Gravagin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT GRAVAGIN (GRAVAGIN)

Composition:

Active substance: metronidazole;

1 suppository contains 500 mg of metronidazole;

Excipient: lipophilic base.

Pharmaceutical form. Suppositories.

Main physicochemical properties: white suppositories with a slightly yellowish or yellowish-greenish tint, egg-shaped (ovules).

Pharmacotherapeutic group. Antimicrobial and antiseptic agents used in gynecology. Imidazole derivatives. ATC code G01AF01.

Pharmacological properties.

Pharmacodynamics.

Metronidazole is a derivative of 5-nitroimidazole with a broad spectrum of antimicrobial activity against gram-positive and gram-negative obligate anaerobic bacteria, as well as protozoa. The drug is active against: Peptostreptococcus spp., Clostridium spp., Bacteroides spp., Fusobacterium spp., Porphyromonas, Bilophila, Helicobacter pylori, Prevotella spp., Veilonella. Metronidazole suppresses the growth of protozoa Trichomonas vaginalis, Entamoeba histolytica, Giardia intestinalis (Lamblia intestinalis). Variable sensitivity is observed for: Bifidobacterium spp., Eubacterium spp. The drug is inactive against: Propionibacterium, Actinomyces, Mobiluncus.

Pharmacokinetics.

After intravaginal administration, systemic absorption of metronidazole is minimal. The elimination half-life of metronidazole entering the systemic circulation is 8–10 hours. Less than 20% of metronidazole is protein-bound. Rapid and extensive diffusion into the lungs, kidneys, liver, bile, cerebrospinal fluid, skin, saliva, and vaginal secretions is observed. The drug crosses the placenta and is excreted in breast milk. Metronidazole is metabolized primarily in the liver, forming two non-conjugated oxidized active metabolites (with 5–30% of the parent drug's activity). The drug is excreted predominantly by the kidneys: 35–65% is eliminated in urine as unchanged drug and metabolites.

Clinical characteristics.

Indications.

Local treatment of trichomonal and nonspecific vaginitis.

Contraindications.

Hypersensitivity to metronidazole or to any of the excipients.

Hypersensitivity to imidazole derivatives.

Patients with Cockayne syndrome (see section "Adverse reactions").

Concomitant administration with disulfiram or alcohol is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Antabuse effect. There are many medicinal products that cause disulfiram-like (Antabuse) reaction to alcohol; their concomitant use with alcohol is not recommended.

Combinations not recommended.

Alcohol (in beverages or medicinal products). Disulfiram-like reaction (flushing, erythema, vomiting, tachycardia). Consumption of alcoholic beverages and use of medicinal products containing alcohol should be avoided.

Disulfiram. Risk of developing acute psychotic episodes or confusion, which are reversible upon discontinuation of the drug.

Busulfan. When high-dose busulfan is administered concomitantly with metronidazole, the blood concentration of busulfan increases twofold.

Combinations requiring precautions during use.

Oral vitamin K antagonist anticoagulants. Enhanced anticoagulant effect and increased risk of hemorrhagic complications due to inhibition of their hepatic metabolism are expected. Frequent and careful monitoring of INR (International Normalized Ratio) and prothrombin time is required. Dose adjustment of the anticoagulant may be necessary during metronidazole therapy and for 8 days after its discontinuation.

Enzyme-inducing anticonvulsants (carbamazepine, fosphenytoin, phenobarbital, phenytoin, primidone). Decreased plasma concentration of metronidazole due to induction of its hepatic metabolism. Clinical monitoring should be performed during and after treatment with these inducers. Dose adjustment of metronidazole may be necessary.

Rifampicin. Decreased plasma concentrations of metronidazole due to induction of its hepatic metabolism by rifampicin. Clinical monitoring should be performed during and after treatment with rifampicin. Dose adjustment of metronidazole may be necessary.

Lithium. Plasma lithium concentration may increase and reach toxic levels with signs of overdose when metronidazole is used concomitantly. Careful monitoring of plasma lithium levels is required, and dose adjustment may be necessary.

Cyclosporine. When used concomitantly, there is a risk of increased cyclosporine plasma concentration. In case such combination is necessary, careful monitoring of serum creatinine and cyclosporine levels is required.

Combinations requiring special attention.

Fluorouracil (as well as tegafur and capecitabine). Reduced clearance of 5-fluorouracil, leading to increased toxicity.

Changes in INR (International Normalized Ratio). Numerous cases of enhanced effect of oral vitamin K antagonist anticoagulants have been reported in patients receiving antibacterial therapy. Risk factors for this condition include infection and/or marked inflammation, age, and general health status. Under these circumstances, it is difficult to determine to what extent the change in INR is due to the infection itself or its treatment. Some classes of antibacterial agents have a greater effect on INR, particularly: fluoroquinolones, macrolides, tetracyclines, co-trimoxazole, and certain cephalosporins.

Laboratory test results. Metronidazole may immobilize treponemes, leading to a false-positive Nelson test.

Special precautions.

In patients with severe, chronic, or progressive diseases of the peripheral or central nervous system, there is a risk of exacerbation of neurological pathology.

Patients with a history of hematological disorders or those receiving the drug in high doses and/or for prolonged periods should undergo regular complete blood counts, especially leukocyte count monitoring.

During prolonged treatment with the drug, patients should be monitored for the development of adverse reactions such as central or peripheral neuropathy (paresthesia, ataxia, dizziness, seizures).

Patients should be informed that metronidazole may darken the urine (due to the active metabolite).

The use of vaginal suppositories together with latex condoms or diaphragms increases the risk of latex rupture.

Hypersensitivity/skin and appendages disorders. Allergic reactions, including life-threatening anaphylactic shock, may occur (see section "Adverse reactions"). In such cases, metronidazole should be discontinued and appropriate treatment initiated.

If generalized erythema and pustular eruptions accompanied by fever develop at the beginning of treatment, acute generalized exanthematous pustulosis (AGEP) should be suspected (see section "Adverse reactions"); in case of such condition, treatment should be stopped, and further use of metronidazole, either as monotherapy or in combination with other drugs, is contraindicated.

Acute skin reactions, including Stevens-Johnson syndrome, Lyell's syndrome (toxic epidermal necrolysis), and acute generalized exanthematous pustulosis (AGEP), have been associated with metronidazole use. Patients should be informed about the symptoms of these reactions, and careful skin monitoring is required.

If symptoms of Stevens-Johnson syndrome, Lyell's syndrome (e.g., progressive rash, skin blisters, or mucosal lesions) or generalized erythema with pustular eruptions accompanied by fever occur, treatment with the drug should be discontinued immediately, and further use of metronidazole, either as monotherapy or in combination with other drugs, is contraindicated.

Central nervous system disorders. If symptoms characteristic of encephalopathy or cerebellar syndrome occur, the patient's treatment should be immediately reassessed and metronidazole discontinued promptly. Cases of encephalopathy have been reported, and MRI changes associated with encephalopathy have been observed (see section "Adverse reactions"). Lesions are most commonly located in the cerebellum (especially in the dentate nucleus) and the corpus callosum. In most cases, encephalopathy and MRI changes resolve after discontinuation of metronidazole. Fatal cases have been very rarely reported.

Patients should be monitored for possible signs of encephalopathy or worsening of symptoms in case of pre-existing CNS disorders.

Re-administration of metronidazole is not recommended in case of aseptic meningitis occurring during treatment; in patients with serious infectious diseases, a re-evaluation of the benefit-risk ratio is required.

Peripheral nervous system disorders. Patients should be monitored for possible signs of peripheral neuropathy, especially during long-term treatment or in the presence of severe, chronic, or progressive peripheral neuropathy.

Psychiatric disorders. Psychotic reactions, including self-harming behavior, may occur after the first dose of the drug, particularly in patients with a history of psychiatric disorders (see section "Adverse reactions"). In such cases, metronidazole treatment should be discontinued, the physician should be notified, and appropriate therapeutic measures should be taken immediately.

Hematological effects. Patients with a history of blood disorders or those receiving the drug in high doses and/or for prolonged periods should undergo regular blood tests, including leukocyte counts. Continuing metronidazole treatment in patients with leukopenia depends on the severity of the underlying infection.

Interaction with other medicinal products. Concomitant use of metronidazole and alcohol is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant use of metronidazole and busulfan is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant use of metronidazole and disulfiram is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Other interactions. The maximum duration of metronidazole treatment should not exceed 10 days, and the number of treatment courses should not exceed 2–3 per year.

The use of suppositories together with latex condoms or diaphragms increases the risk of latex rupture.

In patients with Cockayne syndrome, cases of rapidly developing acute liver failure, including fatal outcomes, have been observed during systemic metronidazole therapy. Metronidazole should be used in these patients only after careful benefit-risk assessment and solely when no alternative treatment is available.

Liver function tests should be performed immediately before starting treatment, during drug administration, and after completion of metronidazole therapy until normalization or return to baseline values. If liver function tests show markedly elevated values during treatment, metronidazole should be discontinued.

Patients with Cockayne syndrome should be advised to immediately inform their physician and discontinue metronidazole treatment if any symptoms suggesting liver dysfunction occur.

Use during pregnancy or breastfeeding.

Animal studies with original metronidazole did not demonstrate teratogenic effects. Since teratogenic effects are not observed in animals, developmental abnormalities in humans are not expected. According to existing data, substances causing developmental abnormalities in humans also show teratogenic effects in animals during adequately conducted studies in two species. Numerous clinical data have not demonstrated any specific teratogenic or fetotoxic effects associated with metronidazole administration during pregnancy. However, the absence of such risk can only be confirmed by epidemiological studies. Therefore, metronidazole should not be prescribed during pregnancy unless clearly necessary.

Metronidazole is excreted in breast milk. Therefore, the use of this medicinal product should be avoided during breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

Patients should be warned about the risk of dizziness, confusion, hallucinations, seizures, and visual disturbances. If such symptoms occur, patients should refrain from driving vehicles or operating machinery.

Method of administration and dosage.

The drug should be used for treatment only in adult female patients.

Remove the suppository from the blister pack and insert deeply into the vagina while lying on the back with knees bent and drawn up to the chest, or in the "on all fours" position.

For the treatment of trichomonal vaginitis, administer 500 mg (1 suppository) once daily at night for 10 consecutive days. In trichomonal vaginitis, treatment should be combined with oral administration of metronidazole.

For the treatment of nonspecific vaginitis, administer 500 mg (1 suppository) once daily for 7 consecutive days. If necessary, oral metronidazole may be prescribed.

Simultaneous treatment of the sexual partner is absolutely essential, even if he is asymptomatic.

Maximum duration of treatment should not exceed 10 days, and the number of treatment courses should not exceed 2–3 per year.

Children.

The drug should be used only in adult female patients.

Overdose.

There are reports of single ingestion of 12 g of metronidazole during suicidal attempts and accidental overdoses. Symptoms may include ataxia, vomiting, and mild disorientation. As there is no specific antidote for metronidazole, symptomatic therapy is recommended.

Adverse reactions.

Gastrointestinal disorders: epigastric pain, anorexia, nausea, vomiting, diarrhea, taste disturbances (metallic taste in the mouth), stomatitis, glossitis with dryness of the mouth, coated tongue, changes in color or appearance of the tongue (fungal infection), isolated cases of pancreatitis, which are reversible.

Skin and subcutaneous tissue disorders: flushing with hyperemia, pruritus, rashes which may be accompanied by fever, isolated cases of acute generalized exanthematous pustulosis (see section "Special precautions"), erythema, urticaria, angioneurotic edema, anaphylactic shock (see section "Special precautions"), toxic epidermal necrolysis, fixed drug eruption, Lyell's syndrome, Stevens-Johnson syndrome.

Nervous system disorders: headache, dizziness, ataxia, somnolence, convulsions, peripheral sensory neuropathy. Very rare cases of encephalopathy (confusion, elevated body temperature, photophobia, torticollis, hallucinations, paralysis, visual and motor disturbances) and subacute cerebellar syndrome (ataxia, dysarthria, gait disturbance, nystagmus, tremor), which may resolve after discontinuation of the drug; aseptic meningitis (see section "Special precautions"), encephalopathy which may be associated with MRI changes, usually reversible (see section "Special precautions"); very rare cases with fatal outcomes have been reported.

Psychiatric disorders: hallucinations, psychotic reactions with paranoia and/or delirium, which in isolated cases may be accompanied by suicidal thoughts or suicide attempts (see section "Special precautions"), depressed and depressive mood.

Eye disorders: transient visual disturbances (blurred vision, diplopia, myopia, blurred images, decreased visual acuity, changes in color perception), optic neuropathy/neuritis.

Blood and lymphatic system disorders: agranulocytosis, neutropenia and thrombocytopenia, pancytopenia and leukopenia.

Hepatobiliary disorders: increased levels of liver enzymes (AST, ALT, alkaline phosphatase); very rare cases of acute cholestatic or mixed hepatitis and hepatocellular injury, sometimes with jaundice, have been reported. Isolated cases of liver failure in patients treated with metronidazole and other antibiotics requiring liver transplantation have been reported.

Cases of severe irreversible hepatotoxicity/acute liver failure, including fatal cases with a very rapid course after initiation of systemic metronidazole administration, have been reported in patients with Cockayne syndrome (see section "Contraindications").

Other: during treatment, urine may turn red-brown due to water-soluble pigments formed during the metabolism of metronidazole.

Reporting suspected adverse reactions.

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

Shelf life.

2 years.

The medicinal product should not be used after the expiry date stated on the packaging.

Storage conditions.

Store at a temperature from 2 °C to 15 °C. Keep out of the reach and sight of children.

Packaging.

5 suppositories per strip made of polyvinyl chloride film. Two strips in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Ukrainian-Spanish joint venture "Sperco Ukraine".

Manufacturer's address and location of business activity.

25, 600-Richchia St., Vinnytsia, 21027, Ukraine.

Tel.: + 38(0432)52-30-36. E-mail: [email protected]

www.sperco.ua