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`CENTER FOR DRUG EVALUATION AND
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`RESEARCH
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`APPLICATION NUMBER:
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`210875Orig1s000
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`LABELING
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`HIGHLIGHTS OF PRESCRIBING INFORMATION
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`
` These highlights do not include all the information needed to use
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` KYNMOBI safely and effectively. See full prescribing information for
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`
`KYNMOBI.
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`KYNMOBI™ (apomorphine hydrochloride) sublingual film
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`Initial U.S. Approval: 2004
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`
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` __________________INDICATIONS AND USAGE _________________
` KYNMOBI is a non-ergoline dopamine agonist indicated for the acute,
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`
` intermittent treatment of “off” episodes in patients with Parkinson’s disease
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`
`
` (1)
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`_______________DOSAGE AND ADMINISTRATION ______________
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`
`
`•
`For sublingual administration only (2.1)
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`•
`Dose initiation should be supervised by a healthcare provider (2.1, 2.3)
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`•
`Treatment with a concomitant antiemetic, e.g. trimethobenzamide, is
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`recommended, beginning 3 days prior to initial dose of KYNMOBI (2.1,
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`5.1)
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`The dose range for KYNMOBI is 10 mg to 30 mg per dose,
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`administered sublingually, as needed (2.2)
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`KYNMOBI doses should be separated by at least 2 hours (2.2)
`•
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`• Maximum of 5 doses per day; maximum single dose is 30 mg (2.2, 2.3)
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` ______________
` _____________
`DOSAGE FORMS AND STRENGTHS
`KYNMOBI sublingual film: 10 mg, 15 mg, 20 mg, 25 mg, and 30 mg of
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`
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`
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`apomorphine hydrochloride (3, 16)
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`___________________ CONTRAINDICATIONS ___________________
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`•
`Concomitant use of KYNMOBI with 5HT3 antagonists (4)
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`•
`Hypersensitivity to apomorphine or any of its ingredients including
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`sodium metabisulfite (4)
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`_______________ WARNINGS AND PRECAUTIONS_______________
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`•
`Nausea and vomiting may occur (2.1, 5.1)
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`•
`Falling asleep during activities of daily living and daytime somnolence
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`may occur, discontinue KYNMOBI if occurs (5.2)
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`•
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`FULL PRESCRIBING INFORMATION: CONTENTS*
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`1
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`2
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`INDICATIONS AND USAGE
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`DOSAGE AND ADMINISTRATION
`
`
`Important Administration Instructions
`2.1
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`2.2 Dosing Information
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`2.3 Dose Titration
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`DOSAGE FORMS AND STRENGTHS
`3
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`CONTRAINDICATIONS
`4
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`5 WARNINGS AND PRECAUTIONS
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`5.1 Nausea and Vomiting
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`5.2
`Falling Asleep During Activities of Daily Living and
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`Somnolence
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`5.3 Hypersensitivity
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`5.4
`Syncope / Hypotension / Orthostatic Hypotension
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`5.5 Oral Mucosal Irritation
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`5.6
`Falls
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`5.7 Hallucinations / Psychotic-Like Behavior
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`5.8
`Impulse Control/Compulsive Behaviors
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`5.9 Withdrawal-Emergent Hyperpyrexia and Confusion
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`5.10 QTc Prolongation and Potential for Proarrhythmic Effects
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`5.11 Fibrotic Complications
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`5.12 Priapism
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`5.13 Retinal Pathology in Albino Rats
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`ADVERSE REACTIONS
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`6.1 Clinical Trials Experience
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`DRUG INTERACTIONS
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`7.1
`5HT3 Antagonists
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`7.2 Antihypertensive Medications and Vasodilators
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`7.3 Alcohol
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`6
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`7
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`•
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`•
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`Syncope and hypotension/orthostatic hypotension may occur, monitor
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`blood pressure (5.3)
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`Oral mucosal irritation may occur, which may require pausing or
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`discontinuing treatment (5.4)
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`Falls may occur, or increase (5.6)
`•
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`• May cause hallucinations and psychotic-like behavior (5.7)
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`• May cause impulse control and impulsive behaviors; consider dose
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`reduction or discontinuing KYNMOBI if occurs (5.8)
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`• Withdrawal-emergent hyperpyrexia and confusion may occur with rapid
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`dose reduction or withdrawal (5.9)
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`• May prolong QTc and cause torsades de pointes or sudden death;
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`consider risk factors prior to initiation (5.10)
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`___________________ ADVERSE REACTIONS ___________________
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`Most common adverse reactions (incidence at least 10% in patients treated
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`with KYNMOBI and with an incidence greater than placebo) were nausea,
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`oral/pharyngeal soft tissue swelling, oral/pharyngeal soft tissue pain and
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`paraesthesia, dizziness, and somnolence (6.1)
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`To report SUSPECTED ADVERSE REACTIONS, contact Sunovion
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`Pharmaceuticals Inc. at 1-877-737-7226 or FDA at 1-800-FDA-1088 or
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`www.fda.gov/medwatch.
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`___________________ DRUG INTERACTIONS____________________
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`•
`Concomitant use of antihypertensive medications and vasodilators may
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`increase risk for hypotension, myocardial infarction, falls and injuries
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`(7.2)
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`•
`Dopamine antagonists may diminish the effectiveness of KYNMOBI
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`(7.4)
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` ______________
` _______________
`USE IN SPECIFIC POPULATIONS
`•
`Pregnancy: Based on animal data, may cause fetal harm (8 1)
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`See 17 for PATIENT COUNSELING INFORMATION and FDA-
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`approved patient labeling.
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`Revised: 5/2020
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`8
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`9
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`7.4 Dopamine Antagonists
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`7.5 Drugs Prolonging the QT/QTc Interval
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`USE IN SPECIFIC POPULATIONS
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`8.1
`Pregnancy
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`8.2 Lactation
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`8.4
`Pediatric Use
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`8.5 Geriatric Use
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`8.6 Renal Impairment
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`8.7 Hepatic Impairment
`DRUG ABUSE AND DEPENDENCE
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`9.1 Controlled Substance
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`9.2 Abuse
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`11 DESCRIPTION
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`12 CLINICAL PHARMACOLOGY
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`12.1 Mechanism of Action
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`12.2 Pharmacodynamics
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`12.3 Pharmacokinetics
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`13 NONCLINICAL TOXICOLOGY
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`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
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`14 CLINICAL STUDIES
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`16 HOW SUPPLIED/STORAGE AND HANDLING
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`16.1 How Supplied
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`16.2 Storage and Handling
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`PATIENT COUNSELING INFORMATION
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`17
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`*Sections or subsections omitted from the full prescribing information
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`are not listed.
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`Reference ID: 4612202
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`1
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`

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`FULL PRESCRIBING INFORMATION
`
`
` 1
` INDICATIONS AND USAGE
`
`
`
`
` KYNMOBI is indicated for the acute, intermittent treatment of “off” episodes in patients with
`
` Parkinson’s disease (PD).
`
`
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` 2
` DOSAGE AND ADMINISTRATION
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` Important Administration Instructions
` 2.1
` Dose initiation should be supervised by a healthcare provider [see Dosage and Administration
`
`
`
` (2.3)].
`
`
` KYNMOBI must be administered whole. Do not to cut, chew, or swallow KYNMOBI.
`
` KYNMOBI will disintegrate in about 3 minutes.
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`
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` Because of the high incidence of nausea and vomiting with KYNMOBI when administered at
` recommended doses, an antiemetic (e.g., trimethobenzamide 300 mg three times a day),
`
`
` beginning 3 days prior to the initial dose of KYNMOBI, is recommended. Treatment with the
`
`antiemetic 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 KYNMOBI [see
`
`Contraindications (4) and Warnings and Precautions (5.1)].
`
`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,
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`palonosetron) and alosetron are contraindicated [see Contraindications (4)].
`
`
` 2.2
` Dosing Information
` The dose range for KYNMOBI is 10 mg to 30 mg per dose, administered sublingually, as
`
`
`
` needed, for the acute, intermittent treatment of “off” episodes.
` Doses should be separated by at least 2 hours. If a single dose of KYNMOBI is ineffective for a
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` particular “off” episode, a second dose should not be given for that “off” episode. The efficacy or
` safety of administering a second dose for a single “off” episode has not been studied.
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` Do not administer more than 5 doses per day.
` The maximum single dose of KYNMOBI is 30 mg.
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` Dose Titration
` 2.3
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` The initial dose is 10 mg. Dose initiation should occur when the patient is in an “off” state and in
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` a setting where a healthcare provider can monitor blood pressure and pulse. In clinical studies of
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` KYNMOBI, the “off” state was achieved by instructing patients to not take their regular morning
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` dose of carbidopa/levodopa or any other adjunctive Parkinson’s disease medications, and to take
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` their last dose of carbidopa/levodopa and any other adjunctive Parkinson’s disease medications
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` no later than midnight the night before [see Clinical Studies (14)].
`2
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`Reference ID: 4612202
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`

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`If the patient tolerates the 10 mg dose, and responds adequately, the starting dose should be 10
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`mg, used on an as needed basis, up to 5 times per day, to treat “off” episodes. If the dose is
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`tolerated but the response is insufficient, the patient’s usual Parkinson’s disease medications
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`should be resumed and up-titration with KYNMOBI continued generally within 3 days. Increase
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`dosage by increments of 5 mg and assess response. Continue to titrate in a similar manner, under
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`the supervision of a healthcare provider, until an effective and tolerable dose is achieved [see
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`Dosage and Administration (2.2) and Clinical Studies (14)].
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` DOSAGE FORMS AND STRENGTHS
` 3
`
`
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`
`
` KYNMOBI sublingual film is a blue to green rectangular film with a white printed number
` identifying the strength (e.g., “10” is 10 mg). KYNMOBI comes in dosage strengths of 10 mg,
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` 15 mg, 20 mg, 25 mg, and 30 mg. Each sublingual film is individually packaged in a sealed foil
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` pouch.
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` CONTRAINDICATIONS
` 4
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` KYNMOBI is contraindicated in patients:
` • Using concomitant 5HT3 antagonists, including antiemetics (e.g., ondansetron,
`
`
`
` granisetron, dolasetron, palonosetron) and alosetron [see Drug Interactions (7.1)]. There
` have been reports of profound hypotension and loss of consciousness when subcutaneous
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`
`
` apomorphine was administered with a 5HT3 antagonist.
` • With hypersensitivity/allergic reaction to apomorphine or to any of the ingredients of
`
`
`
`
` KYNMOBI. Angioedema or anaphylaxis may occur [see Warnings and Precautions
`
`
` (5.3)].
`
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`
` 5
` WARNINGS AND PRECAUTIONS
`
` Nausea and Vomiting
`
`
` 5.1
`
`
` KYNMOBI may cause nausea and vomiting when administered at recommended doses.
` Because of the high incidence of nausea and vomiting with KYNMOBI when administered at
`
`
`
`
` recommended doses, an antiemetic, e.g., trimethobenzamide 300 mg three times a day, is
`
`
`
`
`
` recommended beginning 3 days prior to the initial dose of KYNMOBI. Treatment with the
`
`
`
`antiemetic 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 KYNMOBI [see Dosage
`
`
`
`
`and Administration (2.1)].
`In Study 1 [see Clinical Studies (14)], treatment with an antiemetic (i.e., trimethobenzamide
`
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`hydrochloride; 300 mg by mouth three times daily) was required beginning 3 days before starting
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`KYNMOBI; however, it could be discontinued during the maintenance phase. During the
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`titration phase of Study 1, nausea was reported as an adverse reaction by 21% of patients treated
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`with KYNMOBI, while vomiting was reported as an adverse reaction by 4% of patients treated
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`with KYNMOBI. During the maintenance phase of Study 1, nausea was reported as an adverse
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`reaction by 28% of patients treated with KYNMOBI, compared with 4 % of patients who
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`3
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`Reference ID: 4612202
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`

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`received placebo. During the maintenance phase of Study 1, vomiting was reported as an adverse
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`reaction by 7% of patients treated with KYNMOBI, compared with 0 % of patients who received
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`placebo. Nausea or vomiting was the reason for withdrawal from the study in 2% of patients
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`treated with KYNMOBI during the titration phase and 2% of patients treated with KYNMOBI
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`during the maintenance phase.
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`Concomitantly administered antiemetic drugs other than trimethobenzamide have not been
`
`studied. 5HT3 antagonist antiemetics are contraindicated [see Contraindications (4)].
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`Antiemetics with anti-dopaminergic actions (e.g., haloperidol, chlorpromazine, promethazine,
`prochlorperazine, metoclopramide) have the potential to worsen symptoms in patients with
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`Parkinson’s disease and should be avoided [see Drug Interactions (7.4)].
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`
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` 5.2
` Falling Asleep During Activities of Daily Living and Somnolence
` Patients treated with dopaminergic medications, including apomorphine, have reported falling
`
`
`asleep while engaged in activities of daily living, including the operation of motor vehicles,
` which sometimes has resulted in accidents. Patients may not perceive warning signs, such as
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`
`
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` excessive drowsiness, or they may report feeling alert immediately prior to the event.
` During the titration phase of Study 1, somnolence was reported as an adverse reaction in 11% of
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` patients treated with KYNMOBI. During the maintenance phase of Study 1, somnolence was
` reported as an adverse reaction in 13% of patients treated with KYNMOBI, compared with 2%
`
`
`
`of patients who received placebo.
` Prescribers should reassess patients for drowsiness or sleepiness, especially since some of the
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` events occur well after the start of treatment. Prescribers should also be aware that patients may
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`
` not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or
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` sleepiness during specific activities.
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` Before initiating treatment with KYNMOBI, advise patients of the risk of drowsiness and ask
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` them about factors that could increase the risk with KYNMOBI, such as concomitant sedating
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` medications and the presence of sleep disorders. If a patient develops significant daytime
`
`sleepiness or falls asleep during activities that require active participation (e.g., conversations,
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`
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`eating, etc.), KYNMOBI should ordinarily be discontinued. If a decision is made to continue
`
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`KYNMOBI, patients should be advised not to drive and to avoid other potentially dangerous
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`activities. There is insufficient information to determine whether dose reduction will eliminate
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`episodes of falling asleep while engaged in activities of daily living.
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` 5.3
` Hypersensitivity
` Oral soft tissue swelling (lips, tongue, gingiva, and mouth) was reported as adverse reaction in
`
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` 15% of patients treated with KYNMOBI during the maintenance phase of Study 1, compared
` with 0% of patients who received placebo; 11% of patients discontinued KYNMOBI because of
`
`
` this event.
`
` Swelling of the face, oral allergy syndrome, hypersensitivity, or urticaria were reported as an
` adverse reaction in 6% of patients treated with KYNMOBI during the maintenance phase of
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`
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` Study 1, compared with 0% of patients who received placebo; 4% of patients discontinued
` KYNMOBI because of this event.
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`Reference ID: 4612202
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`4
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` It is not known whether these events are related to apomorphine, sodium metabisulfite, or
` another KYNMOBI excipient.
`
`
` KYNMOBI rechallenge is not generally recommended after discontinuation as oral adverse
` reactions may recur and may be more severe than the initial reaction.
`
`
`
`
` Sulfite Sensitivity
`
`KYNMOBI contains sodium metabisulfite, a sulfite that may cause allergic-type reactions,
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`including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain
`
`susceptible people. The overall prevalence of sulfite sensitivity in the general population is
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`unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in non-
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`asthmatic people.
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` Syncope / Hypotension / Orthostatic Hypotension
` 5.4
`
`
` KYNMOBI may cause syncope, hypotension, or orthostatic hypotension. During the titration
`
`
`
`
` phase of Study 1, syncope, pre-syncope, hypotension, or orthostatic hypotension were reported
`
` as adverse reactions in 4% of patients. During the maintenance phase of Study 1, syncope, pre­
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` syncope, hypotension, or orthostatic hypotension were reported as adverse reactions in 2% of
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`
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` patients treated with KYNMOBI, compared with 0% of patients who received placebo.
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` During the maintenance phase of Study 1, systolic orthostatic hypotension (reduction of 20
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` mmHg or more in standing minus supine/sitting systolic blood pressure) or diastolic hypotension
`
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` (10 mmHg or more for standing minus supine/sitting diastolic blood pressure) occurred in 43%
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` of patients treated with KYNMOBI, and in 36% of patients who received placebo.
`
` Patients treated with KYNMOBI should receive an assessment for hypotension / orthostatic
`
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`
` hypotension, especially if they have a history of hypotension or cardiovascular disease, or if they
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` are currently using antihypertensive medication. Inform patients of the risk of orthostatic
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` hypotension.
` The hypotensive effects of KYNMOBI may be increased by the concomitant use of alcohol,
`
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`antihypertensive medications, and vasodilators (especially nitrates). Patients should avoid
`
`
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`alcohol when using KYNMOBI [see Drug Interactions (7.3), Clinical Pharmacology (12.3)].
`
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`
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`Patients taking KYNMOBI should lie down before and after taking sublingual nitroglycerin [see
`
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`Drug Interactions (7.2), Clinical Pharmacology (12.3)].
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`Monitor patients taking concomitant antihypertensive medications for hypotension and
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`orthostatic hypotension [see Drug Interactions (7.2, 7.3)].
`
`
`
` 5.5
` Oral Mucosal Irritation
` During the titration phase of Study 1, oral mucosal ulceration or stomatitis were reported as
`
`
`
`
`
` adverse reactions in 2% of patients treated with KYNMOBI. During the maintenance phase of
` Study 1, oral mucosal ulceration or stomatitis were reported as adverse reactions in 7% of
`
`
`
`patients treated with KYNMOBI, compared with 0% of patients who received placebo [see
` Adverse Reactions (6.1)].
`
`
`During the titration of Study 1, oral soft tissue pain or paresthesia were reported as adverse
`
` reactions in 2% of patients treated with KYNMOBI. During the maintenance phase of Study 1,
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`Reference ID: 4612202
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`5
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`

`

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` oral soft tissue pain or paresthesia were reported as adverse reactions in 13% of patients treated
`
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`with KYNMOBI, compared with 2% of patients who received placebo.
` In general, oral mucosal irritation reactions were mild to moderate severity, and usually resolved
`
` with treatment discontinuation.
`
`
`
` KYNMOBI rechallenge is not generally recommended after discontinuation as oral adverse
`
` reactions may recur and be more severe than the initial reaction.
`
` Hypersensitivity adverse reactions may also occur during treatment with KYNMOBI [see
`
`
`
` Warnings and Precautions (5.3)].
`
`
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` 5.6
` Falls
` Patients with Parkinson's disease are at risk of falling because of underlying postural instability,
`
`
`
`
`
`
` possible autonomic instability, and syncope caused by the blood pressure lowering effects of the
` drugs used to treat Parkinson's disease [see Clinical Pharmacology (12.2)]. KYNMOBI might
`
`
`
` increase the risk of falling by simultaneously lowering blood pressure and altering mobility [see
`
`
` Warnings and Precautions (5.4)].
`
`
` During the titration period of Study 1, falls were reported as adverse reaction in 4% of patients
` treated with KYNMOBI. During the maintenance period of Study 1, falls were reported as
`
`
`
` adverse reaction in 6% of patients treated with KYNMOBI, compared with 2% of patients who
`
`
`
`
`
` received placebo.
`
`
` Hallucinations / Psychotic-Like Behavior
`
`
` 5.7
`
`
`
` During the maintenance phase of Study 1, hallucinations, delusions, disorientation, or confusion
`
` were reported as adverse reactions in 6% of patients treated with KYNMOBI, compared with 2%
`
`
`
` of patients who received placebo. No patient developed hallucinations or psychotic-like behavior
`
` during the titration phase.
`
`
`
`
`
`
` A total of 4% of patients treated with KYNMOBI discontinued treatment because of
` disorientation, confusional state, or delusions, compared with 2% of patients who received
`
`
` placebo.
` Postmarketing reports with subcutaneous apomorphine indicate that patients may experience new
`
`or worsening mental status and behavioral changes, which may be severe, including psychotic-
`like behavior after starting or increasing the dose of apomorphine. Other drugs prescribed to
`
`improve the symptoms of Parkinson’s disease can have similar effects on thinking and behavior.
`
`This abnormal thinking and behavior can consist of one or more of a variety of manifestations,
`
`
`including paranoid ideation, delusions, hallucinations, confusion, disorientation, aggressive
`
`behavior, agitation, and delirium.
`
`Patients with a major psychotic disorder should ordinarily not be treated with apomorphine
`
`because of the risk of exacerbating psychosis. In addition, certain medications used to treat
`
`
`psychosis may exacerbate the symptoms of Parkinson's disease and may decrease the
`
`effectiveness of KYNMOBI [see Drug Interactions (7.4)].
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`Reference ID: 4612202
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`6
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`

`

`
`
` Impulse Control/Compulsive Behaviors
` 5.8
`
`
`
`
`
` Case reports suggest that patients can experience intense urges to gamble, increased sexual
`urges, intense urges to spend money uncontrollably, and other intense urges and the inability to
`control these urges while taking one or more medications, including KYNMOBI, that increase
`
`
`central dopaminergic tone. In some cases, although not all, these urges were reported to have
`
`stopped when the dose was reduced, or the medication was discontinued. Because patients may
`
`not recognize these behaviors as abnormal, it is important for prescribers to specifically ask
`
`patients or their caregivers about the development of new or increased gambling urges, sexual
`
`urges, uncontrolled spending, binge eating or other urges while being treated with KYNMOBI.
`
`
`
`
`Physicians should consider dose reduction or stopping the medication if a patient develops such
`
`urges while taking KYNMOBI.
`
`
`
`
` Withdrawal-Emergent Hyperpyrexia and Confusion
` 5.9
`
` A symptom complex resembling the neuroleptic malignant syndrome (characterized by elevated
`
`
` temperature, muscular rigidity, altered consciousness, elevated serum creatine kinase, and
`
`
`autonomic instability), with no other obvious etiology, has been reported in association with
`
`rapid dose reduction, withdrawal of, or changes in antiparkinsonian therapy.
`
`
`
` 5.10
` QTc Prolongation and Potential for Proarrhythmic Effects
`
` At exposures achieved with therapeutic doses of subcutaneous apomorphine, a dose-related
` prolongation of QTc has been observed [see Clinical Pharmacology (12.2)]. Although the extent
`
`
`
`
`
`
`
` of the exposure and the Cmax of apomorphine are lower following the maximum recommended
`
`
`
`dose of KYNMOBI (30 mg) than following the maximum recommended dose of subcutaneous
`
`
`apomorphine (6 mg), QTc prolongation with KYNMOBI cannot be excluded.
`
`
`Drugs that prolong the QTc interval have been associated with torsades de pointes and sudden
`
`death. The relationship of QTc prolongation to torsades de pointes is clearest for larger increases
`
`(20 msec and greater), but it is possible that smaller QTc prolongations may also increase risk, or
`increase it in susceptible individuals, such as those with hypokalemia, hypomagnesemia,
`
`
`bradycardia, concomitant use of other drugs that prolong the QTc interval, or genetic
`
`
`predisposition (e.g., congenital prolongation of the QT interval). Although torsades de pointes
`
`
`has not been observed in association with the use of KYNMOBI at recommended doses in
`
`clinical studies, experience is too limited to rule out an increased risk. Palpitations and syncope
`
`may signal the occurrence of an episode of torsades de pointes.
`
`
`
`The risks and benefits of KYNMOBI treatment should be considered prior to initiating treatment
`with KYNMOBI in patients with risk factors for prolonged QTc.
`
`
`
` 5.11
` Fibrotic Complications
` Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, pleural thickening, and
`
`
`
` cardiac valvulopathy have been reported in some patients treated with ergot-derived
`dopaminergic agents. While these complications may resolve when the drug is discontinued,
`complete resolution does not always occur. Although these adverse reactions are believed to be
`related to the ergoline structure of these dopamine agonists, whether other, nonergot derived
`
`
` dopamine agonists, such as KYNMOBI, can cause these reactions is unknown.
`
`
`
`
`
`
`Reference ID: 4612202
`
`7
`
`
`
`
`
`
`
`

`

`
`
`
`
` Priapism
` 5.12
`
`
` Apomorphine may cause prolonged painful erections in some patients. Severe priapism may
`
` require surgical intervention.
`
`
` 5.13
` Retinal Pathology in Albino Rats
` In a 2-year carcinogenicity study of apomorphine in albino rat, retinal atrophy was detected at all
`
`
` subcutaneous doses tested (up to 0.8 mg/kg/day or 2 mg/kg/day in males or females,
`
` respectively). Retinal atrophy/degeneration has been observed in albino rats treated with other
`
` dopamine agonists for prolonged periods (generally during 2-year carcinogenicity studies).
`
`
`
` Retinal findings were not observed in a 39-week subcutaneous toxicity study of apomorphine in
` monkey at doses up to 1.5 mg/kg/day. The clinical significance of the finding in rat has not been
`
`
`
` established but cannot be disregarded because disruption of a mechanism that is universally
`
`
`
`
` present in vertebrates (e.g., disk shedding) may be involved.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 6
`
`
` ADVERSE REACTIONS
` The following serious adverse reactions are discussed in more detail in the Warnings and
`
`
`
` Precautions section of labeling:
`
` • Nausea and Vomiting [see Warnings and Precautions (5.1)]
`
`
`
`
`
`
` • Falling Asleep During Activities of Daily Living and Somnolence [see Warnings and
`
`
`
`
` Precautions (5.2)]
`
`
` • Hypersensitivity [see Warnings and Precautions (5.3)]
`
`
`
` • Syncope/Hypotension/Orthostatic Hypotension [see Warnings and Precautions (5.4)]
`
`
` • Oral Mucosal Irritation [see Warnings and Precautions (5.5)]
`
`
`
`
`
` • Falls [see Warnings and Precautions (5.6)]
`
`
`
`
`
` • Hallucinations/Psychotic Behavior [see Warnings and Precautions (5.7)]
`
`
`
`
`
` •
`
` Impulse Control/Compulsive Behaviors [see Warnings and Precautions (5.8)]
`
` • Withdrawal-Emergent Hyperpyrexia and Confusion [see Warnings and Precautions
`
`
`
` (5.9)]
` • QTc Prolongation and Potential for Proarrhythmic Effects [see Warnings and
`
`
` Precautions (5.10)]
`
` • Fibrotic Complications [see Warnings and Precautions (5.11)]
`
`
` • Priapism [see Warnings and Precautions (5.12)]
`
`
`
`
` • Oral Adverse Events [see Warnings and Precautions (5.13)]
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4612202
`
`
`8
`
`
`
`
`
`
`

`

` Clinical Trials Experience
` 6.1
`
`
`
`
` Because clinical trials are conducted under widely varying conditions, adverse reaction rates
` observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical
`
`
`
` trials of another drug and may not reflect the rates observed in clinical practice.
`
`
`
`
` KYNMOBI safety data presented below is derived from a randomized, double blind, placebo-
`
` controlled study in patients with Parkinson’s disease (Study 1) [see Clinical Studies (14)].
`
`
`
` Study 1 included a titration phase, in which 141 patients received at least one dose of
`
`
`
`
`
` KYNMOBI, followed by a placebo-controlled 12-week maintenance phase. The mean age of
`
`
` patients in Study 1 was 63 years (range 43 to 86 years); 63% of patients were male, and 93%
`
`
`
`
`
`
`
` were Caucasian.
`
`
`
`
` The most common adverse reactions (incidence at least 10% in patients treated with KYNMOBI
` and with an incidence greater than placebo) were nausea, oral/pharyngeal soft tissue swelling,
`
` oral/pharyngeal soft tissue pain and paraesthesia, dizziness, and somnolence.
`
`
`
` Adverse reactions led to discontinuation of KYNMOBI in 9% of patients in the titration phase,
`
`
`
` and 28% of patients in the maintenance phase, compared with 7% of patients on placebo (in the
`
` maintenance phase). The most common adverse reactions leading to discontinuation during the
`
`
` maintenance phase were oral/pharyngeal soft tissue swelling, oral mucosal erythema, and
`
`
`nausea/vomiting.
` Table 1 presents the adverse reactions that occurred in at least 5% of patients treated with
`
`
`
` KYNMOBI during the maintenance phase of Study 1, and with an incidence greater than in
`
` patients who received placebo.
` Adverse Reactions Reported by at Least 5% of Patients Treated with
`
`
`
`
`
`
` Table 1:
`
`
` KYNMOBI during the Maintenance Phase of Study 1, and with an Incidence
`
` Greater than Placebo
`
`
`
`
`
`
`
`
`
` Gastrointestinal disorders
`
`Nausea
`
` Oral/pharyngeal soft tissue swelling1
`
`Oral/pharyngeal soft tissue pain and paraesthesia2
`
`
`
`Oral ulceration and stomatitis3
`
`Oral mucosal erythema
`
`
`Vomiting
`
`Dry mouth
`
` Nervous system disorders
`
` Somnolence
`
` Dizziness
`
` Headache
` Respiratory, thoracic, and mediastinal disorders
`
` Rhinorrhea
`General disorders and administration site
`
` conditions
`
` Fatigue
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4612202
`
` Titration
`
`
` KYNMOBI
`
` (N=141)
`
` %
`
` 21
`
`1
`
`2
`
`2
`
`4
`
`4
`
`1
`
`
`
` 11
`
` 11
`
` 8
`
`
` 6
`
`
`3
`
`
`
` Maintenance
`
` Placebo
`
` KYNMOBI
`
` (N=55)
`
` (N=54)
`
` %
`
` %
`
`
`
` 4
`
` 28
`0
`15
`
`
`2
`13
`
`
`0
`7
`
`
`4
`7
`
`
`0
`7
`
`
`0
`6
`
`
`
`
`
` 2
`
` 13
`
` 0
`
` 9
`
` 0
`
` 6
`
`
`
` 0
`
` 7
`
`
`
`
`0
`7
`
`
`
`
` 9
`
`
`
`
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
` Maintenance
` Titration
`
`
` Placebo
`
` KYNMOBI
`
` KYNMOBI
`
` (N=55)
`
` (N=54)
`
` (N=141)
`
` %
`
` %
`
` %
`
` Injury, poisoning, and procedural complications
`
`
`
`
` 2
`
` 6
`
` 4
`
` Fall
`
` 0
`
` 6
`
` 1
` Laceration
`
` Skin and subcutaneous tissue disorders
`
`
`
`
` 4
`
` 6
`
` 4
`
` Hyperhidrosis
` Immune system disorders
`
`
`
`
` 0
` 6
` 0
`
`
`
`
`Hypersensitivity4
`
`
` 1 Includes lip swelling, lip edema, oropharyngeal swelling, gingival edema, edema mouth, swollen tongue, and
`
` pharyngeal edema
`
`
`
`2 Includes throat irritation, glossodynia, oral pain, oral paresthesia, oropharyngeal pain, gingival pain, and oral
`
`
`hypoesthesia
`
`
`
`
`
`3 Includes lip ulceration, oral mucosal blistering, stomatitis, cheilitis, and tongue ulceration
`
`
`
`
`4 Includes hypersensitivity, swelling face, oral allergy syndrome and urticaria
`
`
` Less Common Adverse Reactions
`
`
`Other adverse reactions including hallucinations, delusions, and impulse control disorder have
`
`
`
`
`been reported in patients treated with KYNMOBI [see Warnings and Precautions (5.7, 5.8)].
`
`
`
`
`
`
`
`Vital Sign Changes
`
`
`
`Blood Pressure
`
`
`
`Decreases in blood pressure have been observed in patients treated with KYNMOBI. During the
`
`titration phase of Study 1, syncope, pre-syncope, hypotension, or orthostatic hypotension were
`
`reported as adverse reaction in 4% of patients treated with KYNMOBI. During the maintenance
`phase of Study 1, syncope, pre-syncope, hypotension, or orthostatic hypotension were reported
`
`
`
`
`as adverse reaction in 2 % of patients treated with KYNMOBI, compared with 0% of patients
`
`
`
`who received placebo [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.2)].
`
`
`
`
`
`
` 7
` DRUG INTERACTIONS
`
`
`
` 7.1
` 5HT3 Antagonists
`
` Based on reports of profound hypotension and loss of consciousness when subcutaneous
`
` apomorphine was administered with ondansetron, the concomitant use of KYNMOBI with 5HT3
`
`
`
` antagonists, including antiemetics (e.g., ondansetron, granisetron, palonosetron) and alosetron, is
`
`
` contraindicated [see Warnings and Precautions (5.4)].
`
`
`
`
`
` 7.2
` Antihypertensive Medications and Vasodilators
`In a study of healthy subjects, concomitant administration of 0.4 mg sublingual nitroglycerin
`
`
` with subcutaneous apomorphine caused greater decreases in blood pressure than with
`
`
` subcutaneous apomorphine alone [see Clinical Pharmacology (12.3)].
`
`
`
`
`
`Reference ID: 4612202
`
`10
`
`
`
`
`
`
`
`

`

` Patients taking KYNMOBI should lie down before and after taking sublingual nitroglycerin [see
`
`
`
` Warnings and Precautions (5.4)].
`
`
` 7.3
` Alcohol
`
`
` In a study of healthy subjects, concomitant administration of high dose (0.6 g/kg) or low dose
`
` (0.3 g/kg) ethanol with subcutaneous apomorphine caused greater decreases in blood pressure
`
`
`
`
` than with subcutaneous apomorphine alone [see Clinical Pharmacology (12.3)].
`
`
`
`
` Patients shoul