Apokinon (Solution) Instructions for Use

Marketing Authorization Holder

Laboratoire Aguettant (France)

Manufactured By

Laboratoire Aguettant (France)

Packaging and Quality Control Release

OCPC, JSC (Russia)

ATC Code

N04BC07 (Apomorphine)

Active Substance

Apomorphine (BAN)

Dosage Form

Apokinon

Solution for subcutaneous administration 5 mg/1 ml: 10 ml amp. 10 pcs.

Dosage Form, Packaging, and Composition

Solution for subcutaneous administration in the form of a transparent, colorless or slightly opalescent liquid.

Excipients : sodium disulfite, hydrochloric acid solution 1M, water for injections.

10 ml – ampoules made of colorless type I glass (5) – plastic containers (2) – cardboard packs.

Clinical-Pharmacological Group

Antiparkinsonian drug – dopaminergic receptor agonist

Pharmacotherapeutic Group

Antiparkinsonian agent. Dopamine receptor agonist.

Pharmacological Action

Apomorphine is a semi-synthetic alkaloid obtained from morphine by treating it with hydrochloric acid. After parenteral administration, the onset of action is noted within 2-10 minutes. The duration of action is 45-90 minutes.

Apomorphine retains some pharmacological properties of morphine. It has weak analgesic activity and exerts a depressant effect on the respiratory center. The effect of apomorphine on the chemoreceptor trigger zone of the medulla oblongata is particularly pronounced; its excitation causes a strong emetic effect. If the first dose of apomorphine does not produce an emetic effect, its repeated administration is also not accompanied by vomiting. The use of apomorphine does not have an emetic effect against the background of suppressed excitability of the vomiting center (for example, during deep anesthesia), as well as against the background of suppression of the chemoreceptor trigger zone by dopamine receptor antagonists (for example, under the influence of neuroleptic substances, metoclopramide).

Due to the ability of apomorphine to cross the blood-brain barrier and exert a central dopaminergic effect (stimulation of central postsynaptic dopamine D₁ and D₂ receptors at the level of nigrostriatal cells), its use for the treatment of parkinsonism is possible. The ability of apomorphine to interact with dopamine receptors is apparently related to the similarity of part of its molecule to the structure of dopamine.

As Parkinson’s disease progresses in severity, the cells of the substantia nigra lose their ability to accumulate and smoothly release dopamine, which is manifested by a gradual weakening of the effect of the taken levodopa. The patient becomes inhibited, and the so-called motor manifestations of Parkinson’s disease intensify.

Shortening of the effect from the last taken dose of levodopa to 2-3 hours leads to an increase in the symptoms of Parkinson’s disease in the morning hours or at the time of taking the next dose of levodopa.

In most patients, motor fluctuations associated with levodopa intake are accompanied by fluctuations in the manifestation of non-motor symptoms – increased heart rate, sweating, changes in blood pressure, mental manifestations (increased irritability, anxiety).

The phenomenon of “wearing-off” of the levodopa dose effect is manifested by a decrease in the duration of the effect of a single dose with a smooth predictable increase in symptoms by the time of the next dose intake.

The “on-off” phenomenon is manifested by a sharp transition from a state of relative well-being against the background of levodopa action to immobility. Impairment of dopaminergic mechanisms may play a certain role in the pathogenesis of chronic alcoholism. A connection has been found between the development of withdrawal syndrome and the accumulation of dopamine in the blood.

Pharmacokinetics

The bioavailability of apomorphine after subcutaneous administration is close to 100%.

Apomorphine is a highly lipophilic compound that is completely absorbed from the gastrointestinal tract but is largely destroyed due to first-pass metabolism through the liver.

After subcutaneous administration, apomorphine is rapidly absorbed; T_max is dose-independent (on average 7.8±1 min). T_max in the cerebrospinal fluid is greater than T_max in plasma by 10-20 minutes. C_max in blood plasma of 10-30 µg/L is achieved 5-15 minutes after administration, and in the cerebrospinal fluid – approximately after 30 minutes. There is a very high correlation between the content of apomorphine in the cerebrospinal fluid and clinical motor responses.

After prolonged subcutaneous infusions of apomorphine, the average concentration of apomorphine in the blood is 27.9±9.3 µg/L at an infusion rate of 90±30 µg/kg/h.

Significant fluctuations in C_max are known, which can differ by 5-10 times in different individuals, which explains the need for individual selection of therapeutic doses of apomorphine. The site and depth of injection, skin temperature, as well as the presence or absence of subcutaneous nodules may contribute to this variability.

After subcutaneous administration, apomorphine is approximately 90% bound to plasma proteins and is poorly displaced by other drugs. It has a large V_d, indicating significant extravascular distribution of the drug, and easily crosses the blood-brain barrier.

Apomorphine is rapidly eliminated from plasma (3-5 L/kg/h) with a T_1/2 of 33 minutes. The apparent T_1/2 from plasma was longer in patients receiving continuous subcutaneous infusion than in patients receiving bolus subcutaneous injection. The short T_1/2 is explained by the rapid and intensive metabolism of apomorphine by the liver.

N-demethylation of apomorphine to norapomorphine by isoenzymes of the cytochrome P450 system plays a role in the metabolism of apomorphine. In addition, oxidation to quinone derivatives may be a quantitatively important process in the metabolism of apomorphine.

Pharmacokinetic studies of apomorphine have not been conducted in patients with hepatic impairment. However, since apomorphine is intensively metabolized in the liver, hepatic impairment is a major contraindication to its use.

Indications

Parkinson’s disease (severe course), insufficiently controlled by oral medications (presence of the “on-off” phenomenon, manifested by a sharp transition from a state of relative well-being against the background of levodopa action to immobility.

ICD codes

Dosage Regimen

Administer Apokinon exclusively by subcutaneous injection or continuous subcutaneous infusion.

Initiate therapy with a test dose of 1 mg (0.2 ml) under medical supervision to assess tolerability and blood pressure response.

Titrate the dose individually based on clinical effect and tolerability. The typical effective bolus dose ranges from 2 mg to 6 mg (0.4 ml to 1.2 ml).

For continuous infusion, the typical daily dosage range is 3 mg to 30 mg over 16 waking hours. Adjust the infusion rate to control motor fluctuations.

Do not exceed a single bolus dose of 10 mg (2 ml). The maximum total daily dose should not exceed 100 mg.

Rotate injection sites systematically to minimize local skin reactions such as nodules and panniculitis.

Premedicate with an antiemetic, such as domperidone, for at least two days prior to initiation and for the first several weeks of therapy to prevent nausea and vomiting.

Monitor for orthostatic hypotension, especially during dose escalation and in elderly or debilitated patients.

Regularly assess patients for the development of dyskinesias, drowsiness, and impulse control disorders.

Adverse Reactions

Blood and lymphatic system disorders uncommon – hemolytic anemia, thrombocytopenia; rare – eosinophilia; frequency unknown – hemolytic anemia.

Immune system disorders rare – due to the presence of sodium metabisulfite, the risk of allergic reactions increases (anaphylactic reactions and bronchospasm).

Psychiatric disorders very common – hallucinations; common – neuropsychiatric disorders (including transient mild confusion and visual hallucinations); frequency unknown – aggressiveness, agitation, impulse control disorders (as with other dopamine agonists (pathological gambling, increased libido, hypersexuality, compulsive spending or buying, binge eating and compulsive eating).

Nervous system disorders common – transient sedative effect with each dose of apomorphine hydrochloride at the beginning of therapy, drowsiness, dizziness; uncommon: Apomorphine may cause dyskinesia during the “on period”, which in some cases can be severe, and in some patients may lead to discontinuation of therapy; frequency unknown – syncope, headache.

Cardiac disorders uncommon – orthostatic hypotension; frequency unknown – pallor.

Gastrointestinal disorders common – nausea, vomiting; frequency unknown – constipation, hypersalivation.

Respiratory, thoracic and mediastinal disorders : common – yawning; uncommon – dyspnea.

Skin and subcutaneous tissue disorders uncommon – local and generalized rash.

General disorders and administration site conditions very common – most patients develop injection site reactions, especially with continuous use, such as subcutaneous nodules, indurations, erythema, tenderness and panniculitis; possible – irritation, itching, bruising and pain may also occur; uncommon – necrosis and ulceration at the injection site; frequency unknown – peripheral edema.

Contraindications

Hypersensitivity to apomorphine, age under 18 years, hepatic failure, respiratory depression, dementia, confusion, manifestations of psychosis, the need for simultaneous use of neuroleptics with antiemetic action, severe dyskinesia or dystonia against the background of levodopa use.

With caution

History of mental disorders after taking antiparkinsonian drugs; recent severe cardiovascular diseases; presence of risk for developing torsades de pointes ventricular tachycardia (Apomorphine, especially in high doses, may increase the risk of QT interval prolongation); severe water-electrolyte balance disorders; tendency to nausea and vomiting.

Intermittent administration of apomorphine, in addition to continuous infusion, is not recommended for patients who have an “on” response to levodopa with severe dyskinesia or dystonia.

Use with particular caution when initiating therapy in elderly and/or debilitated patients. Since Apomorphine can cause arterial hypotension, even when used concomitantly with domperidone, caution is required when using apomorphine in patients with heart disease (especially in individuals with a history of postural hypotension) or in patients taking vasoactive medications (for example, antihypertensive agents).

Use in Pregnancy and Lactation

Currently, there is insufficient data to assess the likelihood of malformations or the manifestation of fetotoxic effects of apomorphine when used during pregnancy. The use of apomorphine is not recommended for pregnant women (the age of the target group makes pregnancy unlikely). Apomorphine is excreted in breast milk; breastfeeding should be avoided during treatment.

Use in Hepatic Impairment

Contraindicated in hepatic failure.

Use in Renal Impairment

No dosage adjustment is required in patients with renal impairment.

Pediatric Use

Contraindicated in children and adolescents under 18 years of age.

Geriatric Use

Elderly patients constitute the largest proportion among patients with Parkinson’s disease. The management of elderly patients receiving Apomorphine does not differ from the management of younger patients; nevertheless, special caution is required at the initiation of therapy in these patients due to the risk of orthostatic hypotension.

Special Precautions

Since Apomorphine can cause arterial hypotension, even when used concomitantly with domperidone, caution should be exercised in patients with heart disease or in patients taking vasoactive medications, such as antihypertensive agents, and especially in patients with a history of orthostatic hypotension.

Before starting and during the use of apomorphine in combination with domperidone, risk factors should be carefully assessed individually for each patient. Important risk factors include serious concomitant heart diseases, such as congestive heart failure, severe hepatic impairment, or significant electrolyte imbalance.

The appropriateness of concomitant use of medications that may affect electrolyte balance or CYP3A4 metabolism should be assessed.

Apomorphine, especially in high doses, can lead to QT interval prolongation. Caution should be exercised when treating patients at risk of developing torsades de pointes arrhythmia.

Cases of hemolytic anemia have been reported in patients receiving levodopa and Apomorphine. Blood tests should be performed regularly with the concomitant use of levodopa and apomorphine.

Caution is recommended when combining apomorphine with other medications, especially those with a narrow therapeutic range. Psychoneurological symptoms are present in many patients with progressive Parkinson’s disease. There is evidence that in some patients they may be aggravated by taking apomorphine. Particular caution should be exercised when using apomorphine in such patients.

Apomorphine may cause drowsiness, and other dopamine agonists may cause episodes of sudden sleep onset, especially in patients with Parkinson’s disease. Patients should be informed about this and exercise caution when driving or operating machinery during treatment with apomorphine. If such side effects are pronounced, a dose reduction or discontinuation of therapy should be considered.

Patients should be regularly monitored for the development of impulse control disorder. Patients themselves and caregivers should be informed about the symptoms of impulse control disorder: pathological urges to gamble, increased libido and hypersexuality, compulsive spending or buying, binge eating and compulsive overeating, which may occur in patients receiving dopamine agonists, including Apomorphine. If such symptoms appear, a dose reduction or discontinuation of the drug should be considered.

Cases of dopamine dysregulation syndrome, leading to excessive consumption of this medication, have been observed in patients receiving Apomorphine. Before starting treatment, patients and caregivers should be warned about the potential risk of its development.

Effect on the ability to drive vehicles and operate machinery

Apomorphine has a minor to moderate influence on the ability to drive and use machines. Patients in whom Apomorphine causes side effects such as drowsiness and/or sudden episodes of sleep should be informed to refrain from driving or participating in activities (e.g., operating machinery) until such side effects subside.

Drug Interactions

Mutual antagonism between a dopaminergic agent and neuroleptics. Antiemetics devoid of extrapyramidal effects should be used.

It is recommended to avoid the combination of apomorphine with other drugs that increase the QT interval.

Mutual antagonism with neuroleptics. Apomorphine may cause or exacerbate psychotic disorders. If neuroleptic treatment is required in patients with Parkinson’s disease who are receiving treatment with dopaminergic drugs, the dose of the latter should be gradually reduced until complete withdrawal (sudden withdrawal of dopaminergic drugs carries the risk of neuroleptic malignant syndrome).

Mutual antagonism between a dopaminergic drug and tetrabenazine.

Ethanol enhances the sedative effect of these substances. Their simultaneous use should be avoided.

When used concomitantly with other sedatives, the depressant effect on the central nervous system is enhanced.

When used concomitantly with dapoxetine, the risk of increased adverse drug reactions, such as, in particular, dizziness or fainting.

There is a potential interaction between clozapine and apomorphine. At the same time, clozapine may also be used to reduce the symptoms of psychotic complications. If patients with Parkinson’s disease receiving treatment with dopamine agonists require the use of neuroleptics, a gradual reduction in the dose of apomorphine may be considered (when administered via a minipump and/or syringe pump); symptoms suggestive of neuroleptic malignant syndrome have rarely been reported upon abrupt withdrawal of dopaminergic therapy.

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.