4.1. Therapeutic indications

Kynmobi is indicated for the intermittent treatment of “OFF” episodes in adult patients with Parkinson's disease (PD) which are not sufficiently controlled by oral anti-Parkinson medication.

4.2. Posology and method of administration

Selection of patients suitable for Kynmobi

Patients selected for treatment with Kynmobi should be able to recognise the onset of their “OFF” symptoms.

If domperidone (an antiemetic) is considered medically warranted, then the lowest effective domperidone dose should be utilized and discontinued as soon as possible. Before the decision to initiate domperidone and apomorphine treatment, risk factors for QT interval prolongation in the individual patient should be carefully assessed to ensure that the benefit outweighs the risk (see section 4.5).

Kynmobi should be initiated in the controlled environment of a specialist clinic. The patient should be supervised by a trained healthcare professional experienced in the treatment of PD (eg. Neurologist).

Posology

Titration

The appropriate dose for each patient is established by incremental dosing schedules. The following schedule is recommended.

The initial dose of Kynmobi is 10 mg. Dose initiation should occur when the patient is having an “OFF” episode. If the patient tolerates the 10 mg dose, and responds adequately (satisfactory motor response within 30 minutes), the maintenance dose should be 10 mg. If the dose is tolerated but the response is insufficient, continue to titrate in 5 mg increments when the patient is having an “OFF” episode and assess response until an effective and tolerable dose is achieved up to a maximum of 30 mg per dose, up to five times a day. The minimal interval between doses is 2 hours, with no more than one dose of Kynmobi for an “OFF” episode.

Kynmobi is available as a treatment initiation pack, containing two sublingual films of each strength. The treatment initiation pack is usually used at the start of treatment to find an effective and tolerable dose. Depending on the patient response not all doses in this pack may be needed.

If an “ON” response is achieved, consider further up-titration as tolerated to achieve a better 'ON' response if clinically warranted.

Maintenance

Once the appropriate dose is determined Kynmobi may be taken, as needed, up to 30 mg up to five times a day. The minimal interval between doses is 2 hours. The total maximum daily dose is 150 mg.

The optimal dose of Kynmobi once established, remains relatively constant for each patient.

Special populations

Elderly

The elderly are well represented in the population of patients with PD and constitute a high proportion of those studied in clinical studies of Kynmobi. The management of elderly patients treated with Kynmobi has not differed from that of younger patients. There is a higher risk of postural hypotension in elderly patients, therefore particular caution should be exercised during the initiation of treatment.

Renal impairment

No dose adjustment is required for patients with mild or moderate renal impairment. There is no clinical experience in patients with severe renal impairment. The use of Kynmobi is not recommended in patients with severe and end-stage renal disease (ESRD) (CLcr <30 mL/min).

Hepatic impairment

There is no clinical experience in patients with hepatic impairment, therefore the use of Kynmobi is not recommended in these patients (see section 5.2.).

Paediatric population

There is no relevant use of Kynmobi in the paediatric population for the indication of Parkinson's disease and motor fluctuations.

Method of administration

For sublingual use.

The sublingual film should dissolve under the tongue. It must be administered whole, must not be cut, chewed, or swallowed.

4.3. Contraindications

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

- Co-administration with 5HT3 antagonists (e.g. granisetron, dolasetron, palonosetron and alosetron) (see section 4.5).

- Concomitant use with ondansetron (see section 4.5)

- Dementia;

- Psychotic disorder;

- Cankers or mouth sores

- Hepatic impairment

- Respiratory depression

4.4. Special warnings and precautions for use

Kynmobi should be given with caution to patients with pulmonary or cardiovascular disease and persons prone to nausea and vomiting.

Syncope, hypotension or orthostatic hypotension

Kynmobi may cause syncope, hypotension or orthostatic hypotension. Patients should be instructed to rise slowly after sitting or lying down after taking Kynmobi. Care should be exercised in patients with pre-existing postural hypotension. The hypotensive effects of Kynmobi may be increased by the concomitant use of antihypertensive medications, vasodilators (especially nitrates) and alcohol (see section 4.5).

Cardiac symptoms and other related disorders

The patient should be instructed to report possible cardiac symptoms including palpitations, syncope, or near-syncope. They should also report clinical changes that could lead to hypokalaemia, such as gastroenteritis or the initiation of diuretic therapy.

QTc prolongation and potential for proarrhythmic effects

Since apomorphine, especially at high doses, may have the potential for QT prolongation, caution should be exercised when treating patients at risk for torsades de pointes arrhythmia.

Palpitations and syncope may signal the occurrence of an episode of torsades de pointes. The risks and benefits of Kynmobi treatment should be considered prior to initiating treatment with Kynmobi in patients with risk factors for prolonged QTc.

Oropharyngeal adverse events

Kynmobi may cause oral mucosal irritation, including erythema in the oral cavity (tongue, lips, gingiva), oral soft tissue swelling (lips, tongue, gingiva), and infrequently systemic hypersensitivity, including facial flushing, increased lacrimation, swelling of the face, or urticaria. It is not known whether these events are related to apomorphine, or any other excipient. Kynmobi rechallenge is not recommended after discontinuation as oral adverse reactions may recur and be more severe than the initial reaction.

Neuropsychiatric disorders

Neuropsychiatric problems co-exist in many patients with advanced Parkinson's disease. There is evidence that for some patients, neuropsychiatric disturbances may be exacerbated by apomorphine. Special care should be exercised when apomorphine is used in these patients. Kynmobi should not be considered for patients with a major psychotic disorder unless the potential benefits outweigh the risks and uncertainties.

Sudden onset of sleep and somnolence

Apomorphine has been associated with somnolence and episodes of sudden sleep onset, particularly in patients with Parkinson's disease. Patients must be informed of this and advised to exercise caution whilst driving or operating machines during treatment with apomorphine. Patients who have experienced somnolence and/or an episode of sudden sleep onset must refrain from driving or operating machines (see section 4.7). Furthermore, a reduction of dose may be considered.

Impulse control disorders

Patients should be regularly monitored for the development of impulse control disorders. Patients and carers should be made aware that behavioural symptoms of impulse control disorders including pathological gambling, increased libido, hypersexuality, compulsive spending or buying, binge eating, and compulsive eating can occur in patients treated with dopamine agonists including apomorphine. Dose reduction/tapered discontinuation should be considered if such symptoms develop.

Dopamine dysregulation Syndrome (DDS)

This is an addictive disorder resulting in excessive use of the medicinal product seen in some patients treated with apomorphine. Before initiation of treatment, patients and caregivers should be warned of the potential risk of developing DDS.

Dopamine Agonist Withdrawal Syndrome (DAWS)

A drug withdrawal syndrome has been reported during tapering or after discontinuation of dopamine agonists. Withdrawal symptoms do not respond to levodopa, and may include apathy, anxiety, depression, fatigue, sweating, panic attacks, insomnia, irritability, and pain. The syndrome has been reported in patients who did or did not develop impulse control disorders. Prior to discontinuation, patients should be informed about potential withdrawal symptoms, and closely monitored during tapering and after discontinuation. In case of severe withdrawal symptoms, temporary re-administration of Kynmobi at the lowest effective dose to manage these symptoms may be considered.

Neuroleptic malignant syndrome

A symptom complex resembling neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, elevated serum creatine kinase, and autonomic instability) with no other obvious aetiology has been reported in association with rapid dose reduction, withdrawal of, or changes in antiparkinsonian therapy.

Haemolytic anaemia and thrombocytopenia

Haemolytic anaemia and thrombocytopenia have been reported in patients treated with apomorphine. Haematology tests should be undertaken at regular intervals as with levodopa, when given concomitantly with apomorphine.

Others

Apomorphine use is associated with increased incidences of penile erection. They may develop into prolonged painful erections in some patients. Severe priapism may require medical attention.

Excipients

Kynmobi contains sodium metabisulphite, which may rarely cause severe allergic reactions and bronchospasm. This medicinal product contains less than 1 mmol sodium (23 mg) per film, i.e. essentially “sodium-free”.

4.5. Interaction with other medicinal products and other forms of interaction

Concomitant use of 5HT3 antagonists, including antiemetics, is contraindicated. There have been reports of profound hypotension and loss of consciousness when subcutaneous apomorphine was administered with a 5HT3 antagonist (e.g. granisetron, dolasetron, palonosetron and alosetron) (see section 4.3).

Concomitant use of apomorphine with ondansetron may lead to severe hypotension and loss of consciousness and is therefore contraindicated (see section 4.3). Such effects might also occur with other 5-HT3 antagonists.

Patients selected for treatment with Kynmobi are almost certain to be taking concomitant medications for their Parkinson's disease. In the initial stages of therapy, the patient should be monitored for unusual side-effects or signs of potentiation of effect.

Neuroleptic medicinal products may have an antagonistic effect if used with apomorphine. Certain medications used to treat psychosis may exacerbate the symptoms of PD and may decrease the effectiveness of Kynmobi. Special care should be exercised when apomorphine is used in these patients. There is a potential interaction between clozapine and apomorphine, however clozapine may also be used to reduce the symptoms of neuropsychiatric complications.

When apomorphine is used in combination with domperidone, risk factors in the individual patient should be carefully assessed. This should be done before treatment initiation, and during treatment. Important risk factors include serious underlying heart conditions such as congestive cardiac failure, severe hepatic impairment or significant electrolyte disturbance. Also, medication possibly affecting electrolyte balance, CYP3A4 metabolism or QT interval should be assessed. Monitoring for an effect on the QTc interval is advisable. An ECG should be performed prior to treatment with domperidone, during the treatment initiation phase or as clinically indicated thereafter.

The hypotensive effects of Kynmobi may be increased by the concomitant use of alcohol, antihypertensive medications, vasodilators (especially nitrates) and cardiac active medicinal products even when co-administered with domperidone (see Section 4.4.). Patients should avoid alcohol when using Kynmobi. Monitor blood pressure for hypotension and orthostatic hypotension in patients taking Kynmobi with concomitant antihypertensive medications and/or vasodilators.

In in vitro studies using primary human hepatocyte cultures, apomorphine sulfate was shown to induce CYP1A2 in a concentration-dependent manner. Although induction results based on in vitro experiments are not necessarily predictive of response in vivo, caution needs to be exercised when Kynmobi at the maximum daily dosage is coadministered with drugs that depend on this enzyme for clearance.

The possible effects of apomorphine on the plasma concentrations of other medicinal products have not been studied. Therefore, caution is advised when combining apomorphine with other medicinal products, especially those with a narrow therapeutic range.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data from the use of apomorphine in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). Kynmobi is not recommended during pregnancy and in women of childbearing potential not using contraception.

Breast-feeding

It is unknown whether apomorphine /metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Kynmobi therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility

Apomorphine did not affect fertility in rats (see section 5.3).

4.7. Effects on ability to drive and use machines

Kynmobi has moderate influence on the ability to drive and use machines.

Apomorphine may cause dizziness, symptomatic orthostatism, and somnolence. Therefore, caution should be exercised when driving or using machines. Patients being treated with apomorphine and presenting with somnolence and/or sudden sleep episodes must be informed to refrain from driving or engaging in activities (e.g. operating machines) where impaired alertness may put themselves or others at risk of serious injury or death until such recurrent episodes and somnolence have resolved (see sections 4.4 and 4.8).

4.8. Undesirable effects

Summary of the safety profile

The most common adverse reactions reported in pooled analyses for two phase II and two phase III clinical studies were nausea (20.5%) during titration phase, and nausea (22.0%), somnolence (8.5%) and dizziness (5.9%) during maintenance phase. Oropharyngeal adverse events (swelling, oedema, pain, irritation, ulceration) were also commonly observed in the patients treated with Kynmobi.

Tabulated summary of adverse reactions

Adverse reactions are presented by system organ class and frequency in Table 1 below. Frequency categories are defined as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), unknown (cannot be estimated from the available data).

Table 1: Adverse Drug Reactions Based Upon Pooled Data from phase II and III studies

Very Common

Common

Uncommon

Rare

Unknown

Infections and infestations

Oral candidiasis

Gingivitis

Immune system disorders

Hypersensitivity

Metabolism and nutrition disorders

Decreased appetite

Psychiatric disorders

Hallucination

Anxiety

Confusional state

Obsessive- compulsive disorder

Psychotic disorder

Dopamine dysregulation syndrome

Agitation

Impulse control disorders:

Gambling disorder

Libido increased

Hypersexuality

Compulsive shopping

Binge eating

Aggression

Nervous system disorders

Somnolence

Dizziness

Dyskinesia

Headache

Syncope

Transient sedation#

Drooling

Sedation

Sudden onset of sleep

Eye disorders

Vision blurred

Lacrimation increased

Cardiac disorders

Cardiac arrest

Atrial fibrillation

Vascular disorders

Orthostatic hypotension

Hypotension

Hot flush

Hypertension

Flushing

Pallor

Respiratory, thoracic and mediastinal disorders

Yawning

Rhinorrhoea

Dyspnoea

Nasal congestion

Gastrointestinal disorders

Nausea

Oral soft tissue sign and symptoms*

Stomatitis and ulceration

Tongue conditions

Vomiting

Oral soft tissue swelling and oedema

Oral dryness and saliva altered

Oral soft tissue disorder

Retching

Gingival disorder, signs and symptoms

Angular cheilitis

Constipation

Dyspepsia

Eructation

Dysphagia

Tooth discoloration

Dental caries

Tongue polyp

Skin and subcutaneous tissue disorders

Rash

Hyperhidrosis

Cold sweat

Reproductive system and breast disorders

Spontaneous penile erection

General disorders and administration site conditions

Fatigue

Feeling abnormal

Feeling cold

Chills

Malaise

Asthenia

Feeling drunk

Oedema peripheral

Investigations

Heart rate decreased

Vitamin B6 increased

Electrocardiogram QT prolonged

Injury, poisoning, and procedural complications

Fall

Blood and lymphatic system disorders

Haemolytic anaemia and thrombocytopenia

Eosinophilia

Investigations

Positive coombs' test

Oropharyngeal Adverse Events (*)

As Kynmobi is administered sublingually, irritation, erythema, oedema, ulceration, pain, para/dysesthesias of oral cavity, teeth colour change, caries, changes in salivary gland secretion were observed in clinical studies. Oral soft tissue sign and symptoms* commonly observed in patients treated with Kynmobi, included oral mucosal erythema, hypoaesthesia oral, oral discomfort, oral mucosal blistering, and uncommonly oral contusion, lip exfoliation, oral dysaesthesia, oral hyperaesthesia, oral mucosal discolouration and oral mucosal exfoliation.

These events were mild to moderate in severity. For most subjects, events were tolerated or resolved either spontaneously or soon after discontinuation of treatment. Kynmobi rechallenge is not recommended after discontinuation as oral adverse reactions may recur and be more severe than the initial reaction.

Transient sedation (#)

Transient sedation with each dose of apomorphine hydrochloride at the start of therapy may occur; this usually resolves over the first few weeks.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

There is little clinical experience of overdose with apomorphine by the sublingual route of administration. Symptoms of overdose may be treated empirically as suggested below:

- excessive emesis may be treated with domperidone

- respiratory depression may be treated with naloxone

- hypotension: appropriate measures should be taken, e.g. raising the foot of the bed

- bradycardia may be treated with atropine