Apomorphine Drug Information

Apomorphine hydrochloride injection is indicated for the acute, intermittent treatment of hypomobility, "off" episodes ("end-of-dose wearing off" and unpredictable "on/off" episodes) in patients with advanced Parkinson's disease. Apomorphine hydrocloride inejction has been studied as an adjunct to other medications . Apomorphine hydrocloride injection is a non-ergoline dopamine agonist 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

Important

Administration Instructions Apomorphine hydrocloride is indicated for subcutaneous administration only and only by a multiple-dose APOKYN ® Pen with supplied cartridges. The APOKYN ® Pen is supplied separately by a different manufacturer. The initial dose and dose titrations should be performed by a healthcare provider.

Blood pressure and pulse should be measured in the supine and standing position before and after dosing. A caregiver or patient may administer apomorphine hydrocloride if a healthcare provider determines that it is appropriate. Instruct patients to follow the directions provided in the Patients Instructions For Use.

Because the APOKYN ® Pen has markings in milliliters (mL), the prescribed dose of apomorphine hydrocloride should be expressed in mL to avoid confusion. Visually inspect the apomorphine hydrocloride drug product through the viewing window for particulate matter and discoloration prior to administration. The solution should not be used if discolored (it should be colorless), or cloudy, or if foreign particles are present.

Rotate the injection site and use proper aseptic technique .

Premedication and

Concomitant Medication Because of the high incidence of nausea and vomiting with apomorphine hydrocloride treatment, an antiemetic, e.g., trimethobenzamide 300 mg three times a day, should be started 3 days prior to the initial dose of apomorphine hydrocloride. Treatment with trimethobenzamide should only be continued as long as necessary to control nausea and vomiting, and generally no longer than two months after initiation of treatment with apomorphine hydrocloride, as trimethobenzamide increases the incidence of somnolence, dizziness and falls in patients treated with apomorphine hydrocloride . Based on reports of profound hypotension and loss of consciousness when apomorphine was administered with ondansetron, the concomitant use of apomorphine with drugs of the 5HT 3 antagonist class including antiemetics (for example, ondansetron, granisetron, dolasetron, palonosetron) and alosetron are contraindicated.

Dosing Information

The recommended starting dose of apomorphine hydrocloride is 0.2 mL (2 mg). Titrate on the basis of effectiveness and tolerance, up to a maximum recommended dose of 0.6 mL (6 mg) . There is no evidence from controlled trials that doses greater than 0.6 mL (6 mg) gave an increased effect and therefore, individual doses above 0.6 mL (6 mg) are not recommended. The average frequency of dosing in the development program was 3 times per day. There is limited experience with single doses greater than 0.6 mL (6 mg), dosing more than 5 times per day and with total daily doses greater than 2 mL (20 mg). Begin dosing when patients are in an "off" state.

The initial dose should be a 0.2 mL (2 mg) test dose in a setting where medical personnel can closely monitor blood pressure and pulse. Both supine and standing blood pressure and pulse should be checked pre-dose and at 20 minutes, 40 minutes, and 60 minutes post-dose (and after 60 minutes, if there is significant hypotension at 60 minutes). Patients who develop clinically significant orthostatic hypotension in response to this test dose of apomorphine hydrocloride should not be considered candidates for treatment with apomorphine hydrocloride. If the patient tolerates the 0.2 mL (2 mg) dose, and responds adequately, the starting dose should be 0.2 mL (2 mg), used on an as needed basis to treat recurring "off" episodes.

If needed, the dose can be increased in 0.1 mL (1 mg) increments every few days on an outpatient basis. The general principle guiding subsequent dosing (described in detail below) is to determine that the patient needs and can tolerate a higher test dose, 0.3 mL or 0.4 mL (3 mg or 4 mg, respectively) under close medical supervision. A trial of outpatient dosing may follow (periodically assessing both efficacy and tolerability), using a dose 0.1 mL (1 mg) lower than the tolerated test dose.

If the patient tolerates the 0.2 mL (2 mg) test dose but does not respond adequately, a dose of 0.4 mL (4 mg) may be administered under medical supervision, at least 2 hours after the initial test dose, at the next observed "off" period. If the patient tolerates and responds to a test dose of 0.4 mL (4 mg), the initial maintenance dose should be 0.3 mL (3 mg) used on an as needed basis to treat recurring "off" episodes as an outpatient. If needed, the dose can be increased in 0.1 mL (1 mg) increments every few days on an outpatient basis.

If the patient does not tolerate a test dose of 0.4 mL (4 mg), a test dose of 0.3 mL (3 mg) may be administered during a separate "off" period under medical supervision, at least 2 hours after the previous dose. If the patient tolerates the 0.3 mL (3 mg) test dose, the initial maintenance dose should be 0.2 mL (2 mg) used on an as needed basis to treat existing "off" episodes. If needed, and the 0.2 mL (2 mg) dose is tolerated, the dose can be increased to 0.3 mL (3 mg) after a few days.

In such a patient, the dose should ordinarily not be increased to 0.4 mL (4 mg) on an outpatient basis.

Dosing in Patients with Renal Impairment For patients with mild and moderate

renal impairment, the test dose and starting dose should be reduced to 0.1 mL (1 mg) .

Re-treatment and Interruption in Therapy

If a single dose of apomorphine hydrocloride is ineffective for a particular "off" period, a second dose should not be given for that "off" episode. The efficacy of the safety of administering a second dose for a single "off" episode has not been studied systematically. Do not administer a repeat dose of apomorphine hydrocloride sooner than 2 hours after the last dose.

Patients who have an interruption in therapy of more than a week should be restarted on a 0.2 mL (2 mg) dose and gradually titrated to effect and tolerability.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the incidence of adverse reactions (number of unique patients experiencing an adverse reaction associated with treatment per total number of patients treated) observed in the clinical trials of a drug cannot be directly compared to the incidence of adverse reactions in the clinical trials of another drug and may not reflect the incidence of adverse reactions observed in practice. In placebo-controlled trials, most patients received only one subcutaneous dose of apomorphine hydrocloride. All patients received concomitant levodopa and 86% received a concomitant dopamine agonist.

All patients had some degree of spontaneously occurring periods of hypomobility ("off episodes") at baseline. The most common adverse reactions (apomorphine hydrocloride incidence at least 10% greater than placebo incidence) observed in a placebo-controlled trial were yawning, drowsiness/somnolence, dyskinesias, dizziness/postural hypotension, rhinorrhea, nausea and/or vomiting, hallucination/confusion, and edema/swelling of extremities. Table 1 presents the most common adverse reactions reported by apomorphine hydrocloride-naïve Parkinson's disease patients who were enrolled in a randomized placebo-controlled, parallel group trial and who were treated for up to 4 weeks (Study 1) . Individual apomorphine hydrocloride doses in this trial ranged from 2 mg to 10 mg, and were titrated to achieve tolerability and control of symptoms.

Table 1: Adverse Reactions Occurring in Two or More Apomorphine Hydrocloride-Treated Patients in Study 1 Apomorphine Hydrocloride (n = 20) PLACEBO (n = 9) % % Yawning 40 0 Dyskinesias 35 11 Drowsiness or Somnolence 35 0 Nausea and/or Vomiting 30 11 Dizziness or Postural Hypotension 20 0 Rhinorrhea 20 0 Chest Pain/Pressure/Angina 15 11 Hallucination or Confusion 10 0 Edema/Swelling of Extremities 10 0 Other Adverse Reactions Injection Site Reactions Patients treated with apomorphine hydrocloride subcutaneous injections during clinical studies, 26% of patients had injection site reactions, including bruising (16%), granuloma (4%), and pruritus (2%). In addition to those in Table 1, the most common adverse reactions in pooled apomorphine hydrocloride trials (occurring in at least 5% of the patients) in descending order were injection site reaction, fall, arthralgia, insomnia, headache, depression, urinary tract infection, anxiety, congestive heart failure, limb pain, back pain, Parkinson's disease aggravated, pneumonia, confusion, sweating increased, dyspnea, fatigue, ecchymosis, constipation, diarrhea, weakness, and dehydration.

Antihypertensive Medications and Vasodilators

In clinical studies, the following adverse events were experienced more commonly in patients receiving concomitant antihypertensive medications or vasodilators (n=94) than in patients not receiving these medications (n=456): hypotension (10% vs 4%) , myocardial infarction (3% vs 1%), serious pneumonia (5% vs 3%), serious falls (9% vs 3%), and bone and joint injuries (6% vs 2%). Some of the events may be related to the increased incidence of hypotension in patients receiving concomitant antihypertensive medications or vasodilators . Concomitant administration of 0.4 mg sublingual nitroglycerin with apomorphine hydrocloride in healthy subjects causes greater decreases in blood pressure compared to apomorphine hydrocloride alone. When nitroglycerin and apomorphine hydrocloride were concomitantly administered to healthy subjects, the mean largest decrease (the mean of each subject's largest drop in blood pressure measured within the 6-hour period following administration of apomorphine hydrocloride) in supine systolic and diastolic blood pressure (measured over 6 hours) was 9.7 mm Hg and 9.3 mm Hg, respectively. The mean largest decrease in standing systolic and diastolic blood pressure was 14.3 mm Hg and 13.5 mm Hg, respectively.

Some individuals experienced very large decreases in standing systolic and diastolic blood pressure, up to a maximum decrease of 65 mm Hg and 43 mm Hg, respectively. In comparison, the mean largest decrease in supine systolic and diastolic blood pressure when apomorphine hydrocloride was administered alone was 6.1 mm Hg and 7.3 mm Hg, respectively, and in standing systolic and diastolic blood pressure was 6.7 mm Hg and 8.4 mm Hg, respectively. Patients taking apomorphine hydrocloride should lie down before and after taking sublingual nitroglycerin.

Alcohol

Concomitant administration of high dose (0.6 g/kg) or low dose (0.3 g/kg) ethanol with apomorphine hydrocloride in healthy subjects causes greater decreases in blood pressure compared to apomorphine hydrocloride alone. When high dose ethanol and apomorphine hydrocloride were concomitantly administered to healthy subjects, the mean largest decrease (the mean of each subject's largest drop in blood pressure measured within the 6-hour period following administration of apomorphine hydrocloride) for supine systolic and diastolic blood pressure was 9.1 mm Hg and 10.5 mm Hg, respectively. The mean largest standing systolic and diastolic blood pressure decrease was 11.3 mm Hg and 12.6 mm Hg, respectively.

In some individuals, the decrease was as high as 61 mm Hg and 51 mm Hg, respectively, for standing systolic and diastolic blood pressure. When low dose ethanol and apomorphine hydrocloride were concomitantly administered, the mean largest decrease in supine systolic and diastolic blood pressure was 10.2 mm Hg and 9.9 mm Hg, respectively. The mean largest decrease in standing systolic and diastolic blood pressure was 8.4 mm Hg and 7.1 mm Hg, respectively.

In comparison, the mean largest decrease in supine systolic and diastolic blood pressure when apomorphine hydrocloride was administered alone was 6.1 mm Hg and 7.3 mm Hg, respectively, and in standing systolic and diastolic blood pressure was 6.7 mm Hg 8.4 mm Hg, respectively. Patients should avoid drinking alcohol after using apomorphine hydrocloride.

Dopamine Antagonists

Since apomorphine hydrocloride is a dopamine agonist, it is possible that concomitant use of dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of apomorphine hydrocloride. Patients with major psychotic disorders, treated with neuroleptics, should be treated with dopamine agonists only if the potential benefits outweigh the risks.

Drugs Prolonging the QT/QTc Interval Caution should be exercised when prescribing apomorphine

hydrocloride concomitantly with drugs that prolong the QT/QTc interval .

Pregnancy Risk Summary There are no adequate data on the developmental risk associated with use of apomorphine hydrocloride in pregnant women. In animal reproduction studies, apomorphine had adverse developmental effects in rats (increased neonatal deaths) and rabbits (increased incidence of malformation) when administered during pregnancy at clinically relevant doses. These doses were also associated with maternal toxicity . In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

The background risk of major birth defects and miscarriage for the indicated population is unknown. Data Animal Data No adverse developmental effects were observed when apomorphine (0.3, 1, or 3 mg/kg/day) was administered by subcutaneous injection to pregnant rats throughout organogenesis; the highest dose tested is 1.5 times the maximum recommended human dose (MRHD) of 20 mg/day on a mg/m 2 basis. Administration of apomorphine (0.3, 1, or 3 mg/kg/day) by subcutaneous injection to pregnant rabbits throughout organogenesis resulted in an increased incidence of malformations of the heart and/or great vessels at the mid and high doses; maternal toxicity was observed at the highest dose tested.

The no-effect dose for adverse developmental effects is less than the MRHD on a mg/m 2 basis. Apomorphine (0.3, 1, or 3 mg/kg/day), administered by subcutaneous injection to females throughout gestation and lactation, resulted in increased offspring mortality at the highest dose tested, which was associated with maternal toxicity. There were no effects on developmental parameters or reproductive performance in surviving offspring.

The no-effect dose for developmental toxicity (1 mg/kg/day) is less than the MRHD on a mg/m 2 basis.

Pediatric Use Safety and effectiveness in pediatric patients have not been established.

Apomorphine hydrocloride is contraindicated in patients: Using concomitant drugs of the 5HT 3 antagonist class including antiemetics (e.g., ondansetron, granisetron, dolasetron, palonosetron) and alosetron . There have been reports of profound hypotension and loss of consciousness when apomorphine hydrocloride was administered with ondansetron. With hypersensitivity/allergic reaction to apomorphine or to any of the excipients of apomorphine hydrocloride, including a sulfite (i.e., sodium metabisulfite). Angioedema or anaphylaxis may occur. Concomitant use of apomorphine hydrocloride with 5HT 3 antagonists, including antiemetics (e.g., ondansetron, granisetron, dolasetron, palonosetron) and alosetron, is contraindicated Hypersensitivity to apomorphine, its excipients or sodium metabisulfite

A 62-year-old man accidentally injected 25 mg of apomorphine hydrocloride subcutaneously. After 3 minutes, the patient felt nauseated and lost consciousness for 20 minutes. Afterwards, he was alert with a heart rate 40/minute and a supine blood pressure of 90/50. He recovered completely within an hour.