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Apokyn

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Apokyn

Apokyn

WARNINGS

Avoid Intravenous Administration: Serious adverse events (such as intravenous crystallization of apomorphine, leading to thrombus formation and pulmonary embolism) have followed the intravenous administration of apomorphine. Consequently, apomorphine should not be administered intravenously.

General

The significant adverse events described below have been reported in association with the use of subcutaneous apomorphine, but almost all of them occurred during open-label, uncontrolled studies. In the development program, the controlled trial data involved relatively few patients, and examined primarily the effects of single doses. Because the background rate of many of these events in a population of patients with advanced Parkinson's disease is unknown, it is difficult to assess the role of apomorphine in their causation.

Nausea and Vomiting

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.

Syncope

In clinical studies, about 2% of patients experienced syncope.

QT Prolongation and Potential for Proarrhythymic Effects

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 ( > 60 msecs 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.

Symptomatic Hypotension

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 mmHg after 2 mg to 16 mmHg after 10 mg. Dose-dependent mean decrements in DBP ranged from 3 mmHg after 2 mg to 8 mmHg 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 (apomorphine) and extra caution should be exercised if APOKYN (apomorphine) must be administered with concomitant antihypertensive medications and/or vasodilators (see PRECAUTIONS: DRUG INTERACTIONS and PATIENT INFORMATION).

Falls

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.

Hallucinations / Psychotic-Like Behavior

During clinical development, hallucinations were reported by 14% of the patients. In one randomized, double-blind, placebo-controlled study, hallucinations or confusion occurred in 10 % of patients treated with APOKYN (apomorphine) and 0 % of patients treated with placebo. Hallucinations resulted in discontinuation of apomorphine in 1% of patients.

Post marketing reports indicate that patients may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior after starting or increasing the dose of APOKYN (apomorphine) . Other drugs prescribed to improve the symptoms of Parkinson's disease can have similar effects on thinking and behavior. This abnormal thinking and behavior can consist of one or more of a variety of manifestations, including paranoid ideation, delusions, hallucinations, confusion, disorientation, aggressive behavior, agitation, and delirium.

Patients with a major psychotic disorder should ordinarily not be treated with APOKYN (apomorphine) because of the risk of exacerbating psychosis. In addition, certain medications used to treat psychosis may exacerbate the symptoms of Parkinson's disease and may decrease the effectiveness of APOKYN. (see PRECAUTIONS: DRUG INTERACTIONS: Dopamine Antagonists)

Falling Asleep During Activities of Daily Living

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 (apomorphine) 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 (apomorphine) , patients should be advised of the possibility that they may develop drowsiness and specifically asked about factors that could increase the risk with APOKYN (apomorphine) , 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 (apomorphine) should ordinarily be discontinued. If a decision is made to continue APOKYN (apomorphine) , 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.

Coronary Events

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.

Contains Sulfite

APOKYN (apomorphine) 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 is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in non-asthmatic people.

Injection Site Reactions

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.

Potential for Abuse

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).

PRECAUTIONS

Dyskinesias

Apomorphine may cause dyskinesia or exacerbate pre-existing 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.

Events Reported with Dopaminergic Therapy

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.

Melanoma: Epidemiological studies have shown that patients with Parkinson's disease have a higher risk (2- to approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk observed was due to Parkinson's disease or other factors, such as drugs used to treat Parkinson's disease, is unclear.

For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using APOKYN (apomorphine) for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).

Priapism

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 Pathology in Albino Rats

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 (apomorphine) 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.

Information for Patients

APOKYN (apomorphine) 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 for the dosing pen. Patients should be instructed to use APOKYN (apomorphine) only as prescribed. Patients and/or caregivers who are advised to administer APOKYN (apomorphine) 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.

In particular, patients and caregivers must receive detailed instruction in the use of the dosing pen, with particular attention paid to two issues: 1) Patients need to be aware that the drug is dosed in milliliters, not milligrams. Patients should be particularly cautioned that a dose of 1 mg is represented on the dosing pen as 0.1 mL, and not as 1.0 (the latter representing a dose of 10 mg). It is critical that patients and caregivers be made to understand this distinction to prevent potentially life-threatening overdose if a dose of 1 mg is prescribed. 2) Patients and caregivers must be informed that it is possible to dial in their usual dose of apomorphine even though the cartridge may contain less than that amount of drug. In this case, they will receive only a partial dose with the injection, and the amount left to inject will appear in the dosing window. To complete the correct dose, patients/caregivers will need to “re-arm” the device and dial in the correct amount of the remaining dose. If at all possible, this situation should be avoided, and patients and caregivers should be alerted to the fact that there may be insufficient drug left in the cartridge to deliver a complete dose (for example, patients and caregivers should be urged to keep records of how many doses they have delivered for each cartridge, so that they can replace any cartridge that has an inadequate amount of drug remaining).

Patients should be instructed to rotate the injection site and to observe proper aseptic technique.

Patients should be informed that hallucinations or other manifestations of psychotic-like behavior can occur. Patients should also be advised that, if they have a major psychotic disorder, that APOKYN (apomorphine) should not ordinarily be used because of the risk of exacerbating the psychosis. Patients with a major psychotic disorder should also be aware that many treatments for psychosis may decrease the effectiveness of APOKYN. (see PRECAUTIONS: DRUG INTERACTIONS: Dopamine Antagonists).

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 (apomorphine) . 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 (apomorphine) , 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 (apomorphine) 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.

There have been reports of patients experiencing intense urges to gamble, increased sexual urges, other intense urges and the inability to control these urges while taking one or more of the medications that increases central dopaminergic tone and that are generally used for the treatment of Parkinson's disease, including APOKYN (apomorphine) . Although it is not proven that the medications caused these events, these urges were reported to have stopped in some cases when the dose was reduced or the medication was stopped. Prescribers should ask patients about the development of new or increased gambling urges, sexual urges or other urges while being treated with APOKYN (apomorphine) . Patients should inform their physician if they experience new or increased gambling urges, increased sexual urges or other intense urges while taking APOKYN (apomorphine) . Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking APOKYN.

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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

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).

Pregnancy

Pregnancy Category C

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.

Nursing Mothers

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.

Pediatric Use

The safety and efficacy of APOKYN (apomorphine) in pediatric patients has not been established.

Geriatric Use

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%).

Last reviewed on RxList: 9/23/2010
This monograph has been modified to include the generic and brand name in many instances.

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