APOMINE™ INJECTION - Medsafe

1 Data Sheet New Zealand 1 Version . apomine INJECTION NAME apomine In jection DESCRIPTION apomine In jection is a sterile soluti on containing 10 mg/m L of apomorphine hydrochloride in Water for In jections . Sodium metabisulfit e 1 mg/mL is included in the formulati on as an antioxidant. The pH of the INJECTION is to The CAS registry number of apomorphine hydrochloride, anhydrous is 41372-20-7 and th e chemical structure is shown below: HO HO H HCl Me N PHARMACOLOGY apomorphine is a directl y acti ng dopamine receptor agonist, structurally related to dopamine. apomorphine has high in vitr o binding affinity for the dopamine D4 and D5 receptor (Ki:4 and 14 nM respecti vely), moderate affinity (Ki: 26 to 130 nM) for the dopamine D2 and D3, adre nergic 1D, 2B, 2C recepto rs, serotonin 5HT1A, 5HT2A, 5HT2B , and 5HT2C receptors and low affi nity for the dopamine D1 recepto r (Ki: 370 nM).

2 apomorphine exhibits no affi nity fo r the adrenergic 1 and 2 or hist amine H1 recepto rs. The effect of apomorphine as an anti parkinsonian agent is belie ved to be the result of dire ct stimulation of postsynaptic D2 dopamine recepto rs, but stimulati on of presynaptic D2 dopamine recepto rs and antagonism of 2 adrenergic receptors may also be important. apomorphine reduces the tr emor, rigidity and bradykinesia in patients receiving levodopa. apomorphine induces vomiting by direct stimulation of the medullary chemoreceptor trigger zone. The peripheral pharmacokinetics of apomorphine have been stu died following subcutaneous injecti on, subcutaneous infusion and intravenous infusion.

3 The peak plasma concentrati on occurs as early as three minute s follo wing subcutaneous bolus INJECTION . The distribution half-lif e was found to be five minutes while the elimination half-life (t1/2) was found to be 33 minute s. The volume of distr ibuti on, plasma clearance and half life were similar for subcutaneous injecti on, subcutaneous infusion and intr avenous inf usion. The rapid and complete absorption fr om s ubcutaneous tissues and rapid clearance is believed to c orrelate w ith the rapid o nset and brief duratio n of actio n respecti vely. Antiparkinsonian effects are observed with in five minutes following subcutaneous bolus administr ation.

4 apomorphine reaches a concentrati on in the brai n which is up to eight ti mes higher than that in plasma, due to high lip id solubility which allows rapid equili brati on between blood and tissue compartments. Following intramuscular or subcutaneous administration apomorphine is reported to be well absorbed, and to be meta bolis ed in the liver. Routes of meta bolism in humans include sulfation, N-demethylation, glucuronidation and oxidatio n to norapomorphine by CYP 2B6, CYP 2C8 Data Sheet New Zealand 2 Version and CYP 3A4. The major metabolite in humans after subli ngual administratio n was apomorphine sulphate.

5 INDICATIONS apomine INJECTION is indicated to reduce th e number and severi ty of off phases in patients with Parkinson s Disease severely disabled by motor fl uctuations refracto ry to conventional therapy. Initiatio n of therapy with apomine In jection should be undertaken in a specialist unit in a hospital setti ng. Conventional th erapy should be conti nued during on phases. CONTRAINDICATIONS apomine In jection is contraindicated in patients with a known hypersensiti vity or allergy to apomorphine , morphine or chemically-related products . apomine Inj ection should not be administered to patients with pre-existing neuropsychiatric problems or dementias due to either path ological processes, eg.

6 Alzheimer s disease, or to patie nts whose on response to l-dopa is marred by severe dyskinesia, hypotonia or psychotoxicity . apomine In jection is also contr aindicated in p atients w ith inadequate renal o r li ver functi on, unstable coronary v ascular di sease, c erebrovascular disease, respiratory depression or CNS depression. apomine In jecti on is also contr aindicated in patients with a known hypersensitivity to sodium meta bisulfite. PRECAUTIONS For Subcutaneous Use Only (see Adverse Effects). Pati ents sensitive to morphine or its derivativ es may be sensitive to apomine Inj ection. apomine Inj ection should therefore not be administered to patients with a known hypersensiti vity or all ergy to apomorphine , morphine or chemically-related compounds (See Contraindications).

7 apomine INJECTION contains sodium metabisulfit e which may cause all ergi c-ty pe reacti ons, including anaphylactic symptoms and life-th reate ning or less severe asthmatic episodes in suscepti ble people. In patients with cardiac decompensation or cerebrovascular disease, vomiting may cause an increase in blood pressure th at may lead to haemorrhage and vascular accidents. apomine In jection is th erefore contraindicated in these patients (See Contraindicati ons). Caution should be used in administe ring apomine INJECTION to pati ents with a predispositi on to nausea and vomiti ng. apomine Inj ectio n may cause an increased ri sk of persistent v omiting.

8 A ris k- benefit assessment should be considered in th ese pati ents. Caution is also recommended in debilitated or geriatr ic patients, since they may show an increased suscepti bility or be more sensitive to the respiratory depressant effects of apomine Inj ecti on. Since apomorphine , especially at high doses, may have the potentia l for QT prolongati on, cauti on should be exercised when treating patients at ris k for Torsades de pointes arrhyth mia. Compulsive behaviour Patients should be regularly monitored for th e development of impulse contr ol disorders. Patients and carers should be made aware th at behavioural symptoms of impulse control disorders including path ological gambling, increased libido, hypersexuality , compulsive spending or buying, binge eati ng and compulsive eati ng can occur in pati ents tr eated with dopamine agonists including apomine Inj ection.

9 Dose reductio n/ta pered discontinuation should be considered if such symptoms develop. apomorphine has been associated with somnolence, and other dopamine agonists can be associated with s udden s leep onset episodes, parti cularly i n patients w ith Parkinson s disease. Patie nts must b e informed of th is and advised to exercise caution while drivi ng or operating machines during tr eatment Data Sheet New Zealand 3 Version with apomorphine . Patients who have experienced somnolence must refrain from driving or operati ng machines. Furthermore a reducti on of dosage or te rmination of therapy may be considered. apomine Inj ection should be used with caution in patients with endocrine, renal, pulmonary or cardiovascular disease.

10 Periodic evaluation of hepatic, haemopoietic, renal and cardiovascular function is advised. Patients with severe renal insufficiency may require the dosing interval for domperidone to be less frequent, see Dosage and Administrati on - Pretreatm ent. EFFECTS ON ABILIT Y TO DRIV E AND USE MACHINES Patients being treated with apomorphine and presentin g with somnolence must be informed to refrain from d riving or e ngaging in acti viti es w here impaired alertness m ay p ut th emselves or others at risk o f serious injury or death ( . operating machines) unless patie nts have overcome such experiences of somnolence (see above).