KYNMOBI (Page 2 of 7)

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)].

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)].

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.

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