apomorphine hydrocloride

1 INDICATIONS AND USAGE 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 [see Clinical Studies (14) ] . 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 ( 1 )

2 DOSAGE AND ADMINISTRATION For subcutaneous use only ( 2.1 ) Always express apomorphine hydrocloride dose in mL to minimize dosing errors ( 2.1 ) The starting dose of apomorphine hydrocloride is 0.2 mL (2 mg); give the first dose under medical supervision; titrate the dose to effect and tolerance; the maximum recommended dose is 0.6 mL ( 2.3 ) Treatment with a concomitant antiemetic, e.g., trimethobenzamide, is recommended, starting 3 days prior to the first 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 ( 2.2 , 5.2 , 6.1 , 17 ) Apomorphine hydrocloride doses must be separated by at least 2 hours ( 2.5 ) Renal impairment: reduce test dose, and reduce starting dose to 0.1 mL (1 mg) ( 2.4 , 8.6 , 12.3 ) 2.1 Important Administration Instructions Apomorphine hydrocloride is indicated for subcutaneous administration only [see Warnings and Precautions (5.1) ] 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 [see How Supplied/Storage and Handling (16) and Patient Counseling Information (17) ] . 2.2 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 [see Warnings and Precautions (5.2) ]. 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 [see Warnings and Precautions (5.2) ] . 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 [see Contraindications (4) ]. 2.3 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) [see Clinical Studies (14) ] . 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 pu…

5 WARNINGS AND PRECAUTIONS For subcutaneous use only; thrombus formation and pulmonary embolism have followed intravenous administration of apomorphine hydrocloride ( 5.1 ) Falling asleep during activities of daily living, and daytime somnolence may occur ( 5.3 ) Syncope and hypotension/orthostatic hypotension may occur ( 5.4 ) Falls may occur, or increase ( 5.5 ) May cause hallucinations and psychotic-like behavior ( 5.6 ) May cause dyskinesia or exacerbate pre-existing dyskinesia ( 5.7 ) May cause problems with impulse control and impulsive behaviors ( 5.8 ) May cause coronary events ( 5.9 ) May prolong QTc and cause torsades de pointes or sudden death ( 5.10 ) 5.1 Serious Adverse Reactions After Intravenous Administration Following intravenous administration of apomorphine hydrocloride, serious adverse reactions including thrombus formation and pulmonary embolism due to intravenous crystallization of apomorphine have occurred. Consequently, apomorphine hydrocloride should not be administered intravenously. 5.2 Nausea and Vomiting Apomorphine hydrocloride causes severe nausea and vomiting when it is administered at recommended doses. Because of this, in domestic clinical studies, 98% of all patients were pre-medicated with trimethobenzamide, an antiemetic, for three days prior to study enrollment, and were then encouraged to continue trimethobenzamide for at least 6 weeks. Even with the use of concomitant trimethobenzamide in clinical studies, 31% and 11% of the apomorphine hydrocloride-treated patients had nausea and vomiting, respectively, and 3% and 2% of the patients discontinued apomorphine hydrocloride due to nausea and vomiting, respectively. Among 522 patients treated, 262 (50%) discontinued trimethobenzamide while continuing apomorphine hydrocloride. The average time to discontinuation of trimethobenzamide was about 2 months (range: 1 day to 33 months). For the 262 patients who discontinued trimethobenzamide, 249 patients continued apomorphine without trimethobenzamide for a duration of follow-up that averaged 1 year (range: 0 years to 3 years). The effect of trimethobenzamide on reducing nausea and vomiting during treatment with apomorphine hydrocloride was evaluated in a 12-week, placebo-controlled study in 194 patients. The study suggests that trimethobenzamide reduces the incidence of nausea and vomiting during the first 4 weeks of apomorphine hydrocloride treatment (incidence of nausea and vomiting 43% on trimethobenzamide vs. 59% on placebo). However, over the 12-week period, compared with placebo, patients treated with trimethobenzamide had a greater incidence of somnolence (19% for trimethobenzamide vs. 12% for placebo), dizziness (14% for trimethobenzamide vs. 8% for placebo), and falls (8% for trimethobenzamide vs. 1% for placebo). Therefore, the benefit of treatment with trimethobenzamide must be balanced with the risk for those adverse events, and treatment with trimethobenzamide should only be continued as long as necessary to control nausea and vomiting, and generally no longer than two months. The ability of concomitantly administered antiemetic drugs (other than trimethobenzamide) has not been studied. Antiemetics with anti-dopaminergic actions (e.g., haloperidol, chlorpromazine, promethazine, prochlorperazine, metaclopramide) have the potential to worsen the symptoms in patients with Parkinson's disease and should be avoided. 5.3 Falling Asleep During Activities of Daily Living and Somnolence There have been reports in the literature of patients treated with apomorphine hydrocloride subcutaneous injections who suddenly fell asleep without prior warning of sleepiness while engaged in activities of daily living. Somnolence is commonly associated with apomorphine hydrocloride, and it is reported that falling asleep while engaged in activities of daily living always occurs in a setting of pre-existing somnolence, even if patients do not give such a history. Somnolence was reported in 35% of patients tre…

4 CONTRAINDICATIONS 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 [see Drug Interactions (7.1) ] . 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 [see Warnings and Precautions (5.12) ]. Concomitant use of apomorphine hydrocloride with 5HT 3 antagonists, including antiemetics (e.g., ondansetron, granisetron, dolasetron, palonosetron) and alosetron, is contraindicated ( 4 ) Hypersensitivity to apomorphine, its excipients or sodium metabisulfite ( 4 , 5.12 )

7 DRUG INTERACTIONS Concomitant use of antihypertensive medications and vasodilators: increased risk for hypotension, myocardial infarction, pneumonia, falls, and injuries ( 7.2 ) Dopamine antagonists such as neuroleptics or metoclopramide, may diminish the effectiveness of apomorphine hydrocloride ( 7.4 ) 7.1 5HT 3 Antagonists Based on reports of profound hypotension and loss of consciousness when apomorphine hydrocloride was administered with ondansetron, the concomitant use of apomorphine hydrocloride with 5HT 3 antagonists including antiemetics (for example, ondansetron, granisetron, dolasetron, palonosetron) and alosetron, is contraindicated. 7.2 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%) [see Warnings and Precautions (5.4) ] , 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 [see Warnings and Precautions (5.4 , 5.5) ] . 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 [see Clinical Pharmacology (12.3) ]. 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 [see Warnings and Precautions (5.4) ]. 7.3 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 [see Clinical Pharmacology (12.3) ]. 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 wa…

8.1 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 [see Data ] . 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.

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in more detail in the Warnings and Precautions section of labeling: Serious Adverse Reactions After Intravenous Administration [see Warnings and Precautions (5.1) ] Nausea and Vomiting [see Warnings and Precautions (5.2) ] Falling Asleep During Activities of Daily Living and Somnolence [see Warnings and Precautions (5.3) ] Syncope/Hypotension/Orthostatic Hypotension [see Warnings and Precautions (5.4) ] Falls [see Warnings and Precautions (5.5) ] Hallucinations/Psychotic-Like Behavior [see Warnings and Precautions (5.6) ] Dyskinesias [see Warnings and Precautions (5.7) ] Impulse Control/Compulsive Behaviors [see Warnings and Precautions (5.8) ] Coronary Events [see Warnings and Precautions (5.9) ] QTc Prolongation and Potential for Proarrhythymic Effects [see Warnings and Precautions (5.10) ] Withdrawal-Emergent Hyperpyrexia and Confusion [see Warnings and Precautions (5.11) ] Hypersensitivity [see Warnings and Precautions (5.12) ] Fibrotic Complications [see Warnings and Precautions (5.13) ] Priapism [see Warnings and Precautions (5.14) ] Most common adverse reactions (incidence at least 10% greater on apomorphine hydrocloride than on placebo) were yawning, drowsiness/somnolence, dyskinesias, dizziness/postural hypotension, rhinorrhea, nausea and/or vomiting, hallucination/confusion, and edema/swelling of extremities ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact TruPharma, LLC at 877-541-5504 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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) [see Clinical Studies (14) ] . 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…