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Help Them Get Up and Go With APOKYN ^®

APOKYN (apomorphine hydrochloride injection) is the first and only prescription medicine that reverses off episodes associated with advancing Parkinson's disease (PD).

About APOKYN
About Off Episodes
About APOKYN Clinical Trials
APOKYN Safety
APOKYN Dosing
How to Initiate APOKYN
How to Obtain APOKYN
The APOKYN Circle of Care™

About APOKYN
APOKYN is indicated for the acute, intermittent treatment of hypomobility, off episodes (end-of-dose wearing-off and unpredictable on-off episodes) associated with advanced Parkinson's disease. APOKYN has been studied as an adjunct to other PD medications.

End-of-dose wearing-off episodes

• Morning off episodes, or early-morning akinesia, as medication levels drop during the night^1-3
• Predictable wearing-off episodes as patients feel the effects of their medications waning between doses^1-3

Unpredictable off episodes

• Delayed on episodes or dose failure as medications take longer to take effect or fail to act at all^1,3
• Unpredictable on-off episodes during which patients may experience abrupt shifts between on and off states despite optimal medication^1,2,4

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About Off Episodes
The prevalence of off episodes is significant and increases with the length of time the patient is on levodopa therapy:

Up to 50%	Approximately 70%	More than 90%
of PD patients treated with levodopa for 5 years or more experienced off episodes.5	of PD patients treated with levodopa for 9 years or more experienced off episodes.5,6	of young-onset patients (who develop PD symptoms before the age of 40 years) treated with levodopa for 5 years developed off episodes.7-9

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About APOKYN Clinical Trials

Who were the patients? In APOKYN clinical trials, 75% of patients were classified as Stage II or III on the Hoehn and Yahr scale, and 22% of the patients were Stage IV.10

Hoehn & Yahr Stage % (n)10 Description12
II 26.2 (142) III 49.0 (266) IV 21.9 (119)	Bilateral involvement but no postural abnormalities     Bilateral involvement with mild postural imbalance; patient leads independent life     Bilateral involvement with postural instability; patient requires substantial help

What were the efficacy results?
In one of the clinical studies involving 20 patients, 90% of patients achieved a therapeutic response within 20 minutes that was approximately equivalent to their usual response to levodopa.¹³

In the 4-week outpatient portion of that study, patients reported that APOKYN successfully reversed 95% of off episodes.¹³

Mean Percentage of Off Episodes Reversed Over 4 Weeks¹³



Prospective, randomized, double-blind, placebo-controlled, parallel-group, two-phase trial was conducted to assess the safety and efficacy of subcutaneous apomorphine for PD patients with motor fluctuations under both inpatient and outpatient conditions. A total of 29 advanced PD patients with 2 or more hours of off time despite aggressive oral therapy were studied; 25 patients completed the outpatient study (APOKYN, n=17; placebo, n=8). Mean dose for the apomorphine-treated group was 0.54±0.05 mL.¹³

In a second trial, APOKYN delivered significant improvement in mobility within 20 minutes vs placebo.¹¹


Mean Reduction in UPDRS* III Motor Scores¹¹


* UPDRS: Unified Parkinson's Disease Rating Scale

Prospective, randomized, placebo-controlled, double-blind, parallel-group, multicenter study in patients with advanced PD who experienced off episodes despite optimal oral therapy. Patients used APOKYN for acute, intermittent therapy for ≥3 months prior to the study. Patients were randomized to receive a single dose of APOKYN or placebo at the typically effective dose, or 0.2 mL higher than that dose, in response to an off episode that occurred ≥1 hour after typical morning dose of oral PD therapy. Mean dose for the apomorphine-treated group was 0.45 mL.¹¹

Adapted from Reference 11.

• Significant mean reduction of 24.2 points with APOKYN vs 7.4 points with placebo on UPDRS III Motor Scores at 20 minutes (P<.0001)¹¹

• Decreasing UPDRS scores equal improving motor function

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APOKYN Safety
Contraindications: APOKYN is contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients (notably metabisulfite). Concomitant use of APOKYN with 5HT₃ antagonists is contraindicated based on reports of profound hypotension and loss of consciousness when apomorphine was administered with ondansetron.

Nausea and Vomiting: At recommended doses of apomorphine, severe nausea and vomiting can be expected. Therefore, trimethobenzamide hydrochloride should be started 3 days prior to the initial dose of APOKYN and continued for at least 2 months. In clinical trials, 50% of patients (262/522) discontinued trimethobenzamide hydrochloride after 2 months of APOKYN.

Symptomatic Hypotension: Dopamine agonists, including APOKYN, can cause hypotension, orthostatic hypotension, and syncope. These adverse events occurred with initial dosing and long-term treatment. Whether hypotension contributes to other significant events seen (eg, falls) is unknown.

SC Injection: APOKYN should be administered by subcutaneous injection, NOT intravenously, because serious adverse events may occur.

Cardiac Effects: QT Prolongation—Caution is recommended when administering APOKYN to patients with increased risk of QT prolongation, such as those with hypokalemia, hypomagnesemia, bradycardia, or a genetic predisposition, or who use other drugs that prolong the QT/QTc interval. Coronary Events—APOKYN reduces resting systolic and diastolic blood pressure and has the potential to exacerbate coronary (and cerebral) ischemia. Therefore, exercise caution when prescribing APOKYN for patients with known cardiovascular and cerebrovascular disease.

Falling Asleep During Activities of Daily Living (ADL): There have been literature reports of patients treated with apomorphine subcutaneous injections who suddenly fell asleep while engaged in ADL. Patients should be advised not to drive or participate in potentially dangerous activities until it is known how APOKYN affects them. Patients should be continually reassessed for daytime drowsiness or sleepiness.

Adverse Events: Injection site reactions, including bruising, granuloma, and pruritus, have been reported. The most common adverse events seen in controlled trials were yawning, dyskinesias, nausea and/or vomiting, somnolence, dizziness, rhinorrhea, hallucinations, edema, chest pain, increased sweating, flushing, and pallor.

Treatment-emergent adverse events (incidence greater than or equal to 10%) and associated rate of treatment discontinuation during open-label, long-term use (N=550)

Adverse Event Incidence* Patients Who Discontinued Treatment* Nausea 31% 3% Falls 30% 1% Dyskinesias 24% 2% Dizziness 19% 2% Somnolence 18% 2% Yawning 16% <1% Injection site bruising 16% <1% Hallucinations 14% 1% Vomiting 11% 2% Arthralgia 10% <1%

*Among all treated patients (N=550)

Please see full Prescribing Information.

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APOKYN Dosing

• The dose of APOKYN must be titrated on the basis of effectiveness and tolerance, starting at 0.2 mL and up to a maximum recommended dose of 0.6 mL
• In the apomorphine development program, most patients studied responded to 0.3 to 0.6 mL
• APOKYN is used prn up to 5 times per day
• In clinical studies, APOKYN was used on average 3 times per day¹³
• APOKYN should be titrated to a levodopa-equivalent efficacy level
• In clinical studies, levodopa dosage was not predictive of apomorphine dose requirements¹³
• APOKYN should not be initiated without use of the concomitant antiemetic Tigan^® (trimethobenzamide HCl)*
• In the apomorphine development program, 50% of patients were able to discontinue trimethobenzamide on average 2 months after starting APOKYN

*Tigan (trimethobenzamide hydrochloride) is a registered trademark of Monarch Pharmaceuticals, Inc.

Important considerations

• The concomitant use of apomorphine with drugs of the 5HT₃ antagonist class (for example, ondansetron, granisetron, dolasetron, palonosetron, and alosetron) is contraindicated
• Apomorphine should not be administered intravenously

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How to Initiate APOKYN

	Start patient on Tigan (trimethobenzamide HCl)* 3 days before initiating APOKYN Tigan may lessen the symptoms of nausea and vomiting that are associated with APOKYN use Patients should continue to receive Tigan at least during the first 2 months of therapy
	Confirm that the patient is in an off episode Monitor supine and standing blood pressure predose
	Administer 0.2-mL test dose Monitor supine and standing blood pressure at 20, 40, and 60 minutes postdose Patients who develop clinically significant orthostatic hypotension to the 0.2-mL test dose should not be considered candidates for treatment If patient tolerates and responds to 0.2-mL test dose, the starting dose should be 0.2 mL, used as needed Starting dose may be increased by 0.1-mL increments every few days on an outpatient basis if needed Exercise caution in patients with hepatic impairment due to the increased Cmax and AUC in these patients. The test dose and subsequent starting dose for patients with mild to moderate renal impairment should be reduced to 0.1 mL

Beyond this, the general principle guiding dosing is to determine a dose (0.3 or 0.4 mL) that the patient will tolerate as a test dose under monitored conditions, and then begin an outpatient dosing trial (periodically assessing both efficacy and tolerability) using a dose 0.1 mL lower than the tolerated test dose.

For more detailed dosing instructions, click here.

*Tigan (trimethobenzamide hydrochloride) is a registered trademark of Monarch Pharmaceuticals, Inc.

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How to Obtain APOKYN

If you are interested in obtaining APOKYN for your patients or you have questions about APOKYN, please call the toll-free APOKYN Call Center at 1‑877‑7APOKYN (1‑877‑727‑6596), Option 2, or speak with your Vernalis CNS Specialist. APOKYN Call Center services are offered Monday through Friday, 8 AM to 8 PM Eastern Time.

APOKYN is not available at retail pharmacies. APOKYN is only available from specialty pharmacy providers (SPPs), which will supply APOKYN, the APOKYN pen, and other related accessories. Specialty pharmacy providers also offer a variety of support services for patients, care partners, and your staff.

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The APOKYN Circle of Care™

The APOKYN Circle of Care is a unique program designed to assist you, your staff, your patients, and their care partners in the use of APOKYN for the treatment of off episodes associated with advancing Parkinson's disease.

For more information, call 1‑877‑7APOKYN (1‑877‑727‑6596), Option 2.

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References

1. Chen JJ, Obering C. A review of intermittent subcutaneous apomorphine injections for the rescue management of motor fluctuations associated with advanced Parkinson's disease. Clin Ther. 2005;27:1710-1724.
2. Poewe WH. Clinical aspects of motor fluctuations in Parkinson's disease. Neurology. 1994;44(suppl 6):S6-S9.
3. Swope DM. Rapid treatment of "wearing off" in Parkinson's disease. Neurology. 2004;62(suppl 4):S27-S31.
4. Dewey RB Jr. Management of motor complications in Parkinson's disease. Neurology. 2004;62(suppl 4):S3-S7.
5. Ahlskog JE, Muenter MD. Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature. Mov Disord. 2001;16:448-458.
6. Nutt JG. Motor fluctuations and dyskinesia. In: Factor SA, Weiner WJ, eds. Parkinson's Disease: Diagnosis and Medical Management. New York, NY: Demos Medical Publishing; 2002:445-453.
7. Quinn N, Critchley P, Marsden CD. Young onset Parkinson's disease. Mov Disord. 1987;2:73-91.
8. Schrag A, Ben-Shlomo Y, Brown R, Marsden CD, Quinn N. Young-onset Parkinson's disease revisited—clinical features, natural history, and mortality. Mov Disord. 1998;13:885-894.
9. Kostic V, Przedborski S, Flaster E, Sternic N. Early development of levodopa-induced dyskinesias and response fluctuations in young-onset Parkinson's disease. Neurology. 1991;41:202-205.
10. Data on file, Clinical Study Report APO401. Morristown, NJ: Vernalis Pharmaceuticals Inc.
11. Pfeiffer RF, Gutmann L, Hull KL Jr, Bottini PB, Sherry JH, and the APO302 Study Investigators. Continued efficacy and safety of subcutaneous apomorphine in patients with advanced Parkinson's disease. Parkinsonism Relat Disord. 2007;13:93-100.
12. Data on file, Clinical Study Report APO302. Morristown, NJ: Vernalis Pharmaceuticals Inc.
13. Dewey RB Jr, Hutton JT, LeWitt PA, Factor SA. A randomized, double-blind, placebo-controlled trial of subcutaneously injected apomorphine for parkinsonian off-state events. Arch Neurol. 2001;58:1385-1392.