Prescription Drug Information: KYNMOBI (Page 2 of 4)

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)].

5.8 Hemolytic Anemia

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.

5.9 Impulse Control/Compulsive Behaviors

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.

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.

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)]
  • Hemolytic Anemia [see Warnings and Precautions (5.8)]
  • Impulse Control/Compulsive Behaviors [see Warnings and Precautions (5.9)]
  • 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
Titration Maintenance
KYNMOBI (N=141) % KYNMOBI (N=54) % Placebo (N=55) %

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

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 21122441 2815137776 4020400
Nervous system disorders Somnolence Dizziness Headache 11118 1396 200
Respiratory, thoracic , and mediastinal disorders Rhinorrhea 6 7 0
General disorders and administration site conditions Fatigue 3 7 0
Injury, poisoning , and procedural complications Fall Laceration 41 66 20
Skin and subcutaneous tissue disorders Hyperhidrosis 4 6 4
Immune system disorders Hypersensitivity4 0 6 0

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)].

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