Instructions for Neo-Penotran Forte vaginal suppositories No. 7
Composition
active ingredients: metronidazole and miconazole nitrate;
1 suppository contains 750 mg of metronidazole and 200 mg of miconazole nitrate;
excipient: vitepsol.
Dosage form
Vaginal suppositories.
Main physicochemical properties: suppositories in the form of a flat body from white to yellowish color.
Pharmacotherapeutic group
Antimicrobial, antiprotozoal, antifungal agents.
ATX code G01A F20.
Pharmacodynamics
Neo-Penotran Forte contains miconazole nitrate with antifungal activity and metronidazole with antibacterial and anti-trichomonas activity. Miconazole nitrate, which is an antifungal agent, a synthetic derivative of imidazole, has a wide spectrum of activity and is particularly effective against pathogenic fungi, including Candida albicans. In addition, miconazole nitrate is effective against gram-positive bacteria. Miconazole exerts its action through the synthesis of ergosterol in the cytoplasmic membrane. Miconazole nitrate changes the permeability of the fungal cell of Candida species and inhibits glucose utilization in vitro.
Metronidazole, a 5-nitroimidazole derivative, is an antiprotozoal and antibacterial agent; it is effective against several infections caused by anaerobic bacteria and protozoa, such as Trichomonas vaginalis, Gardnerella vaginalis, and anaerobic bacteria, including anaerobic streptococci.
Miconazole nitrate and metronidazole do not have synergistic or antagonistic effects.
The clinical cure rate achieved in an open, multicenter, uncontrolled clinical study of the efficacy and safety of Neo-Penotran Forte, with a 7-day treatment of 104 patients with a clinical/microbiological diagnosis of vaginitis, was 96.6% for candidal vulvovaginitis, 98.1% for bacterial vaginosis, 97.3% for trichomonas vaginitis and 98.5% for mixed vaginal infections. The microbiological cure rate was 89.8%, 96.2%, 100% and 91.7% for each type of infection, respectively.
In a randomized, open comparative study of the efficacy, safety, and tolerability of Neo-Penotran Forte, the clinical and microbiological cure rates were 84% and 76%, respectively.
Pharmacokinetics
Absorption.
Miconazole nitrate. Absorption of miconazole nitrate after intravaginal administration is very low (approximately 1.4% of the dose). After intravaginal administration of NEO-PENOTRAN FORTE, miconazole nitrate was not detected in the blood plasma.
Metronidazole: The bioavailability of metronidazole with this route of administration is 20% compared to the oral route. Steady-state plasma levels of metronidazole ranged from 1.1 to 5 μg/ml after daily intravaginal administration of Neo-Penotran Forte.
Distribution.
Miconazole nitrate. Plasma protein binding is 90%-93%. Its penetration into cerebrospinal fluid is low, but it is widely distributed in other tissues. The volume of distribution is 1400 liters.
Metronidazole. Penetrates into tissues and body fluids, including bile, bone, mammary glands, breast milk, cerebral abscesses, cerebrospinal fluid, liver and liver abscesses, saliva, seminal fluid, and vaginal secretions, reaching concentrations similar to those in plasma. It crosses the placental barrier and rapidly penetrates the fetal bloodstream. It is not more than 20% bound to plasma proteins. The volume of distribution is 0.25-0.85 l/kg.
Biotransformation.
Miconazole nitrate. Metabolized in the liver. Two inactive metabolites (2,4-dichlorophenyl-1 H imidazole ethanol and 2,4-dichloromandylacid) are identified.
Metronidazole. Metabolized by the liver by oxidation, the hydroxyl metabolite is active. The main metabolites of metronidazole, hydroxyl and acetic acid metabolites, are excreted in the urine. The hydroxyl metabolite has 30% of the biological activity of metronidazole.
Breeding.
Miconazole nitrate. The half-life is 24 hours. Less than 1% is excreted in the urine. Approximately 50% is excreted in the feces, usually unchanged.
Metronidazole. The half-life is 6-11 hours. Approximately 6-15% of a metronidazole dose is excreted in the feces, 60-80% is unchanged and excreted in the urine, as are its metabolites. Approximately 20% of metronidazole is excreted in the urine as unchanged substance.
Preclinical data.
The results of standard non-clinical studies of repeated dose toxicity, genotoxicity, carcinogenicity and reproductive toxicity do not indicate the existence of a specific risk for humans.
In an in vitro microbiological study, no synergistic or antagonistic interaction was detected between the active substances included in the preparation when acting against Candida albicans, Streptococcus (Gram B according to Lancefield), Gardnerella vaginalis and Trichomonas vaginalis.
In a vaginal mucosal irritation study in female beagle dogs, the same drug combination was found to be non-irritating to the vaginal mucosa and to have no clinical, biochemical or haematological effects. No local or systemic toxic effects were observed in the same study.
Indication
For the treatment of candidal vulvovaginitis caused by Candida albicans, bacterial vaginosis caused by anaerobic bacteria and Gardnerella vaginalis, trichomonas vaginitis caused by Trichomonas vaginalis, and mixed vaginal infections.
Contraindication
- hypersensitivity to any of the active ingredients of the drug or to their derivatives;
- drinking alcoholic beverages during treatment or within 3 days after treatment;
- taking disulfiram during treatment or for 2 weeks after treatment;
- porphyria;
- epilepsy;
- severe liver dysfunction.
Interaction with other medicinal products and other types of interactions
Due to the absorption of metronidazole, drug interaction reactions may occur when used simultaneously with certain substances and medications:
alcohol: the interaction of metronidazole with alcohol can cause a reaction similar to the interaction with disulfiram. Alcohol should not be consumed during therapy and for 3 days after the end of the course; amiodarone: increased risk of cardiotoxicity (QT interval prolongation, ventricular flutter-fibrillation, cardiac arrest); astemizole and terfenadine: metronidazole inhibits the metabolism of these drugs and increases their concentration in the blood plasma; carbamazepine: increased concentration of carbamazepine in the blood; cimetidine: increased level of metronidazole in the blood and the risk of neurological side effects; cyclosporine: increased risk of cyclosporine toxicity; disulfiram: effects on the central nervous system (e.g. psychotic reactions); lithium: increased blood level and toxicity of lithium; phenytoin: increased blood level of phenytoin, decreased blood level of metronidazole; Phenobarbital: decreases the level of metronidazole in the blood; fluorouracil: increases the level and toxicity of fluorouracil in the blood; oral anticoagulants: increases the effect of anticoagulants.
During treatment with metronidazole, its effect on blood levels of liver enzymes, glucose (hexokinase method), theophylline and procainamide was observed.
Due to the peculiarities of miconazole nitrate absorption, the following reactions may occur when the following medicines are used simultaneously:
acenocoumarol, anisindione, dicumarol, phenidone, phenprocoumon, warfarin: increased risk of bleeding; astemizole, cisapride and terfenadine: miconazole inhibits the metabolism of these drugs and increases their concentration in the blood plasma; carbamazepine: reduced metabolism of carbamazepine; cyclosporine: increased risk of cyclosporine toxicity (renal dysfunction, cholestasis, paresthesia); fentanyl: increased or prolonged effect of opioids (central nervous system depression, depression, respiratory depression); phenytoin and fosphenytoin: increased risk of phenytoin toxicity (ataxia, hyperlexia, nystagmus, tremor); glimepiride: increased hypoglycemic effect; oxybutynin: increased plasma concentration or effect of oxybutynin; Oxycodone: increased plasma oxycodone concentration and decreased clearance; Pimozide: increased risk of cardiotoxicity (QT prolongation, ventricular fibrillation, cardiac arrest); Tolterodine: increased bioavailability of Tolterodine in individuals with cytochrome P450 2D6 deficiency; Trimetrexate: increased toxicity of Trimetrexate (bone marrow depression, renal and hepatic dysfunction, and gastric and intestinal ulceration).
Application features
The patient should be warned not to drink alcohol during therapy and for 3 days after the end of the course of treatment due to the possibility of central nervous system reactions similar to the effects of disulfiram.
High doses of the drug and long-term use can cause peripheral neuropathy and seizures.
The suppository base may interact in an undesirable way with rubber or latex, from which contraceptive diaphragms and condoms are made, so their simultaneous use with suppositories is not recommended.
Sexual partners of patients with trichomonas vaginitis should also undergo treatment.
In renal failure, the dose of metronidazole must be reduced.
In severe hepatic impairment, metronidazole clearance may be altered. Metronidazole may worsen symptoms of encephalopathy due to its elevated plasma levels. Therefore, metronidazole should be used with caution in patients with hepatic encephalopathy. The daily dose should be reduced to 1/3 in such patients.
For elderly patients (65 years and older): same recommendations as for other patients.
The drug is not recommended for use in virgin girls.
Metronidazole may increase plasma levels of bisulfan, which may lead to significant bisulfan toxicity. Prothrombin and INR (international normalized ratio) levels should be monitored more frequently when oral anticoagulants are used concomitantly during metronidazole use and for 8 days after discontinuation.
Suppositories should not be used with contraceptives such as diaphragms and condoms, as the suppository base may interact with rubber in an undesirable way.
Other intravaginal products (e.g. tampons, douches or spermicides) should not be used concurrently with treatment.
Sexual partners who are found to have Trichomonas vaginalis should undergo treatment at the same time as the patient.
Ability to influence reaction speed when driving vehicles or other mechanisms
Systemic use of metronidazole may affect the ability to drive or operate machinery. Compared with systemic use, the absorption of metronidazole is significantly lower with vaginal administration. There is a possibility of dizziness, ataxia, psychoemotional disorders. In the presence of such symptoms, it is not recommended to drive or operate machinery.
Use during pregnancy or breastfeeding
Pregnancy - category C.
Since the effects of the active ingredients of NEO-PENOTRAN FORTE on the fetus and development of newborns have not been fully studied, women who need to use this drug should avoid pregnancy using an effective contraceptive method.
Preclinical data in animals are insufficient with respect to pregnancy, embryonic and fetal development, perinatal and/or postnatal development. The potential risk for humans is unknown.
Neo-Penotran Forte should not be used in the first trimester of pregnancy. In the second and third trimesters, the drug can be used only if necessary, if the doctor decides that the benefit outweighs the risk.
There is no evidence of a harmful effect on human or animal fertility when metronidazole or miconazole nitrate are used separately.
Breastfeeding should be discontinued during the use of Neo-Penotran Forte, as metronidazole, one of the active ingredients of the drug, passes into breast milk. Breastfeeding can be resumed 1-2 days after the end of treatment.
Method of administration and doses
1 vaginal suppository should be inserted deep into the vagina at night for 7 days.
For relapses of the disease or vaginitis resistant to other treatments, Neo-Penotran Forte should be used for 14 days.
It is not recommended to use Neo-Penotran Forte during menstruation due to a decrease in the effectiveness of the drug and the possibility of some complications during administration.
Children
The drug is not recommended for use in children.
Overdose
There are no data on overdose of metronidazole when administered vaginally. When administered into the vagina, metronidazole may be absorbed in quantities sufficient to cause systemic effects.
If a large amount of the drug accidentally enters the digestive system, an appropriate gastric lavage method should be used if necessary. Treatment should be carried out in cases where 12 g of metronidazole has entered the digestive system. There is no specific antidote, symptomatic treatment is recommended. In case of an overdose of metronidazole, the following symptoms are observed: nausea, vomiting, abdominal pain, diarrhea, itching, metallic taste in the mouth, ataxia, vertigo, paresthesia, convulsions, leukopenia, darkening of urine.
In case of an overdose of miconazole nitrate, the following symptoms are observed: nausea, vomiting, inflammation of the throat and mouth, anorexia, headache, diarrhea.
Adverse reactions
The frequency of the side effects listed below is defined as follows:
very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000); very rare (<1/10,000), not known (cannot be estimated from available data).
In isolated cases, side effects such as hypersensitivity reactions (including skin rash) and abdominal pain, headache, itching, burning and irritation of the vagina may occur. The incidence of systemic side effects is very low due to the very low level of metronidazole in the blood plasma when the drug is used vaginally (2-12% of the level achieved with oral metronidazole). Another active ingredient of the drug, miconazole nitrate, can cause vaginal irritation (burning, itching), like all other antifungal agents containing imidazole derivatives administered vaginally (2-6%). In case of severe irritation, treatment should be discontinued.
Undesirable effects due to the systemic action of the active ingredients of Neo-Penotran Forte are listed below.
Blood and lymphatic system disorders:
Very rare: agranulocytosis, neutropenia, thrombocytopenia, pancytopenia
Not known: leukopenia.
Immune system disorders:
Rare: anaphylactic shock.
Not known: hypersensitivity reactions, allergic reactions, angioedema, urticaria, fever.
Metabolic and digestive disorders:
Not known: anorexia.
Very rare: disorders of consciousness, including confusion and hallucinations.
Not known: depression.
Nervous system disorders:
Common: dizziness, headache,
Very rare: encephalopathy (e.g. confusion, fever, hypersensitivity to light, torticollis, hallucinations, paralysis, visual and movement disorders) and subacute cerebellar syndrome (e.g. ataxia, dysarthria, gait disturbance, nystagmus, tremor), which may resolve after discontinuation of the drug.
Not known: increased fatigue or weakness, convulsions, peripheral neuropathy due to intensive and/or prolonged metronidazole therapy, aseptic meningitis.
On the part of the organs of vision:
Very rare: temporary visual disturbances such as diplopia, myopia, blurred vision, decreased visual acuity, changes in color perception;
Not known: optic neuropathy/neuritis.
Hepatobiliary disorders:
Very rare: increased liver enzymes (AST, ALT, alkaline phosphatase), cholestatic or mixed hepatitis and liver cell (hepatocyte) damage, sometimes with jaundice; cases of liver failure requiring liver transplantation have been reported in patients treated with metronidazole and other antibiotics.
On the part of the skin and its derivatives:
Very rare: skin rashes, pustular rashes, flushing, itching.
Not known: erythema multiforme, Stevens-Johnson syndrome or toxic epidermal necrolysis.
Musculoskeletal and connective tissue disorders:
Very rare - myalgia, arthralgia.
From the kidneys and urinary tract:
Very rare: darkening of urine (due to the metabolism of metronidazole).
Gastrointestinal disorders:
Not known: taste disturbance, inflammation of the oral mucosa, metallic taste, coated tongue, nausea, vomiting, constipation, gastrointestinal disorders such as epigastric pain and diarrhea, dry mouth, decreased appetite, abdominal pain and cramps.
General disorders and administration site conditions:
Very common: vaginal discharge,
Common: vaginitis, vulvovaginal irritation, pelvic discomfort.
Uncommon: feeling thirsty.
Rare: vaginal burning, itching, irritation, stomach pain, rash.
Not known: local irritation and hypersensitivity, contact dermatitis.
These side effects are rare because the concentration of metronidazole in the blood is low after intravaginal administration.
Expiration date
3 years.
Storage conditions
Store at a temperature not exceeding 25 ° C in a place inaccessible to children. The drug can be stored in a refrigerator at a temperature of 2-8 ° C. Do not freeze.
Packaging
One package contains 7 vaginal suppositories.
Vacation category
According to the recipe.
Producer
Exceltis Ilac Sanai ve Tijaret Anonim Shirketi
Location of the manufacturer and its business address
Tekirdag Province, Cerkezkoy District, Cerkezkoy Organiz Sanayi Belgese, Gaziosmanpaşa Mah., Fati Boulevard, No. 19/2, Turkey.
