Dacepton

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DACEPTON® (DACEPTON®)

Composition:

Active substance: apomorphine hydrochloride hemihydrate;

1 ml of solution contains 10 mg of apomorphine hydrochloride hemihydrate;

Excipients: sodium metabisulfite (E 223), diluted hydrochloric acid, sodium hydroxide, water for injections.

Pharmaceutical form. Solution for injection or infusion.

Main physicochemical properties: clear, colorless or slightly yellow solution, free from mechanical particles.

Pharmacotherapeutic group.

Antiparkinson agents. Dopaminergic agents. Dopamine agonists.

ATC code N04BC07.

Pharmacological properties.

Pharmacodynamics.

Apomorphine is a direct stimulant of D1- and D2-type dopamine receptors. The transport and metabolic pathways of apomorphine and levodopa are different.

Although in intact experimental animals administration of apomorphine reduces the firing rate of neurons in the nigrostriatal system, and at low doses apomorphine decreases motor activity (presumably due to presynaptic inhibition of endogenous dopamine release), its effect on motor disorders in Parkinson's disease is likely mediated via postsynaptic receptors. This biphasic effect is also observed in humans.

Pharmacokinetics.

The pharmacokinetics of apomorphine after subcutaneous administration is described by a two-compartment model, with a distribution half-life of 5 ± 1.1 min and an elimination half-life of 33 ± 3.9 min. The clinical effect depends on the concentration of apomorphine in cerebrospinal fluid; the distribution of the active substance is best described by a two-compartment model. Apomorphine is rapidly and completely absorbed from subcutaneous tissues; the clinical effect begins quickly (within 4–12 minutes) and is short-lived (approximately 1 hour), which is explained by rapid clearance. Apomorphine is metabolized via glucuronidation and sulfation—at least 10% of the total dose; other metabolic pathways have not been described.

Clinical characteristics.

Indications.

Treatment of motor fluctuations ("on-off" phenomenon) in patients with Parkinson's disease whose condition is not adequately controlled by oral anti-Parkinsonian medications.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients.
• Respiratory depression, dementia, psychotic disorders, or hepatic insufficiency.
• Apomorphine hydrochloride must not be used in patients who experience an "on" response to levodopa with severe dyskinesia or dystonia.
• Concomitant use with ondansetron (see section "Interaction with other medicinal products and other forms of interaction").
• The medicinal product Dacepton® 10 mg/mL is contraindicated in children and adolescents under 18 years of age.

Special safety precautions.

Do not use the solution if it has turned green.

The solution should be inspected visually before administration. Only clear, colorless or slightly yellow solution free from mechanical particles should be used, provided the ampoule is undamaged.

The ampoule of solution is intended for single use only. Any unused solution must be disposed of according to local requirements.

Continuous infusion and use of an infusion mini-pump and/or syringe pump

The choice of infusion mini-pump and/or syringe pump, as well as the necessary dosing settings, should be determined by the physician according to the individual patient's needs.

Dacepton® 10 mg/mL is compatible with 0.9% sodium chloride solution.

Interaction with other medicinal products and other forms of interaction.

Patients receiving treatment with apomorphine hydrochloride are almost certainly taking other medicinal products for Parkinson's disease. Therefore, close monitoring for unusual adverse reactions or signs of potentiated drug effects is required at the initiation of apomorphine hydrochloride therapy.

Antagonistic interactions may occur when used concomitantly with neuroleptics. Interaction between clozapine and apomorphine is possible; however, clozapine may also be used to alleviate symptoms of neuropsychiatric complications.

In patients with Parkinson's disease receiving dopamine agonists, if neuroleptic medicinal products need to be administered, gradual reduction of apomorphine dose should be considered when administered via infusion mini-pump and/or syringe pump (rare cases of symptoms suggestive of neuroleptic malignant syndrome have been reported following abrupt interruption of dopaminergic therapy).

The potential effect of apomorphine on plasma concentrations of other medicinal products has not been studied. Therefore, caution is required when using apomorphine in combination with other medicinal products, especially those with a narrow therapeutic index.

Antihypertensive and cardioactive drugs

Even when used concomitantly with domperidone, apomorphine may potentiate the antihypertensive effect of these drugs (see section "Special precautions for use").

Concomitant use of apomorphine with other drugs that prolong the QT interval should be avoided.

Concomitant use of apomorphine with ondansetron may lead to severe hypotension and loss of consciousness and is therefore contraindicated (see section "Contraindications"). These effects may also occur with other 5-HT3 antagonists.

Special precautions for use.

Apomorphine hydrochloride should be used with caution in patients with renal, pulmonary, or cardiovascular disorders, as well as in patients prone to nausea and vomiting.

Particular caution is required during the initial treatment period in elderly patients and/or debilitated patients.

Since apomorphine may cause arterial hypotension even when premedicated with domperidone, special attention should be paid to patients with cardiac disorders, patients receiving vasoactive medicinal products, particularly antihypertensive agents, and especially patients with a history of orthostatic hypotension.

As apomorphine, particularly at high doses, may prolong the QT interval, caution is required when treating patients at risk of developing cardiac arrhythmias of the torsades de pointes type.

When used in combination with domperidone, individual patient risk factors should be carefully assessed. This assessment should be performed both before initiating treatment and during treatment. Important risk factors include serious underlying cardiac conditions such as congestive heart failure, severe hepatic impairment, or significant electrolyte imbalances. Concomitant medicinal products that may affect electrolyte balance, CYP3A4 metabolism, or QT interval should also be evaluated. Monitoring of QTc interval effects is recommended. ECG should be performed:

• before starting domperidone treatment;
• at the beginning of treatment;
• subsequently as clinically indicated.

Patients should be warned to report possible cardiac symptoms, including palpitations, syncope, or pre-syncope. Patients should also report clinical conditions that may lead to hypokalemia, such as gastroenteritis or initiation of diuretic therapy.

Risk factors should be reviewed at every medical visit.

Apomorphine treatment may cause local subcutaneous reactions. These may sometimes be reduced by rotating injection sites. When available, ultrasound imaging may be used to avoid injecting into areas with nodules or indurations.

Cases of hemolytic anemia and thrombocytopenia have been reported in patients receiving apomorphine. As with levodopa therapy, hematological parameters should be monitored regularly during apomorphine treatment.

Caution is required when using apomorphine in combination with other medicinal products, especially those with a narrow therapeutic index (see section "Interaction with other medicinal products and other forms of interaction").

Neuropsychiatric disturbances are common in many patients with progressive Parkinson’s disease. There is evidence that apomorphine may exacerbate neuropsychiatric disturbances in some patients. Special caution is required when administering apomorphine to such patients.

Apomorphine may cause somnolence, and other dopamine agonists have been associated with episodes of sudden sleep onset, particularly in patients with Parkinson’s disease. Patients should be warned of this possibility and advised to exercise caution when driving or operating machinery during treatment with apomorphine. Patients who experience somnolence should refrain from driving or operating machinery. In such cases, dose reduction or discontinuation of therapy should also be considered.

Patients require regular monitoring for the development of impulse control disorders. Patients and caregivers should be informed that treatment with dopamine agonists, including apomorphine, may lead to symptoms of impulse control disorders such as pathological gambling, increased libido, hypersexuality, compulsive shopping or spending, binge eating, and compulsive overeating. If such symptoms occur, consideration should be given to dose reduction or gradual withdrawal of the drug.

Dopamine dysregulation syndrome is an addictive disorder leading to compulsive drug use. This syndrome has been observed in some patients receiving apomorphine. Patients and caregivers should be informed about the potential risk of developing dopamine dysregulation syndrome prior to initiating treatment.

Excipients with known effects

Dacepton® 10 mg/ml contains 1 mg of sodium metabisulfite (E 223) per 1 ml, which may rarely cause severe allergic reactions and bronchospasm.

The product contains less than 1 mmol (23 mg) of sodium in 10 ml, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding.

There is no experience with the use of apomorphine in pregnant women.

In animal reproductive studies, no teratogenic effects were observed; however, administration of toxic doses to pregnant rats resulted in respiratory insufficiency in offspring. The potential risk in humans is unknown.

The medicinal product Dacepton® 10 mg/ml should not be used during pregnancy unless clearly necessary.

There is no information on the excretion of apomorphine into human breast milk. The decision to discontinue/continue breastfeeding or to discontinue/continue treatment with Dacepton® 10 mg/ml should be made taking into account the importance of breastfeeding for the child and the expected benefit of treatment with Dacepton® 10 mg/ml for the woman.

Effect on ability to drive and use machines.

Apomorphine hydrochloride has a minor or moderate effect on the ability to drive and use machines.

Patients treated with apomorphine who experience somnolence and/or sudden sleep episodes should refrain from driving or engaging in other activities (e.g., operating machinery) where reduced attention could place themselves or others at risk of serious injury or death, until such episodes and somnolence have resolved (see also section "Special precautions for use").

Method of Administration and Dosage

Patient Selection for Treatment with Dacepton® 10 mg/mL Injection Solution

Patients prescribed treatment with Dacepton® 10 mg/mL should be able to recognize the onset of their "off" symptoms and be capable of self-administering the injection, or have a responsible caregiver who can administer the injection when necessary.

Patients prescribed apomorphine should generally begin domperidone at least two days prior to initiating therapy. The dose of domperidone should be titrated to the lowest effective dose and discontinued as soon as possible. When deciding on treatment with apomorphine and domperidone, the risk factors for QT interval prolongation should be carefully evaluated for each patient to ensure that benefits outweigh risks (see section "Special Warnings and Precautions for Use").

Treatment with apomorphine should be initiated in a specialized clinical setting. The patient must be under the supervision of a physician experienced in the treatment of Parkinson’s disease (e.g., a neurologist). Prior to initiating treatment with Dacepton® 10 mg/mL, the patient’s therapy with levodopa, with or without dopamine agonists, should be optimized.

Adults

Route of Administration

Dacepton® 10 mg/mL is intended for subcutaneous administration via intermittent bolus injections. Dacepton® 10 mg/mL may also be administered by continuous subcutaneous infusion using an infusion mini-pump and/or syringe pump (see section "Special Precautions").

Apomorphine must not be administered intravenously!

Do not use the solution if it has turned green. The solution should be visually inspected before administration. Only clear, colorless or slightly yellow solution free from particulate matter should be used.

Determination of Threshold Dose

The appropriate dose for each patient should be determined using a dose escalation regimen. The following regimen is recommended:

1 mg of apomorphine hydrochloride (0.1 mL of the solution), approximately equivalent to 15–20 µg/kg body weight, is administered subcutaneously during a period of hypokinesia or "off" episode, followed by observation of motor response for 30 minutes.

If there is no response or an inadequate response, a second subcutaneous dose of 2 mg apomorphine hydrochloride (0.2 mL of the solution) is administered, followed by an additional 30-minute observation period for an adequate motor response.

Doses may be gradually increased with a minimum interval of at least 40 minutes between subsequent injections until a satisfactory motor response is achieved.

Optimization of Treatment Regimen

After the appropriate dose has been determined, a single subcutaneous injection of the solution should be administered into the lower abdominal area or the outer thigh at the first signs of an "off" episode. Variability in apomorphine absorption in the same patient depending on the injection site cannot be excluded. Therefore, the patient should be monitored for one hour after injection to assess the adequacy of the therapeutic response. Based on the patient’s response, the dose may be adjusted.

The optimal dose of apomorphine hydrochloride may vary among patients, but remains relatively constant for an individual patient once established.

Precautions During Continued Treatment

The daily dose of Dacepton® 10 mg/mL varies widely among patients, typically ranging from 3 to 30 mg, administered in 1 to 10 doses per day, and occasionally up to 12 doses per day.

It is recommended that the total daily dose of apomorphine hydrochloride should not exceed 100 mg, and the individual bolus dose should not exceed 10 mg per hour.

During clinical trials, it was generally possible to reduce levodopa doses to some extent; however, this effect varies significantly among patients and therefore requires careful monitoring by an experienced physician.

After optimization of the treatment regimen, domperidone dosage may be gradually reduced in some patients. However, complete discontinuation without symptoms of nausea or arterial hypotension is possible only in a small number of patients.

Continuous Infusions

Patients who show a good "on" response during initial apomorphine treatment but whose condition is poorly controlled with intermittent injections, or who require a high number of injections (more than 10 per day), may be treated with continuous subcutaneous infusion using an infusion mini-pump and/or syringe pump. Initiation or transition to this form of therapy should follow the regimen described below.

Continuous infusion should be initiated at a rate of 1 mg apomorphine hydrochloride (0.1 mL of the solution) per hour, and then increased according to the individual patient’s response. Increases in infusion rate should not exceed 0.5 mg/hour, and intervals between rate increases should be at least 4 hours. The infusion rate may range from 1 mg to 4 mg (0.1–0.4 mL of the solution) per hour, corresponding to 0.015–0.06 mg/kg/hour. Infusions should be administered only during waking hours. If the patient does not experience significant nocturnal symptoms, 24-hour infusion is not recommended. Resistance to therapy is unlikely to develop as long as there is at least a four-hour nocturnal break in drug administration. In all cases, the infusion site must be changed every 12 hours.

If necessary, and at the physician’s discretion, continuous infusion may be combined with intermittent bolus injections of additional doses.

When continuous infusion is used, the potential need to reduce doses of other dopamine agonists should be considered.

Elderly Patients

Elderly patients constitute a large proportion of patients with Parkinson’s disease and were well represented in clinical trials of Dacepton® 10 mg/mL. The treatment regimens for elderly patients do not differ from those for younger patients. However, special caution is required at the beginning of treatment in elderly patients due to the risk of orthostatic hypotension.

Patients with Renal Impairment

For patients with renal impairment, the dosing regimen recommended for adult and elderly patients may be followed (see section "Special Warnings and Precautions for Use").

Children

Dacepton® 10 mg/mL is contraindicated in children and adolescents under 18 years of age (see section "Contraindications").

Overdose

There is limited clinical information regarding apomorphine overdose following subcutaneous administration. Symptomatic treatment of overdose may be empirically managed as follows:

For excessive nausea and vomiting, domperidone may be administered.

In case of respiratory depression, naloxone may be used.

For arterial hypotension, appropriate measures should be taken (e.g., elevating the lower part of the bed).

For bradycardia, atropine may be administered.

Side effects.

Side effects are categorized according to frequency as follows: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10,000, < 1/1000), very rare (< 1/10,000), frequency not known (cannot be estimated from the available data).

Blood and lymphatic system disorders

Uncommon: haemolytic anaemia and thrombocytopenia.

Rare: eosinophilia.

Immune system disorders

Rare: since the preparation contains sodium metabisulphite, allergic reactions (including anaphylaxis and bronchospasm) may occur.

Psychiatric disorders

Very common: hallucinations.

Common: neuropsychiatric disorders (including mild transient confusion and visual hallucinations).

Frequency not known: impulse control disorders (pathological gambling, increased libido, hypersexuality, compulsive shopping or spending, binge eating and compulsive overeating) may occur in patients receiving dopamine agonists, including apomorphine; aggression, anxiety agitation.

Nervous system disorders

Common: a transient sedative effect upon administration of each dose of apomorphine hydrochloride may occur at the beginning of treatment; this effect usually resolves within a few weeks after initiation of therapy; somnolence, dizziness.

Uncommon: apomorphine may induce dyskinesias during the "on" period, which in some cases may be severe and require discontinuation of therapy; episodes of sudden sleep.

Frequency not known: loss of consciousness, headache.

Vascular disorders

Uncommon: orthostatic hypotension, usually transient.

Respiratory, thoracic and mediastinal disorders

Common: yawning.

Uncommon: dyspnoea.

Gastrointestinal disorders

Common: nausea and vomiting, particularly during the initial period of apomorphine treatment, usually in patients not receiving domperidone.

Skin and subcutaneous tissue disorders

Uncommon: local and generalized rashes.

General disorders and administration site conditions

Very common: injection site reactions, especially with continuous use, including subcutaneous nodules, induration, erythema, pain, and panniculitis; other local reactions such as irritation, pruritus, bruising, and pain.

Uncommon: necrosis and ulcers at the injection site.

Frequency not known: peripheral oedema.

Investigations

Uncommon: positive Coombs test.

Shelf life.

Unopened medicinal product in original packaging: 3 years.

After opening the ampoule, the product should be used immediately. Any unused portion should be discarded.

Shelf life after dilution

Solutions prepared by diluting the medicinal product with 0.9% sodium chloride solution have been shown to be chemically and physically stable for 24 hours when stored at 15–25 °C.

From a microbiological standpoint, the diluted product should be used immediately. If not used immediately, the responsible person should monitor the storage duration and conditions. Generally, storage should not exceed 24 hours at 15–25 °C, unless the opening and dilution were performed under controlled and validated aseptic conditions.

Storage conditions.

Store in the original packaging, out of reach of children.

Do not refrigerate or freeze!

Incompatibilities.

The medicinal product must not be mixed with other medicinal products except 0.9% sodium chloride solution.

Packaging.

5 ml (50 mg) in an ampoule; 10 ampoules in a cardboard box.

Prescription status.

Prescription only.

Manufacturer/Marketing Authorisation Holder.

EVER Neuro Pharma GmbH, Austria.

EVER Neuro Pharma GmbH, Austria.

Manufacturer's address and place of business.

Oberburgau, 3, 4866 Unterach am Attersee, Austria.

Oberburgau, 3, 4866 Unterach am Attersee, Austria.