Russian name

Buprenorphine + Naloxone

Latin name of substances Buprenorphine + Naloxone

Buprenorphinum + Naloxonum ( genus. Buprenorphini + Naloxoni)

Pharmacological group of substances Buprenorphine + Naloxone

Nosological classification (ICD-10)

Pharmacology

pharmachologic effect- analgesic (opioid).

Pharmacodynamics

The pharmacological action of the sublingual combination buprenorphine + naloxone is determined by its constituent buprenorphine.

Buprenorphine is an opioid analgesic, a semi-synthetic derivative of thebaine. Refers to partial agonists of the μ-opioid receptor subtype and partial antagonists of the κ-opioid receptors. The severity of analgesic action in equivalent doses is similar to that of morphine. As a partial agonist of opioid receptors, it depresses respiration, affects smooth muscles, although to a lesser extent than morphine and other opiates, has a lower potential for developing physical dependence compared to them. At the same time, activation of μ-opioid receptors determines a certain addictive potential of the buprenorphine + naloxone combination.

Naloxone is an opioid receptor antagonist. Effectively eliminates or weakens the effects of opiates and opioids. Restores breathing, reduces sedative and euphoric effects. May cause opioid withdrawal when previously administered for pain relief or in dependent individuals using opioid analgesics. Pharmacological action develops only with parenteral (in / in, in / m, s / c) route of administration. With the sublingual route of administration, it practically does not enter the systemic circulation and has no effect.

There are no pharmacodynamic effects. Naloxone practically does not exhibit pharmacological activity when taken orally, the ratio of the effectiveness of naloxone for oral and parenteral administration is 1:50.

The onset of action of buprenorphine after sublingual use of the combination buprenorphine + naloxone occurs after 30 minutes. The maximum effect is observed after 3 hours. The duration of the analgesic effect is 5 hours.

Pharmacokinetics

Suction

When taken sublingually, buprenorphine is well absorbed. Systemic bioavailability is about 50-55%. C max in plasma after taking 0.4 mg of buprenorphine is reached after 2 hours and averages 1.13 ng / ml.

With sublingual administration, naloxone is practically not absorbed. Systemic bioavailability is less than 5%. Plasma concentrations are not significant.

Distribution

Buprenorphine penetrates well through the BBB. 96% binds to plasma proteins, primarily to α- and β-globulins. Vd of buprenorphine is 2.5 liters, which indicates its active capture by body tissues.

Naloxone is 45% bound to plasma proteins, mainly to albumin.

Metabolism

Buprenorphine is metabolized in the liver by N-dealkylation with the formation of norbuprenorphine with the participation of the isoenzyme CYP3A4, followed by glucuronidation with the formation of conjugates with glucuronic acid. The main metabolite, norbuprenorphine, has no significant analgesic activity and is also glucuronidated.

According to clinical studies, naloxone has a low bioavailability (9±6%) when administered sublingually. The absorbed small amount of naloxone, which is part of the buprenorphine + naloxone combination, does not create a therapeutic plasma concentration and does not affect the effects and metabolism of buprenorphine.

Naloxone is rapidly metabolized in the liver, undergoing direct glucuronization to naloxone-3-glucuronide, as well as N-dealkylation and reduction (at the 6-oxo group).

breeding

T 1/2 of buprenorphine from blood plasma is 24-42 hours. Excretion of metabolites is carried out by the kidneys (30%) and bile (69%). Only about 1% of buprenorphine is excreted unchanged.

T 1/2 of naloxone is 2-12 hours. Metabolites are excreted mainly by the kidneys.

The use of substances Buprenorphine + Naloxone

Postoperative pain syndrome (strong and moderate intensity); pain syndrome caused by injuries and burns; during diagnostic procedures.

Contraindications

Hypersensitivity to buprenorphine and naloxone; conditions that may lead to respiratory failure or are already accompanied by depression of the respiratory center or severe depression of the central nervous system; simultaneous use with MAO inhibitors, both during the entire period of use of MAO inhibitors, and within 14 days after their withdrawal (see "Interaction"); stomatitis and mucositis, ulcerative-necrotic and inflammatory lesions of the oral mucosa; drug dependence, incl. opioid; convulsive conditions; traumatic brain injury; acute alcohol intoxication; bronchial asthma, status asthmaticus; pulmonary heart failure; heart rhythm disturbances (supraventricular and ventricular paroxysmal tachycardia, atrial fibrillation and flutter, ventricular fibrillation and flutter, extrasystole); paralytic ileus; acute surgical diseases of the abdominal organs before diagnosis; pregnancy; breastfeeding period; age up to 18 years.

Application restrictions

respiratory failure; hepatic and / or renal failure; myxedema; hypothyroidism; adrenal insufficiency; CNS depression; toxic psychosis; prostatic hyperplasia; urethral strictures; alcoholism; old and old age.

Use during pregnancy and lactation

The combination of buprenorphine + naloxone is contraindicated during pregnancy and during breastfeeding. Controlled studies of the use of this combination (sublingual) have not been conducted. The potential risk to humans is unknown.

When using the combination buprenorphine + naloxone at the end of pregnancy, buprenorphine may cause respiratory depression in the newborn, even after a short period of use. Long-term use of buprenorphine during the last 3 months of pregnancy may cause neonatal withdrawal symptoms (including hypertension, tremor, neonatal agitation, myoclonus, or seizures). The syndrome, as a rule, can proceed from several hours to several days after childbirth.

It is not known whether naloxone is excreted in breast milk. Buprenorphine and its metabolites are excreted from the body through breast milk.

In an animal study, buprenorphine was found to inhibit lactation in rats. Therefore, breastfeeding should be discontinued during treatment with buprenorphine + naloxone.

Animal studies have shown a reduction in female fertility at doses many times the average daily human dose.

Side effects of substances Buprenorphine + Naloxone

Information on the incidence of side effects is presented on the basis of data obtained during clinical trials and literature data: very often (≥10%); often (≥1,<10%); нечасто (≥0,1, <1%); редко (≥0,01, <0,1%); очень редко (<0,01%);

The side effects of the buprenorphine + naloxone combination are determined by the buprenorphine it contains.

Allergic reactions: rarely - rash, urticaria.

From the side of the central nervous system: very often - sedation; often - weakness; rarely - confusion, drowsiness, weakness / fatigue, lethargy, slowing down of the rate of mental and motor reactions, slurred speech, paresthesia, euphoria, nervousness, depression, psychosis.

With prolonged use, the development of addiction and opioid dependence is possible.

From the nervous system: often - dizziness, headache; rarely - tinnitus.

From the side of the skin: rarely - cyanosis, itching.

From the urinary system: rarely - urinary retention.

From the side of metabolism: rarely - sweating.

From the digestive system: often - nausea; rarely - vomiting, dry mouth, constipation.

From the respiratory system: rarely - depression of the respiratory center, shortness of breath, hypoventilation.

From the sense organs: often - miosis, blurred vision, diplopia; very rarely - conjunctivitis.

From the CCC: often - increased blood pressure; rarely - tachycardia, bradycardia, chills / cold sensation, flushing.

Interaction

Potentiates the action of neuroleptics, benzodiazepines, phenothiazines, and other tranquilizers; anxiolytics, sedatives, hypnotics, general anesthetics, antihistamines, ethanol.

When combined with MAO inhibitors, malignant hyperthermia, convulsions, coma, arterial hypertension may develop.

When combined with a combination of buprenorphine + naloxone with full opioid agonists, the development of opiate withdrawal syndrome is possible.

When used with valproic acid / sodium valproate, the inhibitory effect on the central nervous system increases.

When taking other analgesics, cerebrospinal fluid pressure may increase, so the combination of buprenorphine + naloxone should be used with caution in cases where cerebrospinal fluid pressure can be increased, because. buprenorphine can lead to miosis and changes in the level of consciousness.

Drugs that inhibit the activity of the CYP3A4 isoenzyme (including ketoconazole, macrolides, erythromycin), or HIV protease inhibitors (ritonavir) may increase the effects and duration of action of buprenorphine, which will require dose adjustment of one or both drugs.

When taken together with inducers of the CYP3A4 isoenzyme (including phenobarbital, carbamazepine, phenytoin, rifampicin), the concentration of buprenorphine in the blood plasma may decrease. Since the interaction of buprenorphine with all CYP3A4 inducers has not been studied, it is recommended to monitor the condition of patients receiving sublingual buprenorphine + naloxone combination for signs and symptoms of withdrawal syndrome.

Phytopreparations can influence the pharmacological activity of buprenorphine. Drugs containing St. John's wort, as inducers of the CYP3A4 isoenzyme, are able to reduce the concentration of buprenorphine in the blood plasma.

Ethanol enhances CNS depression by buprenorphine. At the time of treatment it is necessary to give up alcoholic beverages.

Overdose

Symptoms of an overdose are determined by the buprenorphine that is included in the composition.

Symptoms: nausea, vomiting, sedation, drowsiness, miosis, respiratory depression.

Treatment: physical and verbal stimulation of the patient, symptomatic therapy (oxygen, infusion therapy, parenteral administration of naloxone - a single intravenous or intramuscular injection of naloxone at a dose of 0.4-2 mg is recommended with repetitions after 2-3 minutes up to a total dose of 10 mg and more). Due to the high affinity of buprenorphine for opioid receptors, higher doses of naloxone are used than for poisoning with morphine and other full opioid agonists. If necessary - auxiliary and IVL.

Routes of administration

Sublingual.

Substance Precautions Buprenorphine + Naloxone

Naloxone is included in the buprenorphine + naloxone combination to increase safety in its use. In the case of non-medical use of the combination buprenorphine + naloxone (due to the presence of a narcotic analgesic in the composition), naloxone blocks the effects of buprenorphine and does not lead to the effect that is pursued with the abuse of buprenorphine. In individuals with physical dependence on opioids, this can lead to the development of a withdrawal syndrome.

Liver failure

Buprenorphine is metabolized in the liver. In patients with impaired liver function, the intensity and duration of action of the buprenorphine + naloxone combination may vary. The use of sublingual buprenorphine + naloxone in these patients should be supervised by a specialist.

kidney failure

The pharmacokinetics of buprenorphine in renal failure does not change.

Nicotine addiction

Patients should be warned that nicotine reduces the pharmacological activity of the buprenorphine + naloxone combination.

Influence on the ability to drive vehicles and mechanisms. During the period of treatment, it is necessary to refrain from driving vehicles and engaging in potentially hazardous activities that require an increased concentration of attention and speed of psychomotor reactions.

| Buprenorphine

Analogues (generics, synonyms)

Recipe

Rep.: Tab. Buprenorphini 0.0002 №20

D. S. 200 mcg with an interval of 6-8 hours.

Rp.: Sol. Buprenorphini 0.03% - 1.0

D. No. 10 in amp.

S.: Administer intramuscularly or intravenously slowly at 300 mcg with an interval of 6-8 hours.

pharmachologic effect

Analgesic (opioid).
It is a partial mu opioid receptor agonist and a kappa receptor antagonist. To a lesser extent than morphine, it is addictive and drug dependent.
With sublingual application, Cmax in plasma is achieved on average after 1 hour. T1 / 2 with intramuscular and sublingual use is 3-6 hours. It is evenly distributed over tissues, penetrates through the BBB. It is metabolized in the liver, metabolic products are excreted in the bile, a small amount is excreted by the kidneys.

Mode of application

In / m or / in slowly 300 mcg with an interval of 6-8 hours.
Sublingually - 200 mcg with an interval of 6-8 hours.

Indications

Moderate and severe pain syndrome of various origins.

Contraindications

Respiratory center depression
- pregnancy, lactation
- children's age up to 12 years
- hypersensitivity to buprenorphine.

Side effects

From the digestive system: nausea, vomiting, dry mouth.
- From the side of the central nervous system: headache, depression, lethargy, depression of the respiratory center, slowing down the speed of mental and motor reactions.
- From the side of the cardiovascular system: lowering blood pressure.
- Other: shortness of breath, increased sweating, skin rash.

Release form

Sublingual tablets of 0.0002 g (0.2 mg) of buprenorphine hydrochloride in a package of 10, 20 or 100 pieces;
Solution for injection in ampoules of 1 and 2 ml (1 ml contains 0.00003 g / 0.3 mg / buprenorphine).

ATTENTION!

The information on the page you are viewing was created for informational purposes only and does not promote self-treatment in any way. The resource is intended to familiarize healthcare professionals with additional information about certain medicines, thereby increasing their level of professionalism. The use of the drug "" without fail provides for a consultation with a specialist, as well as his recommendations on the method of application and dosage of the medicine you have chosen.

Buprenorphine (Buprenorphine)

pharmachologic effect

Analgesic (pain reliever) of central action. The mechanism is associated with the high affinity of the drug for opioid receptors. Does not depress the respiratory center. In the tests conducted on long-term use of the drug, the development of addiction (weakening or lack of effect with prolonged repeated use of the drug) and drug dependence (addiction to the drug) was not established.

Indications for use

Pain syndromes of low and medium intensity of various origins.

Mode of application

Enter intramuscularly or intravenously slowly at 0.3 mg (1 ml solution for injection) every 6-8 hours, if necessary, a single dose can be increased. Inside take 1-2 tablets under the tongue every 6-8 hours or as needed.

Side effects

Drowsiness, nausea, vomiting, respiratory depression.

Contraindications

Hypersensitivity to the drug. It is prescribed with caution in violation of respiratory function, against the background of taking MAO inhibitors, as well as agents that depress the central nervous system.

Release form

Sublingual tablets of 0.0002 g (0.2 mg) of buprenorphine hydrochloride in a package of 10, 20 or 100 pieces; solution for injection in ampoules of 1 and 2 ml (1 ml contains 0.00003 g / 0.3 mg / buprenorphine).

Storage conditions

List A (according to the rules established for morphine and other drugs).

Active substance:

buprenorphine

The authors

Links

• The official instructions for the drug Buprenorphine.
• Modern drugs: a complete practical guide. Moscow, 2000. S. A. Kryzhanovsky, M. B. Vititnova.

Attention!
Description of the drug Buprenorphine" on this page is a simplified and supplemented version of the official instructions for use. Before purchasing or using the drug, you should consult a doctor and read the annotation approved by the manufacturer.
Information about the drug is provided for informational purposes only and should not be used as a guide to self-medication. Only a doctor can decide on the appointment of the drug, as well as determine the dose and methods of its use.

Buprenorphine - a semi-synthetic opioid, is a powerful pain reliever.

Chemical Name: 17-(Cyclopropylmethyl)-7,8-dihydro-7-[(1S)-2-hydroxy-3,3-dimethylbutyl-2]-6-methoxy-O-methyl-6,17-ethano-17-normorphine hydrochloride
Chemical formula: С29H42CINO4

Synonyms and slang names for Buprenorphine:

English: Anfin, Burrenal, Вuprenex, Buprex, Lepetan, Norfin, Norphine, Subutex, Temgesic
Russians: Anfin, Norfin, Bupremen, Buprenal, Buprex, Buprenex, Lepetan, Sangezik, Temgezik, Torgesik, Unifin

Buprenorphine is a narcotic analgesic thebaine (opium alkaloid), and similar in chemical structure to morphine. According to their pharmacological properties buprenorphine similar to other medicinal substances of the opiate group.
In appearance it is a white crystalline powder, sparingly soluble in water and readily soluble in ethyl alcohol.

Action of buprenorphine

Buprenorphine begins to act in less than a minute when administered intravenously and after about 15 minutes when administered intramuscularly. The maximum concentration of the drug in plasma is reached after 5-20 minutes.
Insofar as buprenorphine about 30 times stronger than morphine in its analgesic effect, then 0.3 mg of this drug is equivalent to 10 mg of morphine.
Maximum analgesic effect of buprenorphine has a dosage of 1.2-1.5 mg, but such doses of the drug can lead to respiratory depression.
By duration of action of buprenorphine surpasses morphine twice: when administered intravenously and intramuscularly, the effect lasts 6-8 hours.
In general, the effect of the drug is similar to that of other drugs of the opioid group, such as morphine and methadone, but with a more pronounced analgesic (pain-relieving) effect, and less pronounced euphoric. The advantages of the drug in medical use to reduce chronic pain are its low toxicity, speed (even in the case of oral administration (sublingual tablets)) and duration of exposure. In addition, the drug causes much less dependence. Side effects that may occur as a result of a single dose of a high dose of the drug: depression of the respiratory center, bradycardia, tachycardia, hypotension, dizziness, headache, confusion, hallucinations, nausea, vomiting, dry mouth, increased sensitivity to cold, miosis (pupillary constriction ).
When taken simultaneously with other narcotic analgesics, benzodiazepines, sedatives and alcohol, it can cause CNS depression.
Due to tolerance to buprenorphine practically does not grow, and also given its low toxicity, the drug, along with methadone, is widely used in Western medicine for substitution maintenance therapy.

Harm and dependence on buprenorphine

Buprenorphine, unlike illegal drugs, has low toxicity to the liver, internal organs and the body as a whole. Even with long-term use, addiction to the drug occurs much less frequently than to other opiate agonists such as morphine or heroin. This is due to the fact that in terms of the level of euphoria that occurs and other narcotic effects buprenorphine significantly inferior to morphine. In this regard, the Committee of Experts of the World Health Organization (WHO) on drug dependence did not include buprenorphine in the "Single Convention on Narcotic Drugs", but taking into account the psychological effects it causes, it was included in the "Convention on Psychotropic Agents" in 1971 (list III ).
When you stop taking the drug after a long - for several months - its use, a withdrawal syndrome (abstinence) may occur. This syndrome manifests itself in anxiety, irritability, insomnia, chills alternating with fever, convulsive muscle twitches, abdominal cramps, nausea and vomiting. Buprenorphine also readily crosses the placental barrier and may contribute to impaired
prenatal development, so the appointment of buprenorphine is not recommended for pregnant and lactating mothers.

Diagnosis and treatment

Main symptoms of buprenorphine poisoning: drowsiness, heart rhythm disturbance, cramping abdominal pain, vomiting, sweating, tremor, respiratory arrest, coma. In this case, you should immediately stop the administration of the drug, ensure normal ventilation and blood circulation, as well as introduce an antidote.
The most effective antidote for opiate poisoning is Naloxone, which is administered intravenously at 0.4-1 mg every 2-3 minutes until complete stabilization (but not exceeding a total dose of 20-25 mg).
For the treatment of withdrawal symptoms following withdrawal buprenorphine, other analgesics, benzodiazepines and symptomatic therapy are used. To avoid withdrawal, it is best to reduce its dosage gradually, by 50% every 2-3 days.
One of the unpleasant side effects of continuous use buprenorphine are chronic constipation. In addition, this symptom is difficult to treat. The way out of the situation is the daily intake of laxatives.

Legislation

In Russia buprenorphine included List II "Narcotic drugs and psychotropic substances, the circulation of which in the Russian Federation is limited and in respect of which control measures are established in accordance with the legislation of the Russian Federation and international treaties of the Russian Federation"

The drug is an analgesic used to treat opioid dependence, relieve acute pain, as an anesthetic in oncology.

Indications and dosage:

Buprenorphine hydrochloride is used to treat opioid dependence,

for the relief of acute pain, as an anesthetic in oncology.

The drug is prescribed only in special centers and clinics for the treatment of patients under the supervision of a physician. The drug is applied sublingually and is kept in the oral cavity until the tablet is completely dissolved. Tablets should be taken when the patient has objective withdrawal symptoms or at least 6 hours after the last opioid intake.

For the treatment of opioid dependence, the recommended initial dose is 4-8 mg, further titrated depending on the patient's condition to 2-4 mg per day. The interval between taking the drug is 6-8 hours. The maximum daily dose is 32 mg. The duration of treatment depends on the condition of the patient.

Overdose:

Symptoms. In case of accidental overdose, the usual symptomatic therapy should be used, including close monitoring of vital body functions. The main symptom requiring intensive care is respiratory depression, which can lead to respiratory arrest and death. If vomiting occurs, measures must be taken to prevent the vomit from entering the respiratory tract.

Treatment. It is necessary to take intensive care measures and start symptomatic therapy for respiratory failure. The upper airways must be free for forced or controlled ventilation. It is recommended to administer an opioid antagonist (naloxone), which gradually neutralizes the respiratory effects of buprenorphine. If necessary, prescribe oxygen and respiratory analeptics. When performing the above activities, the patient must be in the intensive care unit.

Side effects:

The onset of side effects depends on the tolerance threshold. In drug addicts, this figure is significantly higher than in patients who do not use drugs.

Possible:

Mental disorders: hallucinations.

From the nervous system: insomnia, headache, fainting, dizziness.

From the vascular system: orthostatic hypotension.

Respiratory, thoracic and mediastinal disorders: depression of the respiratory center.

From the gastrointestinal tract: constipation, nausea, vomiting.

General disorders: weakness, drowsiness, excessive sweating.

From the immune system: hypersensitivity reactions (eg, rash, urticaria, itching, bronchospasm), Quincke's disease (angio-neurotic edema), anaphylactic shock.

From the hepatobiliary system: under the right conditions of use in isolated cases - an increase in the level of liver transaminases and jaundice, usually with a favorable clinical course.

In patients with severe physical (somatic) drug dependence, the first sublingual administration of buprenorphine hydrochloride can cause a paradoxical reaction with the development of a withdrawal syndrome similar to naloxone.

Contraindications:

Hypersensitivity to buprenorphine or to any other component of the drug

Acute respiratory failure

Acute liver and kidney failure

Acute alcohol intoxication

alcohol withdrawal syndrome

Acute heart failure

Traumatic brain injury

Pregnancy and lactation period

Age up to 12 years

Buprenorphine is contraindicated during pregnancy. Long-term use of the drug by the mother for more than the first three months of pregnancy, regardless of dose, can cause the development of a withdrawal syndrome, and high doses of buprenorphine, if taken in the last months of pregnancy, even for a short period, can cause respiratory depression in the newborn. So, the newborn should be monitored to exclude the risk of respiratory depression or the development of opium withdrawal syndrome.

Since buprenorphine and its metabolites pass into breast milk, you can not breastfeed the baby during the entire period of use of the drug.

Interaction with other drugs and alcohol:

Alcohol. Alcohol enhances the sedative effect of buprenorphine. Decreased vigilance (attention) increases the danger when driving a car and working with mechanisms. Alcoholic beverages and medications containing alcohol should be avoided.

benzodiazepine tranquilizers. Simultaneous use with benzodiazepines is associated with a risk of death from respiratory failure associated with impaired functioning of the central nervous system.

Other central nervous system depressants. Other opiate derivatives (analgesics, antitussives), some antidepressants, antihistamines (H1 receptor blockers), barbiturates, tranquilizers, clonidine, when used simultaneously with buprenorphine, cause increased depression of the central nervous system.

Monoamine oxidase inhibitors (MAOs). It is possible to increase the effect of opioids when used simultaneously with buprenorphine.

CYP3A 4 inhibitors. An interaction study between buprenorphine and ketoconazole (a potent inhibitor of CYP3A 4) showed an increase in the maximum concentration and AUC of buprenorphine (by 70% and 50%, respectively), to a lesser extent - norbuprenorphine. Thus, patients taking buprenorphine should be monitored closely if they are taking CYP3A4 inhibitors concomitantly, such as protease inhibitors (ritonavir, nelfinavir, indinavir), azole antifungals (ketoconazole, itraconazole). In such cases, it may be justified to reduce the dose of buprenorphine.

CYP3A 4 inducers. The interaction between buprenorphine and CYP3A 4 inducers has not been studied, therefore careful monitoring of patients receiving concomitant CYP3A 4 inducers (phenobarbital, carbamazepine, phenytoin or rifampicin) is recommended.

To date, no significant interaction of buprenorphine with cocaine has yet been identified.

Composition and properties:

1 tablet contains:

Buprenorphine hydrochloride in terms of buprenorphine 2 or 4 mg.

Excipients: celactose 80, mannitol (E 421), corn starch, crospovidone, citric acid, aspartame (E 951), magnesium stearate.

Pharmachologic effect:

According to the mechanism of action, buprenorphine hydrochloride belongs to the group of agonists / antagonists of the opiate receptors in the brain (mu- and kappa receptors). Buprenorphine binds to mu receptors, which after a certain period of time minimizes the patient's pathological craving for drugs.

Due to the specific activity of buprenorphine as an opiate receptor agonist, the drug provides greater safety in the development of respiratory and heart failure compared to morphine.

The latency period to onset of action of buprenorphine hydrochloride following sublingual administration is approximately 30 minutes.

The duration of analgesic action is longer than that of morphine.

Release form:

Tablets 2 mg - No. 25 in a blister, 4, 10 or 50 blisters in a box

Tablets 4 mg - No. 10 in a blister, 1, 5 or 10 blisters in a box

Storage conditions:

Store in the original packaging at a temperature not exceeding 25 ° C, out of the reach of children.

general information

Sales form:

On prescription

Current in-o:

Buprenorphine

Description of the drug "Buprenorphine hydrochloride" on this page is a simplified and supplemented version of the official instructions for use. Before purchasing and using the drug, you should consult a doctor and read the annotation approved by the manufacturer.