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.

Before using apomorphine, tell your doctor if you regularly use other medicines that make you sleepy (such as cold or allergy medicine, sedatives, narcotic pain medicine, sleeping pills, muscle relaxers, and medicine for seizures, depression, or anxiety). They can add to sleepiness caused by apomorphine.

Many drugs can interact with apomorphine. Below is just a partial list. Tell your doctor if you are using:

• arsenic trioxide (Trisenox);
• blood pressure medications;
• metoclopramide (Reglan);
• sildenafil (Viagra), tadalafil (Cialis), or vardenafil (Levitra);
• an antidepressant such as amitriptylline (Elavil, Vanatrip), clomipramine (Anafranil), or desipramine (Norpramin);
• anti-malaria medications such as chloroquine (Arelan), or mefloquine (Lariam);
• an antibiotic such as clarithromycin (Biaxin), erythromycin (E.E.S., EryPed, Ery-Tab, Erythrocin), levofloxacin (Levaquin), moxifloxacin (Avelox), or pentamidine (NebuPent, Pentam);
• heart rhythm medicine such as amiodarone (Cordarone, Pacerone), dofetilide (Tikosyn), disopyramide (Norpace), ibutilide (Corvert), procainamide (Pronestyl), propafenone (Rythmol), quinidine (Quin-G), or sotalol (Betapace);
• medicines to treat psychiatric disorders, such as chlorpromazine (Thorazine), clozapine (FazaClo, Clozaril), haloperidol (Haldol), pimozide (Orap), thioridazine (Mellaril), thiothixene (Navane), or ziprasidone (Geodon);
• migraine headache medicine such as sumatriptan (Imitrex) or zolmitriptan (Zomig);
• narcotic medication such as methadone (Dolophine, Methadose); or
• nitrate medication, such as 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 and other drugs may interact with apomorphine. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

APOKYN (apomorphine hydrochloride injection) contains apomorphine hydrochloride, a non-ergoline dopamine agonist. Apomorphine hydrochloride is chemically designated as 6aβ-Aporphine-10,11-diol hydrochloride hemihydrate with a molecular formula of C17H17NO2 • HCL • ½ H2O. Its structural formula and molecular weight are:

Figure 1 : Structural Formula and Molecular Weight of Apomorphine

Apomorphine hydrochloride appears as minute, white or grayish-white glistening crystals or as white powder that is soluble in water at 80°C.

APOKYN is a clear, colorless, sterile solution for subcutaneous injection and is available in 3 mL (30 mg) multi-dose cartridges. Each mL of solution contains 10 mg of apomorphine hydrochloride, USP as apomorphine hydrochloride hemihydrate, 1 mg of sodium metabisulfite, NF and 5 mg of benzyl alcohol, NF (preservative) 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.

Dosage Forms And Strengths

APOKYN 30 mg/3 mL (10 mg/mL) containing apomorphine hydrochloride (as apomorphine hydrochloride hemihydrate), USP is supplied as a clear, colorless, sterile, solution in a 3 mL (30 mg) cartridge. The 3 mL (30 mg) glass cartridge is used with a manual reusable, multiple-dose pen injector (APOKYN Pen). A single cartridge, pen and needle can deliver doses up to 1 mL (10 mg) in 0.02 mL (0.2 mg) increments. The multiple-dose pen injector is provided in a package with six needles.

Storage And Handling

APOKYN is supplied as a 10 mg/mL clear, colorless, sterile, solution in 3 mL (30 mg) glass cartridges.

NDC 27505-004-05

Cartons of five 3 mL cartridges

The pen injector is provided in a package with six needles and a carrying case.

Store at 25°C (77°F). Excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]

Distributed by: US WorldMeds, LLC 4441 Springdale Rd Louisville, KY 40241. Revised: Mar 2017

Serious side effects have been reported with Apokyn including the following:

• Severe allergic reactions. Severe and potentially life-threatening allergic reactions are possible with Apokyn. Discontinue use and get emergency medical attention immediately if you develop any of the following symptoms of a severe allergic reaction:
  • sudden difficulty breathing
  • sudden and abnormal swelling of the lips, tongue, and/or throat
  • sudden development of a red blister-like skin rash
  • sudden drop in blood pressure
• Blood Clots. Injecting Apokyn into a vein (intravenous) can cause blood clots. Do not inject Apokyn in your vein.
• Nausea and vomiting. Severe nausea and vomiting can happen with Apokyn. Your healthcare provider may prescribe a medicine called trimethobenzamide (Tigan) to help prevent nausea and vomiting. Some patients can stop taking Tigan after using Apokyn for several months. Some patients may need to keep taking Tigan to help prevent nausea and vomiting. Talk to your healthcare provider before you stop taking Tigan.
• Excessive drowsiness during the day. There have been reports of severe episodes of sudden drowsiness in a small number of patients using Apokyn. Your physician will assess your risk for this rare side effect, but it is very important that you notify your physician of any sleeping disorders you have.
• Dizziness. Apokyn can lower your blood pressure and cause dizziness. Dizziness can happen when Apokyn treatment is started or when the Apokyn dose is increased. Do not get up too fast from sitting or after lying down, especially if you have been sitting or lying down for a long period of time.
• Falls. Patients with Parkinson's disease are already at risk of falling due to the nature of the disease. Clinical researchers were unable to determine whether falls that occurred in clinical trials of Apokyn were related to use of Apokyn or only due to underlying Parkinson's disease. Consult with your physician about your risk for falls during treatment with Apokyn.
• Hallucinations and psychotic behavior. Hallucinations and psychotic behavior were reported in a small number of patients during clinical trials with Apokyn. Risk may increase with underlying mental illness. Consult with your physician about your level of risk for developing hallucinations or psychotic behavior during your treatment with Apokyn.
• sudden uncontrolled movements (dyskinesias). Some people with PD may get sudden, uncontrolled movements after treatment with some PD medicines. Apokyn can cause or make dyskinesias worse.
• intense urges. Some people with PD have reported new or increased gambling urges, increased sexual urges, and other intense urges, while taking PD medicines, including Apokyn
• Fainting. In clinical trials, about 2% of patients receiving Apokyn experienced fainting. Consult with your physician about your risk for developing fainting episodes while taking Apokyn.
• Abnormal heart rhythms. Abnormal heart rhythms have been reported in patients receiving Apokyn, especially those already at high risk for developing abnormal heart rhythms. Consult with your physician about your level of risk for developing abnormal heart rhythms during treatment with Apokyn.
• Low blood pressure. Low blood pressure has been known to occur in patients taking medications similar to Apokyn in combination with medications used to treat high blood pressure. Be sure to report all of your medications to your physician prior to beginning treatment with Apokyn.
• Heart problems. Tell your doctor immediately or seek medical attention If you have shortness of breath, fast heartbeat, or chest pain while taking this medication. 
• Injection site reactions. During clinical trials, 26% of patients using Apokyn experienced injection site reactions that included bruising, itching, and other complications. Inform your physician if you have experienced injection site reactions with other medications in the past.
• Fever and confusion. This can happen in some people when their PD medicine is stopped or there is a fast decrease in the dose of their PD medicine.
• Skin cancer (melanoma). Some people with PD may have an increased chance of getting a skin cancer called melanoma. People with PD should have a healthcare provider check their skin for skin cancer regularly.
• Tissue changes. Some people have had changes in the tissues of their pelvis, lungs, and heart valves when taking medicines called nonergot derived dopamine agonists like Apokyn. 
• Drug abuse. Although rare, Apokyn is occasionally abused leading to hallucinations, reduced mobility, and occasional psychotic behavior. Consult with your physician if you have a history of drug abuse prior to beginning treatment with Apokyn.
• Reduced mobility. Although rare, reduced mobility was reported in a small number of patients using Apokyn during clinical trials shortly after receiving Apokyn. Consult with your physician if you believe you are experiencing reduced mobility after administration of Apokyn.
• Priapism. Although rare, painful erections lasting longer than four hours were reported in a small number of male patients during clinical trials of Apokyn. Get medical attention immediately if you experience an erection lasting longer than four hours.

Do not take Apokyn if you

• are allergic to Apokyn, sulfites, or to any of its ingredients
• take 5HT3 antagonists, including antiemetics (e.g., ondansetron, granisetron, dolasetron, palonosetron) and alosetron

Apokyn can also cause dizziness and/or drowsiness. Do not drive or operate heavy machinery until you know how Apokyn affects you.

Do not drink alcohol while you are using Apokyn. It can increase your chance of developing serious side effects.

Do not take medicines that make you sleepy while you are using Apokyn.

Do not change your body position too fast. Get up slowly from sitting or lying. Apokyn can lower your blood pressure and cause dizziness or fainting.

Dosage Forms & Strengths

injection solution

• 10mg/mL (30mg/3mL pen injector)

Parkinson Disease

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

Initial: 2 mg (0.2 mL) SC

Also see Administration for details regarding test dose

Dose titration

• Titrate on the basis of effectiveness and tolerance, up to a maximum dose of 6 mg
• Average frequency of dosing in clinical trials was TID
• Limited experience with single doses >6 mg, dosing >5 times per day, or with total daily doses >20 mg

Premedication

• High incidence of nausea and vomiting with treatment; initiate an antiemetic (eg, trimethobenzamide 300 mg TID) 3 days prior to the initial apomorphine dose
• Treatment with trimethobenzamide should only be continued as long as necessary to control nausea and vomiting, and generally no longer than 2 months after initiation of treatment
• Trimethobenzamide increases the incidence of somnolence, dizziness, and falls
• Based on reports of profound hypotension and loss of consciousness when apomorphine was administered with ondansetron, coadministration with 5HT3 antagonists (eg, ondansetron, granisetron, dolasetron, palonosetron) are contraindicated

Dosage Modifications

Renal impairment

• Mild-to-moderate: Reduce test dose and starting dose to 1 mg (0.1 mL); peak plasma concentration and AUC increased in these patients
• Severe: Not studied

Hepatic impairment

• Mild–to-moderate: Use caution; peak plasma concentration and AUC increased in these patients
• Severe: Not studied

Hepatic Impairment

Mild to moderate impairment: Use caution

Severe impairment: Safety and efficacy not established

Vegetative State (Orphan)

Treatment of patients in a vegetative state or minimally conscious state for up to 12 months following a severe traumatic brain injury

Orphan indication sponsor

• NeuroHealing Pharmaceuticals, Inc; 50 Undine Road; Newton, MA 02135

Safety and efficacy not established

>10%

Dizziness or postural hypotension (20%)

Dyskinesia (35%)

Injection site reaction (26%)

Nausea or vomiting (30%)

Somnolence (35%)

Yawning (40%)

1-10%

Anxiety

Arthralgia

Back pain

CHF

Confusion (10%)

Depression

Edema (10%)

Hallucinations (10%)

Headache

Injection site pain

Insomnia

Limb pain

Rhinorrhea (10%)

UTI

Serious drug interactions can occur when certain medicines are used together with apomorphine. Tell each of your healthcare providers about all medicines you use now, and any medicine you start or stop using.

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

Use the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not use extra medicine to make up the missed dose.

Nonergot-derivative dopamine receptor agonist.1 4

Hypomobility Episodes Associated with Parkinson’s Disease

Acute, intermittent treatment of episodes of hypomobility (i.e., “off” episodes, including end-of-dose “wearing off” and unpredictable “on-off” episodes) associated with advanced Parkinson’s disease (designated an orphan drug by FDA for this use).1 2 3 4 6 5 8 9 11 12 13 14

Used as an adjunct to other antiparkinsonian agents (e.g., levodopa, oral dopamine receptor agonists).1 2 5 8 11

Acute Poisoning

Formerly used to induce vomiting in the early management of acute oral drug overdose and in certain cases of oral poisoning (dose: 5–6 mg sub-Q)†.15

General

• Administer an antiemetic (i.e., trimethobenzamide hydrochloride 300 mg orally 3 times daily) beginning 3 days prior to initiation of apomorphine; continue for the first 2 months of therapy or until tolerance to nausea and vomiting develops.1 11

• Avoid certain other antiemetic agents (i.e., selective 5-HT3 receptor antagonists, dopamine-receptor antagonists [metoclopramide, phenothiazines]).1 4 (See Contraindications under Cautions and Specific Drugs under Interactions.)

Administration

Sub-Q Administration

Administer by sub-Q injection using the dosing pen on an as-needed basis to reverse “off” episodes.1

Administer sub-Q injections in the abdomen, thigh, or upper arm; rotate injection sites.1

Test dose: Administer all test doses in a medical setting where BP can be closely monitored.1 Measure supine and standing BP prior to and 20, 40, and 60 minutes after each test dose.1

Test dose: Determine dose when patient is experiencing an “off” episode.1 Induction of an “off” state can be facilitated by withholding the patient’s antiparkinsonian agents overnight.1

Do not administer IV; possibility of serious adverse effects (e.g., thrombosis, pulmonary embolism).1

Dosage

Available as apomorphine hydrochloride; dosage expressed in terms of the salt.1

Provide dosing instructions for the patient or their caregiver in mL; dose on the dosing pen device is expressed in terms of mL.1

Titrate dose according to patient’s response and tolerance.1

Adults

Initial test dose is 0.2 mL (2 mg).1 If the 0.2-mL (2-mg) dose is effective and tolerated, this dose may be used on an as-needed, outpatient basis.1 If necessary, the dose may be increased in 0.1-mL (1-mg) increments every few days.1

Patient is not a candidate for apomorphine therapy if clinically significant orthostatic hypotension occurs in response to initial 0.2-mL (2-mg) test dose.1

For patients who tolerate, but do not respond to the initial 0.2-mL (2-mg) test dose, administer a second test dose of 0.4 mL (4 mg) at the next observed “off” period, no sooner than 2 hours after the initial test dose.1 If the 0.4-mL (4-mg) dose is effective and tolerated, a 0.3-mL (3-mg) dose may be used on an as-needed, outpatient basis.1 If necessary, the dose may be increased in 0.1-mL (1-mg) increments every few days.1

For patients who respond, but do not tolerate the 0.4-mL (4-mg) test dose, administer a third test dose of 0.3 mL (3 mg) at the next observed “off” period, but no sooner than 2 hours after the 0.4-mL (4-mg) test dose.1 If the 0.3-mL (3-mg) dose is effective and tolerated, a 0.2-mL (2-mg) dose may be used on an as-needed, outpatient basis.1 If the 0.2-mL (2-mg) dose is tolerated, the dose may be increased, if needed, to 0.3 mL (3 mg) after a few days.1 The dose should not usually be increased to 0.4 mL (4 mg) on an outpatient basis in these patients.1

In clinical studies, most patients responded to doses of 0.3–0.6 mL (3–6 mg); average frequency of dosing was 3 times daily.1

If therapy has been interrupted for >1 week, reinitiate at a dose of 0.2 mL (2 mg) and gradually titrate to effect.1

Prescribing Limits

Adults

No more than one dose of apomorphine should be administered for treatment of a single “off” episode.1 Safety and efficacy of a second dose during the same hypomobility episode in patients not responding to the initial dose have not been established.1

Doses >0.6 mL (6 mg) not associated with additional therapeutic effect and are not recommended.1

Limited experience with >5 doses per day or daily dosages >2 mL (20 mg).1

Special Populations

Hepatic Impairment

No special recommendations for patients with hepatic impairment.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

In patients with mild or moderate renal impairment, initial test dose and subsequent starting dose is 0.1 mg (1 mg).1

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Chest pain, discomfort, or pressure
• chills
• cold sweats
• confusion
• dizziness, faintness, or light-headedness when getting up from lying or sitting position
• falling asleep during activity
• mood or mental changes
• seeing, hearing, or feeling things that are not there
• swelling
• twitching, twisting, uncontrolled repetitive movements of tongue, lips, face, arms, or legs

• Arm, back, neck or jaw pain or discomfort
• chest tightness or heaviness
• fainting
• fast or irregular heartbeat
• low blood pressure or pulse
• nausea
• shortness of breath
• sweating
• unconsciousness
• vomiting

• Irregular heartbeat
• recurrent fainting

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Bleeding, blistering, burning, coldness, discoloration of skin, feeling of pressure, hives, infection, inflammation, itching, lumps, numbness, pain, rash, redness, scarring, soreness, stinging, swelling, tenderness, tingling, ulceration, or warmth at injection site
• blurred vision
• dizziness
• drowsiness
• runny nose
• sleepiness
• yawning

• Painful or prolonged erection of the penis

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

• It is used to treat Parkinson's disease.

• If you have an allergy to apomorphine or any other part of Apokyn (apomorphine cartridges and pens).
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you are taking any of these drugs: Alosetron, dolasetron, granisetron, ondansetron, or palonosetron.

This is not a list of all drugs or health problems that interact with this medicine.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take Apokyn with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of a urinary tract infection (UTI) like blood in the urine, burning or pain when passing urine, feeling the need to pass urine often or right away, fever, lower stomach pain, or pelvic pain.
• Signs of dehydration like dry skin, mouth, or eyes; thirst; fast heartbeat; dizziness; fast breathing; or confusion.
• Weakness on 1 side of the body, trouble speaking or thinking, change in balance, drooping on one side of the face, or blurred eyesight.
• Very bad dizziness or passing out.
• Feeling confused.
• Very upset stomach or throwing up.
• A skin lump or growth.
• Change in color or size of a mole.
• Strong urges that are hard to control (such as eating, gambling, sex, or spending money).
• Mood changes.
• Change in the way you act.
• Trouble controlling body movements that is new or worse.
• Hallucinations (seeing or hearing things that are not there).
• Sweating a lot.
• A heartbeat that does not feel normal.
• Shortness of breath, a big weight gain, or swelling in the arms or legs.
• Chest pain or pressure or a fast heartbeat.
• Bruising or dark areas of skin.
• Some people have fallen asleep during activities like driving, eating, or talking. Some people did not feel sleepy and felt alert right before falling asleep. This has happened up to 1 year after this medicine was started. If you fall asleep during activities, do not drive or do other tasks or actions that call for you to be alert while you take Apokyn. Call your doctor right away if this happens or you feel very sleepy.

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

• Nausea and Vomiting [see Warnings and Precautions (5.2)]
• Syncope [see Warnings and Precautions (5.4)]
• Hypotension/Orthostatic Hypotension [see Warnings and Precautions (5.5)]
• Falls [see Warnings and Precautions (5.6)]
• Hallucinations/Psychotic-Like Behavior [see Warnings and Precautions (5.7)]
• Dyskinesias [see Warnings and Precautions (5.8)]
• Coronary Events [see Warnings and Precautions (5.10)]
• Priapism [see Warnings and Precautions (5.15)]

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 (14)]. Individual Apokyn doses in this trial ranged from 2 mg to 10 mg, and were titrated to achieve tolerability and control of symptoms.

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.

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

NDC 27505-004-05
5 X 3 mL Cartridges

Apokyn®
(apomorphine hydrochloride injection)

For use only with the Apokyn®Pen for
subcutaneous administration.
Not for Intravenous Use.

Rx only

30 mg/3 mL
(10 mg/mL)

US WorldMeds

Serious drug interactions can occur when certain medicines are used together with Apokyn. Tell each of your healthcare providers about all medicines you use now, and any medicine you start or stop using.

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

Before using Apokyn, 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.

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 Apokyn.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.