Solution for oral administration from colorless to yellowish color, transparent, with a fruity odor.
1 ml
propranolol hydrochloride 4.28 mg,
which corresponds to the content of propranolol 3.75 mg
Auxiliary substances: hydroxyethyl cellulose 3.5 mg, sodium saccharinate 1.5 mg, strawberry flavor 1.1 mg, vanilla flavor 2.1 mg, citric acid monohydrate - amount necessary to pH 3.0, purified water - amount required up to 1 ml.
propylene glycol (92.0%), ethyl butyrate, vanillin, gamma undaledone, ethyl acetate, ethylproionate, maltol, 4-hydroxy-2,5-dimethylfuran-2 (3H) -one, hexanol, cis-3-hexene-1-ol, Linalool, isoamyl butyrate, ethylhexanoate, ethyl 2-methylbutyrate, [(3Z) -hex-3-en-1-yl] acetate, 5-hexyloxolan-2-one, ras- (2R) -2-butylbutanoic acid, 4- (4-hydroxyphenyl) butan-2-one. methyl dihydrosymnate, methylcinnamate, ethyl isovalerate, hexenal / trans-2- caproic acid, diacetyl, isovaleric acid,? -ionone,? -ionone, gamma-ionone,? -tocopherol.
** Propylene glycol (75.2%), vanillin, water, butyric acid, ethyl butyrate, piperoyl.
120 ml - a bottle of dark glass (1) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2016.
PHARMACHOLOGIC EFFECT
Propranolol - nonselnktivny beta-adrenoblocker, which has antianginal, hypotensive and antiarrhythmic effect.
Neklektivno blocking? -adrenoreceptors, propranolol has a negative chrono-, dromo-, batmo- and inotropic action (reduces heart rate, inhibits conduction and excitability, reduces myocardial contractility).
Characterized by the absence of cardioselective blocking action on? 1- adrenoreceptors, the lack of internal sympathomimetic activity.
Mechanism of action in infantile hemangioma
The pathogenesis of infantile hemangioma has not been fully studied, but it is known that neovascularization and angiogenesis take part in it.
Potential mechanisms of action of propranolol in proliferative infantile hemangioma include the following interrelated therapeutic effects:
- local hemodynamic effect - vasoconstriction due to beta-adrenergic blockade and a decrease in blood flow to the focus of the hemangioma;
- antiangiogenic effect - a decrease in proliferation, neovascularization and tubulogenesis of endothelial cells due to a decrease in the activity of the key migration factor of endothelial cells - matrix metalloproteinase MMP-9;
- the effect of induction of apoptosis in endothelial cells due to blockade of ОІ-adrenoreceptors. Is it known that stimulation? 2- adrenoreceptor can result in the release of VEGF and bFGF receptor endothelial growth factors and induce proliferation of endothelial cells. Propranolol, blocking? 2- adrenoreceptors, inhibits the expression of VEGF and bFGF and inhibits angiogenesis.
Clinical efficacy and safety in a child population
Safety, efficacy and development of propranolol regimens in children aged 5 weeks to 5 months with proliferative infantile hemangiomas were evaluated in a randomized, controlled, multiple-entry, multicenter, adaptive II / III phase, double-blind study. The therapeutic efficacy of propranolol was defined as complete or almost complete involution (resorption) of the hemangioma.
The data obtained show that the effectiveness of propranolol administration did not significantly differ in subgroups separated by age (35-90 days / 91-150 days), sex and location of hemangioma (head / body); Positive dynamics after 5 weeks of treatment with propranolol was noted in 88% of patients.
PHARMACOKINETICS
Absorption
When ingesting propranolol is almost completely absorbed from the digestive tract. As a result of extensive presystemic metabolism in the liver (the effect of "first passage" through the liver) bioavailability averages about 25%, depends on the nature of food and the intensity of the hepatic blood flow. Bioavailability increases by 50% with the intake of foods rich in protein. C max in the blood plasma is achieved 1-4 hours after ingestion.
Propranolol is a substrate for P-glycoprotein (P-gp). It has been shown that P-gp has no effect on the metabolism of proprafolol in the usual therapeutic dose range.
Distribution
Propranolol binds to plasma proteins (albumin and alpha-1 acid glycoprotein) by approximately 90%. V d is about 4 l / kg. Propranolol penetrates through blood-brain and placental barriers, as well as into breast milk.
Metabolism
Propranolol is extensively metabolized in the liver in three main ways: aromatic hydroxylation (42%), N-dealkylation followed by oxidation (41%), and direct glucuridation (17%). The ratio of the pathways of metabolism of propranolol can vary significantly in some cases.
Four major metabolites have been identified: propranolol glucuronide, naphthyloxy-lactic acid, glucuronic acid and complex sulfate compounds of 4-hydroxypropranolol.
According to in vitro studies, isoenzymes of cytochrome P450, mainly the isozyme CYP2D6 (aromatic hydroxylation), the isoenzyme CYP1A2 (oxidation of the chains) and, to a lesser extent, the isoenzyme CYP2C19, participate in the metabolism of proprafolol.
In healthy volunteers, fast and slow metabolizers of the CYP2D6 isoenzyme, there are no significant differences in clearance and T 1/2 of propranolol is not detected.
Excretion
T 1/2 of propranolol is between 3 and 6 hours.
It is excreted mainly by kidneys in the form of metabolites; In unchanged form, less than 1% is deduced.
Pharmacokinetics in children
According to the results of a pharmacokinetics study using Hemangiol 3 mg / kg / day (divided by 2 doses) in children aged 35 to 150 days at the start of treatment, the main pharmacokinetic parameters in the group of children are comparable to those in adults (with correction for body weight). Fast absorption of propranolol was noted. C max propranolol in the blood plasma is reached after 2 hours after taking the drug. The average value of C max in the equilibrium state, regardless of age, is about 79 and g / ml. The average clearance in children in the age groups 65-120 days and 181-240 days is 2.71 l / h / kg and 3.27 l / h / kg, respectively. The metabolite content of 4-hydroxypropranolol in blood plasma is less than 7% of the content of the initial drug substance.
INDICATIONS
Proliferating infantile hemangioma requiring systemic therapy:
- hemangioma, which poses a threat to life or has a negative effect on the functioning of the body's systems;
- ulcerous hemangioma, characterized by pain and / or lack of response to previous measures for the treatment of ulceration;
- hemangioma with a potential risk of persistent scars or deformities. The drug is intended for use in children aged 35 days to 150 days on the day of treatment.
DOSING MODE
Treatment with Hemangiol should be prescribed and controlled by a doctor who has experience in the diagnosis and treatment of infantile hemangioma.
Treatment should be carried out in a clinical setting, in which the necessary means are available to assist the patient in the event of side effects.
Changes in the dose or amount of the drug administered should be performed by a physician who directly administers the patient.
Clinical monitoring of the child's condition and dose adjustment should be done at least once a month.
On the first day of treatment and on the days of the increase in the dose, the child must be in a medical facility under the supervision of the attending physician within 2 hours after the administration of the drug. It is necessary to measure heart rate and assess the overall condition of the child at least every 60 minutes for the first 2 hours after the administration of the drug.
For oral administration.
The drug Hemangiol is intended for use in children aged 5 weeks to 5 months on the day of treatment. For preterm infants, the appropriate age should be determined by subtracting the number of weeks of premature pregnancy from the actual age of the child.
The child should receive the drug in the process of feeding or immediately after it to prevent the risk of hypoglycemia.
If necessary, you can add a metered dose of the drug to the bottle for feeding to a small amount (one teaspoon - for children weighing up to 5 kg, one tablespoon - for children with a body weight of more than 5 kg) of milk or juice. Do not add the drug into a full bottle. Ready mix is ​​allowed to store no more than 2 hours.
Doses
Doses of the drug are indicated in terms of the propranolol base.
The dose for the reception is calculated taking into account the weight of the child.
Recommended initial dose:
1 mg / kg / day in two divided doses (morning and evening at 0.5 mg / kg).
Recommended therapeutic dose:
3 mg / kg / day in two divided doses (morning and evening at 1.5 mg / kg).
The interval between the two methods should be at least 9 hours.
Dose titration scheme:
- 1 mg / kg / day during the first week;
- 2 mg / kg / day for the second week;
- from the third week - 3 mg / kg / day.
When the dose is titrated, the amount of the drug administered is adjusted depending on the weight of the child's body.
Duration of treatment
The recommended duration of treatment with Hemangiol is 6 months.
Stopping the drug does not require a gradual dose reduction.
In the case of relapse after the completion of therapy, treatment may be re-administered if there is a satisfactory response.
Instructions for opening the bottle and handling the dispenser
To measure the exact dose, use the supplied syringe dispenser, calibrated in milligrams for the content of propranolol base.
Do not use other dosing devices!
Do not shake the contents of the bottle!
1. The package contains a glass bottle containing 120 ml of solution, and a special dispensing device, calibrated in milligrams (mg) according to the content of propranolol base.
Remove the vial from the carton and the syringe and dispenser. Remove the dispensing syringe from the protective packaging.
2. Specify the dose of the drug (in mg) prescribed by your doctor. Find the desired digit on the calibration of the syringe dispenser.
3. The bottle cap has the function of protection against opening by children. To open the bottle, press the lid and turn it counter-clockwise (to the left).
Specify the date of the first opening of the vial on the box and label.
4. Lower the piston to the stop, insert the tip of the dispensing syringe into the vial.
5. Fix the syringe dispenser, flip the bottle.
Carefully push the plunger of the dispensing syringe down to the desired calibration value.
6. If air gets into the syringe, carefully push it into the vial by pressing the plunger.
Check if the values ​​of the amount of the drug in the syringe and the dose prescribed by the attending physician are the same.
7. Turn the vial over, remove the syringe.
Push the plunger.
8. Close the vial, turn the lid clockwise (to the right side).
9. Carefully insert the syringe into the baby's mouth. Slowly pour the drug into the baby's mouth.
It is not recommended to pack the baby immediately after the administration of the drug.
10. After each application, rinse an empty syringe in a glass of water, pulling and pushing the plunger at least 3 times, pouring water from the syringe into the sink.The outer part of the syringe dispenser must be wiped dry.
Detergent or alcohol-containing products should not be used to wash the syringe.
Do not wash the syringe in the dishwasher or in the sterilizer.
Do not disassemble the dispensing syringe.
Do not remove the plug from the neck of the vial with the connection device for the syringe dispenser.
To avoid loss or damage, store the syringe with the vial.
SIDE EFFECT
Undesirable reactions are systematized according to the system-organ classes and are listed according to the following gradation: very frequent - 1/10 appointments (? 10%); Frequent - 1/100 appointments (? 1%, <10%): infrequent - 1/1000 appointments (? 0.1%, <1%): rare - 1/10 000 appointments (? 0.01%, <0.1% ); very rare - less than 1/10 000 prescriptions (<0.01%); frequency is unknown - single messages, the frequency can not be estimated from available data.
In each class of organ systems, undesirable drug reactions are given in order of severity.
Infectious and parasitic diseases: very often - bronchitis; often bronchiolitis.
From the side of metabolism and nutrition: often - a decrease in appetite.
Disorders of the psyche: very often - a sleep disorder (insomnia, poor sleep quality, hypersomnia); often - agitation (motor excitement accompanied by anxiety), nightmares, irritability.
From the nervous system: often - drowsiness; frequency is unknown - hypoglycemic convulsions.
From the heart: infrequently - AV blockade; frequency unknown - bradycardia.
From the side of the vessels: often - cold extremities; frequency unknown - decreased blood pressure, angiospasm, Raynaud's disease.
From the respiratory system, chest and mediastinum: often - bronchospasm.
From the digestive tract: very often - diarrhea, vomiting; often - constipation, pain in the abdomen.
From the skin and subcutaneous tissues: often - erythema; infrequently - urticaria rash (urticaria), alopecia.
Laboratory and instrumental data: often - reduction of blood pressure; infrequently - a decrease in the concentration of glucose in the blood plasma, urezhenne heart rate, neutropenia; frequency is unknown - agranulocytosis, hyperkalemia.
If the child has any side effects during the period of using the drug Hemangiol, inform the treating doctor!
CONTRAINDICATIONS
- children breastfeeding, if the mother takes medications that can not be used concomitantly with propranolol;
- hypersensitivity to any of the components of the drug;
- bronchial asthma, bronchospasm in the anamnesis;
- AV-blockade of II-III degree;
- syndrome of weakness of the sinus node, including the sinouauric (sinoatrial) blockade;
- The native of the heart rate is below the following limits:
Age 0-3 months 3-6 months 6-12 months
Heart rate (bpm) 100 90 80
- lower blood pressure below the following limits:
Age 0-3 months 3-6 months 6-12 months
Blood pressure (mmHg) 65/45 70/50 80/55
- cardiogenic shock;
uncontrolled heart failure;
- Prinzmetal angina;
- marked violations of peripheral arterial blood circulation (Raynaud's disease);
- predisposition to hypoglycemia;
- pheochromocytoma (without simultaneous use of alpha-blockers).
Special patient groups
Due to the lack of data on efficacy and safety, Hemangiol is not recommended for use in the following patient groups:
- children under the age of 5 weeks on the day of treatment initiation (for preterm babies, the appropriate age should be determined by subtracting the number of weeks of premature pregnancy from the actual age of the child);
- children older than 5 months on the day of treatment;
- Patients with hepatic and renal insufficiency.
Carefully
Hemapgiol should be used with caution in patients with cardiovascular diseases, heart failure, diabetes mellitus, respiratory diseases, psoriasis, PHAE-syndrome, hyperkalemia, as well as in patients with allergic reactions in the anamnesis.
PREGNANCY AND LACTATION
Propranolol penetrates into breast milk.
Lactating women taking propranolol should inform the child's attending physician about this before using the drug Hemangiol.
APPLICATION FOR FUNCTIONS OF THE LIVER
It is not recommended to use the drug in patients with renal insufficiency.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
It is not recommended to use the drug in patients with hepatic insufficiency.
APPLICATION FOR CHILDREN
Contraindicated in children breastfeeding , if the mother takes medications that can not be used simultaneously with propranolol.
It is not recommended to apply:
- children under the age of 5 weeks on the day of treatment initiation (for preterm infants, the corresponding age should be determined by subtracting the number of weeks of premature pregnancy from the actual age of the child);
- Children older than 5 months on the day of treatment.
SPECIAL INSTRUCTIONS
Before prescribing the drug, Hemangiol should identify potential risks associated with the use of propranolol, study anamnesis, conduct a clinical examination of the patient, including measurement of heart rate, auscultation of the heart and lungs.
In the case of violations of cardiac activity, you should consult a specialist to identify contraindications.
In the case of acute respiratory infection of the respiratory tract, the use of the Hemangiol drug should be suspended until the child is fully recovered.
If the child is unable to eat, refuses to feed, or has a vomiting reflex, it is recommended that you skip the drug.
In the absence of confidence that the child received a full dose of the drug (for example, in case of regurgitation), do not give the child a second dose.
Cardiovascular diseases
Propranolol by virtue of its pharmacological action can reduce heart rate and cause violations of blood pressure. With existing violations of this kind, their aggravation is possible.
In cases of bradycardia or a decrease in blood pressure when using the drug Hemangiol it is necessary to stop taking the drug and consult a doctor. Bradycardia is diagnosed if the heart rate becomes less than the standard at 30 beats per minute.
Should inform your doctor if the child appears, the following symptoms after taking the drug Gemangiol: fatigue, fever, pale or bluish skin color, faint.
Heart failure
The use of beta-blockers, such as propranolol, in patients with heart failure can lead to its aggravation.
Hypoglycemia (decrease in the concentration of glucose in the blood plasma)
drug Gemangiol can provoke hypoglycemia in children, especially in the fasting state.
Symptoms of hypoglycemia: Secondary - paleness, tiredness, increased sweating, tremor, palpitations, anxiety, hunger, difficulty waking up; primary - excessive drowsiness, slow reactions, poor appetite, decreased body temperature, convulsions, brief pauses in breathing, loss of consciousness. Propranolol, inhibiting the regulating action of endogenous catecholamines, masks the adrenergic symptoms of hypoglycemia, particularly tachycardia, tremor, feeling of anxiety, a feeling of hunger. In case of overdose, in case of failure of the child feeding, with vomiting maybe worsening of hypoglycemia. In exceptional cases, hypoglycemia can lead to seizures and / or coma.
To reduce the risk of hypoglycemia should be regularly feed the baby. Feeding of the child and administration of the drug should carry one person. If breast-feeding, and treatment is carried out by different people, it is necessary to ensure interaction between them to ensure the child's safety and reduce the risk of hypoglycemia.
In case of hypoglycemia when using the drug must be given child Gemangiol sugar-containing solution, and suspend the drug to normalize the blood glucose concentration n plasma. If hypoglycemia persists, seek medical advice.
Patients with diabetes should carefully monitor the concentration of glucose in the blood plasma during the time of application Gemangiol drug.
respiratory diseases
Gemangiol application should suspend the drug in the lower respiratory airways infection. accompanied by stertorous difficult (with the characteristic noise stenosis) breathing. Allowed appointment of beta 2 -agonists and inhaled corticosteroids. Resumption Gemangiol dosing is possible only after complete recovery of the patient. When re-infection as well as in the case of isolated bronchoconstriction application Gemangiol drug should be completely discontinued.
Bronchospasm (temporary narrowing of the bronchi, leading to difficulty breathing)
If, after taking the drug Gemangiol your child has symptoms suggestive of bronchoconstriction - cough, shortness of breath or difficulty breathing, wheezing, bluish tinge to the skin, you must stop using the product and consult a doctor immediately.
RNASE syndrome (including hemangiomas segmental face and neck, congenital heart disease, extra- and intracranial arteries anomalies, posterior fossa anomalies, eye pathology)
A limited amount of data regarding the use of propranolol in cases RNASE syndrome.
Propranolol may increase the risk of ischemic stroke with RNASE syndrome patients with severely impaired cerebral circulatory episodes due to reduction of blood pressure and reduction of blood flow in stenotic vessels and obliterated.
Before considering the possibility of treatment of children with proprapololom large hemangioma person necessarily be excluded angiopathy associated with RHACE syndrome, carry out magnetic resonance angiography of the head and neck, perform Imaging studies of the heart and the aortic arch.
Hypersensitivity
in patients with the risk of anaphylactic reactions, regardless of their origin, beta-blocker treatment may provoke the degradation of an anaphylactic reaction and reduce the therapeutic efficacy of the standard dose of epinephrine (adrenaline).
Anesthesia
The use of beta-blockers reduces the reflex tachycardia and increase the risk of blood pressure lowering blood.
Before the local or general anesthesia, the anesthesiologist should be informed in advance that the child takes medication Gemangiol.
If necessary, routine operations, a beta-blocker therapy (including drug Gemapgiol) should terminate not less than 48 hours before surgery.
Hyperkalemia
There have been cases of hyperkalemia in patients with an extensive ulcer hemangioma.
In these patients, it is necessary to control the level of electrolytes in the blood plasma.
Psoriasis
The possibility of exacerbation of psoriasis during treatment with beta-blockers.
It is necessary to weigh the benefits and risks before using propranolol in patients with psoriasis.
Impact on the ability to drive vehicles and manage mechanisms
Not applicable (medicinal product is intended for children).
OVERDOSE
Symptoms
Of the heart: slowing of heart rate, lower blood pressure; in cases of severe intoxication can occur AV-block, intraventricular conduction slowing, congestive heart failure.
The respiratory system: bronchospasm.
Laboratory findings: hypoglycemia (decrease in the concentration of glucose in the blood plasma).
From the nervous system: it may develop seizures as propranolol penetrates the blood-brain barrier.
Treatment
Connect the patient to a heart monitor, monitor the vital signs, the concentration of plasma glucose, psycho-emotional status.
In the case of reducing blood pressure shows the introduction plazmozameshchath solutions; in case of bradycardia administered atropine sulfate. If the patient has not been a corresponding reaction to the introduction of plasma substitutes, should consider receiving glucagon and catecholamines.
When bronchospasm shown administering aminophylline.
DRUG INTERACTION
Special studies of drug interactions Gemangiol preparation has not been provided in the section information is based on experience with the drug propranolol in adult patients in the dosage form of a tablet.
If the child is difficult feeding, then the assessment of possible drug interactions should also take into account the medication that takes the child's mother.
The combined use is not recommended
blockers "slow" calcium channel (diltiazem, verapamil, bepridil)
The combined use of propranolol can cause changes in heart automaticity (excessive bradycardia, sinus arrest (sinus arrest)), violation of sinoatrial and atrioventricular conduction, increases the risk of developing or worsening of ventricular arrhythmias (bidirectional tachycardia) and heart failure.
Propranolol in combination with these agents should be conducted under clinical supervision and under the supervision of the ECG, especially at the beginning of treatment.
Carefully
Propafenone
potentiation of negative inotropic action and beta-blocking.
Quinidine
Reduced metabolism of propranolol, which leads to an increase of its plasma concentrations 2-3 times, as well as a higher degree of beta-blockade.
Amiodarone
Increased expression of negative chronotropic actions of propranolol.
Due to suppression of sympathetic compensatory mechanisms are possible violations automatism functions and myocardial conduction.
Lidocaine
Amplification lidocaine toxicity (solution in / in) due to inhibition of its metabolism and increase in the concentration of 25%. The risk of adverse reactions from the heart and nervous system.
cardiac glycosides
Increased risk of developing or worsening bradycardia.
Blockers "slow" calcium channel dihydropyridine
risk of reduction in blood pressure and heart failure. Co-administration with propranolol can reduce reflex sympathetic reaction occurring when excessive peripheral vasodilatation.
Antihypertensive drugs (inhibitors of AIF, angiotensin II receptor antagonists, diuretics, alpha blockers, reserpine, etc.)
Reducing the risk of blood pressure, in particular - orthostatic hypotension.
Clonidine is
a risk of increased rebound hypertension cases clonidine.
Propranolol should be canceled a few days before you stop taking clonidine (including cases of clonidine in the mother during breastfeeding).
glucocorticosteroids
Patients with infantile hemangioma can be seriously compromised during concurrent or prior treatment with corticosteroids, as suppression of adrenocortical function may lead to a lack kontrregulyatornoy cortisol response and increase the risk of hypoglycemia.
This is also applicable in the treatment of glucocorticoid child's mother during breastfeeding in the case of its application of large doses or prolonged treatment.
Nonsteroidal anti-inflammatory drugs (NSAIDs)
NSAIDs reduce the antihypertensive effect of beta-blockers.
Formulations inducing orthostatic (postural) hypotension
Drugs causing orthostatic (postural) hypotension (nitrates derivatives, phosphodiesterase type 5 inhibitors, tricyclic antidepressants, antipsychotic drugs, dopamine agonists, Levodopa, amifostine, baclofen, etc.) Can enhance the action of beta-blockers.
Inductors microsomal liver enzymes
concentrations of propranolol and blood plasma can be reduced by the joint use with rifampicin and phenobarbital.
Hypoglycemic drugs
propranolol can prolong the hypoglycemic effect of insulin.
Lipid formulations
combined use of colestipol reduces the concentration of propranolol in the blood plasma by 50%.
halogenated anesthetics
Joint application with methoxyflurane or trichlorethylene can lead to inhibition of the contractility of the myocardium.
Iodinated contrast media
Increased risk of anaphylactic reactions.
To prevent the risk of drug interactions should inform your doctor about all the medications taken, receives or will receive soon the baby and the mother when breastfeeding.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be stored protected from light and the reach of children at a temperature not higher than 30 В° C. Do not freeze. Shelf life - 3 years. Shelf life after first opening the bottle during storage in a therapeutic application (Receive 2 times / day) - 2 months.
Do not use after the expiration date stated on the package.
