Apokyn

Name: Apokyn

What should I know about storage and disposal of this medication?

Keep this medication in the cartridge it came in and out of reach of children. Store the cartridge and injector pen in the carrying case, at room temperature away from dust, moisture (not in the bathroom) and cold or hot temperatures. Never store the pen with a needle attached.

Unneeded medications should be disposed of in special ways to ensure that pets, children, and other people cannot consume them. However, you should not flush this medication down the toilet. Instead, the best way to dispose of your medication is through a medicine take-back program. Talk to your pharmacist or contact your local garbage/recycling department to learn about take-back programs in your community. See the FDA's Safe Disposal of Medicines website (http://goo.gl/c4Rm4p) for more information if you do not have access to a take-back program.

It is important to keep all medication out of sight and reach of children as many containers (such as weekly pill minders and those for eye drops, creams, patches, and inhalers) are not child-resistant and young children can open them easily. To protect young children from poisoning, always lock safety caps and immediately place the medication in a safe location – one that is up and away and out of their sight and reach. http://www.upandaway.org

Side effects

The following adverse reactions are discussed in more detail in the Warnings and Precautions section of labeling:

  • Nausea and Vomiting [see WARNINGS AND PRECAUTIONS]
  • Syncope [see WARNINGS AND PRECAUTIONS]
  • Hypotension/Orthostatic Hypotension [see WARNINGS AND PRECAUTIONS]
  • Falls [see WARNINGS AND PRECAUTIONS]
  • Hallucinations/Psychotic-Like Behavior [see WARNINGS AND PRECAUTIONS]
  • Dyskinesias [see WARNINGS AND PRECAUTIONS]
  • Coronary Events [see WARNINGS AND PRECAUTIONS]
  • Priapism [see WARNINGS AND PRECAUTIONS]

Clinical Trial 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 APOKYN. 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 (APOKYN 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 APOKYN-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]. Individual APOKYN 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 APOKYN-Treated Patients in Study 1

  APOKYN
(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 APOKYN 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 APOKYN 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.

Clinical pharmacology

Mechanism Of Action

APOKYN is a non-ergoline dopamine agonist with high in vitro binding affinity for the dopamine D4 receptor, and moderate affinity for the dopamine D2, D3, and D5, and adrenergic α1D, α2B, α2C receptors. 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.

Pharmacodynamics

Prolongation Of The QTc Interval

In a placebo-controlled study in which patients received increasing single doses of APOKYN from 2 mg to up to 10 mg, the mean difference in QTc (measured by Holter monitor) between APOKYN and placebo 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 APOKYN (mean dose of 5.2 mg; range of 2 mg to 10 mg), the mean difference between APOKYN and placebo in the change in QTc was about 3 msec at 20 minutes and 90 minutes. In the entire database, 2 patients (one at 2 mg and 6 mg, one at 6 mg) exhibited large QTc increments ( > 60 msec from pre-dose) and had QTc intervals greater than 500 msec acutely after dosing. Doses of 6 mg or less thus are associated with minimal increases in QTc.

Decreases In Blood Pressure

Dose-dependent mean decrements in systolic blood pressure ranged from 5 mmHg after 2 mg to 16 mmHg after 10 mg. Dose-dependent mean decrements in diastolic blood pressure ranged from 3 mmHg after 2 mg to 8 mmHg after 10 mg. These changes were observed at 20 minutes, and were maximal between 20 and 40 minutes after dosing. Lesser, but still noteworthy blood pressure decrements persisted up to at least 90 minutes after dosing.

Pharmacokinetics

Absorption

Apomorphine hydrochloride is a lipophilic compound that is rapidly absorbed (time to peak concentration ranges from 10 minutes 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 mg to 8 mg following a single subcutaneous injection of APOKYN 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 218 L (123 L to 404 L). Maximum concentrations in cerebrospinal fluid (CSF) are less than 10% of maximum plasma concentrations and occur 10 minutes to 20 minutes later.

Metabolism And Elimination

The mean apparent clearance (range) is 223 L/hr (125 L/hr to 401 L/hr) and the mean terminal elimination half-life is about 40 minutes (range about 30 minutes 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 auto-oxidation.

Special Populations

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.

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 APOKYN 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 DOSAGE AND ADMINISTRATION and Use in Specific Populations].

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 APOKYN into the abdominal wall. Studies in subjects with severe hepatic impairment have not been conducted [see DOSAGE AND ADMINISTRATION and Use in Specific Populations].

Drug-Drug Interactions

Carbidopa/levodopa: Levodopa pharmacokinetics were unchanged when subcutaneous APOKYN 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 on 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 APOKYN with catechol-O-methyl transferase (COMT) inhibitors or drugs metabolized by this route is unlikely since apomorphine appears not to be metabolized by COMT.

Clinical Studies

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), in patients with advanced Parkinson's disease was established in three randomized, controlled trials of APOKYN given subcutaneously (Studies 1, 2, and 3). At baseline in these trials, the mean duration of Parkinson's disease was approximately 11 years. Whereas all patients were using concomitant L-dopa at baseline, 86% of patients were using a concomitant oral dopaminergic agonist, 31% were using a concomitant COMT inhibitor, and 10% were using a concomitant monoamine B oxidase inhibitor. Study 1 was conducted in patients who did not have prior exposure to APOKYN (i.e., APOKYN naïve) and Studies 2 and 3 were conducted in patients with at least 3 months of APOKYN use immediately prior to study enrollment. Almost all patients without prior exposure to APOKYN began taking an antiemetic (trimethobenzamide) three days prior to starting APOKYN and 50% of patients were able to discontinue the concomitant antiemetic, on average 2 months after initiating APOKYN.

The change from baseline in Part III (Motor Examination) of the Unified Parkinson's Disease Rating Scale (UPDRS) served as the primary outcome assessment measure in Studies 1, 2, and 3. 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) in patients with Parkinson's disease.

Study 1

Study 1 was a randomized, double-blind, placebo-controlled, parallel-group trial in 29 patients with advanced Parkinson's disease who had at least 2 hours of “off” time per day despite an optimized oral regimen for Parkinson's disease including levodopa and an oral dopaminergic agonist. Patients with atypical Parkinson's disease, psychosis, dementia, hypotension, or those taking dopamine antagonists were excluded from participation. 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 on study treatment in a 2:1 ratio (2 mg of APOKYN or placebo given subcutaneously). At least 2 hours after the first dose, patients were given additional doses of study medication until they achieved a “therapeutic response” (defined as a response similar to the patient's response to their usual dose of levodopa) or until 10 mg of APOKYN or placebo equivalent was given. At each injection re-dosing, the study drug dose was increased in 2 mg increments up to 4 mg, 6 mg, 8 mg, 10 mg of APOKYN) or placebo equivalent.

Of the 20 patients randomized to APOKYN, 18 achieved a “therapeutic response” at about 20 minutes. The mean APOKYN dose was 5.4 mg (3 patients on 2 mg, 7 patients on 4 mg, 5 patients on 6 mg, 3 patients on 8 mg, and 2 patients on 10 mg). In contrast, of the 9 placebo-treated patients, none reached a “therapeutic response.” The mean change-from-baseline for UPDRS Part III score for APOKYN group (highest dose) was statistically significant compared to that for the placebo group (Table 2).

Table 2: Mean Change from Baseline in UPDRS Motor Score for Intent-to-Treat Population in Study 1

Treatment Baseline UPDRS Motor Score Mean Change from Baseline Difference from Placebo
Placebo 36.3 - 0.1 NA
APOKYN 39.7 -23.9 -23.8

Study 2

Study 2 used a randomized, placebo-controlled crossover design of 17 patients with Parkinson's disease who had been using APOKYN 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 APOKYN (at their usual dose) and placebo on different days in random order. UPDRS Part III scores were evaluated over time. The mean dose of APOKYN was 4 mg (2 patients on 2 mg, 9 patients on 3 mg, 2 patients on 4 mg, and 1 patient each on 4.5 mg, 5 mg, 8 mg, and 10 mg). The mean change-from-baseline UPDRS Part III score for the APOKYN group was statistically significant compared to that for the placebo group (Table 3).

Table 3: Mean Change from Baseline in UPDRS Motor Score for Intent-to-Treat Population in Study 2

Treatment Baseline UPDRS Motor Score Mean Change from Baseline Difference from Placebo
Placebo 40.1 - 3.0 NA
APOKYN 41.3 -20.0 - 17.0

Study 3

Study 3 used a randomized withdrawal design in 4 parallel groups from 62 patients (APOKYN-35; Placebo-27) with Parkinson's disease who had been using APOKYN for at least 3 months. Patients were randomized to one of the following 4 treatments dosed once by subcutaneous administration: APOKYN at the usual dose (mean dose 4.6 mg), placebo at a volume matching the usual APOKYN dose, APOKYN at the usual dose + 2 mg (0.2 mL) (mean dose 5.8 mg), or placebo at a volume matching the usual APOKYN dose + 0.2 mL. 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. APOKYN doses ranged between 2 mg to 10 mg. The mean change-from-baseline for the APOKYN group for UPDRS Part III scores at 20 minutes post dosing was statistically significant compared to that for the placebo group (Table 4). Figure 2 describes the mean change from baseline in UPDRS Motor Scores over time for pooled APOKYN and placebo administration.

Table 4: Mean Change from Baseline in UPDRS Motor Score for Intent-to-Treat Population in Study 3

Treatment Baseline UPDRS Motor Score Mean Change from Baseline Difference from Placebo
Placebo (Pooled) 40.6 - 7.4 NA
APOKYN (Pooled) 42.0 -24.2 - 16.8

Figure 2: Mean Change from Baseline in UPDRS Motor Scores of Pooled APOKYN Groups and Placebo Group in Study 3

In Study 3, the mean changes-from-baseline for UPDRS Part III scores at 20 minutes post dosing for the APOKYN and higher dose APOKYN groups were 24 and 25, respectively. This result 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 also an increased incidence of adverse reactions in patients randomized to higher APOKYN dose.

Manufacturer

  • US WorldMeds, LLC

Apokyn Usage

Recieve Apokyn exactly as prescribed.

  • Apokyn comes in an injectable form to be given directly under the skin, typically at the onset of an 'off period'. 
  • Do not inject Apokyn unless you and your caregiver have been taught the correct way and both of you understand all of the directions. Ask your healthcare provider if you do not understand something.
  • Your healthcare provider will tell you what dose of Apokyn to use and how often you should take it. Your healthcare provider will also tell you how to change your dose of Apokyn, if needed. Do not change your dose of Apokyn or use it more often unless your healthcare provider has told you to.

Injecting Apokyn:

  • Apokyn is a clear and colorless liquid. Do not use Apokyn if it appears cloudy, colored, or to contain particles, and call your pharmacist.
  • Choose an injection site on your stomach area, upper arm, or upper leg. Change your injection site each time Apokyn is used, this will lower your chances of having a skin reaction at the site where you inject Apokyn. Do not inject Apokyn into an area of skin that is sore, red, infected or damaged.
  • Inject Apokyn under your skin (subcutaneously). Do not inject Apokyn into a vein.
  • Keep a record of how much Apokyn you have used each time you inject or your care partner gives you an injection.
  • Use a new needle with each injection. Never reuse a needle.
  • Do not give another dose of Apokyn sooner than 2 hours after the last dose.
  • The maximum dosing is 5 times per day and with total daily doses greater than 2 mL (20 mg).
  • Your healthcare provider will prescribe Apokyn that comes in prefilled glass cartridges that are used with a special multiple-dose injector pen.
  • Your Apokyn pen is dosed in milliliters (mL), not milligrams (mg). Make sure your prescription tells you how many milliliters (mL) to use.
  • Your healthcare provider may prescribe another medicine called an antiemetic to take while you are using Apokyn. Antiemetic medicines help to decrease the symptoms of nausea and vomiting that can happen with Apokyn.
  • If you take too much Apokyn, you may experience more side effects than usual and they may be stronger than usual. If you are experiencing severe or serious side effects, such as such as chest pain or prolonged erection lasting more than 4 hours,contact your healthcare provider immediately. If you are unable to contact your healthcare provider, you should have someone take you to the Emergency Room.

Other Requirements

  • Store at room temperature, 68°F to 77°F (20°C to 25°C)
  • Keep this and all medicines out of the reach of children

What is apomorphine?

Apomorphine has some of the same effects as a chemical called dopamine, which occurs naturally in your body. Low levels of dopamine in the brain are associated with Parkinson's disease.

Apomorphine is used to treat "wearing-off" episodes (muscle stiffness, loss of muscle control) in people with advanced Parkinson's disease.

Apomorphine may also be used for purposes not listed in this medication guide.

What should I discuss with my healthcare provider before using apomorphine?

You should not use apomorphine if you are allergic it.

Some medicines can cause unwanted or dangerous effects when used with apomorphine. Your doctor may need to change your treatment plan if you use any of the following drugs:

  • alosetron (Lotronex);

  • dolasetron (Anzemet);

  • granisetron (Kytril);

  • ondansetron (Zofran); or

  • palonosetron (Aloxi).

To make sure apomorphine is safe for you, tell your doctor if you have ever had:

  • heart disease, or a family history of heart rhythm problems;

  • low blood pressure or dizzy spells;

  • a heart attack, stroke, or coronary artery disease;

  • liver disease;

  • kidney disease;

  • asthma or sulfite allergy;

  • narcolepsy or a history of falling asleep during the daytime; or

  • a history of mental illness or psychosis.

People with Parkinson's disease may have a higher risk of skin cancer (melanoma). Talk to your doctor about this risk and what skin symptoms to watch for.

It is not known whether this medicine will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant.

It is not known whether apomorphine passes into breast milk or if it could affect the nursing baby. Tell your doctor if you are breast-feeding.

How should I use apomorphine?

Follow all directions on your prescription label. Your doctor may occasionally change your dose. Never use apomorphine in larger amounts, or use it for longer than recommended. Tell your doctor if the medicine seems to stop working as well.

Apomorphine is injected under the skin. You may be shown how to use injections at home. Do not give yourself this medicine if you do not understand how to use the injection and properly dispose of used needles and syringes.

Do not inject apomorphine into a vein.

Your care provider will show you the best places on your body to inject apomorphine. Use a different place each time you give an injection. Do not inject into the same place two times in a row.

Read all patient information, medication guides, and instruction sheets provided to you. Ask your doctor or pharmacist if you have any questions.

Apomorphine can cause severe nausea and vomiting. To prevent these symptoms, you may be given anti-nausea medication to start taking a few days before you start using apomorphine. Keep taking the anti-nausea medicine throughout your treatment with apomorphine.

Do not take any anti-nausea medicine without first asking your doctor. Some anti-nausea medicines can increase certain side effects of apomorphine, or can make your Parkinson's symptoms worse.

Measuring your apomorphine dose correctly is extremely important. When you use an injection pen with apomorphine, the medicine is measured in milliliters (mL) marked on the pen. However, your prescribed dose may be in milligrams (mg). One milligram, or 1 mg, of apomorphine is equal to 0.1 mL marked on the injection pen.

Do not use apomorphine if it has changed colors or has particles in it. Call your pharmacist for new medication.

When you dial in your dose on the injection pen, make sure there is enough medicine inside the apomorphine cartridge to make up the full dose. Ask your pharmacist if you have any questions about how to correctly measure your dose.

Your blood pressure will need to be checked often.

Do not stop using apomorphine suddenly, or you could have unpleasant withdrawal symptoms. Ask your doctor how to safely stop using apomorphine.

If you stop using apomorphine for 7 days or longer, ask your doctor before restarting the medication. You may need to restart with a lower dose.

Use a disposable needle only once. Follow any state or local laws about throwing away used needles and syringes. Use a puncture-proof "sharps" disposal container (ask your pharmacist where to get one and how to throw it away). Keep this container out of the reach of children and pets.

Store apomorphine cartridges at room temperature away from moisture and heat.

Apomorphine side effects

Get emergency medical help if you have signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

  • nausea or vomiting that continues after taking an anti-nausea medication;

  • twitching or uncontrollable movements of your eyes, lips, tongue, face, arms, or legs;

  • worsening of your Parkinson symptoms;

  • a light-headed feeling, like you might pass out;

  • severe headache;

  • daytime sleepiness or drowsiness;

  • depression, confusion, unusual or inappropriate behavior;

  • paranoia, delusions, hallucinations, delirium, aggressive behavior, agitation;

  • slow heart rate, weak pulse, fainting, slow breathing (breathing may stop);

  • penis erection that is painful or lasts 4 hours or longer;

  • heart problems--chest pain or pressure, shortness of breath, fast heart rate; or

  • lung problems--new or worsening cough, pain when you breathe, feeling short of breath while lying down, wheezing, gasping for breath, cough with foamy mucus, fever.

You may have increased sexual urges, unusual urges to gamble, or other intense urges while using this medicine. Talk with your doctor if this occurs.

Common side effects may include:

  • nausea, vomiting;

  • drowsiness, dizziness;

  • involuntary muscle movement;

  • chest pain;

  • pale skin, increased sweating, flushing (warmth, redness, or tingly feeling);

  • swelling in your arms, hands, legs, or feet;

  • yawning;

  • runny nose; or

  • itching, bruising, or hardening of your skin where the medicine was injected.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Interactions for Apokyn

Drugs That Prolong QT Interval

Potential pharmacologic interaction (additive effect on QT interval prolongation).1 (See Prolongation of QT Interval under Cautions.)

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interaction unlikely.1

Specific Drugs

Drug

Interaction

Comments

Antihypertensive agents and vasodilators

Potential pharmacologic interaction (additive hypotensive effects)1

Concomitant use associated with increased incidence of hypotension, MI, pneumonia, serious falls, bone and joint injuries1

Caution1

Catecho-O-methyltransferase (COMT) inhibitors

Pharmacokinetic interaction unlikely1 7

CNS depressants

Alcohol: Potential pharmacologic interaction (additive sedative and hypotensive effects)1

CNS depressants: Potential pharmacologic interaction (additive sedative effects)1

5-HT3 receptor antagonists (dolasetron, granisetron, ondansetron, palonosetron)

Potential pharmacologic interaction (profound hypotension and loss of consciousness)1

Concomitant use contraindicated1

Dopamine-receptor antagonists (e.g., phenothiazines, butyrophenones, thioxanthenes, metoclopramide)

Potential pharmacologic interaction (reduced efficacy of apomorphine)1

Phenothiazines, butyrophenones, thioxanthenes: Weigh benefits and risks of therapy with a dopamine agonist in patients receiving one of these dopamine-receptor antagonists for the treatment of major psychosis1

Levodopa/carbidopa

Potential pharmacologic interaction (additive neurologic effect; used to therapeutic effect)1

Pharmacokinetic interaction unlikely1

Commonly used brand name(s)

In the U.S.

  • Apokyn

Available Dosage Forms:

  • Solution

Therapeutic Class: Antiparkinsonian

Pharmacologic Class: Dopamine Agonist

Apokyn Dosage and Administration

Important Administration Instructions

Apokyn is indicated for subcutaneous administration only [see Warnings and Precautions (5.1)] and only by a multiple-dose Apokyn Pen with supplied cartridges. 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 Apokyn 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 Apokyn should be expressed in mL to avoid confusion.

Visually inspect the Apokyn 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)].

Premedication and Concomitant Medication

Because of the high incidence of nausea and vomiting with Apokyn treatment, an antiemetic, e.g., trimethobenzamide 300 mg three times a day, should be started 3 days prior to the initial dose of Apokyn [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 Apokyn, as trimethobenzamide increases the incidence of somnolence, dizziness and falls in patients treated with Apokyn [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 5HT3 antagonist class including antiemetics (for example, ondansetron, granisetron, dolasetron, palonosetron) and alosetron are contraindicated [see Contraindications (4)].

Dosing Information

The recommended starting dose of Apokyn 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 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 Apokyn should not be considered candidates for treatment with Apokyn.

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) [see Clinical Pharmacology (12.3) and Use in Specific Populations (8.6)].

. Dosing in Patients with Hepatic Impairment

Closely monitor patients with mild and moderate hepatic impairment [see Clinical Pharmacology (12.3) and Use in Specific Populations (8.7)].

Re-treatment and Interruption in Therapy

If a single dose of Apokyn 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 Apokyn 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.

Use in specific populations

Pregnancy

Risk Summary

There are no adequate data on the developmental risk associated with use of Apokyn 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/m2 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/m2 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/m2 basis.

Lactation

Risk Summary

There are no data on the presence of apomorphine in human milk, the effects of apomorphine on the breastfed infant, or the effects of apomorphine on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Apokyn and any potential adverse effects on the breastfed infant from Apokyn or from the underlying maternal condition.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

In the Apokyn clinical development program, there were 239 patients less than age 65 treated with Apokyn and 311 patients who were age 65 years of age or older. Confusion and hallucinations were reported more frequently with patients age 65 and older compared to patients with less than age 65. Serious adverse reactions (life-threatening events or events resulting in hospitalization and/or increased disability) were also more common in patients age 65 and older. Patients age 65 and older were more likely to fall (experiencing bone and joint injuries), have cardiovascular events, develop respiratory disorders, and have gastrointestinal events. Patients age 65 and above were also more likely to discontinue Apokyn treatment as a result of one or more adverse reactions.

Renal Impairment

The starting Apokyn dose should be reduced in patients with mild or moderate renal impairment because the concentration and exposure (Cmax and AUC) are increased in these patients. Studies in subjects with severe renal impairment have not been conducted [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].

Hepatic Impairment

Caution should be exercised when administrating Apokyn 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 Dosage and Administration (2.5) and Clinical Pharmacology (12.3)].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Lifetime carcinogenicity studies of apomorphine were conducted in male (0.1, 0.3, or 0.8 mg/kg/day) and female (0.3, 0.8, or 2 mg/kg/day) rats. Apomorphine was administered by subcutaneous injection for 22 months or 23 months, respectively. In males, there was an increase in Leydig cell tumors at the highest dose tested, which is less than the MRHD (20 mg) on a mg/m2 basis. This finding is of questionable significance because the endocrine mechanisms believed to be involved in the production of Leydig cell tumors in rats are not relevant to humans. No drug-related tumors were observed in females; the highest dose tested is similar to the MRHD on a mg/m2 basis.

In a 26-week carcinogenicity study in P53-knockout transgenic mice, there was no evidence of carcinogenic potential when apomorphine was administered by subcutaneous injection at doses up to 20 mg/kg/day (male) or 40 mg/kg/day (female).

Mutagenesis

Apomorphine was mutagenic in the in vitro bacterial reverse mutation (Ames) and the in vitro mouse lymphoma tk assays. Apomorphine was clastogenic in the in vitro chromosomal aberration assay in human lymphocytes and in the in vitro mouse lymphoma tk assay. Apomorphine was negative in the in vivo micronucleus assay in mice.

Impairment of Fertility

Apomorphine was administered subcutaneously at doses up to 3 mg/kg/day (approximately 1.5 times the MRHD on a mg/m2 basis) to male and female rats prior to and throughout the mating period and continuing in females through gestation day 6. There was no evidence of adverse effects on fertility or on early fetal viability. A significant decrease in testis weight was observed in a 39-week study in cynomolgus monkey at all subcutaneous dose tested (0.3, 1, or 1.5 mg/kg/day); the lowest dose tested is less than the MRHD on a mg/m2 basis.

In a published fertility study, apomorphine was administered to male rats at subcutaneous doses of 0.2, 0.8, or 2 mg/kg prior to and throughout the mating period. Fertility was reduced at the highest dose tested.

Clinical Studies

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), in patients with advanced Parkinson's disease was established in three randomized, controlled trials of Apokyn given subcutaneously (Studies 1, 2, and 3). At baseline in these trials, the mean duration of Parkinson's disease was approximately 11 years. Whereas all patients were using concomitant L-dopa at baseline, 86% of patients were using a concomitant oral dopaminergic agonist, 31% were using a concomitant catechol-ortho-methyl transferase (COMT) inhibitor, and 10% were using a concomitant monoamine B oxidase inhibitor. Study 1 was conducted in patients who did not have prior exposure to Apokyn (i.e., Apokyn naïve) and Studies 2 and 3 were conducted in patients with at least 3 months of Apokyn use immediately prior to study enrollment. Almost all patients without prior exposure to Apokyn began taking an antiemetic (trimethobenzamide) three days prior to starting Apokyn and 50% of patients were able to discontinue the concomitant antiemetic, on average 2 months after initiating Apokyn.

The change from baseline 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.

Study 1

Study 1 was a randomized, double-blind, placebo-controlled, parallel-group trial in 29 patients with advanced Parkinson's disease who had at least 2 hours of "off" time per day despite an optimized oral regimen for Parkinson's disease including levodopa and an oral dopaminergic agonist. Patients with atypical Parkinson's disease, psychosis, dementia, hypotension, or those taking dopamine antagonists were excluded from participation. 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 on study treatment in a 2:1 ratio (2 mg of Apokyn or placebo given subcutaneously). At least 2 hours after the first dose, patients were given additional doses of study medication until they achieved a "therapeutic response" (defined as a response similar to the patient's response to their usual dose of levodopa) or until 10 mg of Apokyn or placebo equivalent was given. At each injection re-dosing, the study drug dose was increased in 2 mg increments up to 4 mg, 6 mg, 8 mg, 10 mg of Apokyn) or placebo equivalent.

Of the 20 patients randomized to Apokyn, 18 achieved a "therapeutic response" at about 20 minutes. The mean Apokyn dose was 5.4 mg (3 patients on 2 mg, 7 patients on 4 mg, 5 patients on 6 mg, 3 patients on 8 mg, and 2 patients on 10 mg). In contrast, of the 9 placebo-treated patients, none reached a "therapeutic response." The mean change-from-baseline for UPDRS Part III score for Apokyn group (highest dose) was statistically significant compared to that for the placebo group (Table 2).

Table 2: Mean Change from Baseline in UPDRS Motor Score for Intent-to-Treat Population in Study 1
Treatment Baseline UPDRS Motor Score Mean Change from Baseline Difference from placebo
Placebo 36.3 - 0.1 NA
Apokyn 39.7 - 23.9 - 23.8

Study 2

Study 2 used a randomized, placebo-controlled crossover design of 17 patients with Parkinson's disease who had been using Apokyn 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 Apokyn (at their usual dose) and placebo on different days in random order. UPDRS Part III scores were evaluated over time. The mean dose of Apokyn was 4 mg (2 patients on 2 mg, 9 patients on 3 mg, 2 patients on 4 mg, and 1 patient each on 4.5 mg, 5 mg, 8 mg, and 10 mg). The mean change-from-baseline UPDRS Part III score for the Apokyn group was statistically significant compared to that for the placebo group (Table 3).

Table 3: Mean Change from Baseline in UPDRS Motor Score for Intent-to-Treat Population in Study 2
Treatment Baseline UPDRS Motor Score Mean Change from Baseline Difference from placebo
Placebo 40.1 - 3.0 NA
Apokyn 41.3 - 20.0 - 17.0

Study 3

Study 3 used a randomized withdrawal design in 4 parallel groups from 62 patients (Apokyn-35; Placebo-27) with Parkinson's disease who had been using Apokyn for at least 3 months. Patients were randomized to one of the following 4 treatments dosed once by subcutaneous administration: Apokyn at the usual dose (mean dose 4.6 mg), placebo at a volume matching the usual Apokyn dose, Apokyn at the usual dose + 2 mg (0.2 mL) (mean dose 5.8 mg), or placebo at a volume matching the usual Apokyn dose + 0.2 mL. 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. Apokyn doses ranged between 2 mg – 10 mg. The mean change-from-baseline for the Apokyn group for UPDRS Part III scores at 20 minutes post dosing was statistically significant compared to that for the placebo group (Table 4). Figure 2 describes the mean change from baseline in UPDRS Motor Scores over time for pooled Apokyn and placebo administration.

Table 4: Mean Change from Baseline in UPDRS Motor Score for Intent-to-Treat Population in Study 4
Treatment Baseline UPDRS Motor Score Mean Change from Baseline Difference from placebo
Placebo (Pooled) 40.6 - 7.4 NA
Apokyn (Pooled) 42.0 - 24.2 - 16.8
Figure 2: Mean Change from Baseline in UPDRS Motor Scores of Pooled Apokyn Groups and Placebo Group in Study 3

In Study 3, the mean changes-from-baseline for UPDRS Part III scores at 20 minutes post dosing for the Apokyn and higher dose Apokyn groups were 24 and 25, respectively. This result 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 also an increased incidence of adverse reactions in patients randomized to higher Apokyn dose.

Patient Counseling Information

See FDA-approved patient labeling (Patient Information and Instructions for Use)

Administration with the Apokyn Pen

Instruct patients and caregivers to read the "Apokyn Pen Instructions for Use" and Patient Information. Instruct patients to use Apokyn only as prescribed [See Dosage and Administration (2)].

Instruct patients and caregivers that the Apokyn Pen is dosed in milliliters, not milligrams.

Inform patients and caregivers that it is possible to dial in their usual dose of Apokyn 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. 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).

Instruct patients to rotate the injection site and to observe proper aseptic technique.

Advise patients that Apokyn is intended only for subcutaneous injection and must not be given intravenously because of the risk of serious complications such as thrombus formation and pulmonary embolism due to crystallization [see Warnings and Precautions (5.1)].

Avoidance of Concomitant Antiemetic Drugs of 5HT3 Antagonist Class

Advise patients that they should not use concomitant drugs of the 5HT3 antagonist class including antiemetics (e.g., ondansetron, granisetron, dolasetron, palonosetron) and alosetron with Apokyn. Use of Apokyn with concomitant antiemetic drugs of the 5HT3 antagonist class is contraindicated because there have been reports of profound hypotension and loss of consciousness when Apokyn was administered with ondansetron [see Contraindications (4)].

Hypersensitivity / Allergic Reactions

Advise patients that hypersensitivity/allergic reaction characterized by urticaria, rash, pruritus, and/or various manifestations of angioedema may occur because of Apokyn or any of its excipients including a sulfite (i.e., sodium metabisulfite). Inform patients with a sulfite sensitivity that they may experience various allergic-type reactions, including anaphylactic symptoms and life-threatening asthmatic attacks. Advise patients who experience any hypersensitivity/allergic reaction to Apokyn that they should avoid taking Apokyn again [see Contraindications (4)].

Nausea and Vomiting

Advise patients that they may experience severe nausea and/or vomiting and that they should begin taking trimethobenzamide 300 mg orally 3 times per day for 3 days prior to starting Apokyn injections. Advise patients that Apokyn taken with trimethobenzamide may increase the risks for somnolence, dizziness, and falls. Inform patients that their healthcare provider will tell them when trimethobenzamide can be discontinued [see Warnings and Precautions (5.2)].

Falling Asleep Suddenly and Sedation / Sleepiness

Alert patients to the potential sedating effects of Apokyn, including somnolence and falling asleep while engaged in activities of daily living. Instruct patients not to drive a car or 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. Advise patients that if increased somnolence or episodes of falling asleep during activities of daily living (e.g., watching television, passenger in a car, etc.) occur, they should not drive or participate in potentially dangerous activities until they have contacted their physician. Because of possible additive effects of alcohol use, advise patients to limit their alcohol intake [see Warnings and Precautions (5.3)].

Syncope

Advise patients that Apokyn may cause syncope [see Warnings and Precautions (5.4)].

Hypotension / Orthostatic Hypotension

Advise patients 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). Instruct patients to rise slowly after sitting or lying down after taking Apokyn. Instruct patients to limit their alcohol intake because it may potentiate the hypotensive effect of Apokyn [see Warnings and Precautions (5.5)].

Falls

Alert patients that they may have increased risk for falling when using Apokyn [see Warnings and Precautions (5.6)].

Hallucinations and/or Psychotic-Like Behavior

Inform patients that hallucinations or other manifestations of psychotic-like behavior can occur. Tell patients if they have a major psychotic disorder, ordinarily they should not use Apokyn 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 Warnings and Precautions (5.7)].

Dyskinesia

Inform patients that Apokyn may cause and/or exacerbate pre-existing dyskinesias [see Warnings and Precautions (5.8)].

Impulse Control / Compulsive Behaviors

Patients and their caregivers should be alerted to the possibility that they may experience intense urges to spend money uncontrollably, intense urges to gamble, increased sexual urges, binge eating and/or other intense urges and the inability to control these urges while taking Apokyn [see Warnings and Precautions (5.9)].

Coronary Events

Inform patients that Apokyn may cause coronary events including angina and myocardial infarction and these outcomes could possibly be related to significant hypotension/orthostatic hypotension [see Warnings and Precautions (5.10)].

QTc Prolongation and Potential for Proarrhythymic Effects

Alert patients that Apokyn may cause QTc prolongation and might produce proarrhythmic effects that could cause torsades de pointes and sudden death. Palpitations and syncope may signal the occurrence of an episode of torsades de pointes [see Warnings and Precautions (5.11)].

Withdrawal-Emergent Hyperpyrexia and Confusion

Advise patients to contact their healthcare provider if they wish to discontinue Apokyn or decrease the dose of Apokyn [see Warnings and Precautions (5.12)].

Melanoma

Advise patients with Parkinson's disease that they have a higher risk of developing melanoma. Advise patients to have a qualified healthcare provider examine that patient's skin periodically for melanomas on a regular basis when using Apokyn [see Warnings and Precautions (5.13)].

Priapism

Advise patients that Apokyn may cause prolonged painful erections and that if this occurs that they should seek medical attention immediately [see Warnings and Precautions (5.15)].

Injection Site Reactions

Inform patients that injections of Apokyn may result in injection site reactions including bruising, granuloma, and pruritus [see Adverse Reactions (6.1)].

Distributed by:

US WorldMeds, LLC
4441 Springdale Rd
Louisville, KY 40241

US WorldMeds, LLC is the exclusive licensee and distributor of Apokyn in the United States and Its territories.
© 2017. Apokyn is a registered trademark of BRITUSWIP.

What is the most important information i should know about apomorphine (apokyn)?

You should not use apomorphine if you also taking alosetron (Lotronex), dolasetron (Anzemet), granisetron (Kytril), ondansetron (Zofran), or palonosetron (Aloxi).

Before using apomorphine, tell your doctor if you have an electrolyte imbalance (such as low levels of potassium or magnesium in your blood), a slow heart rate, low blood pressure or dizzy spells, a history of "Long QT syndrome," a history of stroke or heart attack, asthma, sulfite allergy, or liver or kidney disease.

Apomorphine may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

Some people using this medicine have fallen asleep during normal daytime activities such as talking, eating, or driving. You may fall asleep suddenly, even after feeling alert. If this happens to you, stop taking apomorphine and talk with your doctor.

You may have increased sexual urges, unusual urges to gamble, or other intense urges while taking this medication. Talk with your doctor if you believe you have any intense or unusual urges while taking apomorphine.

What should i avoid while using apomorphine (apokyn)?

Apomorphine may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Get up slowly and steady yourself to prevent a fall.

Do not drink alcohol. It can further lower your blood pressure and may increase certain side effects of apomorphine.

Where can i get more information?

Your doctor or pharmacist can provide more information about apomorphine.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

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What other drugs will affect Apokyn?

Taking this medicine with other drugs that make you sleepy can worsen this effect. Ask your doctor before taking Apokyn with a sleeping pill, narcotic medicine, muscle relaxer, or medicine for anxiety, depression, or seizures.

Some medicines can cause unwanted or dangerous effects when used with Apokyn. Tell each of your healthcare providers about all medicines you use now, and any medicine you start or stop using, especially:

  • blood pressure medication;

  • a "vasodilator"; or

  • nitrate medication--nitroglycerin (Nitro Dur, Nitrolingual, Nitrostat, Transderm Nitro, and others), isosorbide dinitrate (Dilatrate, Isordil, Isochron), or isosorbide mononitrate (Imdur, ISMO, Monoket).

This list is not complete. Other drugs may interact with apomorphine, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

Apomorphine Pregnancy Warnings

Apomorphine has been assigned to pregnancy category C by the FDA. Animal reproduction studies have not been conducted with apomorphine. There are no controlled data from human pregnancy studies. It is also not known whether apomorphine can cause fetal harm when administered to a pregnant woman. Apomorphine should only be given during pregnancy when benefit outweighs risk.

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