Apomorphine Hydrocloride

Dosage for apomorphine must be highly individualized and is always determined through a supervised titration process initiated by a healthcare professional.

Subcutaneous Injection (e.g., Apokyn)

• Starting Dose: The typical starting dose is 0.2 mL (2 mg) as needed to treat an 'off' episode.
• Titration: If the 2 mg dose is tolerated but ineffective, the healthcare provider may increase the dose in increments of 0.1 mL (1 mg) at subsequent 'off' periods.
• Maintenance Range: Most patients find relief with doses between 0.3 mL (3 mg) and 0.6 mL (6 mg).
• Maximum Dose: The maximum recommended single dose is 0.6 mL (6 mg), and the medication should not be used more than 5 times per day. The total daily dose should generally not exceed 2.0 mL (20 mg).

Sublingual Film (e.g., Kynmobi)

• Starting Dose: Usually 10 mg placed under the tongue.
• Titration: Doses may be increased by 5 mg increments at intervals of at least 3 days until an effective dose is reached.
• Maximum Dose: The maximum single dose is 30 mg, with a limit of 5 doses per day.

Apomorphine is not approved for use in pediatric patients. The safety and effectiveness of apomorphine in individuals under the age of 18 have not been established. Parkinson's disease is extremely rare in children, and the pharmacological profile of apomorphine has not been studied in this population.

Renal Impairment

For patients with mild to moderate renal impairment, the starting dose of the subcutaneous injection is typically reduced to 0.1 mL (1 mg). Close monitoring for hypotension (low blood pressure) and nausea is required. Use in patients with severe renal impairment (end-stage renal disease) is generally not recommended due to a lack of clinical data.

Hepatic Impairment

Apomorphine is metabolized by the liver. While mild to moderate hepatic impairment (Child-Pugh Class A and B) may not require an immediate dose reduction, patients should be monitored closely. It is not recommended for use in patients with severe hepatic impairment.

Elderly Patients

Clinical studies have shown that patients over the age of 65 may be more sensitive to the hypotensive effects of apomorphine. Dosing should be approached with caution, starting at the lowest possible dose and titrating slowly.

Pretreatment with Antiemetics

Because apomorphine is a potent trigger for the brain's vomiting center, almost all patients must begin taking an anti-nausea medication (antiemetic) before starting apomorphine.

• Trimethobenzamide: Usually started at 300 mg three times daily, beginning three days before the first dose of apomorphine.
• Note: 5-HT3 antagonists like ondansetron (Zofran) are strictly contraindicated with apomorphine.

Administration Technique

• Injection: Rotate injection sites (abdomen, upper arm, or upper thigh) to prevent skin irritation or nodules. Do not inject into areas that are red, bruised, or tender.
• Sublingual Film: Place the film under the tongue and allow it to dissolve completely. Do not chew or swallow the film. Avoid eating or drinking until the film has fully dissolved.

Apomorphine is used on an 'as-needed' basis for acute symptoms. Therefore, there is no schedule for missed doses. If you experience an 'off' episode and have not exceeded your maximum daily doses, you may take the prescribed dose. Do not take two doses at once to 'make up' for a previous 'off' period that was not treated.

Symptoms of an apomorphine overdose may include severe nausea, projectile vomiting, profound hypotension (low blood pressure), bradycardia (slow heart rate), hallucinations, and excessive sleepiness.

• Emergency Measures: If an overdose is suspected, contact emergency services immediately. Treatment is supportive, focusing on maintaining blood pressure and respiratory function. In cases of severe bradycardia, atropine may be considered by medical professionals.

> Important: Follow your healthcare provider's dosing instructions exactly. Do not adjust your dose or frequency of use without explicit medical guidance, as this can increase the risk of serious side effects.

Side effects are very common with apomorphine, particularly during the initial titration phase. According to clinical trial data (FDA, 2024), more than 10% of patients experience the following:

• Nausea and Vomiting: This is the most frequent side effect. It occurs because apomorphine stimulates the chemoreceptor trigger zone in the brain. While antiemetics help, some degree of nausea may persist.
• Yawning: An unusual but very common side effect associated with dopamine agonists. It is generally harmless but can be frequent.
• Drowsiness/Somnolence: Many patients feel a significant 'heavy' feeling or sleepiness shortly after administration.
• Dizziness: Often related to changes in blood pressure when moving from a sitting to a standing position.
• Injection Site Reactions: Redness, swelling, or the formation of small, hard lumps (nodules) under the skin at the site of injection.

• Orthostatic Hypotension: A sudden drop in blood pressure upon standing, which can lead to fainting (syncope).
• Dyskinesias: Involuntary, jerky movements. While apomorphine treats 'off' periods, it can sometimes trigger 'on' period dyskinesias if the dopamine levels become too high.
• Hallucinations: Seeing or hearing things that are not there. This is more common in elderly patients or those with pre-existing cognitive impairment.
• Rhinorrhea: A runny nose, specifically noted with the sublingual film formulation.
• Edema: Swelling in the lower legs or hands due to fluid retention.

• Sudden Sleep Attacks: Falling asleep without warning during daily activities, including driving. This is a characteristic side effect of dopamine agonists.
• Impulse Control Disorders: Patients may experience intense urges to gamble, increased sexual urges, or binge eating. These behaviors are often unrecognized by the patient.
• Fibrotic Complications: Rare cases of retroperitoneal, pulmonary, or cardiac valve fibrosis have been reported with dopamine agonists, though this was more common with older, ergot-derived drugs.

> Warning: Stop taking Apomorphine and call your doctor or emergency services immediately if you experience any of the following:

• Syncope (Fainting): This may indicate a dangerous drop in blood pressure or a heart rhythm issue.
• Chest Pain or Shortness of Breath: Could indicate cardiac stress or a rare allergic reaction.
• Prolonged Erection (Priapism): Apomorphine can cause an erection lasting longer than 4 hours. This is a medical emergency that requires immediate treatment to prevent permanent tissue damage.
• Severe Mental Status Changes: Acute confusion, extreme agitation, or aggressive behavior.
• Signs of Anaphylaxis: Hives, swelling of the face or throat, and difficulty breathing.

With prolonged use, some patients may develop 'skin nodules' at injection sites that can become permanent if the site is not rotated. Additionally, the risk of impulse control disorders may increase over time as the brain's reward system is repeatedly stimulated by dopamine agonists. Chronic use also requires ongoing monitoring for 'melanoma' (skin cancer), as patients with Parkinson's disease have a higher risk, and it is unclear if dopamine agonists contribute to this risk.

No FDA black box warnings currently exist for Apomorphine. However, the FDA does require prominent warnings regarding the risk of severe hypotension when used with 5-HT3 antagonists and the risk of falling asleep during activities of daily living.

Report any unusual symptoms or changes in behavior to your healthcare provider immediately. Side effects can often be managed by adjusting the dose or changing the timing of the medication.

Apomorphine is a potent medication that requires careful management. Patients must be aware that the first dose should always be administered in a setting where a healthcare professional can monitor blood pressure and heart rate. Because of the risk of profound low blood pressure and fainting, you should not attempt to use this medication for the first time alone.

As of 2026, there are no FDA black box warnings for Apomorphine. However, the 'Warnings and Precautions' section of the official label is extensive and carries significant weight for patient safety.

• Severe Hypotension and Syncope: Apomorphine can cause a significant drop in blood pressure, especially when starting the drug or increasing the dose. This risk is dramatically increased if the drug is taken with alcohol or certain antihypertensive medications.
• Falling Asleep During Activities of Daily Living: There are documented cases of patients falling asleep while driving or operating machinery. This can occur without any prior warning signs of sleepiness.
• Impulse Control/Compulsive Behaviors: Patients and caregivers should monitor for new or increased gambling urges, sexual urges, uncontrolled spending, or binge eating. Because patients may not recognize these as abnormal, caregivers play a vital role in monitoring.
• Hallucinations and Psychotic-like Behavior: Apomorphine can cause or exacerbate symptoms of psychosis. Patients with a major psychotic disorder should generally not use apomorphine.
• QT Prolongation: Apomorphine can slightly prolong the QT interval (a measure of heart rhythm). This increases the risk of a rare but serious heart rhythm disorder called Torsade de Pointes, especially in patients taking other QT-prolonging drugs.
• Priapism: This medication can cause painful, long-lasting erections. If an erection lasts more than 4 hours, seek emergency medical help immediately.

Your healthcare provider will likely require the following monitoring schedule:

1. 1Blood Pressure: Checked while sitting and standing (orthostatic vitals) during the initial dose and titration.
2. 2Skin Examination: Regular checks for melanoma and injection site reactions.
3. 3Mental Health Screening: Periodic evaluation for depression, hallucinations, and impulse control issues.
4. 4Renal Function: Periodic blood tests (BUN and Creatinine) to ensure the kidneys are clearing the drug effectively.

Do not drive, operate heavy machinery, or engage in dangerous activities until you know how apomorphine affects you. If you experience a 'sleep attack' or feel excessively drowsy, you must stop these activities entirely and consult your doctor.

Alcohol should be strictly avoided or significantly limited. Alcohol enhances the blood-pressure-lowering effects of apomorphine, which can lead to severe dizziness, fainting, and injury.

Do not stop taking apomorphine suddenly if you have been using it frequently. While it is an 'as-needed' medication, abrupt cessation of high-dose dopamine agonists can rarely lead to a condition called Neuroleptic Malignant-Like Syndrome, characterized by high fever, muscle rigidity, and mental changes.

> Important: Discuss all your medical conditions, especially heart rhythm problems or history of fainting, with your healthcare provider before starting Apomorphine.

• 5-HT3 Antagonists (e.g., Ondansetron, Granisetron, Dolasetron): These medications, commonly used for nausea, must NEVER be used with apomorphine. The combination has been reported to cause severe, profound hypotension (extremely low blood pressure) and complete loss of consciousness. This interaction is potentially life-threatening.

• Antihypertensive Medications: Drugs used to treat high blood pressure (such as beta-blockers, ACE inhibitors, or diuretics) can have an additive effect with apomorphine. This significantly increases the risk of orthostatic hypotension and fainting.
• Dopamine Antagonists: Medications like haloperidol, risperidone, or metoclopramide work by blocking dopamine receptors. Since apomorphine works by stimulating these same receptors, these drugs will cancel each other out, making apomorphine ineffective and potentially worsening Parkinson's symptoms.
• QT-Prolonging Drugs: Caution is required when combining apomorphine with other drugs known to prolong the QT interval, such as certain antipsychotics (e.g., ziprasidone), antibiotics (e.g., erythromycin), or antiarrhythmics (e.g., amiodarone).

• Nitroglycerin and Nitrates: Used for chest pain, these drugs also lower blood pressure and can increase the risk of fainting when used alongside apomorphine.
• CNS Depressants: Medications like benzodiazepines (e.g., lorazepam), sleep aids, or muscle relaxants can worsen the drowsiness and 'sleep attack' risks associated with apomorphine.

• High-Fat Meals: For the sublingual film, high-fat meals do not significantly change the total absorption but may slightly delay the time it takes to reach peak concentration. For the injection, food is not a factor.
• Alcohol: As previously mentioned, alcohol is a major concern due to the additive risk of hypotension and sedation.
• Grapefruit: While not a major CYP3A4 substrate, some studies suggest caution with large amounts of grapefruit juice, though no formal restriction is usually required.

• St. John’s Wort: May potentially alter the metabolism of apomorphine, though the clinical significance is low.
• Kava and Valerian: These sedative herbs can increase the risk of excessive sleepiness.
• Iron Supplements: While iron can interfere with levodopa absorption, it does not significantly impact apomorphine, which bypasses the digestive tract.

Apomorphine is not known to interfere significantly with standard laboratory tests (such as blood counts or metabolic panels). However, it may rarely cause a false-positive result on certain urine drug screens for opiates due to its chemical structure, despite not being an opiate. Always inform the laboratory if you are taking this medication.

Management Strategy

To manage these interactions, your doctor will perform a 'reconciliation' of all your current medications. If you must take a blood pressure medication, your doctor may suggest taking it at a different time of day than your apomorphine doses. If you require an anti-nausea drug, only trimethobenzamide is typically recommended.

> Important: Tell your doctor about ALL medications, supplements, and herbal products you are taking, including those purchased over-the-counter.

Apomorphine is strictly prohibited in the following circumstances:

1. 1Concomitant Use with 5-HT3 Antagonists: As detailed in the interactions section, using apomorphine with drugs like ondansetron (Zofran) is absolutely contraindicated due to the risk of severe hypotension and loss of consciousness.
2. 2Hypersensitivity: Patients with a known allergy to apomorphine hydrochloride or any of the inactive ingredients (such as sodium metabisulfite) must not use this drug. Some formulations contain sulfites, which can cause life-threatening anaphylactic reactions in sensitive individuals, particularly those with asthma.

These are conditions where the risk may outweigh the benefit, requiring a careful assessment by a specialist:

• Severe Hepatic Impairment: Because the liver is the primary site of metabolism, severe liver disease can lead to toxic levels of the drug accumulating in the body.
• Severe Cardiovascular Disease: Patients with a history of recent heart attack, unstable angina, or severe heart failure are at high risk for complications if their blood pressure drops suddenly.
• Pre-existing Psychosis: Since apomorphine increases dopamine activity, it can severely worsen symptoms of schizophrenia or other psychotic disorders.
• History of Addiction: While apomorphine itself is not addictive, the impulse control disorders it can cause (like compulsive gambling) may be more likely in patients with a history of addictive behavior.

Patients who have had allergic reactions to other dopamine agonists (like pramipexole or ropinirole) should be monitored closely, although there is no direct cross-reactivity established. The most significant cross-sensitivity concern involves sulfite sensitivity. Many apomorphine injections contain sodium metabisulfite; patients with a known sulfite allergy must avoid these specific formulations.

> Important: Your healthcare provider will evaluate your complete medical history, including any history of asthma or heart disease, before prescribing Apomorphine.

Apomorphine is categorized as Pregnancy Category C (under the older FDA system). There are no adequate and well-controlled studies in pregnant women. Animal studies have shown some evidence of developmental toxicity at very high doses. It is unknown whether apomorphine can cause fetal harm when administered to a pregnant woman or if it can affect reproductive capacity. Apomorphine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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 (such as extreme drowsiness or low blood pressure), a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Safety and effectiveness in pediatric patients have not been established. Parkinson's disease is not a pediatric condition, and apomorphine has no approved indications for children. Use in this population is generally discouraged outside of highly specialized clinical trials.

In clinical trials, a large percentage of patients were over age 65. While the effectiveness was similar to younger adults, elderly patients were found to be more prone to:

• Confusion and Hallucinations: Increased risk of mental status changes.
• Falls: Due to the combination of Parkinson's symptoms and orthostatic hypotension.
• Cardiovascular Stress: The heart may not compensate as well for the rapid drops in blood pressure.

Renal impairment reduces the clearance of apomorphine. For patients with moderate renal impairment (Creatinine Clearance 30-50 mL/min), the starting dose of the injection should be reduced to 1 mg. Data for patients with severe renal impairment (CrCl <30 mL/min) is insufficient, and use is generally not recommended.

For patients with mild to moderate hepatic impairment, no specific starting dose adjustment is mandated, but titration should be extremely cautious. Apomorphine has not been studied in patients with severe hepatic impairment (Child-Pugh Class C), and its use in this group is not recommended due to the high risk of drug accumulation.

> Important: Special populations require individualized medical assessment and more frequent monitoring by a neurology specialist.

Apomorphine is a non-ergoline dopamine agonist with high in vitro binding affinity for the dopamine D2, D3, and D5 receptors. The precise mechanism of action as a treatment for Parkinson's disease is believed to be related to its ability to stimulate post-synaptic dopamine D2-type receptors within the caudate-putamen (the 'striatum'). By stimulating these receptors, it compensates for the lack of endogenous dopamine, thereby restoring the function of the motor circuits that control voluntary movement.

Apomorphine produces a rapid improvement in motor function. The onset of action for the subcutaneous injection is typically 7 to 15 minutes, and for the sublingual film, it is approximately 15 to 30 minutes. The duration of the effect is relatively short, usually lasting between 45 and 90 minutes. Unlike some other dopamine agonists, apomorphine does not significantly affect serotonin or norepinephrine receptors at clinical doses, which limits certain types of side effects but focuses its action on the motor system.

| Parameter | Value |

|---|---|

| Bioavailability | 100% (Subcutaneous); ~20% (Sublingual) |

| Protein Binding | 10% - 15% |

| Half-life | 60 - 90 minutes |

| Tmax | 10 - 60 minutes (Injection); 30-60 mins (Film) |

| Metabolism | Glucuronidation, Sulfation, N-demethylation |

| Excretion | Renal 93%, Fecal <2% |

• Molecular Formula: C17H17NO2 (as free base); C17H18ClNO2 (as hydrochloride)
• Molecular Weight: 303.8 g/mol (Hydrochloride)
• Solubility: Sparingly soluble in water; soluble in alcohol.
• Structure: It is a tetracyclic compound derived from morphine through treatment with concentrated acids, which causes a rearrangement of the molecular skeleton, removing the analgesic properties of the parent compound.

Apomorphine is classified therapeutically as a Dopamine Agonist. In the context of the provided EPC data, it is listed as a Non-Standardized Plant Allergenic Extract [EPC], though this is a regulatory classification and not a description of its clinical use in neurology.