Apomorphine Hydrocloride

APOMORPHINE HYDROCLORIDE- apomorphine hydrochloride injection
TruPharma, LLC

1 INDICATIONS AND USAGE

Apomorphine hydrochloride injection is indicated for the acute, intermittent treatment of hypomobility, “off” episodes (“end-of-dose wearing off” and unpredictable “on/off” episodes) in patients with advanced Parkinson’s disease. Apomorphine hydrocloride inejction has been studied as an adjunct to other medications [see Clinical Studies (14)].

2 DOSAGE AND ADMINISTRATION

2.1 Important Administration Instructions

Apomorphine hydrocloride is indicated for subcutaneous administration only [see Warnings and Precautions (5.1)] and only by a multiple-dose APOKYN® Pen with supplied cartridges. The APOKYN® Pen is supplied separately by a different manufacturer. The initial dose and dose titrations should be performed by a healthcare provider. Blood pressure and pulse should be measured in the supine and standing position before and after dosing.

A caregiver or patient may administer apomorphine hydrocloride if a healthcare provider determines that it is appropriate. Instruct patients to follow the directions provided in the Patients Instructions For Use. Because the APOKYN® Pen has markings in milliliters (mL), the prescribed dose of apomorphine hydrocloride should be expressed in mL to avoid confusion.

Visually inspect the apomorphine hydrocloride drug product through the viewing window for particulate matter and discoloration prior to administration. The solution should not be used if discolored (it should be colorless), or cloudy, or if foreign particles are present. Rotate the injection site and use proper aseptic technique [see How Supplied/Storage and Handling (16) and Patient Counseling Information (17)].

2.2 Premedication and Concomitant Medication

Because of the high incidence of nausea and vomiting with apomorphine hydrocloride treatment, an antiemetic, e.g., trimethobenzamide 300 mg three times a day, should be started 3 days prior to the initial dose of apomorphine hydrocloride [see Warnings and Precautions (5.2)]. Treatment with trimethobenzamide should only be continued as long as necessary to control nausea and vomiting, and generally no longer than two months after initiation of treatment with apomorphine hydrocloride, as trimethobenzamide increases the incidence of somnolence, dizziness and falls in patients treated with apomorphine hydrocloride [see Warnings and Precautions (5.2)].

Based on reports of profound hypotension and loss of consciousness when apomorphine was administered with ondansetron, the concomitant use of apomorphine with drugs of the 5HT3 antagonist class including antiemetics (for example, ondansetron, granisetron, dolasetron, palonosetron) and alosetron are contraindicated [see Contraindications (4)].

2.3 Dosing Information

The recommended starting dose of apomorphine hydrocloride is 0.2 mL (2 mg). Titrate on the basis of effectiveness and tolerance, up to a maximum recommended dose of 0.6 mL (6 mg) [see Clinical Studies (14)].

There is no evidence from controlled trials that doses greater than 0.6 mL (6 mg) gave an increased effect and therefore, individual doses above 0.6 mL (6 mg) are not recommended. The average frequency of dosing in the development program was 3 times per day. There is limited experience with single doses greater than 0.6 mL (6 mg), dosing more than 5 times per day and with total daily doses greater than 2 mL (20 mg).

Begin dosing when patients are in an “off” state. The initial dose should be a 0.2 mL (2 mg) test dose in a setting where medical personnel can closely monitor blood pressure and pulse. Both supine and standing blood pressure and pulse should be checked pre-dose and at 20 minutes, 40 minutes, and 60 minutes post-dose (and after 60 minutes, if there is significant hypotension at 60 minutes). Patients who develop clinically significant orthostatic hypotension in response to this test dose of apomorphine hydrocloride should not be considered candidates for treatment with apomorphine hydrocloride.

If the patient tolerates the 0.2 mL (2 mg) dose, and responds adequately, the starting dose should be 0.2 mL (2 mg), used on an as needed basis to treat recurring “off” episodes. If needed, the dose can be increased in 0.1 mL (1 mg) increments every few days on an outpatient basis.

The general principle guiding subsequent dosing (described in detail below) is to determine that the patient needs and can tolerate a higher test dose, 0.3 mL or 0.4 mL (3 mg or 4 mg, respectively) under close medical supervision. A trial of outpatient dosing may follow (periodically assessing both efficacy and tolerability), using a dose 0.1 mL (1 mg) lower than the tolerated test dose.

If the patient tolerates the 0.2 mL (2 mg) test dose but does not respond adequately, a dose of 0.4 mL (4 mg) may be administered under medical supervision, at least 2 hours after the initial test dose, at the next observed “off” period. If the patient tolerates and responds to a test dose of 0.4 mL (4 mg), the initial maintenance dose should be 0.3 mL (3 mg) used on an as needed basis to treat recurring “off” episodes as an outpatient. If needed, the dose can be increased in 0.1 mL (1 mg) increments every few days on an outpatient basis.

If the patient does not tolerate a test dose of 0.4 mL (4 mg), a test dose of 0.3 mL (3 mg) may be administered during a separate “off” period under medical supervision, at least 2 hours after the previous dose. If the patient tolerates the 0.3 mL (3 mg) test dose, the initial maintenance dose should be 0.2 mL (2 mg) used on an as needed basis to treat existing “off” episodes. If needed, and the 0.2 mL (2 mg) dose is tolerated, the dose can be increased to 0.3 mL (3 mg) after a few days. In such a patient, the dose should ordinarily not be increased to 0.4 mL (4 mg) on an outpatient basis.

2.4 Dosing in Patients with Renal Impairment

For patients with mild and moderate renal impairment, the test dose and starting dose should be reduced to 0.1 mL (1 mg) [see Clinical Pharmacology (12.3) and Use in Specific Populations (8.6)].

2.5 Re-treatment and Interruption in Therapy

If a single dose of apomorphine hydrocloride is ineffective for a particular “off” period, a second dose should not be given for that “off” episode. The efficacy of the safety of administering a second dose for a single “off” episode has not been studied systematically. Do not administer a repeat dose of apomorphine hydrocloride sooner than 2 hours after the last dose.

Patients who have an interruption in therapy of more than a week should be restarted on a 0.2 mL (2 mg) dose and gradually titrated to effect and tolerability.

3 DOSAGE FORMS AND STRENGTHS

Apomorphine hydrocloride 30 mg/3 mL (10 mg/mL) containing apomorphine hydrochloride (as apomorphine hydrochloride hemihydrate), USP is supplied as a clear, colorless, sterile, solution in a 3 mL (30 mg) cartridge. The 3 mL (30 mg) glass cartridge for single-patient-use is used with a manual reusable pen injector (APOKYN® Pen) which is supplied separately by a different manufacturer. A single cartridge, pen and needle can deliver doses up to 1 mL (10 mg) in 0.02 mL (0.2 mg) increments. The APOKYN® pen injector is provided in a package with six needles.

4 CONTRAINDICATIONS

Apomorphine hydrocloride is contraindicated in patients:

  • Using concomitant drugs of the 5HT3 antagonist class including antiemetics (e.g., ondansetron, granisetron, dolasetron, palonosetron) and alosetron [see Drug Interactions (7.1)]. There have been reports of profound hypotension and loss of consciousness when apomorphine hydrocloride was administered with ondansetron.
  • With hypersensitivity/allergic reaction to apomorphine or to any of the excipients of apomorphine hydrocloride, including a sulfite (i.e., sodium metabisulfite). Angioedema or anaphylaxis may occur [see Warnings and Precautions (5.12)].

5 WARNINGS AND PRECAUTIONS

5.1 Serious Adverse Reactions After Intravenous Administration

Following intravenous administration of apomorphine hydrocloride, serious adverse reactions including thrombus formation and pulmonary embolism due to intravenous crystallization of apomorphine have occurred. Consequently, apomorphine hydrocloride should not be administered intravenously.

5.2 Nausea and Vomiting

Apomorphine hydrocloride causes severe nausea and vomiting when it is administered at recommended doses. Because of this, in domestic clinical studies, 98% of all patients were pre-medicated with trimethobenzamide, an antiemetic, for three days prior to study enrollment, and were then encouraged to continue trimethobenzamide for at least 6 weeks. Even with the use of concomitant trimethobenzamide in clinical studies, 31% and 11% of the apomorphine hydrocloride-treated patients had nausea and vomiting, respectively, and 3% and 2% of the patients discontinued apomorphine hydrocloride due to nausea and vomiting, respectively. Among 522 patients treated, 262 (50%) discontinued trimethobenzamide while continuing apomorphine hydrocloride. The average time to discontinuation of trimethobenzamide was about 2 months (range: 1 day to 33 months). For the 262 patients who discontinued trimethobenzamide, 249 patients continued apomorphine without trimethobenzamide for a duration of follow-up that averaged 1 year (range: 0 years to 3 years).

The effect of trimethobenzamide on reducing nausea and vomiting during treatment with apomorphine hydrocloride 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 apomorphine hydrocloride 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.

The ability of concomitantly administered antiemetic drugs (other than trimethobenzamide) has not been studied. Antiemetics with anti-dopaminergic actions (e.g., haloperidol, chlorpromazine, promethazine, prochlorperazine, metaclopramide) have the potential to worsen the symptoms in patients with Parkinson’s disease and should be avoided.

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