Source: FDA, National Drug Code (US) Revision Year: 2020
KYNMOBI is contraindicated in patients:
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 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 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)].
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.
Oral soft tissue swelling (lips, tongue, gingiva, and mouth) was reported as 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 an adverse reaction in 6% of patients treated with KYNMOBI during the maintenance phase of 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.
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)].
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, 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 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)].
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.
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)].
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.
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.
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.
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.
Apomorphine may cause prolonged painful erections in some patients. Severe priapism may require surgical intervention.
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.
The following serious adverse reactions are discussed in more detail in the Warnings and Precautions section of labeling:
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:
| Titration | Maintenance | ||
|---|---|---|---|
| KYNMOBI (N=141) % | KYNMOBI (N=54) % | Placebo (N=55) % | |
| 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 | 21 1 2 2 4 4 1 | 28 15 13 7 7 7 6 | 4 0 2 0 4 0 0 |
| Nervous system disorders | |||
| Somnolence Dizziness Headache | 11 11 8 | 13 9 6 | 2 0 0 |
| Respiratory, thoracic, and mediastinal disorders | |||
| Rhinorrhea | 6 | 7 | 0 |
| General disorders and administration site conditions | |||
| atigue | 3 | 7 | 0 |
| Injury, poisoning, and procedural complications | |||
| Fall Laceration | 4 1 | 6 6 | 2 0 |
| Skin and subcutaneous tissue disorders | |||
| Hyperhidrosis | 4 | 6 | 4 |
| Immune system disorders | |||
| Hypersensitivity4 | 0 | 6 | 0 |
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
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)].
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)].
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)].
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)].
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)].
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)].
Caution should be exercised when prescribing KYNMOBI concomitantly with drugs that prolong the QT/QTc interval [see Warnings and Precautions (5.10) and Clinical Pharmacology (12.2)].
There are no adequate data on the developmental risk associated with use of KYNMOBI in pregnant women. In animal reproduction studies, apomorphine had adverse developmental effects in rats (increased neonatal deaths) and rabbits (increased incidence of malformation) when administered during pregnancy at clinically relevant doses. These doses were also associated with maternal toxicity [see Data]. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.
No adverse developmental effects were observed when apomorphine (0.3, 1, or 3 mg/kg/day) was administered by subcutaneous injection to pregnant rats throughout organogenesis. Administration of apomorphine (0.3, 1, or 3 mg/kg/day) by subcutaneous injection to pregnant rabbits throughout organogenesis resulted in an increased incidence of malformations of the heart and/or great vessels at the mid and high doses; maternal toxicity was observed at the highest dose tested.
Apomorphine (0.3, 1, or 3 mg/kg/day), administered by subcutaneous injection to females throughout gestation and lactation, resulted in increased offspring mortality at the highest dose tested, which was associated with maternal toxicity. There were no effects on developmental parameters or reproductive performance in surviving offspring.
There are no data on the presence of apomorphine in human milk, the effects of apomorphine on the breastfed infant, or the effects of apomorphine on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for KYNMOBI and any potential adverse effects on the breastfed infant from KYNMOBI or from the underlying maternal condition.
The safety and effectiveness in pediatric patients have not been established.
Clinical studies of KYNMOBI did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In Study 1, 78 patients below 65 years of age and 63 patients 65 years of age or older received at least one dose of KYNMOBI. Clinical experience with subcutaneous use of apomorphine has shown that the following adverse reactions were reported more frequently in patients 65 years of age or older compared to patients less than 65 years of age: confusion; hallucinations; serious adverse reactions (life-threatening events or events resulting in hospitalization and/or increased disability); fall (experiencing bone and joint injuries); cardiovascular events; respiratory disorders; gastrointestinal events; and discontinuation of treatment as a result of one or more adverse reactions.
In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Avoid use of KYNMOBI in patients with severe and end-stage renal disease (ESRD) (CLcr <30 mL/min). No dosage adjustment is required for patients with mild or moderate renal impairment. However, because of a potential for increased exposure, titrate KYNMOBI under medical supervision [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].
Avoid use of KYNMOBI in patients with severe hepatic impairment (Child-Pugh Class C). No dosage adjustment is required for patients with mild or moderate hepatic impairment (Child-Pugh Class A and B). However, because of a potential for increased exposure, titrate KYNMOBI under medical supervision [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].
KYNMOBI contains apomorphine, which is not a controlled substance.
In premarketing clinical experience, KYNMOBI did not reveal any tendency for a withdrawal syndrome or any drug-seeking behavior. However, there are rare postmarketing reports of abuse of medications containing apomorphine. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. In general, these reports for apomorphine consist of patients taking increasing doses of medication in order to achieve a euphoric state.
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