•
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`KYNMOBI safely and effectively. See full prescribing information for
`KYNMOBI.
`
`KYNMOBI® (apomorphine hydrochloride) sublingual film
`Initial U.S. Approval: 2004
`
` _________________ RECENT MAJOR CHANGES _________________
`Warnings and Precautions, Hemolytic Anemia (5.8)
`5/2022
` __________________ INDICATIONS AND USAGE _________________
`KYNMOBI is a non-ergoline dopamine agonist indicated for the acute,
`intermittent treatment of “off” episodes in patients with Parkinson’s disease
`(1)
` _______________ DOSAGE AND ADMINISTRATION ______________
`For sublingual administration only (2.1)
`•
`Dose initiation should be supervised by a healthcare provider (2.1, 2.3)
`•
`•
`Treatment with a concomitant antiemetic, e.g., trimethobenzamide, is
`recommended, beginning 3 days prior to initial dose of KYNMOBI (2.1,
`5.1)
`The dose range for KYNMOBI is 10 mg to 30 mg per dose,
`administered sublingually, as needed (2.2)
`KYNMOBI doses should be separated by at least 2 hours (2.2)
`•
`• Maximum of 5 doses per day; maximum single dose is 30 mg (2.2, 2.3)
` ______________ DOSAGE FORMS AND STRENGTHS _____________
`KYNMOBI sublingual film: 10 mg, 15 mg, 20 mg, 25 mg, and 30 mg of
`apomorphine hydrochloride (3, 16)
` ___________________ CONTRAINDICATIONS ___________________
`Concomitant use of KYNMOBI with 5HT3 antagonists (4)
`•
`Hypersensitivity to apomorphine or any of its ingredients including
`•
`sodium metabisulfite (4)
` _______________ WARNINGS AND PRECAUTIONS _______________
`Nausea and vomiting may occur (2.1, 5.1)
`•
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1
`INDICATIONS AND USAGE
`2
`DOSAGE AND ADMINISTRATION
`2.1
`Important Administration Instructions
`2.2 Dosing Information
`2.3 Dose Titration
`DOSAGE FORMS AND STRENGTHS
`3
`CONTRAINDICATIONS
`4
`5 WARNINGS AND PRECAUTIONS
`5.1 Nausea and Vomiting
`5.2
`Falling Asleep During Activities of Daily Living and
`Somnolence
`5.3 Hypersensitivity
`5.4
`Syncope / Hypotension / Orthostatic Hypotension
`5.5 Oral Mucosal Irritation
`5.6
`Falls
`5.7 Hallucinations / Psychotic-Like Behavior
`5.8 Hemolytic Anemia
`5.9
`Impulse Control/Compulsive Behaviors
`5.10 Withdrawal-Emergent Hyperpyrexia and Confusion
`5.11 QTc Prolongation and Potential for Proarrhythmic Effects
`5.12 Fibrotic Complications
`5.13 Priapism
`5.14 Retinal Pathology in Albino Rats
`ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2 Postmarketing Experience
`DRUG INTERACTIONS
`7.1
`5HT3 Antagonists
`7.2 Antihypertensive Medications and Vasodilators
`
`6
`
`7
`
`
`
`•
`
`•
`
`•
`
`Falling asleep during activities of daily living and daytime somnolence
`may occur; discontinue KYNMOBI if this occurs (5.2)
`Syncope and hypotension/orthostatic hypotension may occur; monitor
`blood pressure (5.4)
`Oral mucosal irritation may occur, which may require pausing or
`discontinuing treatment (5.5)
`Falls may occur or increase (5.6)
`•
`• May cause hallucinations and psychotic-like behavior (5.7)
`• May cause hemolytic anemia (5.8)
`• May cause impulse control and impulsive behaviors; consider dose
`reduction or discontinuing KYNMOBI if this occurs (5.9)
`• Withdrawal-emergent hyperpyrexia and confusion may occur with rapid
`dose reduction or withdrawal (5.10)
`• May prolong QTc and cause torsades de pointes or sudden death;
`consider risk factors prior to initiation (5.11)
` ___________________ ADVERSE REACTIONS ___________________
`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 (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Sunovion
`Pharmaceuticals Inc. at 1-877-737-7226 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch.
` ___________________ DRUG INTERACTIONS____________________
`Concomitant use of antihypertensive medications and vasodilators may
`•
`increase risk for hypotension, myocardial infarction, falls and injuries
`(7.2)
`Dopamine antagonists may diminish the effectiveness of KYNMOBI
`•
`(7.4)
` ______________ USE IN SPECIFIC POPULATIONS _______________
`Pregnancy: Based on animal data, may cause fetal harm (8.1)
`•
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved patient labeling.
`
`Revised: 5/2022
`
`8
`
`9
`
`7.3 Alcohol
`7.4 Dopamine Antagonists
`7.5 Drugs Prolonging the QT/QTc Interval
`USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`8.2 Lactation
`8.4
`Pediatric Use
`8.5 Geriatric Use
`8.6 Renal Impairment
`8.7 Hepatic Impairment
`DRUG ABUSE AND DEPENDENCE
`9.1 Controlled Substance
`9.2 Abuse
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`16.1 How Supplied
`16.2 Storage and Handling
`PATIENT COUNSELING INFORMATION
`
`17
`
`*Sections or subsections omitted from the full prescribing information
`are not listed.
`
`
`
`
`Reference ID: 4979043
`
`1
`
`
`
`
`
`

`

`FULL PRESCRIBING INFORMATION
`
`INDICATIONS AND USAGE
`1
`KYNMOBI is indicated for the acute, intermittent treatment of “off” episodes in patients with
`Parkinson’s disease (PD).
`
`DOSAGE AND ADMINISTRATION
`2
`Important Administration Instructions
`2.1
`KYNMOBI is for sublingual administration only.
`Dose initiation should be supervised by a healthcare provider [see Dosage and Administration
`(2.3)].
`KYNMOBI must be administered whole. Do not cut, chew, or swallow KYNMOBI. KYNMOBI
`will disintegrate in about 3 minutes.
`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 2 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,
`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
`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.
`Do not administer more than 5 doses per day.
`The maximum single dose of KYNMOBI is 30 mg.
`2.3
`Dose Titration
`The initial dose is 10 mg. Dose initiation should occur when the patient is in an “off” state and in
`a setting where a healthcare provider can monitor blood pressure and pulse. In clinical studies of
`KYNMOBI, the “off” state was achieved by instructing patients to not take their regular morning
`dose of carbidopa/levodopa or any other adjunctive Parkinson’s disease medications, and to take
`
`
`
`
`Reference ID: 4979043
`
`2
`
`
`
`
`
`

`

`their last dose of carbidopa/levodopa and any other adjunctive Parkinson’s disease medications
`no later than midnight the night before [see Clinical Studies (14)].
`If the patient tolerates the 10 mg dose, and responds adequately, the starting dose should be 10
`mg, used on an as-needed basis, up to 5 times per day, to treat “off” episodes. If the dose is
`tolerated but the response is insufficient, the patient’s usual Parkinson’s disease medications
`should be resumed and up-titration with KYNMOBI continued generally within 3 days. Increase
`dosage by increments of 5 mg and assess response. Continue to titrate in a similar manner, under
`the supervision of a healthcare provider, until an effective and tolerable dose is achieved [see
`Dosage and Administration (2.2) and Clinical Studies (14)].
`
`DOSAGE FORMS AND STRENGTHS
`3
`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,
`15 mg, 20 mg, 25 mg, and 30 mg. Each sublingual film is individually packaged in a sealed foil
`pouch.
`
`CONTRAINDICATIONS
`4
`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
`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)].
`
`WARNINGS AND PRECAUTIONS
`5
`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 2 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
`hydrochloride; 300 mg by mouth three times daily) was required beginning 3 days before starting
`KYNMOBI; however, it could be discontinued during the maintenance phase. During the
`titration phase of Study 1, nausea was reported as an adverse reaction by 21% of patients treated
`
`
`
`
`Reference ID: 4979043
`
`3
`
`
`
`
`
`

`

`with KYNMOBI, while vomiting was reported as an adverse reaction by 4% of patients treated
`with KYNMOBI. During the maintenance phase of Study 1, nausea was reported as an adverse
`reaction by 28% of patients treated with KYNMOBI, compared with 4% of patients who
`received placebo. During the maintenance phase of Study 1, vomiting was reported as an adverse
`reaction by 7% of patients treated with KYNMOBI, compared with 0% of patients who received
`placebo. Nausea or vomiting was the reason for withdrawal from the study in 2% of patients
`treated with KYNMOBI during the titration phase and 2% of patients treated with KYNMOBI
`during the maintenance phase.
`Concomitantly administered antiemetic drugs other than trimethobenzamide have not been
`studied. 5HT3 antagonist antiemetics are contraindicated [see Contraindications (4)].
`Antiemetics with anti-dopaminergic actions (e.g., haloperidol, chlorpromazine, promethazine,
`prochlorperazine, metoclopramide) have the potential to worsen symptoms in patients with
`Parkinson’s disease and should be avoided [see Drug Interactions (7.4)].
`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
`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
`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
`events occur well after the start of treatment. Prescribers should also be aware that patients may
`not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or
`sleepiness during specific activities.
`Before initiating treatment with KYNMOBI, advise patients of the risk of drowsiness and ask
`them about factors that could increase the risk with KYNMOBI, such as concomitant sedating
`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,
`eating, etc.), KYNMOBI should ordinarily be discontinued. If a decision is made to continue
`KYNMOBI, patients should be advised not to drive and to avoid other potentially dangerous
`activities. There is insufficient information to determine whether dose reduction will eliminate
`episodes of falling asleep while engaged in activities of daily living.
`5.3
`Hypersensitivity
`Oral soft tissue swelling (lips, tongue, gingiva, and mouth) was reported as an adverse reaction in
`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
`adverse reactions in 6% of patients treated with KYNMOBI during the maintenance phase of
`
`
`
`
`Reference ID: 4979043
`
`4
`
`
`
`
`
`

`

`Study 1, compared with 0% of patients who received placebo; 4% of patients discontinued
`KYNMOBI because of this event.
`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,
`including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain
`susceptible people. The overall prevalence of sulfite sensitivity in the general population is
`unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in non-
`asthmatic people.
`5.4
`Syncope/Hypotension/Orthostatic Hypotension
`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-
`syncope, hypotension, or orthostatic hypotension were reported as adverse reactions in 2% of
`patients treated with KYNMOBI, compared with 0% of patients who received placebo.
`During the maintenance phase of Study 1, systolic orthostatic hypotension (reduction of 20
`mmHg or more in standing minus supine/sitting systolic blood pressure) or diastolic hypotension
`(10 mmHg or more for standing minus supine/sitting diastolic blood pressure) occurred in 43%
`of patients treated with KYNMOBI, and in 36% of patients who received placebo.
`Patients treated with KYNMOBI should receive an assessment for hypotension/orthostatic
`hypotension, especially if they have a history of hypotension or cardiovascular disease, or if they
`are currently using antihypertensive medication. Inform patients of the risk of orthostatic
`hypotension.
`The hypotensive effects of KYNMOBI may be increased by the concomitant use of alcohol,
`antihypertensive medications, and vasodilators (especially nitrates). Patients should avoid
`alcohol when using KYNMOBI [see Drug Interactions (7.3), Clinical Pharmacology (12.3)].
`Patients taking KYNMOBI should lie down before and after taking sublingual nitroglycerin [see
`Drug Interactions (7.2), Clinical Pharmacology (12.3)].
`Monitor patients taking concomitant antihypertensive medications for hypotension and
`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)].
`
`
`
`
`Reference ID: 4979043
`
`5
`
`
`
`
`
`

`

`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,
`oral soft tissue pain or paresthesia were reported as adverse reactions in 13% of patients treated
`with KYNMOBI, compared with 2% of patients who received placebo.
`In general, oral mucosal irritation reactions were mild to moderate in 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)].
`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 an adverse reaction in 4% of
`patients treated with KYNMOBI. During the maintenance period of Study 1, falls were reported
`as an adverse reaction in 6% of patients treated with KYNMOBI, compared with 2% of patients
`who received placebo.
`5.7
`Hallucinations/Psychotic-Like Behavior
`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)].
`
`
`
`
`Reference ID: 4979043
`
`6
`
`
`
`
`
`

`

`Hemolytic Anemia
`5.8
`Hemolytic anemia requiring hospitalization has been reported with apomorphine treatment in the
`postmarketing setting. Many of the reported cases included a positive direct antiglobulin test
`(Coombs test), suggesting a potential immune-mediated hemolysis. Severe anemia, angina, and
`dyspnea have occurred with hemolytic anemia. Some patients were treated with high dose
`glucocorticoids or blood transfusions. Hemolytic anemia can appear at any time after
`apomorphine treatment. If a patient develops anemia while taking KYNMOBI, consider a
`workup for hemolytic anemia. If hemolytic anemia occurs, consider discontinuing KYNMOBI
`treatment.
`Impulse Control/Compulsive Behaviors
`5.9
`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.
`5.10 Withdrawal-Emergent Hyperpyrexia and Confusion
`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.
`5.11
`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.
`
`
`
`
`Reference ID: 4979043
`
`7
`
`
`
`
`
`

`

`The risks and benefits of KYNMOBI treatment should be considered prior to initiating treatment
`with KYNMOBI in patients with risk factors for prolonged QTc.
`5.12
`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, non-ergot-derived
`dopamine agonists, such as KYNMOBI, can cause these reactions is unknown.
`5.13
`Priapism
`Apomorphine may cause prolonged painful erections in some patients. Severe priapism may
`require surgical intervention.
`5.14
`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.
`
`ADVERSE REACTIONS
`6
`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)]
`• Hemolytic Anemia [see Warnings and Precautions (5.8)]
`Impulse Control/Compulsive Behaviors [see Warnings and Precautions (5.9)]
`•
`
`
`
`
`Reference ID: 4979043
`
`8
`
`
`
`
`
`

`

`• Withdrawal-Emergent Hyperpyrexia and Confusion [see Warnings and Precautions
`(5.10)]
`• QTc Prolongation and Potential for Proarrhythmic Effects [see Warnings and
`Precautions (5.11)]
`• Fibrotic Complications [see Warnings and Precautions (5.12)]
`• Priapism [see Warnings and Precautions (5.13)]
`• Retinal Pathology in Albino Rats [see Warnings and Precautions (5.14)]
`6.1
`Clinical Trials Experience
`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.
`Table 1:
`Adverse Reactions Reported by at Least 5% of Patients Treated with
`KYNMOBI during the Maintenance Phase of Study 1, and with an Incidence
`Greater than Placebo
`
`
`
`
`Maintenance
`KYNMOBI
`Placebo
`(N=54)
`(N=55)
`%
`%
`
`28
`15
`13
`7
`7
`7
`
`
`0
`2
`0
`4
`0
`
` 4
`
`
`
`Gastrointestinal disorders
`Nausea
`Oral/pharyngeal soft tissue swelling1
`Oral/pharyngeal soft tissue pain and paraesthesia2
`Oral ulceration and stomatitis3
`Oral mucosal erythema
`Vomiting
`
`
`
`
`Reference ID: 4979043
`
`Titration
`KYNMOBI
`(N=141)
`%
`
`21
`1
`2
`2
`4
`4
`
`9
`
`
`

`

`
`
`Dry mouth
`
`Titration
`KYNMOBI
`(N=141)
`%
`1
`
`Maintenance
`KYNMOBI
`Placebo
`(N=54)
`(N=55)
`%
`%
`6
`0
`
` 2
`
`
`0
`0
`
`
`
`
`
` 0
`
`
`
` 0
`
`
`13
`9
`6
`
`
`
`
`
` 7
`
`
`
` 7
`
`
`11
`11
`8
`
`
`
`
`
` 6
`
`
`
` 3
`
`Nervous system disorders
`Somnolence
`Dizziness
`Headache
`Respiratory, thoracic, and mediastinal disorders
`Rhinorrhea
`General disorders and administration site
`conditions
`Fatigue
`
`Injury, poisoning, and procedural complications
`Fall
`Laceration
`Skin and subcutaneous tissue disorders
`Hyperhidrosis
`Immune system disorders
`
`
`
` 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, 5.9)].
`
`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 reactions 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 reactions 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)].
`
` 6
`
`
`6
`
`
`
` 6
`
` 6
`
` 4
`
`
`1
`
`
`
` 4
`
` 0
`
` 2
`
`
`0
`
`
`
` 4
`
` 0
`
`
`
`
`Reference ID: 4979043
`
`10
`
`
`
`
`
`

`

`
`Postmarketing Experience
`6.2
`The following adverse reactions have been identified during postapproval use of apomorphine.
`Because these reactions are reported voluntarily from a population of uncertain size, it is not
`always possible to reliably estimate their frequency or establish a causal relationship to drug
`exposure.
`Hematologic and Lymphatic Systems: Hemolytic anemia [see Warnings and Precautions (5.8)].
`
`DRUG INTERACTIONS
`7
`5HT3 Antagonists
`7.1
`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)].
`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 should avoid drinking alcohol after using KYNMOBI [see Warnings and Precautions
`(5.4)].
`Dopamine Antagonists
`7.4
`Since KYNMOBI is a dopamine agonist, it is possible that concomitant use of dopamine
`antagonists, such as the neuroleptics (e.g., phenothiazines, butyrophenones, thioxanthenes) or
`metoclopramide, may diminish the effectiveness of KYNMOBI. Antiemetics with anti-
`dopaminergic actions should be avoided [see Warnings and Precautions (5.1)]. Patients with
`major psychotic disorders receiving neuroleptics should be treated with dopamine agonists only
`if the potential benefits outweigh the risks [see Warnings and Precautions (5.7)].
`
`
`
`
`Reference ID: 4979043
`
`11
`
`
`
`
`
`

`

`Drugs Prolonging the QT/QTc Interval
`7.5
`Caution should be exercised when prescribing KYNMOBI concomitantly with drugs that
`prolong the QT/QTc interval [see Warnings and Precautions (5.11) and Clinical Pharmacology
`(12.2)].
`
`USE IN SPECIFIC POPULATIONS
`8
`Pregnancy
`8.1
`Risk Summary
`There are no adequate data on th