Drug Safety-related Labeling Changes (SrLC)

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APOKYN (NDA-021264)

(APOMORPHINE HYDROCHLORIDE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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06/22/2022 (SUPPL-21)

Approved Drug Label (PDF)

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined

Nausea and Vomiting

Advise patients they may experience nausea and/or vomiting, which may be severe, and that treatment with oral trimethobenzamide 300 mg 3 times per day for 3 days prior to starting APOKYN injections has been used to help minimize these symptoms. Alternatively, starting APOKYN at a lower dose and titrating based on individual tolerance and treatment effect may be attempted. Advise patients that APOKYN taken with trimethobenzamide may increase the risks for somnolence, dizziness, and falls, and to consult their healthcare provider before discontinuing trimethobenzamide [see Warnings and Precautions (5.2)].

PATIENT INFORMATION

Additions and/or revisions underlined

What are the possible side effects of APOKYN?

  • nausea and vomiting. Nausea and vomiting, which may be severe, can happen with APOKYN. Your healthcare provider may prescribe a medicine to help decrease nausea and vomiting. Follow your healthcare providers instructions on how to take and when to stop this medicine.

05/05/2022 (SUPPL-22)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.8 Hemolytic Anemia

Newly added subsection:

Hemolytic anemia requiring hospitalization has been reported with apomorphine treatment in the postmarketing setting. Many of the reported cases included 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 APOKYN, consider a workup for hemolytic anemia. If hemolytic anemia occurs, consider discontinuing APOKYN treatment.

6 Adverse Reactions

Addition of the following to the bulleted line listing:

·         Hemolytic Anemia [see Warnings and Precautions (5.8)

6.2 Postmarketing Experience

Newly added subsection:

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)]

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Newly added information:

Hemolytic Anemia

Inform patients and caregivers that hemolytic anemia may occur and to contact their healthcare provider if they develop any signs or symptoms [see Warnings and Precautions (5.8)].

PATIENT INFORMATION

Newly added section; please refer to label

05/01/2020 (SUPPL-18)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.10 QTc Prolongation and Potential for Proarrhythymic Effects

(additions underlined)

There is a dose-related prolongation of QTc interval after apomorphine exposure similar to that achieved with therapeutic doses of APOKYN. Doses greater than 6 mg do not provide additional clinical benefit and are not recommended.

05/20/2019 (SUPPL-16)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.12 Hypersensitivity

(new subsection added)

Hypersensitivity/allergic reactions characterized by urticaria, rash, pruritus, and/or various manifestations of angioedema may occur because of APOKYN or because of its sulfite excipient. APOKYN 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 nonasthmatic people.

5.4 Syncope /Hypotension / Orthostatic Hypotension

(additions underlined)

In a study of healthy subjects, the hypotensive effect of APOKYN on systolic and diastolic blood pressure was exacerbated by the concomitant use of alcohol or sublingual nitroglycerin (0.4 mg). Patients should avoid alcohol when using APOKYN. Patients taking APOKYN should lie down before and after taking sublingual nitroglycerin. Other vasodilators and antihypertensives may also increase the hypotensive effects of APOKYN. Monitor blood pressure for hypotension and orthostatic hypotension in patients taking APOKYN with concomitant antihypertensive medications or vasodilators.

6 Adverse Reactions

(additions underlined)

 

The following serious adverse reactions are discussed in more detail in the Warnings and Precautions section of labeling:

 

  • Serious Adverse Reactions After Intravenous Administration

  • Nausea and Vomiting

  • Falling Asleep During Activities of Daily Living and Somnolence

  • Syncope/Hypotension/Orthostatic Hypotension

  • Falls

  • Hallucinations/Psychotic-Like Behavior

  • Dyskinesias

  • Impulse Control/Compulsive Behaviors

  • Coronary Events

  • QTc Prolongation and Potential for Proarrhythymic Effects

  • Withdrawal-Emergent Hyperpyrexia and Confusion

  • Hypersensitivity

  • Fibrotic Complications

  • Priapism

7 Drug Interactions

7.2 Antihypertensive Medications and Vasodilators

(additions underlined)

Some of the events may be related to the increased incidence of hypotension in patients receiving concomitant antihypertensive medications or vasodilators.

Concomitant administration of 0.4 mg sublingual nitroglycerin with APOKYN in healthy subjects   causes greater decreases in blood pressure compared to APOKYN alone. When nitroglycerin and APOKYN 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 APOKYN) 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 APOKYN 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.

Patients taking APOKYN should lie down before and after taking sublingual nitroglycerin.

7.3 Alcohol

(new subsection added)

 

Concomitant administration of high dose (0.6 g/kg) or low dose (0.3 g/kg) ethanol with APOKYN in healthy subjects causes greater decreases in blood pressure compared to APOKYN alone.

 

When high dose ethanol and APOKYN 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 APOKYN) 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 and APOKYN 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 APOKYN 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.

 

Patients should avoid drinking alcohol after using APOKYN.

8 Use in Specific Populations

8.7 Hepatic Impairment

(addition underlined)

Caution should be exercised when administrating APOKYN to patients with mild and moderate hepatic impairment because of the increased Cmax and AUC in these patients. Closely monitor patients with mild and moderate hepatic impairment. Studies of subjects with severe hepatic impairment have not been conducted.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

(additions underlined)

Hypotension / Orthostatic Hypotension

 

Inform patients that alcohol and  nitroglycerin (and possibly other vasodilators and antihypertensive medications) may potentiate the hypotensive effect of APOKYN. Instruct patients ideally to lie down before taking sublingual nitroglycerin and to remain supine and avoid standing for at least 45 minutes after nitroglycerin. Instruct patients taking APOKYN to avoid alcohol while using APOKYN and of the increased hypotensive effects of APOKYN taken with nitroglycerin or by taking APOKYN after alcohol ingestion.

 

PATIENT INFORMATION

(updates made, please refer to label for more information)

03/16/2017 (SUPPL-14)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Nausea and Vomiting

(Additions and/or revisions are underlined)

The effect of trimethobenzamide on reducing nausea and vomiting during treatment with APOKYN was evaluated in a 12-week, placebo-controlled study in 194 patients. The study suggests that trimethobenzamide reduces the incidence of nausea and vomiting during the first 4 weeks of APOKYN treatment (incidence of nausea and vomiting 43% on trimethobenzamide vs. 59% on placebo). However, over the 12-week period, compared with placebo, patients treated with trimethobenzamide had a greater incidence of somnolence (19% for trimethobenzamide vs. 12% for placebo), dizziness (14% for trimethobenzamide vs. 8% for placebo), and falls (8% for trimethobenzamide vs. 1% for placebo). Therefore, the benefit of treatment with trimethobenzamide must be balanced with the risk for those adverse events, and treatment with trimethobenzamide should only be continued as long as necessary to control nausea and vomiting, and generally no longer than two months.

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; additions and/or revisions are underlined)

Risk Summary

There are no adequate data on the developmental risk associated with use of APOKYN 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. 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

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; the highest dose tested is 1.5 times the maximum recommended human dose (MRHD) of 20 mg/day on a mg/m squared basis. 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. The no- effect dose for adverse developmental effects is less than the MRHD on a mg/m squared basis.

 

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

8.2 Lactation

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; additions and/or revisions are underlined)

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 APOKYN and any potential adverse effects on the breastfed infant from APOKYN or from the underlying maternal condition.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Administration with the APOKYN Pen

Instruct patients and caregivers to read the “APOKYN Pen Instructions for Use” and Patient Information

Nausea and Vomiting

Advise patients that APOKYN taken with trimethobenzamide may increase the risks for somnolence, dizziness, and falls. Inform patients that their healthcare provider will tell them when trimethobenzamide can be discontinued.

Questions related to the drug data in these files should be directed to the Center for Drug Evaluation and Research, Division of Drug Information
druginfo@fda.hhs.gov.

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