KYNMOBI: Package Insert and Label Information (Page 2 of 4)

5.12 Priapism

Apomorphine may cause prolonged painful erections in some patients. Severe priapism may require surgical intervention.

5.13 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)]
  • Impulse Control/Compulsive Behaviors [see Warnings and Precautions (5.8)]
  • Withdrawal-Emergent Hyperpyrexia and Confusion [see Warnings and Precautions (5.9)]
  • QTc Prolongation and Potential for Proarrhythmic Effects [see Warnings and Precautions (5.10)]
  • Fibrotic Complications [see Warnings and Precautions (5.11)]
  • Priapism [see Warnings and Precautions (5.12)]
  • Retinal Pathology in Albino Rats [see Warnings and Precautions (5.13)]

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, 5.8)].

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 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)].

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 (5.10) 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); 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.

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
(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 five 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, hypromellose, maltodextrin, (-)-menthol, pyridoxine hydrochloride, sodium hydroxide, sodium metabisulfite, sucralose, and white ink.

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