Corvaldin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CORVALDIN® (CorvalDINUM®)

Composition:

Active substances: ethyl ether of α-bromoisovaleric acid, phenobarbital, peppermint oil, hop oil;

1 ml of solution (26 drops) contains: ethyl ether of α-bromoisovaleric acid, calculated as 100 % substance – 20 mg, phenobarbital – 18 mg, peppermint oil – 1.4 mg, hop oil – 0.2 mg;

Excipients: stabilizer, ethanol 96 %, purified water.

Pharmaceutical form. Oral drops.

Main physicochemical properties: clear, colorless liquid with a specific odor.

Pharmacotherapeutic group.

Hypnotics and sedatives. Barbiturates in combination with other components. ATC code N05C B02.

Pharmacological Properties.

Pharmacodynamics.

Corvaldin**®** is a sedative and spasmolytic medicinal product, whose action is determined by the substances contained in its composition.

Ethyl ether of α-bromoisovaleric acid has sedative and spasmolytic effects, caused by stimulation of receptors in the oral cavity and nasopharynx, reduction of reflex excitability in central parts of the nervous system, enhancement of neuronal inhibition in the cerebral cortex and subcortical structures of the brain, as well as reduction of vasomotor center activity and direct local spasmolytic action on vascular smooth muscles.

Phenobarbital suppresses the excitatory influence of the reticular formation centers on the cerebral cortex. The sedative, tranquilizing, or hypnotic effects depend on the dose of the drug.

Peppermint oil and hop oil exert reflex vasodilatory and spasmolytic effects by stimulating "cold" receptors in the oral cavity, have choleretic action, and relieve symptoms of meteorism.

Pharmacokinetics.

Phenobarbital is rapidly absorbed (directly in the stomach). Approximately 35% of it binds to plasma proteins; the unbound portion is filtered in the kidneys. Reabsorption occurs at low pH levels. Reverse diffusion does not occur due to the alkalinity of urine. Approximately 30% of phenobarbital is excreted unchanged in urine, and only a small portion is oxidized in the liver. With prolonged use, accumulation of the active substance in blood plasma occurs, as well as induction of liver enzymes. As a result of this induction, the oxidation processes of phenobarbital and other medicinal products are accelerated.

Bromine in ethylbromoisovalerate is slowly excreted from the body. If the drug is used for a prolonged period, bromine accumulates in the CNS, leading to chronic bromine intoxication.

Clinical characteristics.

Indications.

• Neuroses with increased irritability;
• insomnia;
• as part of complex therapy for hypertensive disease and vegetative-vascular dystonia;
• mild spasms of coronary vessels, tachycardia;
• intestinal spasms caused by neurovegetative disorders (as a spasmolytic agent).

Contraindications.

Hypersensitivity to the active substances or to any other component of the drug, bromine; acute hepatic porphyria; severe impairment of liver and kidney function; diabetes mellitus; myasthenia gravis. Medicinal products containing phenobarbital are contraindicated in alcoholism, drug or narcotic dependence (including in medical history); in respiratory diseases with dyspnea, obstructive syndrome, marked arterial hypotension, acute myocardial infarction; in depression and depressive disorders with patient's tendency to suicidal behavior.

Interaction with other medicinal products and other forms of interaction.

When used concomitantly with other medicinal products that depress the CNS, mutual enhancement of effects (sedative-hypnotic effect) is possible, which may be accompanied by respiratory depression. Alcohol enhances the effect of the drug and may increase its toxicity.

Medicinal products containing valproic acid enhance the effect of barbiturates.

Phenobarbital induces liver enzymes and thus may accelerate the metabolism of certain drugs metabolized by liver enzymes (e.g., coumarin derivatives, antibiotics, sulfonamides, antivirals, oral hypoglycemics, hormonal, immunosuppressive, cytostatic, antiarrhythmic, antihypertensive agents). Phenobarbital enhances the effect of analgesics, anesthetics, anesthetic agents, neuroleptics, and tranquilizers; it reduces the effect of paracetamol, indirect anticoagulants, metronidazole, tricyclic antidepressants, salicylates, and cardiac glycosides.

Possible influence on blood concentrations of phenytoin, as well as carbamazepine and clonazepam. Monoamine oxidase inhibitors (MAOIs) prolong the effect of phenobarbital. Rifampicin may reduce the effect of phenobarbital. When used concomitantly with gold-containing drugs, the risk of kidney damage increases. With prolonged concomitant use of nonsteroidal anti-inflammatory drugs, there is a risk of gastric ulcer formation and bleeding. Simultaneous use of medicinal products containing phenobarbital and zidovudine enhances the toxicity of both agents. Undesirable interaction of Corvaldin® (containing phenobarbital) with antiepileptic drugs, thyroid hormones, doxycycline, chloramphenicol, antifungals (azole group), griseofulvin, glucocorticoids, and oral contraceptives due to the possibility of reduced efficacy of these drugs.

The medicinal product increases the toxicity of methotrexate.

Special precautions for use.

During treatment with this medicinal product, activities requiring heightened attention and rapid psychomotor reactions should be avoided.

Concomitant use of alcohol-containing beverages should be avoided.

Life-threatening skin reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported during treatment with phenobarbital.

Patients should be informed about the signs and symptoms and closely monitored for skin reactions. The highest risk of Stevens-Johnson syndrome or toxic epidermal necrolysis occurs during the first weeks of treatment.

If symptoms of Stevens-Johnson syndrome or toxic epidermal necrolysis occur (e.g., progressive skin rash, often with blisters, and mucosal lesions), treatment must be discontinued immediately.

The best outcomes in treating Stevens-Johnson syndrome or toxic epidermal necrolysis are observed with early diagnosis and immediate discontinuation of any suspected causative medicinal product. Prognosis is significantly improved by prompt withdrawal of the suspected drug.

If a patient has developed Stevens-Johnson syndrome or toxic epidermal necrolysis while taking Corvaldin®, this medicinal product must never be administered to that patient again.

If chest pain persists after taking the medicinal product, medical advice should be sought to exclude acute coronary syndrome. Use with caution in patients with hyperkinesia, hyperthyroidism, adrenal insufficiency, decompensated heart failure, arterial hypotension, persistent pain, or acute intoxication with medicinal products.

This medicinal product contains 60 vol.% ethanol (alcohol).

The minimum dose (15 drops) contains 271 mg of ethanol, equivalent to 6.9 mL of beer or 2.9 mL of wine. This is harmful for patients suffering from alcoholism. Caution is advised when administering to patients with liver disease or epilepsy.

Prolonged use is not recommended due to the risk of developing drug dependence, possible accumulation of bromine in the body, and bromine poisoning.

Use during pregnancy or breastfeeding.

Do not use during pregnancy or breastfeeding.

Ability to influence reaction speed when driving or operating machinery.

Corvaldin® contains phenobarbital and ethanol, which may cause impaired coordination, slowed psychomotor reactions, drowsiness, and dizziness during treatment. Therefore, activities requiring heightened attention, including driving or operating machinery, should be avoided.

Dosage and Administration.

Take orally before meals, 15–30 drops with a small amount of liquid (30–50 mL) 2–3 times daily. The single dose may be increased, if necessary, to 40–50 drops.

The duration of treatment is determined by the physician depending on the clinical response and drug tolerability.

Children.

There is no experience with the use of this drug in pediatric patients; therefore, the drug should not be used in pediatric practice.

Overdose.

Symptoms.

Acute (mild to moderate) barbiturate poisoning:

dizziness, fatigue, and even deep sleep from which the patient cannot be awakened.

Hypersensitivity reactions may occur: angioneurotic edema, urticaria, pruritus, rash.

Acute severe poisoning:

deep coma associated with tissue hypoxia, shallow respiration initially rapid and later slowed, tachycardia, cardiac arrhythmia, low blood pressure, bradycardia, vascular collapse, diminished or absent reflexes, nystagmus, headache, nausea, weakness, cardiac disturbances, decreased body temperature, slowed pulse, reduced diuresis.

If not treated, poisoning may result in death due to circulatory failure, respiratory paralysis, or pulmonary edema.

Overdose may occur during prolonged use of the drug due to accumulation of its components. Long-term and continuous use may lead to dependence, withdrawal syndrome, and psychomotor agitation.

Prolonged use of drugs containing bromine may lead to bromism, characterized by the following symptoms: confusion, ataxia, apathy, depressive mood, conjunctivitis, cold-like symptoms, acne, or purpura.

Treatment.

Cases of acute poisoning with Korvaldin® should be treated as poisoning with other hypnotics and barbiturates, depending on the severity of symptoms. The patient should be transferred to an intensive care unit. Respiratory and circulatory functions must be stabilized and normalized. Respiratory failure is managed by artificial ventilation; shock is treated by infusion of plasma and plasma substitutes. If a significant time has passed since ingestion, gastric lavage should be performed (introduce 10 g of activated charcoal powder and sodium sulfate into the stomach). To accelerate elimination of barbiturates from the body, forced alkaline diuresis, hemodialysis, and/or hemoperfusion may be performed.

Treatment of bromine poisoning: elimination of bromide ions from the body can be accelerated by administration of a large volume of saline solution together with saluretic agents.

In case of hypersensitivity reactions, administer desensitizing agents.

Adverse reactions.

Central nervous system: asthenia, weakness, impaired motor coordination, nystagmus, ataxia, hallucinations, paradoxical excitement, insomnia (in elderly patients), decreased attention span, fatigue, slowed reaction time, headache, cognitive disturbances. In individual cases, drowsiness and mild dizziness, confusion of consciousness may occur.

Musculoskeletal system: with prolonged use of products containing phenobarbital, there is a risk of impaired osteogenesis. Cases of decreased bone mineral density, osteopenia, osteoporosis, and fractures have been reported in patients receiving long-term phenobarbital therapy. The mechanism by which phenobarbital affects bone metabolism has not been established.

Gastrointestinal tract: nausea, vomiting, constipation, epigastric fullness; with prolonged use – liver function disturbances.

Hematopoietic system: agranulocytosis, megaloblastic anemia, thrombocytopenia, anemia.

Cardiovascular system: decreased blood pressure, bradycardia.

Skin and mucous membranes: Stevens–Johnson syndrome, toxic epidermal necrolysis, allergic reactions, including rash, pruritus, urticaria.

Immune system: hypersensitivity reactions, including angioedema, dyspnea, facial swelling.

Prolonged use of drugs containing bromide may lead to bromism, characterized by the following symptoms: central nervous system depression, depression, confusion, ataxia, apathy, conjunctivitis, rhinitis, lacrimation, acne, or purpura.

Shelf life.

3 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions.

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

Packaging. 25 ml in a bottle. 1 bottle per pack.

Prescription status. Over-the-counter.

Manufacturer. JSC "Farmak".

Manufacturer’s address and place of business.

74, Kyrylivska Street, Kyiv, 04080, Ukraine.

INSTRUCTIONS

for medical use of the medicinal product

CORVALDIN®

(CorvalDINUM®)

Composition:

Active ingredients: ethyl ether of α-bromoisovaleric acid, phenobarbital, peppermint oil, hop oil;

1 ml of solution (26 drops) contains: ethyl ether of α-bromoisovaleric acid, calculated as 100 % substance – 20 mg, phenobarbital – 18 mg, peppermint oil – 1.4 mg, hop oil – 0.2 mg;

Excipients: stabilizer, ethanol 96 %, purified water.

Pharmaceutical form. Oral drops.

Main physicochemical properties: clear, colorless liquid with a specific odor.

Pharmacotherapeutic group.

Hypnotics and sedatives. Barbiturates in combination with other components. ATC code N05C B02.

Pharmacological properties.

Pharmacodynamics.

Corvaldin**®** is a sedative and spasmolytic medicinal product, whose action is determined by the substances included in its composition.

Ethyl ether of α-bromoisovaleric acid has sedative and spasmolytic effects, caused by stimulation of receptors in the oral cavity and nasopharynx, reduction of reflex excitability in central parts of the nervous system, enhancement of inhibition in cortical and subcortical neurons of the brain, as well as decreased activity of vasomotor centers and direct local spasmolytic action on smooth muscles of blood vessels.

Phenobarbital suppresses excitatory influence of reticular formation centers on the cerebral cortex. The sedative, tranquilizing, or hypnotic effects depend on the dose of the drug.

Peppermint oil and hops oil exert reflex vasodilatory and spasmolytic effects by stimulating "cold" receptors in the oral cavity, have choleretic action, and relieve symptoms of meteorism.

Pharmacokinetics.

Phenobarbital is rapidly absorbed (directly in the stomach). Approximately 35% of it is bound to plasma proteins; the unbound portion is filtered in the kidneys. Reabsorption occurs at low pH levels. Reverse diffusion does not occur due to alkalinity of urine. Approximately 30% of phenobarbital is excreted unchanged in urine, and only a small portion is oxidized in the liver. With prolonged use, accumulation of the active substance in blood plasma occurs, as well as induction of liver enzymes. As a result of this induction, the oxidation process of phenobarbital and other medicinal agents is accelerated.

Bromine in ethylbromoisovalerate is slowly eliminated from the body. With prolonged administration, bromine accumulates in the central nervous system (CNS), leading to chronic bromine intoxication.

Clinical characteristics.

Indications.

• Neuroses with increased irritability;
• insomnia;
• as part of combination therapy for hypertension and vegetative-vascular dystonia;
• mild spasms of coronary vessels, tachycardia;
• intestinal spasms caused by neurovegetative disorders (as a spasmolytic agent).

Contraindications.

Hypersensitivity to the active substances or to any other component of the drug, bromine; acute hepatic porphyria; severe liver and kidney dysfunction; diabetes mellitus; myasthenia gravis. Medicinal products containing phenobarbital are contraindicated in alcoholism, drug or narcotic dependence (including in medical history); in respiratory diseases with dyspnea, obstructive syndrome, pronounced arterial hypotension, acute myocardial infarction; in depression and depressive disorders with a tendency towards suicidal behavior.

Interaction with other medicinal products and other forms of interaction.

When used concomitantly with other central nervous system (CNS) depressants, mutual enhancement of effects (sedative and hypnotic effects) is possible, which may be accompanied by respiratory depression. Alcohol enhances the effect of the drug and may increase its toxicity.

Medicinal products containing valproic acid enhance the effects of barbiturates.

Phenobarbital induces liver enzymes and thus may accelerate the metabolism of certain drugs metabolized by hepatic enzymes (e.g., coumarin derivatives, antibiotics, sulfonamides, antivirals, oral hypoglycemics, hormonal, immunosuppressive, cytostatic, antiarrhythmic, antihypertensive agents). Phenobarbital enhances the effects of analgesics, anesthetics, anesthetic agents, neuroleptics, and tranquilizers; it reduces the effects of paracetamol, indirect anticoagulants, metronidazole, tricyclic antidepressants, salicylates, and cardiac glycosides.

Possible effects on blood concentrations of phenytoin, as well as carbamazepine and clonazepam, may occur. Monoamine oxidase inhibitors (MAOIs) prolong the effect of phenobarbital. Rifampicin may reduce the effect of phenobarbital. When used concomitantly with gold-containing drugs, the risk of kidney damage increases. With prolonged concurrent use with nonsteroidal anti-inflammatory drugs (NSAIDs), there is an increased risk of gastric ulceration and bleeding. Concurrent use of medicinal products containing phenobarbital with zidovudine enhances the toxicity of both agents. Unfavorable interaction of Corvaldin® (containing phenobarbital) with antiepileptic drugs, thyroid hormones, doxycycline, chloramphenicol, antifungals (azole group), griseofulvin, glucocorticoids, and oral contraceptives due to the potential reduction in efficacy of these drugs.

The medicinal product increases methotrexate toxicity.

Special precautions for use.

During treatment with this medicinal product, activities requiring increased attention and rapid psychomotor reactions should be avoided.

Concomitant use of alcoholic beverages should be avoided.

Life-threatening skin reactions, such as Stevens–Johnson syndrome and toxic epidermal necrolysis, have been reported during treatment with phenobarbital.

Patients should be informed about the signs and symptoms of these skin reactions and closely monitored. The highest risk of Stevens–Johnson syndrome or toxic epidermal necrolysis occurs during the first weeks of treatment.

If symptoms of Stevens–Johnson syndrome or toxic epidermal necrolysis occur (e.g., progressive skin rash, often with blisters, and mucosal lesions), treatment must be discontinued immediately.

The best outcomes in managing Stevens–Johnson syndrome or toxic epidermal necrolysis are associated with early diagnosis and immediate discontinuation of any suspected causative drug. Prognosis is significantly improved by prompt withdrawal of the suspected medicinal product.

If a patient has developed Stevens–Johnson syndrome or toxic epidermal necrolysis while receiving Corvaldin®, this medicinal product must never be used again in such patients.

If chest pain does not resolve after taking the medicinal product, medical advice must be sought to rule out acute coronary syndrome. Use with caution in patients with hyperkinesias, hyperthyroidism, adrenal insufficiency, decompensated heart failure, arterial hypotension, persistent pain, or acute intoxication with medicinal products.

This medicinal product contains 60 vol.% ethanol (alcohol).

The minimum dose (15 drops) contains 271 mg of ethanol, equivalent to 6.9 mL of beer or 2.9 mL of wine. This is harmful for patients suffering from alcoholism. Caution is advised when administering to patients with liver disease or epilepsy.

Prolonged use is not recommended due to the risk of developing drug dependence, possible accumulation of bromide in the body, and bromide poisoning.

Use during pregnancy or breastfeeding.

Do not use during pregnancy or breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

Corvaldin® contains phenobarbital and ethanol, which may cause impaired coordination, slowed psychomotor reactions, drowsiness, and dizziness during treatment. Therefore, activities requiring heightened attention, including driving vehicles or operating machinery, should be avoided.

Dosage and Administration.

Take orally before meals, 15–30 drops with a small amount of liquid (30–50 mL) 2–3 times daily. The single dose may be increased, if necessary, to 40–50 drops.

The duration of treatment is determined by the physician depending on the clinical response and tolerability of the drug.

Children.

There is no experience with the use of the drug in children; therefore, the drug should not be used in pediatric practice.

Overdose.

Symptoms.

Acute (mild to moderate) barbiturate poisoning:

dizziness, fatigue, even deep sleep from which the patient cannot be awakened.

Hypersensitivity reactions may occur: angioneurotic edema, urticaria, pruritus, rash.

Severe acute poisoning:

deep coma associated with tissue hypoxia, shallow respiration initially rapid and later slowed, tachycardia, cardiac arrhythmia, low blood pressure, bradycardia, vascular collapse, diminished or absent reflexes, nystagmus, headache, nausea, weakness, disturbances in cardiac function, decreased body temperature, slowed pulse, reduced diuresis.

If untreated, poisoning may result in death due to circulatory failure, respiratory paralysis, or pulmonary edema.

Overdose may occur during prolonged use of the drug due to accumulation of its components. Long-term and continuous use may lead to dependence, withdrawal syndrome, psychomotor agitation.

Prolonged use of drugs containing bromine may lead to bromism, characterized by the following symptoms: confusion, ataxia, apathy, depressive mood, conjunctivitis, cold-like symptoms, acne, or purpura.

Treatment.

Cases of acute poisoning with Korvaldin® should be treated as poisoning with other hypnotics and barbiturates, depending on the severity of symptoms. The patient should be transferred to an intensive care unit. Respiratory and circulatory functions require stabilization and normalization. Respiratory failure should be managed by artificial ventilation; shock should be treated with plasma and plasma substitutes infusion. If a significant time has passed since ingestion, gastric lavage is indicated (10 g of activated charcoal powder and sodium sulfate should be administered into the stomach). To accelerate elimination of barbiturates from the body, forced alkaline diuresis, hemodialysis, and/or hemoperfusion may be performed.

Treatment of bromine poisoning: elimination of bromide ions from the body can be accelerated by administration of a large volume of sodium chloride solution together with saluretic agents.

In case of hypersensitivity reactions, desensitizing agents should be administered.

Adverse reactions.

Central nervous system: asthenia, weakness, impaired motor coordination, nystagmus, ataxia, hallucinations, paradoxical excitation, insomnia (in elderly patients), decreased concentration, fatigue, slowed reaction time, headache, cognitive disturbances. In individual cases, drowsiness and mild dizziness, confusion may occur.

Musculoskeletal system: with prolonged use of products containing phenobarbital, there is a risk of impaired osteogenesis. Cases of decreased bone mineral density, osteopenia, osteoporosis, and fractures have been reported in patients receiving long-term phenobarbital therapy. The mechanism by which phenobarbital affects bone metabolism has not been established.

Gastrointestinal tract: nausea, vomiting, constipation, epigastric fullness; with prolonged use – impaired liver function.

Hematopoietic system: agranulocytosis, megaloblastic anemia, thrombocytopenia, anemia.

Cardiovascular system: decreased blood pressure, bradycardia.

Skin and mucous membranes: Stevens-Johnson syndrome, toxic epidermal necrolysis, allergic reactions, including rash, pruritus, urticaria.

Immune system: hypersensitivity reactions, including angioedema, dyspnea, facial swelling.

Prolonged use of drugs containing bromide may lead to bromism, characterized by the following symptoms: central nervous system depression, depression, confusion, ataxia, apathy, conjunctivitis, rhinitis, lacrimation, acne, or purpura.

Shelf life.

3 years.

Do not use the drug after the expiry date stated on the package.

Storage conditions.

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

Packaging. 50 ml in a bottle. 1 bottle per pack.

Prescription status. Prescription only.

Manufacturer: JSC "Farmak".

Manufacturer's address and place of business.

74, Kyrylivska Street, Kyiv, 04080, Ukraine.