Pharmacology Update

Apomorphine Injection (ApokynTM)

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD

The FDA has approved an injectable drug for treating Parkinson’s patients during hypomobility periods known as off periods. In this state, patients become immobile or unable to perform normal daily activities. Apomorphine is the first drug to be approved for this use and is marketed by Mylan Bertek Pharmaceuticals as Apokyn. It has been used in Europe for more than a decade for intractable off periods in Parkinson’s patients.1

Indications

Apomorphine is indicated for the acute, intermittent treatment of hypomotility, "off" episodes (end-of-dose wearing off and unpredictable on/off episodes) associated with advanced Parkinson’s disease.2

Dosage

The dose of apomorphine must be titrated on the basis of effectiveness and tolerance. The starting dose is 0.2 mL (2 mg) given subcutaneously and up to a maximum of 0.6 mL (6 mg). After the first (test) dose, both supine and standing blood pressure should be checked at 20, 40, and 60 minutes postdose. Patients with mild and moderate hepatic impairment should use a test dose of 0.1 mL (1 mg). If there is no clinically significant orthostatic hypotension and the patient responds, this will be the starting dose. If needed, an increase of 0.1 mL every few days is reasonable. Patients with significant orthostatic hypotension are not candidates for apomorphine.2

Apomorphine is supplied as 2 mL glass ampule and 3 mL cartridge. The cartridge is intended for multiple uses with an injector pen. The concentration is 10 mg/mL.

Potential Advantages

Apomorphine has been shown to be effective in reversing off-state in patients with off-time despite aggressive oral therapy.2,3 Effectiveness was assessed by change from baseline for Unified Parkinson Disease Rating Scale motor score (Part III).

Potential Disadvantages

Apomorphine causes severe nausea and vomiting and must be taken with an antiemetic such as trimethobenzamide. The use of 5HT3 antagonists is contraindicated due to reports of severe hypotension and loss of consciousness.2 Common side effects associated with apomorphine include yawning (40%), dyskinesias (35%), drowsiness, or somnolence (35%), nausea and/or vomiting (30%), injection site reactions (26%), dizziness or postural hypotension (20%), rhinorrhea (20%), chest pain/pressure or angina (15%), hallucinations or confusion (10%), and edema (10%).2 Caution should be exercise in patients at risk for QT prolongation as apomorphine may prolong QT interval. Other drugs that lower blood pressure may enhance the hypotensive effect of apomorphine.

Comments

Apomorphine is a dopamine receptor agonist. Due to significant first-pass metabolism, the drug the drug cannot be given orally. Given subcutaneously it has a rapid onset of action—generally within 10 minutes with benefit lasting up to 2 hours (usually 60-90 minutes).1,4 While the drug has been used in Europe for decades, approval in the United States was based on 3 randomized, controlled trials involving 108 patients.2 In one trial, patients were naïve to apomorphine while in the other two, patients used the drug for at least 3 months. Significant improvements were observed with apomorphine compared to placebo and the magnitude of effect appeared to be comparable to that of a usual dose of levodopa.1,2,4 The persistence of benefit has been reported in other studies to be as long as 5 years although the frequency of injection increased.1,5 Co-administration of apomorphine and levodopa results in increase duration of effect but not in the maximal response to levodopa.2 The need for concomitant antiemetic prophylaxis may decrease over time.1 Apomorphine is associated with a variety of side effects, potential drug interactions, and generally must be taken with an antiemetic.

The cost of apomorphine was not available at the time of this review. Apomorphine is expected to be available through a few selected specialty pharmacies to ensure proper patient/caregiver education and training.

Clinical Implications

Apomorphine offers an effective treatment in advanced Parkinson patients with recurring off periods. It is estimated that this affects about 10% of Parkinson patients who are unresponsive to standard therapy.

Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; Asst. Clinical Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Both are Associate Editors of Internal Medicine Alert.

References

1. Factor SA. Neurology. 2004;62(6 suppl 4):S12-S17.

2. Apokyn Product Information. Mylan Bertek Pharmaceuticals. April 2004.

3. Dewey, RB et al. Arch Neurol. 2001;58(9):1385-92.

4. Stacy M. Neurology. 2004; 62(6 suppl 4):S18-S21.

5. Pietz, K. et al. J Neurol Neurosurg Psychiatry. 1998;65(5):709-716.