Doxylamine-krevel

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DOXYLAMINE-KREVEL

Composition:

Active substance: doxylamine succinate;

1 ml (22 drops) contains doxylamine succinate 25 mg;

Excipients: ethanol 96%, peppermint oil, purified water.

Medicinal form. Oral drops, solution.

Main physico-chemical properties: clear, colorless solution with a minty odor.

Pharmacotherapeutic group. Antihistamines for systemic use. Aminoalkyl ether derivatives. ATC code R06A A09.

Hypnotics and sedatives. Other hypnotics and sedatives. ATC code N05C M.

Pharmacological properties.

Pharmacodynamics.

Doxylamine succinate is an antihistamine (a derivative of monoethanolamine) with sedative properties. Antihistamines, also known as H1-receptor antagonists, are well known for producing sedative effects in humans. Doxylamine reduces many of the effects of endogenous histamine by blocking H1-receptors. The central nervous system (CNS) depressant effect is most likely due to its high affinity for H1-receptors in the brain.

Due to its sedative properties, doxylamine succinate is used for the short-term treatment of sleep disturbances. Doxylamine succinate improves sleep, decreasing sleep onset latency and increasing sleep duration.

Many H1-receptor antagonists inhibit the action of acetylcholine on muscarinic receptors. Related possible anticholinergic adverse effects are listed in the section "Adverse Reactions". Anticholinergic properties do not affect the efficacy of doxylamine.

Pharmacokinetics.

After oral administration, doxylamine is rapidly and almost completely absorbed. The effect of the drug begins to manifest within 30 minutes. The maximum plasma concentration of 99 ng/mL is reached 2.4 hours after oral administration of a 25 mg dose. The duration of action is 3–6 hours.

Doxylamine is primarily metabolized in the liver. Metabolites identified include N-desmethyl doxylamine, N,N-didesmethyl doxylamine, and their N-acetyl conjugates. The elimination half-life of the parent compound ranges from 10.1 to 12 hours. A large portion of the administered dose (approximately 60%) is excreted unchanged in urine, while the remainder is eliminated via various metabolic pathways.

Clinical characteristics.

Indications.

Symptomatic treatment of occasional sleep disturbances (difficulty falling asleep or maintaining sleep) in adults.

Contraindications.

• Hypersensitivity to the active substance, peppermint oil, or to any excipient of the medicinal product.
• Hypersensitivity to antihistamine medicinal products.
• Acute asthma attack.
• Closed-angle glaucoma.
• Congenital long QT syndrome.
• Phaeochromocytoma.
• Prostatic hypertrophy with urinary retention.
• Acute intoxication with alcohol, sedatives, analgesics, or psychotropic agents (neuroleptics, tranquillisers, antidepressants, lithium preparations).
• Epilepsy.
• Concomitant treatment with monoamine oxidase inhibitors.
• Breastfeeding.

Patients with bronchial asthma or other respiratory disorders characterised by increased airway sensitivity should not use Doxylamine-Crevell due to the presence of peppermint oil, inhalation of which may provoke bronchospasm.

Interaction with other medicinal products and other forms of interaction.

Concomitant use of the medicinal product Doxylamine-Crevell with centrally acting CNS depressants (e.g., neuroleptics, tranquillisers, antidepressants, hypnotics, analgesics, anaesthetics, antiepileptic agents) may enhance the effects of these medicinal products. Caution should be exercised when combining with procarbazine or other antihistamines due to the potential for mutual potentiation of CNS depressant effects. Alcohol should not be consumed during treatment with Doxylamine-Crevell, as alcohol may unpredictably enhance the effect of doxylamine succinate.

Results from mouse experiments show dose-dependent increased enzymatic activity of hepatic cytochrome P450 (CYP450). Administration of doxylamine led to significant induction of CYP2B enzymes and moderate induction of CYP3A and CYP2A. Interactions with medicinal products metabolised by these CYP enzymes cannot be excluded (e.g., antiarrhythmics, protease inhibitors, neuroleptics, beta-blockers, immunosuppressants, antiepileptics).

The anticholinergic effect of doxylamine succinate may be unpredictably increased and prolonged when used concomitantly with other medicinal products exhibiting anticholinergic activity (e.g., atropine, biperiden, tricyclic antidepressants). Doxylamine succinate must not be combined with monoamine oxidase inhibitors. The anticholinergic effect of doxylamine succinate may be enhanced when used concomitantly with monoamine oxidase inhibitors, potentially resulting in life-threatening paralytic ileus, urinary retention, or acute glaucoma. Furthermore, interaction between doxylamine and monoamine oxidase inhibitors may lead to hypotension, central nervous system and respiratory depression.

Concomitant use of the medicinal product Doxylamine-Crevell with centrally acting antihypertensives (e.g., guanabenz, clonidine, alpha-methyldopa) may enhance sedative effects.

Symptoms of early inner ear toxicity (tinnitus, vertigo, clouding of consciousness) caused by ototoxic medicinal products (e.g., aminoglycosides, salicylates, diuretics) may be masked by concomitant use with antihistamines.

Following treatment with doxylamine succinate, skin test results may be falsely negative.

Epinephrine (adrenaline) must not be used to treat hypotension in patients taking doxylamine succinate, as epinephrine (adrenaline) may exacerbate hypotension. In severe shock states, norepinephrine (noradrenaline) may be used (see section "Overdose").

Concomitant use of medicinal products with photosensitising effects and antihistamines may result in enhanced photosensitisation.

Special precautions for use.

Doxylamine-Krevel should be used with caution in:

• hepatic function disorders;
• cardiac insufficiency and hypertension;
• chronic dyspnea and bronchial asthma;
• gastroesophageal reflux;
• pyloric stenosis;
• cardia achalasia.

Doxylamine-Krevel should be administered with particular caution to patients with focal lesions of the cerebral cortex or a history of seizures, as even small doses of the medicinal product may provoke severe epileptic seizures.

It should be noted that even relatively low doses of doxylamine succinate may induce convulsions in patients with organic brain lesions or a history of seizures. EEG (electroencephalography) monitoring is recommended. Anticonvulsant therapy should not be discontinued during treatment with Doxylamine-Krevel.

During antihistamine therapy, regular monitoring of cardiac function is recommended, as there have been reports of ECG changes, particularly due to alterations in the repolarization phase. This is especially important for elderly patients and those with cardiac insufficiency. Particular caution is required when treating patients with arterial hypertension, as antihistamines may increase blood pressure.

Doxylamine-Krevel is not prescribed to children.

Doxylamine-Krevel contains 55% v/v ethanol (ethyl alcohol), amounting to up to 0.9 g of ethyl alcohol per single dose (up to 44 drops).

The medicinal product may be hazardous for individuals suffering from alcoholism, pregnant women, breastfeeding women, and patients with liver disease, epilepsy, or organic brain disorders.

The effects of other medicinal products may be reduced or enhanced.

As with other hypnotic agents, oral administration of doxylamine succinate may lead to the development of physical and psychological dependence. The risk of dependence increases with higher doses and longer treatment duration and is further elevated in patients with a history of alcohol or drug dependence, medication-related or otherwise.

After repeated use of oral sedative/hypnotic agents, loss of efficacy (development of tolerance) may occur.

Note. Not all sleep disorders require pharmacological treatment. Often, sleep disturbances are associated with deteriorating health or mental disorders and may be resolved by other means or by treating the underlying condition. Long-term treatment of chronic sleep disorders (including difficulty falling asleep or maintaining sleep) with Doxylamine-Krevel should not be undertaken without consulting a physician.

Use during pregnancy or breastfeeding.

Epidemiological studies of medicinal products containing doxylamine have not revealed signs of teratogenic effects in humans. Experience with doxylamine use during the second and third trimesters is insufficient. A pharmacological effect on the fetus cannot be excluded. There is insufficient preclinical data on reproductive toxicity (animal studies have shown that doxylamine crosses the placenta in mice. Doxylamine can be detected in embryos at concentrations higher than those in plasma of pregnant females). The use of Doxylamine-Krevel is therefore not recommended during pregnancy.

Physicochemical data indicate that doxylamine succinate is excreted into breast milk. Since newborns may be more sensitive to the effects of antihistamines and may experience paradoxical excitation and restlessness, a risk to breastfed infants cannot be excluded. Therefore, doxylamine is contraindicated during breastfeeding (see section "Special precautions for use").

There are no data on the potential effect of doxylamine on human fertility. Animal studies have not shown any effect on fertility, even at doses significantly higher than those recommended for clinical practice (no effect on fertility was observed in rats, even after administration of doses substantially exceeding the recommended clinical doses). Data on peri- and postnatal development are lacking.

Ability to affect reaction speed when driving or operating machinery.

The medicinal product (even when used appropriately) may negatively affect reaction speed, ability to drive a vehicle, and operate machinery, especially when used concomitantly with alcohol. Therefore, driving, operating machinery, and other potentially hazardous activities should be avoided at least during the initial phase of treatment.

Method of Administration and Dosage

Unless otherwise prescribed by a physician, the single dose of the medicinal product Doxylamine-Krevel for adults is 22 drops (corresponding to 25 mg of doxylamine succinate). In cases of persistent sleep disturbances, the patient may take up to 44 drops of Doxylamine-Krevel (50 mg of doxylamine succinate) – the maximum dose. The maximum daily dose must not be exceeded.

Patients with impaired kidney or liver function, elderly patients, and debilitated patients, who may be more sensitive to the effects of doxylamine, should receive a reduced dose of the medicinal product.

The drops should be taken with sufficient fluid (water) 30 minutes to 1 hour before bedtime.

After taking Doxylamine-Krevel, it is important to ensure an adequate duration of sleep to avoid impaired reaction speed in the morning.

In cases of acute sleep disturbances, a single dose should be sufficient. The duration of treatment should be as short as possible. Generally, treatment should last only a few days and must not exceed 14 days of continuous daily use. If sleep disturbances persist, a physician must be consulted.

Children

The medicinal product must not be used in children.

Overdose

Poisoning should be considered in cases of ingestion of large doses of the medicinal product with suicidal intent.

Symptoms:

• Ranging from drowsiness to coma, sometimes with agitation and delirium;
• Anticholinergic effects: blurred vision, acute glaucoma, decreased intestinal peristalsis, urinary retention;
• Cardiovascular system: arterial hypotension, tachycardia or bradycardia, ventricular tachyarrhythmia, cardiac failure;
• Hypothermia or hyperthermia;
• Cerebral seizures;
• Respiratory complications: cyanosis, respiratory depression, apnea, aspiration.

Cases of rhabdomyolysis due to doxylamine succinate poisoning have been reported.

A 2002 publication (Lee and Lee) reported a case in which a patient who took 500 mg of doxylamine due to chronic insomnia developed acute pancreatitis and acute renal failure.

Treatment is symptomatic and based on general principles of poisoning management, with the following specific considerations:

• In cases of large oral ingestion, early gastric lavage or induction of vomiting should be performed;
• Central nervous system stimulants (analeptics) are contraindicated, as they may lower the seizure threshold further due to the effects of doxylamine, increasing the risk of cerebral seizures;
• In cases of hypotension, paradoxical worsening may occur; therefore, cardiovascular agents such as epinephrine (adrenaline) should not be used. Instead, agents such as norepinephrine (noradrenaline) should be administered, for example, continuous intravenous infusion of norepinephrine (noradrenaline) or angiotensinamide. Beta-agonists should be avoided, as they may exacerbate vasodilation;
• In cases of severe poisoning (loss of consciousness, cardiac arrhythmia) or development of anticholinergic syndrome, under intensive care conditions (ECG monitoring), the antidote physostigmine salicylate may be administered;
• In cases of recurrent epileptic seizures, anticonvulsant drugs may be administered, but only if artificial ventilation of the lungs can be provided, due to the increased risk of respiratory depression.

Hemodialysis, hemofiltration, and peritoneal dialysis have not been studied in cases of doxylamine overdose and are unlikely to be effective due to the large volume of distribution. The efficacy of forced diuresis has not been established.

Adverse Reactions

The frequency of the adverse reactions listed below is defined as follows:

• very common (> 1/10);
• common (> 1/100, < 1/10);
• uncommon (> 1/1,000, < 1/100);
• rare (> 1/10,000, < 1/1,000);
• very rare (> 1/10,000);
• unknown (frequency cannot be estimated from available data).

Haematological and lymphatic system disorders: in exceptional cases, following administration of antihistamines, leukopenia, thrombocytopenia, and hemolytic anemia may occur. Very rarely, aplastic anemia and agranulocytosis have been observed.

Endocrine system disorders: in patients with pheochromocytoma, administration of antihistamines may lead to increased release of catecholamines.

Psychiatric disorders: adverse effects dependent on individual sensitivity and dose include: slowed reaction time, difficulty concentrating, depression.

Paradoxical reactions (e.g., restlessness, excitation, anxiety, insomnia, nightmares, confusion, hallucinations, tremor) may occur. Abrupt discontinuation of the medicinal product after prolonged use may lead to worsening of sleep disturbances.

Dependence: with the use of doxylamine succinate, as with other hypnotics, physical and psychological dependence may develop. The risk of dependence increases with higher doses and longer duration of treatment, and is higher in patients with a history of alcohol or drug dependence.

Rebound insomnia: abrupt discontinuation of doxylamine succinate, even after short-term use, may be accompanied by temporary sleep disturbances. Therefore, if discontinuation is necessary, it is recommended to taper the dose gradually.

Anterograde amnesia: hypnotics, even at therapeutic doses, may cause anterograde amnesia, particularly in the first hours after intake. The risk increases with higher doses but may be reduced by achieving prolonged and uninterrupted sleep (7–8 hours).

Nervous system disorders: dizziness, headache, drowsiness. Cerebral seizures are possible in rare cases.

Eye disorders: accommodation disorders, increased intraocular pressure.

Ear and labyrinth disorders: tinnitus.

Cardiac and vascular disorders: tachycardia, cardiac arrhythmias, arterial hypotension, hypertension, and decompensated heart failure. In some cases, ECG changes have been observed.

Respiratory, thoracic and mediastinal disorders: thickening of secretions, bronchoconstriction, and bronchospasm may lead to impaired lung function.

Gastrointestinal disorders: autonomic side effects may occur: dry mouth, constipation, nausea, vomiting, diarrhea, loss or increased appetite, epigastric pain; in very rare cases – life-threatening paralytic ileus.

Hepatobiliary disorders: there have been reports of impaired liver function (cholestatic jaundice) during antihistamine therapy.

Skin and subcutaneous tissue disorders: allergic skin reactions, photosensitization, and disturbances in thermoregulation have been reported during antihistamine treatment.

Musculoskeletal and connective tissue disorders: muscle weakness.

Renal and urinary disorders: urinary retention.

General disorders: nasal congestion, fatigue, weakness.

Prolonged use of sedative/hypnotic agents may lead to loss of efficacy – development of tolerance.

Note: careful individual dose titration can reduce the frequency and severity of adverse reactions. The likelihood of adverse reactions is higher in elderly patients. This patient group also has an increased risk of loss of consciousness (unconsciousness).

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives are encouraged to report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua/.

Shelf life: 5 years.

Shelf life after first opening of the bottle: 6 months.

Storage conditions:

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging:

20 ml or 50 ml in a dropper bottle; 1 dropper bottle in a cardboard box.

Supply category: Over-the-counter – 20 ml; prescription only – 50 ml.

Manufacturer:

Krewel Meuselbach GmbH.

Manufacturer's address:

Krewelstrasse 2, 53783 Eitorf, Germany.