Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

REQUIP XL (NDA-022008)

(ROPINIROLE HYDROCHLORIDE)

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

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07/12/2021 (SUPPL-12)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.5 Hallucinations/Psychotic-Like Behavior

(Additions and/or revisions underlined)

In a placebo-controlled flexible-dose trial in patients with advanced Parkinson’s disease

(Study 1), 8% of patients on REQUIP XL reported hallucination, compared with 2% of patients on placebo [see Adverse Reactions (6.1)]. Hallucinations led to discontinuation of treatment in 2% of patients on REQUIP XL and 1% of patients on placebo. The incidence of hallucination was increased in elderly patients (i.e., older than 65 years) treated with REQUIP XL [see Use in Specific Populations (8.5)].

In a placebo-controlled fixed-dose trial in patients with advanced Parkinson’s disease (Study 2), the incidence of hallucination was 3% in patients on REQUIP XL compared with 0% in patients on placebo [see Adverse Reactions (6.1)]. The most common adverse reaction associated with study discontinuation for any dose of REQUIP XL was hallucination (2%).

Postmarketing reports indicate that patients with Parkinson’s disease may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during treatment with REQUIP XL or after starting or increasing the dose of REQUIP XL. 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, psychotic-like behavior, symptoms of mania (e.g., insomnia, psychomotor agitation), disorientation, aggressive behavior, agitation, and delirium.

Patients with a major psychotic disorder should ordinarily not be treated with REQUIP XL because of the risk of exacerbating the psychosis. In addition, certain medications used to treat psychosis may exacerbate the symptoms of Parkinson’s disease and may decrease the effectiveness of REQUIP XL [see Drug Interactions (7.3)].

5.7 Impulse Control/Compulsive Behaviors

(Additions and/or revisions underlined)

Reports suggest that patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge or compulsive eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including REQUIP XL, 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 or compulsive eating, or other urges while being treated with REQUIP XL for Parkinson’s disease. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking REQUIP XL.

5.9 Withdrawal Symptoms

(Newly added subsection)

Symptoms including insomnia, apathy, anxiety, depression, fatigue, sweating, and pain have been reported during taper or after discontinuation of dopamine agonists, including REQUIP XL. These symptoms generally do not respond to levodopa.

Prior to discontinuation of REQUIP XL, patients should be informed about the potential withdrawal symptoms and monitored during and after discontinuation. In case of severe withdrawal symptoms, a trial re-administration of a dopamine agonist at the lowest effective dose may be considered.

6 Adverse Reactions

(Addition of the following to the bulleted line listing)

Withdrawal symptoms [see Warnings and Precautions (5.9)]

6.3 Postmarketing Experience

(Newly added subsection)

The following adverse reactions have been identified during postapproval use of REQUIP XL. 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.

General Disorders and Administration Site Conditions

Withdrawal Symptoms [see Warnings and Precautions (5.9)]

7 Drug Interactions

7.1 Cytochrome P450 1A2 Inhibitors and Inducers

(Subsection title revised; Additions and/or revisions underlined)

In vitro metabolism studies showed that cytochrome P450 1A2 (CYP1A2) is the major enzyme responsible for the metabolism of ropinirole. There is thus the potential for inducers or inhibitors of this enzyme to alter the clearance of ropinirole. Therefore, if therapy with a drug known to be a potent inducer or inhibitor of CYP1A2 is stopped or started during treatment with

REQUIP XL, adjustment of the dose of REQUIP XL may be required. Coadministration of ciprofloxacin, an inhibitor of CYP1A2, with immediate-release ropinirole increases the AUC and Cmax of ropinirole [see Clinical Pharmacology (12.3)]. Cigarette smoking is expected to increase the clearance of ropinirole since CYP1A2 is known to be induced by smoking [see Clinical Pharmacology (12.3)].

7.2 Estrogens

(Additions and/or revisions underlined)

Population pharmacokinetic analysis revealed that higher doses of estrogens (usually associated with hormone replacement therapy) reduced the clearance of ropinirole. Starting or stopping hormone replacement therapy may require adjustment of dosage of REQUIP XL [see Clinical Pharmacology (12.3)].

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

8.5 Geriatric Use

(Additions and/or revisions underlined)

Dose adjustment is not necessary in elderly (65 years and older) patients, as the dose of REQUIP XL is individually titrated to clinical therapeutic response and tolerability.

Pharmacokinetic trials conducted in patients demonstrated that oral clearance of ropinirole is reduced by 15% in patients older than 65 years compared with younger patients [see Clinical Pharmacology (12.3)].

In flexible-dose clinical trials of REQUIP XL, 387 patients were 65 years and older and 107 patients were 75 years and older. Among patients receiving REQUIP XL, hallucination was more common in elderly patients (10%) compared with non-elderly patients (2%). In these trials, the incidence of overall adverse reactions increased with increasing age for both patients receiving REQUIP XL and placebo.

In the fixed-dose clinical trials of REQUIP XL, 176 patients were 65 years and older and 73 were 75 and older. Among patients with advanced Parkinson’s disease receiving REQUIP XL, vomiting and nausea were more common in patients greater than 65 years (5% and 9%, respectively) compared with patients less than 65 (1% and 7%, respectively).

PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

…

Hallucinations/Psychotic-Like Behavior

Inform patients that they may experience hallucinations (unreal visions, sounds, or sensations), and that other psychotic-like behavior can occur while taking REQUIP XL. In patients with Parkinson’s disease, the elderly are at greater risk than younger patients. This risk is greater in patients who are taking REQUIP XL with L-dopa or taking higher doses of REQUIP XL, and may also be further increased in patients taking any other drugs that increase dopaminergic tone. Tell patients to report hallucinations or psychotic-like behavior to their healthcare provider promptly should they develop [see Warnings and Precautions (5.5)].

Dyskinesia

Inform patients that REQUIP XL may cause and/or exacerbate pre-existing dyskinesias [see Warnings and Precautions (5.6)].

Impulse Control/Compulsive Behaviors

Advise patients that they may experience impulse control and/or compulsive behaviors while taking REQUIP XL. Advise patients to inform their physician or healthcare provider if they develop new or increased gambling urges, sexual urges, uncontrolled spending, binge or compulsive eating, or other urges while being treated with REQUIP XL. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking REQUIP XL [see Warnings and Precautions (5.7)].

Withdrawal-Emergent Hyperpyrexia and Confusion

Advise patients to contact their healthcare provider if they wish to discontinue REQUIP XL or decrease the dose of REQUIP XL. Advise patients who have been prescribed a lower dose or who have been withdrawn from the drug to notify their healthcare provider if they present with fever, muscular rigidity, or altered consciousness [see Warnings and Precautions (5.8)].

Withdrawal Symptoms

Advise patients that withdrawal symptoms may occur during or after discontinuation or dose reduction of REQUIP XL. Advise patients who have been prescribed a lower dose or who have been withdrawn from the drug to notify their healthcare provider if they have withdrawal symptoms such as apathy, anxiety, depression, fatigue, insomnia, sweating, or pain. Notify patients that in case of severe withdrawal symptoms, a trial re-administration of a dopamine agonist at the lowest effective dose may be considered [see Warnings and Precautions (5.9)].

PATIENT INFORMATION

(Extensive changes; please refer to label)

07/12/2021 (SUPPL-13)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.5 Hallucinations/Psychotic-Like Behavior

(Additions and/or revisions underlined)

In a placebo-controlled flexible-dose trial in patients with advanced Parkinson’s disease

5.7 Impulse Control/Compulsive Behaviors

(Additions and/or revisions underlined)

5.9 Withdrawal Symptoms

(Newly added subsection)

6 Adverse Reactions

(Addition of the following to the bulleted line listing)

Withdrawal symptoms [see Warnings and Precautions (5.9)]

6.3 Postmarketing Experience

(Newly added subsection)

General Disorders and Administration Site Conditions

Withdrawal Symptoms [see Warnings and Precautions (5.9)]

7 Drug Interactions

7.1 Cytochrome P450 1A2 Inhibitors and Inducers

(Subsection title revised; Additions and/or revisions underlined)

7.2 Estrogens

(Additions and/or revisions underlined)

8 Use in Specific Populations

8.5 Geriatric Use

(Additions and/or revisions underlined)

Dose adjustment is not necessary in elderly (65 years and older) patients, as the dose of REQUIP XL is individually titrated to clinical therapeutic response and tolerability.

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

PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

…

Hallucinations/Psychotic-Like Behavior

Dyskinesia

Inform patients that REQUIP XL may cause and/or exacerbate pre-existing dyskinesias [see Warnings and Precautions (5.6)].

Impulse Control/Compulsive Behaviors

Withdrawal-Emergent Hyperpyrexia and Confusion

Withdrawal Symptoms

PATIENT INFORMATION

(Extensive changes; please refer to label)

03/23/2017 (SUPPL-9)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Falling Asleep during Activities of Daily Living and Somnolence

(Additions and/or revisions are underlined)

Among the 613 patients who received REQUIP XL in flexible-dose clinical trials (Study 1 and Study 3), <1% of patients reported sudden onset of sleep and <1% of patients reported a motor vehicle accident in which it is not known if falling asleep was a contributing factor.

In a placebo-controlled fixed-dose trial in patients with advanced Parkinson’s disease (Study 2), sudden onset of sleep was reported in 4% of 276 patients on REQUIP XL compared with 3% of 74 patients on placebo. In a placebo-controlled fixed-dose trial in patients with early Parkinson’s disease (Study 4), sudden onset of sleep was reported in 5% of 146 patients on REQUIP XL compared with 0% of 40 patients on placebo. The incidence of sudden onset of sleep was not dose-related in either trial.

During a placebo-controlled flexible-dose trial in patients with advanced Parkinson’s disease (Study 1), somnolence was reported in 7% of 202 patients on REQUIP XL compared with 4% of 191 patients on placebo. During a flexible-dose, active-control, crossover trial in early Parkinson’s disease (Study 3), somnolence was reported in 11% of 140 patients on REQUIP XL compared with 15% of 149 patients on an immediate-release formulation of REQUIP.

In a placebo-controlled fixed-dose trial in patients with advanced Parkinson’s disease (Study 2), somnolence was reported in 8% of 276 patients on REQUIP XL compared with 5% of 74 patients on placebo. In a placebo-controlled fixed-dose trial in patients with early Parkinson’s disease (Study 4), somnolence was reported in 10% of 146 patients on REQUIP XL compared with 5% of 40 patients on placebo. The frequency of reported somnolence was not dose-related.

REQUIP XL such as concomitant sedating medications or alcohol, the presence of sleep disorders, and concomitant medications that increase ropinirole plasma levels (e.g., ciprofloxacin)…

5.11 Retinal Pathology

(Additions and/or revisions are underlined)

…The lowest dose tested (1.5 mg/kg/day) is less than the maximum recommended human dose (MRHD) of24 mg/day on a mg/m squared basis…

5.2 Syncope

(Additions and/or revisions are underlined)

In a placebo-controlled flexible-dose trial in patients with advanced Parkinson’s disease (Study 1), syncope occurred in 1% of patients on REQUIP XL compared with 0% of patients on placebo.

In the placebo-controlled fixed-dose trials (Study 2 and Study 4), one patient on REQUIP XL with advanced Parkinson's disease) and one patient on REQUIP XL with early Parkinson's disease experienced syncope during the titration period for REQUIP XL. Both patients discontinued prematurely from the respective trials.

Because the trials conducted with REQUIP XL excluded patients with significant cardiovascular disease, patients with significant cardiovascular disease should be treated with caution.

5.3 Hypotension/Orthostatic Hypotension

(Additions and/or revisions are underlined)

Patients with Parkinson’s disease may have impaired ability to respond normally to a fall in blood pressure after standing from lying down or seated position. Patients on REQUIP XL should be monitored for signs and symptoms of orthostatic hypotension, especially during dose escalation, and should be informed of the risk for syncope and hypotension.

In a placebo-controlled flexible-dose trial in patients with advanced Parkinson’s disease (Study 1), hypotension was reported as an adverse reaction in 2% of patients on REQUIP XL, compared with 0% of patients on placebo. In this study, orthostatic hypotension was reported as an adverse reaction in 5% of patients on REQUIP XL and 1% of patients on placebo. Some patients experienced hypotension or orthostatic hypotension that started in the titration and persisted into the maintenance period. There was also a higher incidence for the combined adverse reaction terms of “hypotension”, “orthostatic hypotension”, “dizziness”, “vertigo”, and "blood pressure decreased” in 7% of patients on REQUIP XL compared with 3% of patients on placebo. The increased incidence of those events with REQUIP XL was observed in a setting in which patients were very carefully titrated, and patients with clinically relevant cardiovascular disease or symptomatic orthostatic hypotension at baseline had been excluded from this trial. The frequency of orthostatic hypotension (systolic blood pressure decrements greater then or equal to 20 mm Hg) at any time during the trial was 38% for REQUIP XL vs. 31% for placebo.

In a placebo-controlled fixed-dose trial in patients with advanced Parkinson’s disease (Study 2), a decrease in standing systolic blood pressure of greater than or equal to 20 mm Hg was observed in 26% of patients on REQUIP XL compared with 18% of patients on placebo.

In a placebo-controlled fixed-dose trial of patients with early Parkinson's disease (Study 4), a decrease in standing systolic blood pressure of greater than or equal to 20 mm Hg was observed in 14% of patients on REQUIP XL compared with 10% of patients on placebo.

5.4 Elevation of Blood Pressure and Changes in Heart Rate

(Additions and/or revisions are underlined)

The potential for elevation in blood pressure and changes in heart rate should be considered when treating patients with cardiovascular disease with REQUIP XL.

In a placebo-controlled flexible-dose trial in patients with advanced Parkinson’s disease (Study 1), the frequency of systolic blood pressure (greater than or equal to 40mm Hg) in the semi-supine position was 8% of patients on REQUIP XL vs. 5% of patients on placebos. In the standing position, the frequency of systolic blood pressure increase (greater than or equal to 40 mm Hg) was 9% for REQUIP XL vs. 6% for placebo. There was no clear effect of REQUIP XL on average heart rate.

In a placebo-controlled fixed-dose trial in patients with advanced Parkinson’s disease (Study 2), hypertension was reported as an adverse reaction in 3% of patients on REQUIP XL, compared with 1% of patients on placebo.

In a placebo-controlled, fixed-dose trial in patients with early Parkinson’s disease (Study 4), hypertension was reported as an adverse reaction in 5% of patients on REQUIP XL, compared with 0% of patients on placebo.

5.5 Hallucinations/Psychotic-like Behavior

(Additions and/or revisions are underlined)

In a placebo-controlled flexible-dose trial in patients with advanced Parkinson’s disease (Study 1), 8% of patients on REQUIP XL reported hallucination, compared with 2% of patients on placebo…

In a placebo-controlled fixed-dose trial in patients with advanced Parkinson’s disease (Study 2), the incidence of hallucination was 3% in patients on REQUIP XL compared with 0% in patients on placebo. The most common adverse reaction associated with study discontinuation for any dose of REQUIP XL was hallucination (2%).

5.6 Dyskinesia

(Additions and/or revisions are underlined)

In a placebo-controlled flexible-dose trial in patients with advanced Parkinson’s disease (Study 1), the incidence of dyskinesia was 13% in patients on REQUIP XL and 3% in patients on placebo.

In a placebo-controlled, fixed-dose trial in patients with advanced Parkinson’s disease (Study 2), the incidence of dyskinesia was 7% in patients on REQUIP XL compared with 1% in patients on placebo.

6 Adverse Reactions

(Additions and/or revisions are underlined)

The following adverse reactions are described in more detail in other sections of the label:

Retinal Pathology

6.1 Clinical Trials Experience

(Additions and/or revisions are underlined)

…During the premarketing development of REQUIP XL, patients with advanced Parkinson’s disease received REQUIP XL or placebo as adjunctive therapy with L-dopa in a flexible-dose clinical trial. In a flexible-dose trial, patients with early Parkinson’s disease were treated with REQUIP XL or the immediate-release formulation of REQUIP without L-dopa. In addition, placebo-controlled, fixed-dose, postmarketing trials evaluated the dose response of REQUIP XL in patients with advanced Parkinson’s disease taking L-dopa and in patients with early Parkinson’s disease without concomitant L-dopa.

Advanced Parkinson’s Disease (with L-dopa)

Study 1 was a 24-week, double-blind, placebo-controlled, flexible-dose trial in patients with advanced Parkinson’s disease. In Study 1, the most commonly observed adverse reactions…

In Study 1, approximately 6% of patients treated with REQUIP XL discontinued treatment due to adverse reactions, compared with 5% of patients who received placebo. The most common adverse reaction in patients treated with REQUIP XL causing discontinuation of treatment with REQUIP XL in Study 1 was hallucination (2%).

Table 2 lists adverse reactions that occurred in at least 2% (and were numerically greater than placebo) of patients with advanced Parkinson’s disease treated with REQUIP XL who participated in Study 1…

Table 2. Incidence of Adverse Reactions in a Placebo-Controlled Flexible-Dose Trial inAdvanced Stage Parkinson’s Disease in Patients Taking L-dopa (Study 1) (Events Greater than or Equal to 2% of Patients Treated with REQUIP XL and More Common than on Placebo) (superscript a)

During the titration phase, the incidence of adverse reactions in descending order of percent treatment difference was dyskinesia, nausea, abdominal pain/discomfort, orthostatic hypotension, dizziness, vertigo, hypertension, peripheral edema, and dry mouth. During the maintenance phase, the most frequently observed adverse reactions were dyskinesia, nausea, dizziness, hallucination, somnolence, fall, hypertension, abnormal dreams, constipation, chest pain,bronchitis, and nasopharyngitis…

The incidence of adverse reactions was similar in women and men.

Study 2 was an 18-week, double-blind, placebo-controlled, fixed-dose, dose-response trial in patients with advanced Parkinson’s disease. In Study 2, approximately 7% of patients treated with any dose of REQUIP XL discontinued prematurely during the titration phase because of adverse reactions, compared with 4% of patients on placebo. The percentage of patients who discontinued from the study because of an adverse reaction was 4% for REQUIP XL 4 mg, 9% for REQUIP XL 8 mg, 8% for REQUIP XL 12 mg, 8% for REQUIP XL 16 mg, and 0% for REQUIP XL 24 mg. Table 3 lists adverse reactions with an incidence of at least 5% of patients in any dose group of REQUIP XL and numerically higher than on placebo in Study 2. The most common adverse reaction (incidence for REQUIP XL all doses at least 5% greater than placebo) was dyskinesia.

Table 3. Incidence of Adverse Reactions in a Placebo-Controlled Fixed-Dose Trial in Advanced Stage Parkinson’s Disease in Patients Taking L-dopa (Study 2) (Events Greater than or Equal to 5% of Patients Treated with any Dose of REQUIP XL and More Common than on Placebo) (Table has been added; please refer to label)

Early Parkinson’s Disease (without L-dopa)

Study 3 was a 36-week, flexible-dose crossover trial in patients with early Parkinson’s disease who were first treated with REQUIP XL or the immediate-release formulation of REQUIP and then crossed over to treatment with the other formulation. In Study 3, the most commonly observed adverse reactions (greater than or equal to 5%) in patients treated with REQUIP XL were nausea (19%), somnolence (11%), abdominal pain/discomfort (7%), dizziness (6%), headache (6%), and constipation (5%).

Study 4 was an 18-week, double-blind, placebo-controlled, fixed-dose, dose-response trial in patients with early Parkinson’s disease. Overall, 7% of patients treated with any dose of REQUIP XL, including 6% during the titration phase, discontinued prematurely from the study because of adverse reactions compared with 5% of patients on placebo. The percentage of patients discontinuing prematurely because of an adverse reaction was 8% for REQUIP XL 2 mg, 5% for REQUIP XL 4 mg, 8% for REQUIP XL 8 mg, 5% for REQUIP XL 12 mg, and 15% for REQUIP XL 24 mg.

Table 4 lists adverse reactions with an incidence of at least 10% of patients in any dose group of REQUIP XL and numerically higher than on placebo in Study 4. The most common adverse reactions (incidence for REQUIP XL all doses at least 5% greater than placebo) were nausea, somnolence, sudden onset of sleep, hypertension, and headache.

Table 4. Incidence of Adverse Reactions in a Double-Blind, Placebo-Controlled, Fixed- Dose, Trial in Early Stage Parkinson’s Disease (Study 4) (Events Greater than or Equal to 10% of Patients Treated with any Dose of REQUIP XL and Greater % than on Placebo) (Table has been added; please refer to label)

Laboratory Abnormalities

In the fixed-dose trial in advanced Parkinson's disease (Study 2), 11% of patients on REQUIP XL exhibited a shift in serum creatine phosphokinase (CPK) from normal at baseline to above the normal reference range during treatment, compared with 6% of patients on placebo. There was no clear dose-response for abnormal shifts in CPK levels in patients with early or advanced stage Parkinson’s disease in either fixed-dose trial.

In the fixed-dose trial in early Parkinson's disease patients (Study 4), serum CPK shifted during treatment from normal to above the normal reference range in 10% of patients on REQUIP XL and in 5% of patients on placebo.

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 the use of REQUIP XL in pregnant women. In animal studies, ropinirole had adverse effects on development when administered to pregnant rats at doses similar to (neurobehavioral impairment) or greater than (teratogenicity and embryolethality at >36 times) the maximum recommended human dose (MRHD) for Parkinson’s disease. Ropinirole doses associated with teratogenicity and embryolethality in pregnant rats were associated with maternal toxicity. In pregnant rabbits, ropinirole potentiated the teratogenic effects of L-dopa when these drugs were administered in combination.

In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The background risk of major birth defects and miscarriage in the indicated populations is unknown.

Data

Animal Data: Oral administration of ropinirole (0, 20, 60, 90, 120, or 150 mg/kg/day) to pregnant rats during organogenesis resulted in embryolethality, increased incidence of fetal malformations (digit, cardiovascular, and neural tube defects) and variations, and decreased fetal weight at the two highest doses. These doses were also associated with maternal toxicity. The highest no-effect dose for adverse effects on embryofetal development (90 mg/kg/day) is approximately 36 times the MRHD for Parkinson’s disease (24 mg/day) on a body surface area (mg/m squared) basis.

No effect on embryofetal development was observed in rabbits when ropinirole was administered alone during organogenesis at oral doses of 0, 1, 5, or 20 mg/kg/day (up to 16 times the MRHDon a mg/m2 basis). In pregnant rabbits, there was a greater incidence and severity of fetal malformations (primarily digit defects) when ropinirole (10 mg/kg/day) was administered orally during gestation in combination with L-dopa (250 mg/kg/day) than when L-dopa was administered alone. This drug combination was also associated with maternal toxicity.

Oral administration of ropinirole (0, 0.1, 1, or 10 mg/kg/day) to rats during late gestation and continuing throughout lactation resulted in neurobehavioral impairment (decreased startle response) and decreased body weight in offspring at the highest dose. The no-effect dose of 1 mg/kg/day is less than the MRHD on a mg/m squared basis.

8.2 Lactation

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

There are no data on the presence of ropinirole in human milk, the effects of ropinirole on the breastfed infant, or the effects of ropinirole on milk production. However, inhibition of lactation is expected because ropinirole inhibits secretion of prolactin in humans. Ropinirole or metabolites, or both, are present in rat milk.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for REQUIP XL and any potential adverse effects on the breastfed infant from ropinirole or from the underlying maternal condition.

8.5 Geriatric Use

(Additions and/or revisions are underlined)

In flexible-dose clinical trials of REQUIP XL, 387 patients were 65 years and older and 107 were 75 and older…

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Nursing Mothers

Because of the possibility that ropinirole may be excreted in breast milk, discuss the developmental and health benefits of breastfeeding along with the mother’s clinical need for REQUIP XL and any potential adverse effects on the breastfed child from ropinirole or from the underlying maternal condition…

Pregnancy

Because experience with ropinirole in pregnant women is limited and ropinirole has been shown to have adverse effects on embryofetal development in animals, including teratogenic effects, advise patients of this potential risk. Advise patients to notify their physician if they become pregnant or intend to become pregnant during therapy.

PATIENT INFORMATION REQUIP

(Additions and/or revisions are underlined)

If you have Restless Legs Syndrome (RLS), read this side.

If you have Parkinson’s disease, read the other side.

Important Note: REQUIP XL has not been studied in Restless Legs Syndrome (RLS) and is not approved for the treatment of RLS.

What is the most important information I should know about REQUIP?

Hallucinations and other psychotic-like behavior. REQUIP can cause or worsen psychotic-like behavior including hallucinations (seeing or hearing things that are not real), confusion, excessive suspicion, aggressive behavior, agitation, delusional beliefs (believing things that are not real), and disorganized thinking. The chances of having hallucinations or these other psychotic-like changes are higher in people with Parkinson’s disease who are taking REQUIP or taking higher doses of these drugs. If you have hallucinations or any of these other psychotic-like changes, talk with your healthcare provider.
Uncontrolled sudden movements. REQUIP may cause uncontrolled sudden movements or make such movements you already have worse or more frequent. Tell your healthcare provider if this happens. The doses of your anti-Parkinson’s medicine may need to be changed.

Do not take REQUIP if you:

Get help right away if any of the symptoms of an allergic reaction cause problems swallowing or breathing.

Call your healthcare provider if you have any of the symptoms of an allergic reaction.

Before taking REQUIP, tell your healthcare provider about all of your medical conditions, including if you:

are pregnant or plan to become pregnant. It is not known if REQUIP can harm your unborn baby.
are breastfeeding or plan to breastfeed. It is not known if REQUIP passes into your breast milk. The amount of breast milk you make may be decreased while taking REQUIP. Talk to your healthcare provider to decide if you should breastfeed while taking REQUIP.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

How should I take REQUIP?

Do not suddenly stop taking REQUIP without talking to your healthcare provider. If you stop this medicine suddenly, you may develop fever, confusion, or severe muscle stiffness.

What are the possible side effects of REQUIP?

…These are not all of the possible side effects with REQUIP…

General information about the safe and effective use of REQUIP:

…You can ask your pharmacist or healthcare provider for information about REQUIP that is written for health professionals.

PATIENT INFORMATION REQUIP XL

(Additions and/or revisions are underlined)

If you have Parkinson’s disease, read this side.

If you have Restless Legs Syndrome (RLS), read the other side.

Important Note: REQUIP XL has not been studied in Restless Legs Syndrome (RLS) and is not approved for the treatment of RLS. However, an immediate-release form of ropinirole (REQUIP) is approved for the treatment of moderate to severe primary RLS (see other side of this leaflet).

Do not take REQUIP or REQUIP XL if you:

Get help right away if any of the symptoms of an allergic reaction cause problems swallowing or breathing.

Call your healthcare provider if you have any of the symptoms of an allergic reaction.

Before taking REQUIP or REQUIP XL, tell your healthcare provider about all of your medical conditions, including if you:

are pregnant or plan to become pregnant. It is not known if REQUIP or REQUIP XL can harm your unborn baby.
are breastfeeding or plan to breastfeed. It is not known if REQUIP or REQUIP XL passes into your breast milk. The amount of breast milk you make may be decreased while taking REQUIP or REQUIP XL. Talk to your healthcare provider to decide if you should breastfeed while taking REQUIP or REQUIP XL.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Some of these medicines may increase your chances of getting side effects while taking REQUIP or REQUIP XL.

What are the possible side effects of REQUIP and REQUIP XL?

The most common side effects of REQUIP and REQUIP XL include:

constipation
suddenly falling asleep
high blood pressure (hypertension)

…These are not all of the possible side effects with REQUIP and REQUIP XL…