Prescription Drug Information: KYNMOBI (Page 3 of 4)

6.2 Postmarketing Experience

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)].

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)].

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)].

7.4 Dopamine Antagonists

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)].

7.5 Drugs Prolonging the QT/QTc Interval

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)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

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.

Data

Animal Data

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.

8.2 Lactation

Risk Summary

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.

8.4 Pediatric Use

The safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

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); falls (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.

8.6 Renal Impairment

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)].

8.7 Hepatic Impairment

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)].

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

KYNMOBI contains apomorphine, which is not a controlled substance.

9.2 Abuse

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.

11 DESCRIPTION

KYNMOBI (apomorphine hydrochloride) sublingual film contains apomorphine hydrochloride, a non-ergoline dopamine agonist. Apomorphine hydrochloride is chemically designated as 6aβ-Aporphine-10,11-diol hydrochloride hemihydrate with a molecular formula of C17 H17 NO2 HCl ½ H2 O. Its structural formula and molecular weight are:

Figure 1: Structural Formula and Molecular Weight of Apomorphine Hydrochloride

Figure 1: Structural Formula and Molecular Weight of Apomorphine Hydrochloride
(click image for full-size original)

The molecular weight is 312.79 (hydrochloride hemihydrate salt).

Apomorphine hydrochloride is white to grayish glistening crystals or white powder that is sparingly soluble in water and alcohol at ambient temperature.

KYNMOBI is intended for sublingual administration only and is available in 5 dosage strengths. Each film contains 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg of apomorphine hydrochloride (equivalent to 8.8 mg, 13.2 mg, 17.6 mg, 22.0 mg, and 26.4 mg of apomorphine, respectively). Each film also contains the following inactive ingredients: disodium EDTA dihydrate, FD&C Blue #1, glycerol, glyceryl monostearate, hydroxyethyl cellulose, hydroxypropyl cellulose, maltodextrin, (-)-menthol, pyridoxine hydrochloride, sodium hydroxide, sodium metabisulfite, sucralose, and white ink.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

KYNMOBI is a non-ergoline dopamine agonist with high in vitro binding affinity for the dopamine D4 receptor, and moderate affinity for the dopamine D2 , D3 , and D5 , and adrenergic α1 D, α2 B, α2 C receptors. The precise mechanism of action of KYNMOBI as a treatment for “off” episodes associated with Parkinson’s disease is unknown, although it is believed to be due to stimulation of post-synaptic dopamine D2 -type receptors within the caudate-putamen in the brain.

12.2 Pharmacodynamics

Cardiac Electrophysiology

In a thorough QT study with subcutaneous apomorphine at exposures similar to those achieved with the recommended subcutaneous apomorphine dosing (i.e, 6 mg), apomorphine resulted in a prolongation of QTcF of 10 msec (90% upper confidence interval of 16 msec). The thorough QT study also identified a significant exposure-response relationship between apomorphine concentration and QTcF.

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 recommend dose of subcutaneous apomorphine (6 mg), QTc prolongation with KYNMOBI cannot be excluded.

Decreases in Blood Pressure

In 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, compared to 36% of patients who received placebo [see Warnings and Precautions (5.4) and Drug Interactions (7.2, 7.3)].

12.3 Pharmacokinetics

Absorption

Following sublingual administration of 15 mg of apomorphine, the time to maximum concentration (Tmax ) ranged from 0.5 to 1 hour. Apomorphine exhibits less than dose-proportional increase in exposures over a dose range of 10 mg to 35 mg (1.2 times the highest recommended dosage) following a single sublingual administration of KYNMOBI in patients with Parkinson’s disease.

Distribution

Following sublingual administration of 15 mg of apomorphine, the geometric mean (CV%) of the apparent volume of distribution was 3630 L (66%).

Elimination

Metabolism

The major metabolic pathways for sublingual apomorphine are sulfation by multiple sulfotransferase (SULT) enzymes; glucuronidation by multiple glycosyltransferase (UGT) enzymes; N-demethylation catalyzed by multiple enzymes, including CYP2B6, CYP2C8, and CYP3A4/5; followed by conjugation. Metabolism of sublingual apomorphine results in 3 major inactive metabolites: apomorphine sulfate, apomorphine glucuronide, and norapomorphine glucuronide.

Excretion

Following sublingual administration of 15 mg of apomorphine, the geometric mean (CV%) of the apparent clearance was 1440 L/h (68%), and the geometric mean of the terminal elimination half-life is about 1.7 hours (range about 0.8 hour to 3 hours).

Specific Populations

The apparent clearance of apomorphine does not appear to be influenced by age, gender, race, weight, duration of Parkinson’s disease, levodopa dose, use of antiemetic, or duration of therapy.

Renal Impairment

The clinical studies of KYNMOBI included patients with mild renal impairment (CLcr of ≥60 mL/min and <90 mL/min). There were no differences in apomorphine exposure after administration of KYNMOBI in patients with mild renal impairment as compared to patients with normal renal function (CLcr of ≥90 mL/min). Studies with KYNMOBI in patients with moderate to severe renal impairment have not been conducted.

In a study with subcutaneous apomorphine comparing patients with moderate renal impairment (as determined by estimated creatinine clearance) to healthy matched volunteers, the AUC0- and Cmax values were increased by approximately 16% and 50%, respectively, following a single administration. The mean time to peak concentrations and the mean terminal half-life of apomorphine were unaffected by the renal status of the individual.

Since the Cmax and AUC0- of apomorphine following the sublingual administration are lower as compared to the subcutaneous route of administration and the KYNMOBI dose is titrated individually, these changes are not expected to be clinically significant for patients with mild or moderate renal impairment [see Use in Specific Populations (8.6)].

Hepatic Impairment

Studies with KYNMOBI in patients with hepatic impairment have not been conducted.

In a study with subcutaneous apomorphine comparing patients with moderate hepatic impairment (as determined by the Child-Pugh classification method) to healthy matched volunteers, the AUC0- and Cmax values were increased by approximately 10% and 25%, respectively, following a single administration. These changes are not expected to be clinically significant for patients with mild or moderate hepatic impairment [see Use in Specific Populations (8.7)].

Drug Interaction Studies

Carbidopa/levodopa

Levodopa pharmacokinetics were unchanged when subcutaneous apomorphine and levodopa were co-administrated in patients. However, motor response differences were significant. The threshold levodopa concentration necessary for an improved motor response was reduced significantly, leading to an increased duration of effect without a change in the maximal response to levodopa therapy.

Nitroglycerin

Co-administration of nitroglycerin (0.4 mg) with subcutaneous apomorphine in healthy subjects did not have a significant impact on the pharmacokinetics of apomorphine. However, concomitant administration of nitroglycerin (0.4 mg) with subcutaneous apomorphine caused greater decreases in blood pressure than with subcutaneous apomorphine alone [see Warnings and Precautions (5.4) and Drug Interactions (7.2)].

When nitroglycerin and subcutaneous apomorphine were concomitantly administered to healthy subjects, the mean largest decrease (the mean of each subject’s largest drop in blood pressure measured within the 6-hour period following administration of subcutaneous apomorphine) in supine systolic and diastolic blood pressure (measured over 6 hours) was 9.7 mm Hg and 9.3 mm Hg, respectively. The mean largest decrease in standing systolic and diastolic blood pressure was 14.3 mm Hg and 13.5 mm Hg, respectively. Some individuals experienced very large decreases in standing systolic and diastolic blood pressure, up to a maximum decrease of 65 mm Hg and 43 mm Hg, respectively. In comparison, the mean largest decrease in supine systolic and diastolic blood pressure when subcutaneous apomorphine was administered alone was 6.1 mm Hg and 7.3 mm Hg, respectively, and in standing systolic and diastolic blood pressure was 6.7 mm Hg and 8.4 mm Hg, respectively.

A similar study has not been performed with KYNMOBI.

Ethanol

Co-administration of low-dose ethanol (0.3 g/kg) with subcutaneous apomorphine in healthy subjects did not have a significant impact on the pharmacokinetics of apomorphine, but high-dose ethanol (0.6 g/kg), equivalent to approximately 3 standardized alcohol-containing beverages, increased the Cmax of apomorphine by about 63%.

When high-dose ethanol (0.6 g/kg) and subcutaneous apomorphine were concomitantly administered to healthy subjects, the mean largest decrease (the mean of each subject’s largest drop in blood pressure measured within the 6-hour period following administration of subcutaneous apomorphine) for supine systolic and diastolic blood pressure was 9.1 mm Hg and 10.5 mm Hg, respectively. The mean largest standing systolic and diastolic blood pressure decrease was 11.3 mm Hg and 12.6 mm Hg, respectively. In some individuals, the decrease was as high as 61 mm Hg and 51 mm Hg, respectively, for standing systolic and diastolic blood pressure.

When low-dose ethanol (0.3 g/kg) and subcutaneous apomorphine were concomitantly administered, the mean largest decrease in supine systolic and diastolic blood pressure was 10.2 mm Hg and 9.9 mm Hg, respectively. The mean largest decrease in standing systolic and diastolic blood pressure was 8.4 mm Hg and 7.1 mm Hg, respectively. In comparison, the mean largest decrease in supine systolic and diastolic blood pressure when subcutaneous apomorphine was administered alone was 6.1 mm Hg and 7.3 mm Hg, respectively, and in standing systolic and diastolic blood pressure was 6.7 mm Hg 8.4 mm Hg, respectively.

A similar study has not been performed with KYNMOBI.

COMT Interactions

A pharmacokinetic interaction of apomorphine with catechol-O-methyl transferase (COMT) inhibitors or drugs metabolized by this route is unlikely since apomorphine appears not to be metabolized by COMT.

In vitro studies

Based on in vitro studies, the potential for KYNMOBI to interact with concomitant medications to cause a CYP metabolism or transporter-based drug-drug interaction is considered low.

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