DESCRIPTION: APOKYNO (apomorphine hydrochloride, USP) is a non-ergoline dopamine agonist. Apomorphine hydrochloride is chemically designated as 6a$-Aporphine-10,11-diol hydrochloride hemihydrate with a molecular formula of C17H17NO2 * HCl * 1/2H2O. Its structural formula and molecular weight are:
OH
HO
CH
HCl *1/2 H2O
M.W. 312.79 Apomorphine hydrochloride appears as minute, white or grayish-white glistening crystals or as white powder that is soluble in water at 80deg C. APOKYN(tm) 10 mg/mL is a clear, colorless, sterile solution for subcutaneous injection and is available in 2 mL ampules and 3 mL cartridges. Each mL of solution contains 10 mg of apomorphine hydrochloride, USP as apomorphine hydrochloride hemihydrate and 1 mg of sodium metabisulfite, NF in water for injection, USP. In addition, each mL of solution may contain sodium hydroxide, NF and/or hydrochloric acid, NF to adjust the pH of the solution. In addition, the cartridges contain 5 mg/mL of benzyl alcohol.
: APOKYN is a non-ergoline dopamine agonist with high in vitro binding affinity for the dopamine D4 receptor (Ki = 4.4 nM), moderate affinity for the dopamine D2, D3, and D5 (Ki = 35-83, 26, and 15 nM, respectively), and adrenergic a1D, a2B, a2C (Ki = 65, 66, and 36 nM, respectively) receptors, and low affinity for the dopamine D1, serotonin 5HT1A, 5HT2A, 5HT2B, and 5HT2C (Ki = 370, 120, 120, 130, and 100 nM, respectively) receptors. Apomorphine exhibits no affinity for the adrenergic b1 and b2 or histamine H1 receptors (Ki >10,000 nM). The precise mechanism of action of APOKYN as a treatment for Parkinson's disease is unknown, although it is believed to be due to stimulation of post-synaptic dopamine D2-type receptors within the caudate-putamen in the brain. Apomorphine has been shown to improve motor function in an animal model of Parkinson's disease. In particular, apomorphine attenuates the motor deficits induced by lesions in the ascending nigrostriatal dopaminergic pathway with the neurotoxin 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine (MPTP) in primates.
Apomorphine hydrochloride is a lipophilic compound that is rapidly absorbed (time to peak concentration ranges from 10 to 60 minutes) following subcutaneous administration into the abdominal wall. After subcutaneous administration, apomorphine appears to have bioavailability equal to that of an intravenous administration. Apomorphine exhibits linear pharmacokinetics over a dose range of 2 to 8 mg following a single subcutaneous injection of apomorphine into the abdominal wall in patients with idiopathic Parkinson's disease.
Distribution:
The plasma-to-whole blood apomorphine concentration ratio is equal to one. Mean (range) apparent volume of distribution was 218L (123 - 404 L). Maximum concentrations in cerebrospinal fluid (CSF) are less than 10% of maximum plasma concentrations and occur 10 to 20 minutes later.
Metabolism and Elimination:
The mean apparent clearance (range) is 223 L/hr (125 - 401 L/hr) and the mean terminal elimination half-life is about 40 minutes (range about 30 to 60 minutes).
The route of metabolism in humans is not known. Potential routes of metabolism in humans include sulfation, N-demethylation, glucuronidation and oxidation. In vitro, apomorphine undergoes rapid autooxidation.
: The clearance of apomorphine does not appear to be influenced by age, gender, weight, duration of Parkinson's disease, levodopa dose or duration of therapy.
Hepatic Impairment: In a study comparing subjects with hepatic impairment (moderately impaired as determined by the Child-Pugh classification method) to healthy matched volunteers, the AUC0-[?] and Cmax values were increased by approximately 10% and 25%, respectively, following a single subcutaneous administration of apomorphine into the abdominal wall. Studies in subjects with severe hepatic impairment have not been conducted (see PRECAUTIONS and DOSAGE AND ADMINISTRATION). Renal Impairment: In a study comparing renally-impaired subjects (moderately impaired as determined by estimated creatinine clearance) to healthy matched volunteers, the AUC0-[?] and Cmax values were increased by approximately 16% and 50%, respectively, following a single subcutaneous administration of apomorphine into the abdominal wall. The mean time to peak concentrations and the mean terminal half-life of apomorphine were unaffected by the renal status of the individual. Studies in subjects with severe renal impairment have not been conducted. The starting dose for patients with mild or moderate renal impairment should be reduced (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).
Levodopa pharmacokinetics were unchanged when subcutaneous apomorphine and levodopa were co-administrated in patients. However, motor response differences were significant. The threshold levodopa concentration necessary for an improved motor response was reduced significantly, leading to an increased duration of effect without a change in the maximal response to levodopa therapy.
Other Drugs Eliminated Via Hepatic Metabolism: Based upon an in vitro study, cytochrome P450 enzymes play a minor role in the metabolism of apomorphine. In vitro studies have also demonstrated that drug interactions are unlikely due to apomorphine acting as a substrate, an inhibitor, or an inducer of cytochrome P450 enzymes.
COMT Interactions:
A pharmacokinetic interaction of apomorphine with catechol-O-methyl transferase (COMT) inhibitors or drugs metabolized by this route is unlikely since apomorphine appears not to be metabolized by COMT.
The effectiveness of APOKYN in the acute symptomatic treatment of the recurring episodes of hypomobility, "off" episodes ("end-of-dose wearing off" and unpredictable "on/off" episodes), associated with advanced Parkinson's disease was established in three randomized, controlled trials. On average, patients participating in these trials had Parkinson's disease for 11.3 years and were being treated with L-dopa and at least one other agent, usually an oral dopamine agonist. One of the three studies was conducted in patients who did not have prior exposure to apomorphine and two were conducted in patients with at least 3 months of apomorphine use immediately prior to study enrollment. Almost all patients without prior exposure to apomorphine began taking an antiemetic (trimethobenzamide) three days prior to starting apomorphine. After exposure to apomorphine, 50% of patients were able to discontinue use of a concomitant antiemetic, on average 2 months after initiating apomorphine.
Change in Part III (Motor Examination) of the Unified Parkinson's Disease Rating Scale (UPDRS) served as the primary outcome assessment measure in each study. Part III of the UPDRS contains 14 items designed to assess the severity of the cardinal motor findings (e.g., tremor, rigidity, bradykinesia, postural instability, etc.) in patients with Parkinson's disease. The first trial used a parallel design, randomizing 29 patients with advanced Parkinson's disease to subcutaneous apomorphine or placebo in a 2:1 ratio. Patients had no prior exposure to apomorphine. In an office setting, hypomobility was allowed to occur by withholding the patients' Parkinson's disease medications overnight. The following morning, patients (in a hypomobile state) were started in a blinded fashion on study treatment (placebo or 2 mg of apomorphine) and redosed at increasing doses, after at least 2 hours, until a therapeutic response approximately equivalent to the individual patient's response to their usual dose of levodopa was observed (or until 10 mg apomorphine or placebo equivalent was given). At each redosing, study drug was increased by 2 mg or 0.2 mL (to 4 mg, 6 mg, 8 mg, or 10 mg of apomorphine) or placebo equivalent. Of the 20 patients assigned to apomorphine, 18 achieved a therapeutic response at about 20 minutes that was approximately equivalent to the therapeutic response to a usual dose of levodopa. The average apomorphine dose was 5.4 mg (3 patients on 2 mg, 7 on 4 mg, 5 on 6 mg, 3 on 8 mg, and 2 on 10 mg). In contrast, of the 9 patients assigned to placebo, none reached such a therapeutic response. The mean changes-from-baseline for UPDRS Part III scores at the best dose were 23.9 and 0.1 for the apomorphine and placebo respectively (p < 0.0001). The second trial used a crossover design, randomizing 17 patients who had been using apomorphine for at least 3 months. Patients received their usual morning doses of Parkinson's disease medications and were followed until hypomobility occurred, at which time they received either a single dose of subcutaneous apomorphine (at their usual dose) or placebo. Their UPDRS Part III scores were then evaluated over time. The average dose of apomorphine was 4 mg (2 patients on 2 mg, 9 on 3 mg, 2 on 4 mg, and 1 each on 4.5 mg, 5 mg, 8 mg, and 10 mg). On average, the mean changes-from-baseline UPDRS Part III scores at 20 minutes were 20.0 and 3.0 points for the apomorphine and placebo groups respectively (p < 0.0001). The third trial used a parallel design, randomizing 62 patients who had been using apomorphine for at least 3 months. Patients were randomized in a 2:1 (active: placebo) ratio to one of four groups and were dosed once. The groups were: apomorphine at the usual dose, placebo at a volume matching the usual apomorphine dose, apomorphine at the usual dose + 2mg (0.2mL), or placebo at a volume matching the usual apomorphine dose + 0.2mL. Patients received their usual morning doses of Parkinson's disease medications and were followed until hypomobility occurred, at which time they received the randomized treatment. The mean changes-from-baseline for UPDRS Part III scores at 20 minutes post dosing were 24.2 and 7.4 points for the pooled apomorphine groups and the pooled placebo groups, respectively (p<0.0001). The figure below describes the mean change in UPDRS Motor Scores over time after pooled apomorphine and pooled placebo administration.
UPDRS Motor Scores
Change from Predose
-5.00
-10.00
-15.00
-20.00
-25.00
-30.00
0 10 20 30 40 50 60 70 80 90 100
Time (min)
Pooled Apomorphine Placebo
In this third trial, comparing patients randomized to apomorphine at the usual dose (mean dose about 4.5 mg) and patients randomized to apomorphine + 2 mg (mean dose about 6 mg), the mean changes- from-baseline for UPDRS Part III scores at 20 minutes post dosing were 24 and 25 , respectively. This suggests that patients chronically treated at a dose of 4 mg might derive little additional benefit from a dose increment of 2 mg. There was an increased incidence of adverse events in patients randomized to apomorphine + 2 mg.
APOKYNO (apomorphine hydrochloride injection) 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 medications (see CLINICAL PHARMACOLOGY: Clinical Trials).
At the recommended doses of apomorphine, severe nausea and vomiting can be expected. Because of this, in domestic clinical studies, 98% of all patients were treated with the antiemetic trimethobenzamide for three days prior to beginning apomorphine and were then encouraged to continue trimethobenzamide for at least 6 weeks. Among 522 patients treated, 262 (50%) discontinued trimethobenzamide while continuing apomorphine. 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: 0-3 years). Even with the use of trimethobenzamide in clinical trials, 31% of the patients experienced nausea and 11% of the patients experienced vomiting. In clinical trials, 3% of the patients discontinued apomorphine due to nausea and 2% discontinued due to vomiting.
In the domestic development of apomorphine, there was no experience with antiemetics other than trimethobenzamide. Some antiemetics with anti-dopaminergic actions have the potential to worsen the clinical state of patients with Parkinson's disease and should be avoided.
: In clinical studies, about 2% of patients experienced syncope.
In a study in which patients received increasing single doses of apomorphine from 2 to 10 mg (if tolerated) as well as placebo, the mean difference in QTc between apomorphine and placebo, as measured by Holter monitor, was 0 msec at 4
mg, 1 msec at 6 mg, and 7 msec at 8 mg. Too few patients received a 10 mg dose to be able to adequately characterize the change in QTc interval at that dose. In a controlled trial in which patients were administered placebo or a single dose of apomorphine (mean dose of 5.2 mg; range of 2-10 mg, with 30 of 35 patients receiving a dose of 6 mg or less), the mean difference between apomorphine and placebo in the change in QTc was about 3 msec at 20 and 90 minutes. In the entire database, 2 patients (one at 2 and 6 mg, one at 6 mg) exhibited large QTc increments (> 60msecs from pre-dose) and had QTc intervals greater than 500 msecs acutely after dosing. Doses of 6 mg or less thus are associated with minimal increases in QTc. Doses greater than 6 mg do not provide additional clinical benefit and are not recommended Some drugs that prolong the QT/QTc interval have been associated with the occurrence of torsades de pointes and with sudden unexplained death. The relationship of QT prolongation to torsades de pointes is clearest for larger increases (20 msec and greater) but it is possible that smaller QT/QTc prolongations may also increase risk, or increase it in susceptible individuals, such as those with hypokalemia, hypomagnesemia, bradycardia, concomitant use of other drugs that prolong the QTc interval, or genetic predisposition (e.g., congenital prolongation of the QT interval). Although torsades de pointes has not been observed in association with the use of apomorphine at recommended doses in premarketing studies, experience is too limited to rule out an increased risk. Palpitations and syncope may signal the occurrence of an episode of torsades de pointes. Caution is recommended when administering apomorphine to patients with the risk factors described above.
: Dopamine agonists may cause orthostatic hypotension at any time, especially during dose escalation. Parkinson's disease patients, in addition, may have an impaired
capacity to respond to an orthostatic challenge. For these reasons, Parkinson's disease patients being treated with dopaminergic agonists ordinarily require careful monitoring for signs and symptoms of orthostatic hypotension, especially during dose escalation, and should be informed of this risk. Apomorphine causes dose-related decreases in systolic (SBP) and diastolic blood pressure (DBP). Dose-dependent mean decrements in SBP ranged from 5 mm Hg after 2 mg to 16 mm Hg after 10 mg. Dose-dependent mean decrements in DBP ranged from 3 mm Hg after 2 mg to 8 mm Hg after 10 mg. These changes were observed at 10 minutes, appeared to peak at about 20 minutes after dosing, and persisted up to at least 90 minutes post-dosing. Patients undergoing titration of apomorphine showed an increased incidence (from 4% pre-dose to 18% post-dose) of systolic orthostatic hypotension (> 20 mmHg decrease) when evaluated at various times after in-office dosing. A small number of patients developed severe systolic orthostatic hypotension (> 30 mmHg decrease and systolic BP < 90 mmHg) after subcutaneous apomorphine injection. In clinical trials of apomorphine in patients with advanced Parkinson's disease, 59 of 550 patients (11%) had orthostatic hypotension, hypotension, and/or syncope. These events were considered serious in 4 patients (<1%) and resulted in withdrawal of apomorphine in 10 patients (2%). These events occurred both with initial dosing and during long-term treatment. Whether or not hypotension contributed to other significant adverse events seen (e.g., falls), is unknown. The effects of apomorphine on blood pressure may be increased by the concomitant use of alcohol, antihypertensive medications, and vasodilators (especially nitrates). Alcohol should be avoided when using Apokyn and extra caution should be exercised if Apokyn must be administered with concomitant antihypertensive medications and/or vasodilators (see PRECAUTIONS: Drug Interactions and Information for Patients).
Patients with Parkinson's disease (PD) are at risk of falling due to the underlying postural instability and concomitant autonomic instability seen in some patients with PD, and from syncope caused by the blood pressure lowering effects of the drugs used to treat PD. Subcutaneous apomorphine might increase the risk of falling by simultaneously lowering blood pressure and altering mobility (see WARNINGS: Symptomatic Hypotension; PRECAUTIONS: Dyskinesias).
In clinical trials, 30% of patients had events that could reasonably be considered falls and about 5% of patients had falls that were considered serious. Because these data were obtained in open, uncontrolled studies, and given the unknown background rate of falls in a population of patients with advanced Parkinson's disease, it is impossible to definitively assess the contribution of apomorphine to these events.
During clinical development, hallucinations were reported by 14% of the patients. Hallucinations resulted in discontinuation of apomorphine in 1% of patients.
There have been reports in the literature of patients treated with apomorphine subcutaneous injections who suddenly fell asleep without prior warning of sleepiness while engaged in activities of daily living. It is clear that somnolence is commonly associated with APOKYN and many clinical experts believe 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. Prescribers should therefore continually reassess patients for drowsiness or sleepiness, especially since some of the events occur well after the start of treatment. Prescribers should also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities.
Before initiating treatment with APOKYN, patients should be advised of the possibility that they may develop drowsiness and specifically asked about factors that could increase the risk with APOKYN, such as concomitant sedating medications and the presence of sleep disorders. If a patient develops significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc. ), APOKYN should ordinarily be discontinued. If a decision is made to continue APOKYN, patients should be advised not to drive and to avoid other potentially dangerous activities. There is insufficient information to determine whether dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.
During clinical development, 4% of patients treated with apomorphine experienced angina, myocardial infarction, cardiac arrest and/or sudden death; some cases of angina and myocardial infarction occurred in close proximity to apomorphine dosing (within 2 hours), while other cases of cardiac arrest and sudden death were observed at times unrelated to dosing. Apomorphine has been shown to reduce resting systolic and diastolic blood pressure and, as such, it has the potential to exacerbate coronary (and cerebral) ischemia. Extra caution should be used in prescribing apomorphine for patients with known cardiovascular and cerebrovascular disease. If patients develop signs and symptoms of coronary or cerebral ischemia, the continued use of apomorphine should be carefully re- evaluated.
: APOKYN contains sodium metabisulfite, a sulfite that may cause allergic-type reactions, including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population in unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in non- asthmatic people.
Among the 550 patients treated with apomorphine subcutaneous injections during development, 26% of patients complained of injection site reactions, including bruising (16%), granuloma (4%), and pruritus (2%). There was a limited experience (both for overall numbers of patients as well as the total number of injections per patient) with apomorphine injections in controlled trials. In this limited controlled experience, the number of injection site reactions reported by patients receiving apomorphine was similar to that reported by patients receiving placebo.
: There are rare reports of apomorphine abuse by patients with Parkinson's disease in other countries. These cases are characterized by increasingly frequent dosing leading to hallucinations, dyskinesia, and abnormal behavior. Psychosexual stimulation with increased libido is believed to underlie these cases. Prescribers should be vigilant for evidence that patients are abusing apomorphine, such as use out of proportion to motor signs (see DRUG ABUSE AND DEPENDENCE).
Dyskinesias:
Apomorphine may cause dyskinesia or exacerbate preexisting dyskinesia. During clinical development, dyskinesia or worsening of dyskinesia was reported in 24% of patients. Overall, 2% of patients withdrew from studies due to dyskinesias.
: Although the events enumerated below have not been reported in association with the use of apomorphine, they are associated with the use of other dopaminergic drugs.
Withdrawal-emergent Hyperpyrexia and Confusion:
Although not reported with apomorphine, a symptom complex resembling the neuroleptic malignant syndrome (characterized by elevated
temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in antiparkinsonian therapy.
Fibrotic Complications:
Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, pleural thickening, and cardiac valvulopathy have been reported in some patients treated with ergot- derived dopaminergic agents. While these complications may resolve when the drug is discontinued, complete resolution does not always occur. Although these adverse events are believed to be related to the ergoline structure of these compounds, whether other, nonergot derived dopamine agonists can cause them is unknown.
Apomorphine may cause prolonged painful erections in some patients. During clinical development, painful erections were reported by 3 of 361 males (<1%), and one patient withdrew from apomorphine therapy because of priapism. Although no patients in the clinical development program required surgical intervention, severe priapism may require surgical intervention.
Hepatic Impairment: Caution should be exercised when administrating apomorphine to patients with mild and moderate hepatic impairment due to the increased Cmax and AUC in these patients. Studies of subjects with severe hepatic impairment have not been conducted (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). Renal Impairment: The starting dose should be reduced to 1 mg when administrating apomorphine to patients with mild or moderate renal impairment because the Cmax and AUC are increased in these patients. Studies in subjects with severe renal impairment have not been conducted (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
: Retinal degeneration has been observed in albino rats treated with dopamine agonists for prolonged periods (generally during 2-year carcinogenicity studies). This lesion has also been observed when albino rats were exposed to these agents for shorter periods under higher intensity light exposures. Similar changes have not been observed in 2-year carcinogenicity studies in albino mice or in rats or monkeys treated for 1 year. APOKYN has not been tested in carcinogenicity studies, but based on its mechanism of action it would be expected to cause similar toxicity. The significance of this effect in humans has not been established, but cannot be disregarded because disruption of a mechanism that is universally present in vertebrates (e.g., disk shedding) may be involved.
APOKYN is intended only for subcutaneous injection and must not be given intravenously. Patients and caregivers should be urged to read the attached Patient Package Insert and Directions for Use of the ampule and dosing pen. Patients should be instructed to use APOKYN only as prescribed. Patients and/or caregivers who are advised to administer APOKYN in medically unsupervised situations should receive instruction on the proper use of the product from the physician or other suitably qualified health care professional and then observed during the initial dosing.
Patients should be instructed to rotate the injection site and to observe proper aseptic technique. Patients should be informed that hallucinations can occur. Patients should be advised that they may develop postural (orthostatic) hypotension with or without symptoms such as dizziness, nausea, syncope, and sometimes sweating. Hypotension and/or orthostatic symptoms may occur more frequently during initial therapy or with an increase in dose at any time (cases have been seen after months of treatment). Accordingly, patients should be cautioned against rising rapidly after sitting or lying down, especially if they have been sitting or lying for prolonged periods, and especially at the initiation of treatment with APOKYN. Alcohol, antihypertensive medications, and vasodilating medications may potentiate the hypotensive effect of apomorphine (see WARNINGS: Symptomatic Hypotension; PRECAUTIONS: Drug Interactions). Patients should be alerted to the potential sedating effects of APOKYN, including somnolence and the possibility of falling asleep while engaged in activities of daily living. Since somnolence is a frequent adverse event with potentially serious consequences, patients should neither drive a car nor engage in other potentially dangerous activities until they have gained sufficient experience with APOKYN to gauge whether or not it affects their mental and/or motor performance adversely. Patients should be advised that if increased somnolence or episodes of falling asleep during activities of daily living (e.g., watching television, passenger in a car, etc.) are experienced at any time during treatment, they should not drive or participate in potentially dangerous activities until they have contacted their physician. Because of possible additive effects, caution should be advised when patients are taking other sedating medications or alcohol in combination with APOKYN. Because apomorphine has not been evaluated for effects on reproduction and embryo-fetal development, patients should be advised to notify their physicians if they become pregnant or intend to become pregnant (see PRECAUTIONS: Pregnancy). Because of the possibility that apomorphine may be excreted in breast milk, patients should be advised to notify their physicians if they intend to breast-feed. Rare cases of abuse (use of apomorphine significantly in excess of prescribed frequency) have been reported. Apomorphine abuse may be associated with inappropriate sexual behavior.
5HT3 Antagonists: 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 5HT3 antagonist class (including, for example, ondansetron, granisetron, dolasetron, palonosetron, and alosetron) is contraindicated (see Contraindications).
Antihypertensive Medications and Vasodilators:
The following adverse events were experienced more commonly in patients receiving concomitant antihypertensive medications or vasodilators (n=94) compared to patients not receiving these concomitant drugs (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%. The mechanism underlying many of these events is unknown, but may represent increased hypotension (see WARNINGS: Symptomatic Hypotension).
Dopamine Antagonists:
Since apomorphine is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of APOKYN. 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 concomitantly with drugs that prolong the QT/QTc interval (see WARNINGS: QT Prolongation and Potential for Proarrhythmic Effects).
Drug/Laboratory Test Interactions:
There are no known interactions between APOKYN and laboratory tests.
Carcinogenicity studies have not been conducted with APOKYN.
Apomorphine was mutagenic in the in vitro bacterial Ames test and the in vitro mammalian mouse lymphoma assay. Apomorphine was also clastogenic in the in vitro chromosomal aberration assay in human lymphocytes and the in vitro mouse lymphoma assay. Apomorphine was negative in the in vivo micronucleus assay in mice. In a published fertility study in male rats, an adverse effect on fertility was observed at a dose of 2 mg/kg administered subcutaneously (0.6 times the MRHD in a mg/m2 basis). A significant decrease in testis weight was observed in a 39-week study in cynomolgus monkey at subcutaneous doses of 1.0 and 1.5 mg/kg (0.6 and 1 times the MRHD on a mg/m2 basis).
: Reproduction studies have not been conducted with apomorphine. It is also not known whether apomorphine can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Apomorphine should be given to a pregnant woman only if clearly needed.
: It is not known whether apomorphine is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from apomorphine, a decision should be made as to whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
: The safety and efficacy of APOKYN in pediatric patients has not been established.
: In the apomorphine clinical development program, there were 239 patients less than 65 years of age and 311 who were 65 years of age or older. Adverse events were about equally common in older and younger patients (90 vs 87%), but with older patients more likely to experience confusion and hallucinations. Serious adverse events (life-threatening events or events resulting in hospitalization and/or increased disability) were also more common in older patients (27 vs 17%), with older patients
more likely to fall (experiencing bone and joint injuries), have cardiovascular events, develop respiratory disorders, and have gastrointestinal events. Older patients were more likely to discontinue apomorphine treatment as a result of adverse events (29 vs 21%).
Adverse Event Incidence in Controlled Clinical Studies:
APOKYN(tm) has been administered to 550 Parkinson's disease patients who were taking some form of L-Dopa along with other Parkinson's disease medications. Eighty-six percent of patients were taking a concomitant dopamine agonist. All patients had some degree of spontaneously occurring hypomobility ("Off episodes") at baseline. Adverse events were recorded by the clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals having adverse events, similar types of events were grouped into a smaller number of standardized categories using MEDRA dictionary terminology.
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. The most extensive experience with apomorphine in randomized, controlled trials comes from a multicenter randomized placebo-controlled parallel group trial conducted in apomorphine-naive PD patients treated for up to 4 weeks (Table 1). Individual apomorphine doses in this trial ranged from 2- 10 mg, optimized to achieve control of symptoms comparable to each patient's response to his or her usual dose of L-dopa. The prescriber should be aware that these figures cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical studies. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. However, the cited figures do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the adverse- event incidence rate in the population studied.
| Table 1 Summary of Adverse Events Occurring in Two or More Patients | ||||
| Adverse Event | APOMORPHINE | PLACEBO | ||
| n = 20 | n = 9 | |||
| N | % | N | % | |
| Any Adverse Reaction | 17 | 85 | 8 | 89 |
| Yawning | 8 | 40 | 0 | 0 |
| Dyskinesias | 7 | 35 | 1 | 11 |
| Drowsiness or Somnolence | 7 | 35 | 0 | 0 |
| Nausea and/or Vomiting | 6 | 30 | 1 | 11 |
| Dizziness or Postural Hypotension | 4 | 20 | 0 | 0 |
| Rhinorrhea | 4 | 20 | 0 | 0 |
| Chest Pain / Pressure / Angina | 3 | 15 | 1 | 11 |
| Hallucination or Confusion | 2 | 10 | 0 | 0 |
| Edema / Swelling of Extremities | 2 | 10 | 0 | 0 |
Other Adverse Events Observed During All Phase 2/3 Clinical Trials
: APOKYN has been administered to 550 patients; 89% had at least one adverse event (AE). The most common AEs in
addition to those in Table 1 (occurring in at least 5% of the patients and at least plausibly related to treatment) in descending order were injection site complaint, 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.
Potential for Abuse:
A rarely reported motivation for apomorphine abuse (escalation of dose beyond prescribed frequency) is the use of apomorphine to attempt to avoid all symptoms of all "Off" events when "Off" events occur frequently. A second, rarely reported, motivation for apomorphine abuse is a psychosexual reaction related to the stimulation of penile erection and increase in libido. Adverse events that have been reported in males with overuse include frequent penile erections, atypical sexual behavior, heightened libido, dyskinesias, agitation, confusion, and depression. No studies have been conducted to evaluate the potential for dependence when apomorphine is used as acute (rescue) treatment of "Off" episodes in the patients with "On/Off" or "Wearing-Off" effects associated with late stage Parkinson's disease.
Journal of Neurology, Neurosurgery, and
Intermittent Injection: A report of an accidental overdose of 25 mg injected subcutaneously in a 62 year old man was published in
Psychiatry
(1990), Vol. 53, pp. 96-102. 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.
: