Eldepryl® [Selegiline]

Pharmacological properties

Selegiline is a selective mao-b inhibitor that also inhibits dopamine reuptake and the dysamine presynaptic receptor. these effects potentiate dopaminergic function in the brain. Selegiline potentiates and prolongs the effect of levodopa, which reduces the dose of the latter. in combination with levodopa preparations, Selegiline increases the duration of the “on” period, reduces the duration of the “off” period, and reduces the severity of the phenomenon of depletion of the final dose. Selegiline does not potentiate the hypertensive effect of substances such as tyramine (cheese effect).

Pharmacokinetics Selegiline is rapidly absorbed in the digestive tract. C_max in the blood is achieved 30–45 minutes after ingestion. Bioavailability is low; on average, 10% of unchanged Selegiline reaches the systemic circulation (however, there is a significant difference between different patients). Selegiline is a lipophilic compound with a slightly alkaline reaction that easily penetrates tissues, including the brain. It is rapidly distributed in the body, the volume of distribution is about 500 l after iv administration at a dose of 10 mg. When used in therapeutic doses, 75–85% of Selegiline binds to plasma proteins. Selegiline is rapidly metabolized (mainly in the liver) to desmethylSelegiline, 1-methamphetamine and 1-amphetamine. These three metabolites are detected in blood plasma and urine after a single and multiple administration of Selegiline. Average T_½ is 1.5–3.5 hours. The total clearance of Selegiline in the body is about 240 l / h. Selegelin metabolites are mainly excreted in the urine, about 15% - with feces. Due to the irreversible inhibition of MAO-B, the duration of the therapeutic effect does not depend on the time of elimination of Selegiline, therefore, taking the drug once a day is sufficient.

Indications

Parkinsons disease or symptomatic parkinsonism - as monotherapy at an early stage of the disease or in combination with levodopa drugs (in combination with or without peripheral decarboxylase inhibitors).

Application

Selegiline is used as monotherapy at an early stage of the disease or in combination with levodopa preparations (in combination with or without peripheral decarboxylase inhibitors). in both cases, the initial dose is 5 mg, which is taken in the morning. the dose of Eldepryl can be increased to 10 mg / day (can be taken in the morning or divided into two doses).

If, when using the drug as an adjunctive therapy, levodopa preparations cause adverse reactions predefined by levodopa, the dose of the latter should be reduced.

Liver failure. Information on dose changes in patients with liver failure is not available.

Renal failure. Information on dosage changes in patients with renal failure is not available.

Contraindications

Hypersensitivity to Selegiline or any of the excipients.

An ulcer of the stomach and duodenum in the acute stage.

Concomitant use with serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors (venlafaxine), tricyclic antidepressants, sympathomimetics, MAO inhibitors (linezolid) or opioids (petidine) (see INTERACTIONS).

When combining Selegiline with levodopa, contraindications to the use of levodopa should be taken into account.

Side effects

The incidence of adverse reactions has the following classification: very often (≥1 / 10); often (≥1 / 100, 1/10); infrequently (≥1 / 1000, 1/100); rarely (≥1 / 10,000–1 / 1000); very rarely (1/10 000), the frequency is unknown (it is impossible to determine from the available data).

Mental disorders: often - confusion, hallucinations; infrequently - mood swings; frequency unknown - impulse control and compulsion disorders (such as hypersexuality).

Violations of the nervous system: often - involuntary movements (dyskinesias), dizziness, headache; infrequently - passing sleep disturbances (insomnia); rarely - excitement.

Cardiac disorders: often - bradycardia; infrequently - supraventricular tachycardia; rarely - arrhythmias.

Disorders from the vascular system: rarely - postural hypotension.

Digestive tract disorders: often - nausea; infrequently - dry mouth.

Disorders from the hepatobiliary system: often - increased levels of liver enzymes.

Disorders from the skin and subcutaneous tissue: rarely - rash.

Disorders from the kidneys and urinary system: rarely - difficulty urinating; frequency unknown - urinary retention.

When using the drug, side effects such as psychosis, depression, tremors, chest pain, back pain, joints, throat, vertigo, blurred vision, vomiting, constipation, diarrhea also occur.

When combined with levodopa. Since the drug enhances the effect of levodopa, the side effects of levodopa (such as anxiety, hyperkinesia, atypical movements, agitation, confusion, hallucinations, postural hypotension, cardiac arrhythmias, dysphonia) may intensify with combination therapy (levodopa should usually be used in combination with a peripheral inhibitor decarboxylases). If, when using the drug in combination with levodopa preparations, adverse reactions occur, predetermined by levodopa, the dose of the latter should be reduced. Therefore, with the start of treatment with Selegiline, the dose of levodopa can be reduced by an average of 30%.

special instructions

Selegiline in combination with levodopa is especially indicated for patients whose condition changes due to treatment with levodopa drugs at maximum doses (the occurrence of fluctuations as a result of dose depletion).

Special care should be taken when using Selegiline in patients with duodenal ulcer, labile hypertension, cardiac arrhythmia, severe angina pectoris, severe hepatic or renal failure, or psychosis.

Since Selegiline potentiates the effect of levodopa, adverse reactions due to levodopa may intensify, especially with the use of high doses of levodopa. Patients receiving such treatment should be carefully monitored. When Selegiline is added to levodopa, symptoms such as spontaneous movements and / or agitation may appear, which disappear when the dose of levodopa is reduced. Therefore, with the start of treatment with Selegiline, the dose of levodopa can be reduced by an average of 30%.

At high doses (exceeding 10 mg / day), the selectivity of Selegiline relative to MAO-B begins to decrease, which leads to increased inhibition of MAO-A. Thus, the risk of hypertension increases.

In patients taking MAO inhibitors, caution should be exercised when performing general anesthesia in surgical practice.

Impulse control disorders and compulsive motivation have been reported, such as pathological gambling, increased libido and hypersexuality, bulimia, squandering, and other compulsive or repetitive actions in patients with Parkinsons disease during treatment with dopamine agonists or other dopaminergic drugs, such as Selegiline.

The results of some studies suggest that in patients taking Selegiline and levodopa at the same time, the mortality rate is higher compared to patients taking levodopa only. But it must be taken into account that in these studies, numerous methodological shortcomings were identified and that meta-analysis and large-scale cohort studies led to the conclusion that between the mortality rate of patients who received Selegiline and patients receiving comparison drugs or a combination of Selegiline / levodopa statistically significant difference.

The combination of Selegiline and levodopa is impractical in patients with dose-independent changes in response to treatment.

Caution is advised to combine Selegiline with drugs that act predominantly on the central nervous system.

The simultaneous use of Selegiline with alcohol should be avoided.

Use during pregnancy and lactation. Since the available data regarding the safety of Selegiline during pregnancy and lactation are insufficient, Selegiline cannot be used in this category of patients.

Children. Information on the use of the drug in children is not available, therefore, the use of the drug in this category of patients is not shown.

The ability to influence the reaction rate when driving vehicles or working with other mechanisms. The effect of Selegiline on the ability to drive a car or machinery has not been studied. During treatment with Selegiline, dizziness may occur. In such cases, one should refrain from driving vehicles or working with other mechanisms.

Interactions

The following combinations are contraindicated

Sympathomimetics. Concomitant use of Selegiline with sympathomimetics may result in severe hypertension.

Petidine. The simultaneous use of Selegiline (a selective MAO inhibitor) and pethidine is contraindicated. It is known that Selegiline and pethidine interact with each other with a potentially fatal outcome, but the mechanism of this interaction has not yet been studied.

Tramadol may also interact with Selegiline.

Selective serotonin reuptake inhibitors and serotonin and norepinephrine reuptake inhibitors (venlafaxine). With a combination of fluoxetine with Selegiline, sweating, hyperemia, ataxia, tremor, hyperthermia, arterial hyper and hypotension, convulsions, accelerated heartbeat, dizziness, agitation, confusion, hallucinations, delirium, and coma can be noted. Since fluoxetine and its active metabolites have a long T_½, between the withdrawal of fluoxetine and the initiation of Selegiline therapy, at least 5 weeks should elapse. Selegiline and its metabolites have a short T_½, therefore, between the withdrawal of Selegiline and the start of fluoxetine, a 2-week interval is sufficient.

Tricyclic antidepressants. With the combination of Selegiline with tricyclic antidepressants, toxic effects from the central nervous system (dizziness, tremor, convulsions) may occur; sometimes - arterial hyper- or hypotension, increased sweating. Since the mechanism of these reactions is not well understood, the simultaneous use of Selegiline and tricyclic antidepressants is contraindicated.

MAO inhibitors. The use of MAO inhibitors simultaneously with Selegiline can lead to severe arterial hypotension or hypertension.

Not recommended combinations

Oral contraceptives. Caution should be exercised while using Selegiline with combined oral contraceptives (gestagen / ethinyl estradiol or levonorgestrel / ethinyl estradiol), since they can increase the bioavailability of Selegiline.

Food interactions. Unlike traditional MAO enzyme inhibitors, which suppress both MAO-A and MAO-B, Selegiline is a selective MAO-B inhibitor.

When using Selegiline in recommended doses, after eating a meal with a low tyramine content, no hypertensive reaction was detected (the so-called cheese effect - “cheese-effect”). Therefore, in this case, there is no need to follow a diet.

However, with a combination of Selegiline and traditional MAO inhibitors or MAO-A inhibitors, it is recommended to strictly adhere to a diet (avoid foods high in tyramine - mature cheese and products containing yeast).

Overdose

There are no data on clinically significant drug overdoses. the effect of Selegiline as a selective MAO-B inhibitor is achieved when used in doses recommended for the treatment of Parkinsons disease (5-10 mg / day).overdose symptoms may be similar to overdose symptoms of non-selective MAO inhibitors (such as drowsiness, dizziness, irritability, agitation, hyperactivity, tremor, anxiety, severe muscle cramps, severe headache, hallucinations, ag, arterial hypotension, chest pain, accelerated and uneven pulse, vascular collapse, respiratory failure, respiratory depression, increased sweating, hyperthermia, coma, convulsions). overdose symptoms may develop within 24 hours. There is no specific antidote, the treatment is symptomatic.

Storage conditions

At room temperature 15–25 ° c.