above 6 kg, the daily dose should be calculated at 20–30 mg/kg body weight, divided into two doses.

Patients with hepatic impairment.

In patients with liver cirrhosis, the dosing interval should be doubled.

Patients with renal impairment.

In patients with impaired renal function, pharmacokinetics are not altered. Ornidazole is eliminated by hemodialysis.

Hemodialysis.

Ornidazole is removed during hemodialysis; therefore, an additional dose of 500 mg ornidazole should be administered before the start of hemodialysis if the daily dose is 2 g per day, or an additional 250 mg ornidazole if the daily dose is 1 g per day.

Administration method

Do not insert needle(s) into non-designated areas of the polymer vial—only into sterile ports!

For infusion therapy, follow this procedure:

1. Remove the protective plastic cap with tamper-evident feature (if present);
2. Tear off protective seal(s) No. 1 as shown in Figures 1 and 2 (manufacturer may use different types and materials for protective seals);
3. Remove the needle cap and insert the needle into any of the designated sterile ports No. 2 of the infusion vial (see Figures 1 and 2);
4. The other sterile port may be used to introduce other medicinal products into the infusion vial (No. 4, see Figure 3), or, if flow rate is insufficient, for a venting needle (No. 4, see Figure 3);
5. Hang the solution vial using the special ring No. 3 located at the bottom of the vial (see Figure 3).

Children.

Use in children with body weight above 6 kg.

Overdose.

Symptoms: in case of overdose, symptoms described in the section "Adverse reactions" may occur, but in a more pronounced form.

Treatment: symptomatic; no specific antidote is known. In case of seizures, intravenous diazepam is recommended.

Adverse Reactions

All adverse reactions are listed by system organ class and frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from the available data).

Respiratory, thoracic and mediastinal disorders: very rare – bronchospasm.

Gastrointestinal disorders: common – nausea, vomiting, metallic taste in mouth; very rare – abdominal pain.

Hepatobiliary disorders: frequency not known – hepatitis, changes in liver function tests.

Renal and urinary disorders: darkening of urine color.

Psychiatric disorders: frequency not known – mood changes.

Nervous system disorders: rare – tremor, muscle rigidity, coordination disturbances, seizures, impaired consciousness, signs of sensory or mixed peripheral neuropathy; frequency not known – ataxia, dizziness, somnolence, headache, loss of consciousness, confusion, asthenia, dysgeusia.

Blood and lymphatic system disorders: uncommon – bone marrow suppression, neutropenia; very rare – transient hematological changes (leukopenia, agranulocytosis, aplastic anemia, thrombocytopenia).

Immune system disorders: very rare – hypersensitivity reactions, including anaphylactic shock.

Skin and subcutaneous tissue disorders: uncommon – skin rashes, urticaria, pruritus; very rare – angioneurotic edema; frequency not known – fixed drug eruptions.

Musculoskeletal and connective tissue disorders: very rare – joint pain; frequency not known – musculoskeletal stiffness.

Infections and infestations: frequency not known – vaginal superinfection with Candida albicans.

General disorders and administration site conditions: increased body temperature; chills; general weakness; fatigue; dyspnea; reactions at the injection site, including pain, redness, burning sensation at the injection site.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after marketing authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report any suspected adverse reactions and/or lack of efficacy of the medicinal product via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Do not freeze.

Keep out of reach of children.

Incompatibilities.

The solution must not be mixed with other medicinal products.

Packaging.

100 ml in a vial, 1 vial in a carton.

Prescription status. Prescription only.

Manufacturer. JSC "Pharmaceutical Company "Darnitsya".

Manufacturer's address and place of business.

13 Borispilska Street, Kyiv, 02093, Ukraine.