Gemangiol^® (Solution) Instructions for Use

Marketing Authorization Holder

Pierre Fabre Medicament (France)

Manufactured By

Pierre Fabre Medicament Production (France)

ATC Code

C07AA05 (Propranolol)

Active Substance

Propranolol

Dosage Form

Gemangiol®

Oral solution 3.75 mg/1 ml: fl. 120 ml 1 pc. in a set with a dosing syringe

Dosage Form, Packaging, and Composition

Oral solution from colorless to yellowish, transparent, with a fruity odor.

Excipients: hydroxyethyl cellulose – 3.5 mg, sodium saccharin – 1.5 mg, strawberry flavor – 1.1 mg, vanilla flavor – 2.1 mg, citric acid monohydrate – quantity required to adjust pH to 3.0, purified water – quantity sufficient to 1 ml.

Composition of strawberry flavor propylene glycol (92.0%), ethyl butyrate, vanillin, gamma-undecalactone, ethyl acetate, ethyl propionate, maltol, 4-hydroxy-2,5-dimethylfuran-2(3H)-one, hexanol, cis-3-hexen-1-ol, linalool, isoamyl butyrate, ethyl hexanoate, ethyl-2-methylbutyrate, [(3Z)-hex-3-en-1-yl]acetate, 5-hexyloxolan-2-one, rac-(2R)-2-methylbutanoic acid, 4-(4-hydroxyphenyl)butan-2-one, methyldihydrojasmonate, methyl cinnamate, ethyl isovalerate, hexenal/trans-2-, caproic acid, diacetyl, isovaleric acid, alpha-ionone, beta-ionone, gamma-ionone, alpha-tocopherol.
Composition of vanilla flavor propylene glycol (75.2%), vanillin, water, butyric acid, ethyl butyrate, piperonal.

120 ml – dark glass bottles (1) with first-opening control, in a set with a dosing syringe – cardboard packs.

Clinical-Pharmacological Group

Beta₁-, beta₂-adrenergic blocker. Drug for the treatment of proliferating infantile hemangioma

Pharmacotherapeutic Group

Beta-adrenoblocker

Pharmacological Action

Non-selective beta-adrenergic blocker. It has antihypertensive, antianginal and antiarrhythmic effects. Due to the blockade of β-adrenergic receptors, it reduces the catecholamine-stimulated formation of cAMP from ATP, as a result of which it reduces the intracellular influx of calcium ions, and has negative chronotropic, dromotropic, bathmotropic and inotropic effects (reduces heart rate, inhibits conduction and excitability, reduces myocardial contractility). At the beginning of the use of beta-adrenergic blockers, the total peripheral vascular resistance increases in the first 24 hours (as a result of a reciprocal increase in the activity of α-adrenergic receptors and the elimination of stimulation of β₂-adrenergic receptors of skeletal muscle vessels), but after 1-3 days it returns to the original level, and with prolonged use it decreases.

The hypotensive effect is associated with a decrease in minute blood volume, sympathetic stimulation of peripheral vessels, a decrease in the activity of the renin-angiotensin system (important in patients with initial hypersecretion of renin), sensitivity of the aortic arch baroreceptors (their activity does not increase in response to a decrease in blood pressure) and the effect on the central nervous system. The hypotensive effect stabilizes by the end of the 2nd week of course administration.

The antianginal effect is due to a decrease in myocardial oxygen demand (due to negative chronotropic and inotropic effects). A decrease in heart rate leads to a lengthening of diastole and an improvement in myocardial perfusion. Due to an increase in the end-diastolic pressure in the left ventricle and an increase in the stretching of the muscle fibers of the ventricles, it can increase the oxygen demand, especially in patients with chronic heart failure.

The antiarrhythmic effect is due to the elimination of arrhythmogenic factors (tachycardia, increased activity of the sympathetic nervous system, increased cAMP content, arterial hypertension), a decrease in the rate of spontaneous excitation of the sinus and ectopic pacemakers and a slowdown in AV conduction. Inhibition of impulse conduction is noted mainly in the antegrade and to a lesser extent in the retrograde directions through the AV node and along additional pathways. It belongs to class II antiarrhythmic drugs. Reducing the severity of myocardial ischemia is due to a decrease in myocardial oxygen demand; postinfarction mortality can also decrease due to the antiarrhythmic effect.

The ability to prevent the development of vascular headache is due to a decrease in the severity of the expansion of cerebral arteries as a result of beta-adrenergic blockade of vascular receptors, inhibition of catecholamine-induced platelet aggregation and lipolysis, a decrease in platelet adhesiveness, prevention of activation of blood coagulation factors during adrenaline release, stimulation of oxygen delivery to tissues and a decrease in renin secretion.

The reduction of tremor during propranolol use is mainly due to the blockade of peripheral β₂-adrenergic receptors.

It increases the atherogenic properties of blood. It enhances uterine contractions (spontaneous and those caused by agents that stimulate the myometrium). It increases bronchial tone. In high doses, it causes a sedative effect.

Potential mechanisms of action of propranolol in infantile hemangioma include the following interrelated therapeutic effects: local hemodynamic effect (vasoconstriction due to beta-adrenergic blockade and reduced blood flow to the hemangioma focus); antiangiogenic effect (reduction of proliferation, neovascularization and tubulogenesis of endothelial cells by reducing the activity of the key factor of endothelial cell migration – matrix metalloproteinase MMP-9); effect of induction of apoptosis in endothelial cells due to blockade of β-adrenergic receptors. It is known that stimulation of β₂-adrenergic receptors can lead to the release of vascular endothelial growth factors VEGF and bFGF and induce the proliferation of endothelial cells. Propranolol, by blocking β₂-adrenergic receptors, suppresses the expression of VEGF and bFGF and inhibits angiogenesis. The therapeutic efficacy of propranolol was defined as complete or almost complete involution (resorption) of the hemangioma. Data obtained during clinical studies show that the efficacy of propranolol use did not differ significantly in subgroups divided by age (35-90 days/91-150 days), gender and location of the hemangioma (head/body); positive dynamics after 5 weeks of propranolol treatment was noted in 88% of patients.

Pharmacokinetics

After oral administration, about 90% of the taken dose is absorbed, but bioavailability is low due to metabolism during the “first pass” through the liver. C_max in blood plasma is reached after 1-1.5 hours. Protein binding is 93%. T_1/2 is 3-5 hours. It is excreted by the kidneys mainly in the form of metabolites, unchanged – less than 1%.

Indications

Arterial hypertension; exertional angina, unstable angina; sinus tachycardia (including in hyperthyroidism), supraventricular tachycardia, tachyarrhythmic form of atrial fibrillation, supraventricular and ventricular extrasystole, essential tremor, migraine prevention, alcohol withdrawal (agitation and tremor), anxiety, pheochromocytoma (adjuvant treatment), diffuse toxic goiter and thyrotoxic crisis (as an adjuvant, including in case of intolerance to thyrostatic drugs), sympathoadrenal crises against the background of diencephalic syndrome.

Proliferating infantile hemangioma requiring systemic therapy: hemangioma that is life-threatening or has a negative impact on the functioning of body systems; ulcerated hemangioma characterized by pain and/or lack of response to previous ulceration treatment measures; hemangioma with a potential risk of permanent scarring or deformities.

ICD codes

Dosage Regimen

For adults when taken orally, the initial dose is 20 mg, a single dose is 40-80 mg, the frequency of administration is 2-3 times/day.

IV bolus slowly – initial dose 1 mg; then after 2 min the same dose is repeated. In the absence of effect, repeated administration is possible.

Maximum doses when taken orally – 320 mg/day; with repeated IV bolus administration, the total dose is 10 mg (under the control of blood pressure and ECG).

For children aged from 35 days to 150 days on the day of treatment initiation, it is intended for oral administration in a special dosage form. For premature infants, the appropriate age should be determined by subtracting the number of weeks of premature pregnancy from the child’s actual age. The initial dose is 1 mg/kg/day in 2 doses (morning and evening, 0.5 mg/kg each). The recommended therapeutic dose is 3 mg/kg/day in 2 doses (morning and evening, 1.5 mg/kg each). The interval between two doses should be at least 9 hours. Dose titration scheme: 1 mg/kg/day during the 1st week; 2 mg/kg/day during the 2nd week; from the 3rd week – 3 mg/kg/day. When dose titration is completed, the amount of drug administered is adjusted depending on the child’s body weight. Clinical monitoring of the child’s condition and dose adjustment should be carried out at least once a month. On the first day of treatment and on the days of dose increase, the child should be in a medical institution under the supervision of the attending physician for 2 hours after drug administration. It is necessary to measure heart rate and assess the general condition of the child at least every 60 minutes during the first 2 hours after drug administration. The duration of treatment is 6 months. Discontinuation of the drug does not require gradual dose reduction. In case of disease recurrence after completion of therapy, treatment can be repeated if there is a satisfactory response.

Adverse Reactions

From the nervous system increased fatigue, weakness, dizziness, headache, drowsiness or insomnia, vivid dreams, depression, anxiety, confusion, hallucinations, tremor, nervousness, restlessness.

From the sensory organs decreased secretion of tear fluid (dryness and soreness of the eyes).

From the cardiovascular system sinus bradycardia, AV block (up to the development of complete transverse block and cardiac arrest), arrhythmias, development (worsening) of chronic heart failure, decreased blood pressure, orthostatic hypotension, manifestation of angiospasm (increased peripheral circulation disorders, cold lower extremities, Raynaud’s syndrome), chest pain.

From the digestive system: nausea, vomiting, epigastric discomfort, constipation or diarrhea, impaired liver function (dark urine, jaundice of the sclera or skin, cholestasis), taste changes, increased activity of liver transaminases, LDH.

From the respiratory system nasal congestion, bronchospasm.

From the endocrine system changes in blood glucose concentration (hypo- or hyperglycemia).

From the hematopoietic system thrombocytopenia (unusual bleeding and hemorrhage), leukopenia.

Dermatological reactions increased sweating, psoriasis-like skin reactions, exacerbation of psoriasis symptoms.

Allergic reactions itching, skin rash, urticaria.

Other back pain, arthralgia, decreased potency, withdrawal syndrome (increased angina attacks, myocardial infarction, increased blood pressure).

In newborns and infants

From the nervous system: insomnia, poor sleep quality, hypersomnia, nightmares, agitation, irritability, drowsiness.

From the cardiovascular system AV block, bradycardia, decreased blood pressure, angiospasm, Raynaud’s disease.

From the respiratory system bronchitis, bronchiolitis, bronchospasm.

From the digestive system decreased appetite, diarrhea, vomiting, constipation, abdominal pain.

From the skin and subcutaneous tissues erythema, urticaria, alopecia.

Other cold extremities, decreased plasma glucose concentration, hyperkalemia, agranulocytosis, hypoglycemic convulsions.

Contraindications

AV block II and III degree, sinoatrial block, severe bradycardia (less than 50 beats/min), arterial hypotension, acute or chronic heart failure in the stage of decompensation, acute myocardial infarction (systolic blood pressure less than 100 mm Hg), cardiogenic shock, pulmonary edema, sick sinus syndrome, Prinzmetal’s angina, cardiomegaly (without signs of heart failure), severe peripheral vascular disorders, metabolic acidosis (including diabetic acidosis), pheochromocytoma (without simultaneous use of alpha-adrenergic blockers), bronchial asthma, chronic obstructive pulmonary disease, tendency to bronchospastic reactions, simultaneous use with antipsychotics and anxiolytics (chlorpromazine, trioxazine and others), MAO inhibitors.

For newborns and infants. Decrease in heart rate below the following limits: in children aged from 0 to 3 months – 100 beats/min, from 3 months to 6 months – 90 beats/min, from 6 months to 12 months – 80 beats/min; decrease in blood pressure below the following limits: in children aged from 0 to 3 months – 65/45 mm Hg, from 3 months to 6 months – 70/50 mm Hg, from 6 months to 12 months – 80/55 mm Hg. Breastfed children, if the mother is taking medications that are not recommended for simultaneous use with propranolol.

Hypersensitivity to propranolol.

Use in Pregnancy and Lactation

The use of propranolol during pregnancy is possible only if the intended benefit to the mother outweighs the potential risk to the fetus. If it is necessary to use during this period, careful monitoring of the condition of the fetus is necessary; 48-72 hours before delivery, Propranolol should be discontinued.

It should be borne in mind that a negative effect on the fetus is possible: intrauterine growth retardation, hypoglycemia, bradycardia.

Propranolol is excreted in breast milk. If it is necessary to use during lactation, medical supervision of the child should be established or breastfeeding should be discontinued.

Use in Hepatic Impairment

Use with caution in patients with hepatic insufficiency.

Use in Renal Impairment

Use with caution in patients with renal insufficiency.

Pediatric Use

Use with caution in children (efficacy and safety have not been established).

Geriatric Use

Use with caution in elderly patients.

Special Precautions

Use with caution in patients with bronchial asthma, COPD, with bronchitis, decompensated heart failure, diabetes mellitus, with renal and/or hepatic insufficiency, hyperthyroidism, depression, myasthenia gravis, psoriasis, occlusive peripheral vascular diseases, during pregnancy, during lactation, in elderly patients, in children (efficacy and safety have not been established).

With caution in newborns and infants: cardiovascular diseases, heart failure; diabetes mellitus; respiratory diseases; psoriasis; PHACE syndrome; hyperkalemia; history of allergic reactions.

During treatment, exacerbation of psoriasis is possible.

In pheochromocytoma, Propranolol can be used only after taking an alpha-adrenergic blocker.

After a long course of treatment, Propranolol should be discontinued gradually, under medical supervision.

During treatment with propranolol, IV administration of verapamil, diltiazem should be avoided. Several days before anesthesia, it is necessary to stop taking propranolol or select an anesthetic agent with minimal negative inotropic effect.

Effect on the ability to drive vehicles and mechanisms

In patients whose activities require increased attention, the issue of outpatient propranolol use should be decided only after assessing the patient’s individual response.

Drug Interactions

When used concomitantly with hypoglycemic agents, there is a risk of hypoglycemia due to the enhanced effect of the hypoglycemic agents.

When used concomitantly with MAO inhibitors, there is a possibility of undesirable drug interaction manifestations.

Cases of marked bradycardia have been described with the use of propranolol for arrhythmia caused by digitalis preparations.

When used concomitantly with agents for inhalation anesthesia, the risk of myocardial function depression and the development of arterial hypotension increases.

When used concomitantly with amiodarone, arterial hypotension, bradycardia, ventricular fibrillation, and asystole are possible.

When used concomitantly with verapamil, arterial hypotension, bradycardia, and dyspnea are possible. The C_max in blood plasma increases, the AUC increases, and the clearance of propranolol decreases due to inhibition of its metabolism in the liver under the influence of verapamil.

Propranolol does not affect the pharmacokinetics of verapamil.

A case of severe arterial hypotension and cardiac arrest has been described with concomitant use with haloperidol.

When used concomitantly with hydralazine, the C_max in blood plasma and the AUC of propranolol increase. It is believed that hydralazine may reduce hepatic blood flow or inhibit the activity of liver enzymes, which leads to a slowdown in propranolol metabolism.

When used concomitantly, Propranolol may inhibit the effects of glibenclamide, glyburide, chlorpropamide, and tolbutamide, because non-selective beta₂-adrenergic blockers are able to block the β₂-adrenergic receptors of the pancreas associated with insulin secretion.

The insulin release from the pancreas caused by the action of sulfonylurea derivatives is inhibited by beta-blockers, which to some extent prevents the development of the hypoglycemic effect.

When used concomitantly with diltiazem, the concentration of propranolol in blood plasma increases due to inhibition of its metabolism under the influence of diltiazem. An additive depressant effect on heart activity is observed due to the slowing of impulse conduction through the AV node caused by diltiazem. There is a risk of developing marked bradycardia, and stroke volume and minute volume are significantly reduced.

When used concomitantly, cases of increased plasma concentrations of warfarin and phenindione have been described.

When used concomitantly with doxorubicin, experimental studies have shown an increase in cardiotoxicity.

When used concomitantly, Propranolol prevents the development of the bronchodilatory effect of isoprenaline, salbutamol, and terbutaline.

When used concomitantly, cases of increased plasma concentration of imipramine have been described.

When used concomitantly with indomethacin, naproxen, piroxicam, and acetylsalicylic acid, a decrease in the antihypertensive effect of propranolol is possible.

When used concomitantly with ketanserin, the development of an additive hypotensive effect is possible.

When used concomitantly with clonidine, the antihypertensive effect is enhanced.

In patients receiving Propranolol, abrupt withdrawal of clonidine may lead to the development of severe arterial hypertension. It is believed that this is due to an increase in the content of catecholamines in the circulating blood and an enhancement of their vasoconstrictive action.

When used concomitantly with caffeine, a decrease in the effectiveness of propranolol is possible.

When used concomitantly, the effects of lidocaine and bupivacaine (including toxic ones) may be enhanced, apparently due to the slowing of the metabolism of local anesthetics in the liver.

A case of bradycardia development has been described with concomitant use with lithium carbonate.

When used concomitantly, a case of increased side effects of maprotiline has been described, which is apparently due to a slowdown in its metabolism in the liver and accumulation in the body.

When used concomitantly with mefloquine, the QT interval increases, a case of cardiac arrest has been described; with morphine – the depressant effect on the central nervous system caused by morphine is enhanced; with sodium amidotrizoate – cases of severe arterial hypotension have been described.

When used concomitantly with nisoldipine, an increase in the C_max and AUC of propranolol and nisoldipine in blood plasma is possible, leading to severe arterial hypotension. There is a report of enhanced beta-blocking action.

Cases of increased C_max and AUC of propranolol, arterial hypotension, and decreased heart rate have been described with concomitant use with nicardipine.

When used concomitantly with nifedipine in patients with coronary artery disease, the development of marked arterial hypotension, an increased risk of heart failure and myocardial infarction is possible, which may be due to an enhancement of the negative inotropic effect of nifedipine.

In patients receiving Propranolol, there is a risk of developing marked arterial hypotension after taking the first dose of prazosin.

When used concomitantly with prenylamine, the QT interval increases.

When used concomitantly with propafenone, the concentration of propranolol in blood plasma increases and toxic effects develop. It is believed that propafenone inhibits the metabolism of propranolol in the liver, reducing its clearance and increasing serum concentrations.

When used concomitantly with reserpine and other antihypertensive agents, the risk of arterial hypotension and bradycardia increases.

When used concomitantly, the C_max and AUC of rizatriptan increase; with rifampicin – the concentration of propranolol in blood plasma decreases; with suxamethonium chloride, tubocurarine chloride – a change in the action of muscle relaxants is possible.

When used concomitantly, the clearance of theophylline decreases due to the slowing of its metabolism in the liver. There is a risk of bronchospasm in patients with bronchial asthma or COPD. Beta-adrenergic blockers may block the inotropic effect of theophylline.

When used concomitantly with phenindione, cases of some increased bleeding without changes in blood coagulation parameters have been described.

When used concomitantly with flecainide, an additive cardiodepressant effect is possible.

Fluoxetine inhibits the CYP2D6 isoenzyme, which leads to inhibition of propranolol metabolism and its accumulation and may enhance the cardiodepressant effect (including bradycardia). Fluoxetine and, mainly, its metabolites are characterized by a long T_1/2, so the likelihood of a drug interaction persists even several days after discontinuation of fluoxetine.

Quinidine inhibits the CYP2D6 isoenzyme, which leads to inhibition of propranolol metabolism, thereby reducing its clearance. Enhancement of the beta-adrenergic blocking action and orthostatic hypotension are possible.

When used concomitantly, the plasma concentrations of propranolol, chlorpromazine, and thioridazine increase. A sharp decrease in blood pressure is possible.

Cimetidine inhibits the activity of liver microsomal enzymes (including the CYP2D6 isoenzyme), this leads to inhibition of propranolol metabolism and its accumulation: an enhancement of the negative inotropic effect and the development of a cardiodepressant effect are observed.

When used concomitantly, the hypertensive effect of epinephrine is enhanced, and there is a risk of developing severe, life-threatening hypertensive reactions and bradycardia. The bronchodilatory effect of sympathomimetics (epinephrine, ephedrine) is reduced.

When used concomitantly, cases of decreased effectiveness of ergotamine have been described.

There are reports of changes in the hemodynamic effects of propranolol when used concomitantly with ethanol.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.