Requip XL

Oral Administration

May take with or without food

If a significant interruption in therapy has occurred, retitration of the drug is warranted

Conversion from immediate-release to extended-release formulation

• Choose extended-release strength that most closely matches total daily dose of immediate-release formulation

Discontinuation

• Abrupt withdrawal or significant dosage reduction associated with syndrome resembling neuroleptic malignant syndrome (see Cautions)
• Parkinson disease: Discontinued gradually over a 7-day period; administration frequency should be reduced from TID to BID for 4 days, and then once daily for the remaining 3 days prior to completely withdrawing the drug
• Restless leg syndrome: Gradually reduce the daily dose

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

• Hypersensitivity [see CONTRAINDICATIONS]
• Falling Asleep during Activities of Daily Living and Somnolence [see WARNINGS AND PRECAUTIONS]
• Syncope [see WARNINGS AND PRECAUTIONS]
• Hypotension/Orthostatic Hypotension [see WARNINGS AND PRECAUTIONS]
• Elevation of Blood Pressure and Changes in Heart Rate [see WARNINGS AND PRECAUTIONS]
• Hallucinations/Psychotic-like Behavior [see WARNINGS AND PRECAUTIONS]
• Dyskinesia [see WARNINGS AND PRECAUTIONS]
• Impulse Control/Compulsive Behaviors [see WARNINGS AND PRECAUTIONS]
• Withdrawal-Emergent Hyperpyrexia and Confusion [see WARNINGS AND PRECAUTIONS]
• Melanoma [see WARNINGS AND PRECAUTIONS]
• Fibrotic Complications [see WARNINGS AND PRECAUTIONS]
• Retinal Pathology [see WARNINGS AND PRECAUTIONS]

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 with rates in the clinical trials of another drug (or of another development program of a different formulation of the same drug) and may not reflect the rates observed in practice.

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 patients treated with REQUIP XL (incidence at least 5% greater than placebo) were dyskinesia, nausea, dizziness, and hallucinations.

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. In this trial, either REQUIP XL or placebo was used as an adjunct to L-dopa.

Table 2: Incidence of Adverse Reactions in a Placebo-Controlled Flexible-Dose Trial in Advanced Stage Parkinson's Disease in Patients Taking L-dopa (Study 1) (Events ≥ 2% of Patients Treated with REQUIP XL and More Common than on Placebo)a

Body System/Adverse Reaction	REQUIP XL (n = 202) %	Placebo (n = 191) %
Ear and labyrinth disorders
Vertigo	4	2
Gastrointestinal disorders
Nausea	11	4
Abdominal pain/discomfort	6	3
Constipation	4	2
Diarrhea	3	2
Dry mouth	2	< 1
General disorders
Edema peripheral	4	1
Injury, poisoning, and procedural complications
Fallb	2	1
Musculoskeletal and connective tissue disorders
Back pain	3	2
Nervous system disorders
Dyskinesiab	13	3
Dizziness	8	3
Somnolence	7	4
Psychiatric disorders
Hallucination	8	2
Anxiety	2	1
Vascular disorders
Orthostatic hypotension	5	1
Hypertensionb	3	2
Hypotension	2	0
a Patients may have reported multiple adverse reactions during the trial or at discontinuation; thus, patients may be included in more than one category. b Dose-related.

Although this trial was not designed for optimally characterizing dose-related adverse reactions, there was a suggestion (based upon comparison of incidence of adverse reactions across dose ranges for REQUIP XL and placebo) that the incidence for dyskinesia, hypertension, and fall was dose-related to REQUIP XL.

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. Some adverse reactions developing in the titration phase persisted ( ≥ 7 days) into the maintenance phase. These “persistent” adverse reactions included dyskinesia, hallucination, orthostatic hypotension, and dry mouth.

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 [see WARNINGS AND PRECAUTIONS]. 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 ≥ 5% of Patients Treated with any Dose of REQUIP XL and More Common than on Placebo)

Adverse Reaction	Placebo N = 74 %	REQUIP XL
		4 mg N = 25 %	8 mg N = 76 %	12 mg N = 75 %	16 mg N = 75 %	24 mg N = 25 %	All Doses N = 276 %
Nervous system disorders
Somnolence	5	4	5	12	11	0	8
Dyskinesia	1	4	4	7	11	4	7
Dizziness	3	8	4	8	5	4	6
Sudden onset of sleep	3	8	5	4	1	0	4
Vascular disorders
Hypertension	1	8	1	1	4	8	3
Infections and infestations
Nasopharyngitis	1	0	3	3	0	8	2
Musculoskeletal and connective tissue disorders
Arthralgia	0	0	3	0	3	8	2
Psychiatric disorders Insomnia	0	0	0	1	5	0	2

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 ( ≥ 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 ≥ 10% of Patients Treated with any Dose of REQUIP XL and Greater % than on Placebo)

Adverse Reactions	Placebo N = 40 %	REQUIP XL
		2 mg N = 13 %	4 mg N = 41 %	8 mg N = 40 %	12 mg N = 39 %	24 mg N = 13 %	All Doses N = 146 %
Gastrointestinal disorders
Nausea	8	8	15	33	10	15	18
Vomiting	5	0	5	10	0	0	4
Nervous system disorders
Somnolence	5	15	12	10	8	8	10
Headache	3	8	10	8	5	15	8
Dizziness	5	0	5	10	8	8	7
Sudden onset of sleep	0	0	5	0	10	8	5
Vascular disorders
Hypertension	0	0	5	5	3	15	5
Musculoskeletal and connective tissue disorders
Back pain	3	0	5	3	3	15	4

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.

Adverse Reactions Observed During The Clinical Development Of The Immediate-Release Formulation Of REQUIP For Parkinson's Disease (Advanced and Early)

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug (or of another development program of a different formulation of the same drug) and may not reflect the rates observed in practice.

In patients with advanced Parkinson's disease who were treated with the immediate-release formulation of REQUIP, the most common adverse reactions ( ≥ 5% treatment difference from placebo presented in order of decreasing treatment difference frequency) were dyskinesia (21%), somnolence (12%), nausea (12%), dizziness (10%), confusion (7%), hallucinations (6%), headache (5%), and increased sweating (5%). In patients with early Parkinson's disease who were treated with the immediate-release formulation of REQUIP, the most common adverse reactions ( ≥ 5% treatment difference from placebo presented in order of decreasing treatment difference frequency) were nausea (38%), somnolence (34%), dizziness (18%), syncope (11%), asthenic condition (11%), viral infection (8%), leg edema (6%), vomiting (5%), and dyspepsia (5%).

Read the entire FDA prescribing information for Requip XL (Ropinirole Extended Release Tablets)

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• GlaxoSmithKline LLC

Requip XL is part of the drug class:

• Dopamine agonists

• Most people who take Requip XL tolerate it well. The most commonly reported side effects in people taking Requip XL are nausea, headache, dizziness, drowsiness or sleepiness.
• You should be careful until you know if Requip XL affects your ability to remain alert while doing normal daily activities, and you should watch for the development of significant daytime sleepiness or episodes of falling asleep. It is possible that you could fall asleep while doing normal activities such as driving a car, doing physical tasks, or using hazardous machinery while taking Requip XL. Your chances of falling asleep while doing normal activities while taking Requip XL are greater if you are taking other medicines that cause drowsiness.
• When you start taking Requip XL or when you increase your dose, you may feel dizzy, nauseated, sweaty or faint, when first standing up from sitting or lying down. Therefore, do not stand up quickly after sitting or lying down, particularly if you have been sitting or lying down for a long period of time. Take a minute sitting on the edge of the bed or chair before you get up.
• Hallucinations (unreal visions, sounds, or sensations) have been reported in patients taking Requip XL. The risk is greater in patients with Parkinson's disease who are elderly, taking Requip XL with L-dopa, or taking higher amounts of Requip XL.
• If you are taking L-dopa for Parkinson's disease, Requip XL may make some of the side effects of L-dopa worse. Requip XL may cause uncontrolled sudden movements or make such movements you already have worse or more frequent.

Some patients taking Requip XL get urges to behave in a way unusual for them. Examples of this are an unusual urge to gamble or increased sexual urges and behaviors. If you notice or your family notices that you are developing any unusual behaviors, talk to your healthcare provider.

This is not a complete list of side effects and should not take the place of discussions with your healthcare providers. Your doctor or pharmacist can give you a more complete list of possible side effects.

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take:

• other dopamine antagonists (such as phenothiazines, butyrophenones, thioxanthenes and metoclopramide)
• estrogens
• ciprofloxacin

This is not a complete list of Requip XL drug interactions. Ask your doctor or pharmacist for more information.

Medicines can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of Requip XL there are no specific foods that you must exclude from your diet when receiving Requip XL.

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Take with or without food. Take with food if it causes an upset stomach.
• To gain the most benefit, do not miss doses.
• Keep taking Requip XL as you have been told by your doctor or other health care provider, even if you feel well.
• If you stop taking this medicine, talk with your doctor. You may need to be restarted at a lower dose and raise the dose slowly.
• Swallow whole. Do not chew, break, or crush.

What do I do if I miss a dose?

• Take a missed dose as soon as you think about it.
• If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses.
• If you miss a few days of Requip XL (ropinirole extended-release tablets), call your doctor to find out how to restart.

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

• Hypersensitivity [see Contraindications (4)] • Falling Asleep during Activities of Daily Living and Somnolence [see Warnings and Precautions (5.1)] • Syncope [see Warnings and Precautions (5.2)] • Hypotension/Orthostatic Hypotension [see Warnings and Precautions (5.3)] • Elevation of Blood Pressure and Changes in Heart Rate [see Warnings and Precautions (5.4)] • Hallucinations/Psychotic-like Behavior [see Warnings and Precautions (5.5)] • Dyskinesia [see Warnings and Precautions (5.6)] • Impulse Control/Compulsive Behaviors [see Warnings and Precautions (5.7)] • Withdrawal-Emergent Hyperpyrexia and Confusion [see Warnings and Precautions (5.8)] • Melanoma [see Warnings and Precautions (5.9)] • Fibrotic Complications [see Warnings and Precautions (5.10)] • Retinal Pathology [see Warnings and Precautions (5.11)]

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 with rates in the clinical trials of another drug (or of another development program of a different formulation of the same drug) and may not reflect the rates observed in practice.

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 patients treated with REQUIP XL (incidence at least 5% greater than placebo) were dyskinesia, nausea, dizziness, and hallucinations.

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. In this trial, either REQUIP XL or placebo was used as an adjunct to L‑dopa.

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

	REQUIP XL	Placebo
	(n = 202)	(n = 191)
Body System/Adverse Reaction	%	%
Ear and labyrinth disorders
Vertigo	4	2
Gastrointestinal disorders
Nausea	11	4
Abdominal pain/discomfort	6	3
Constipation	4	2
Diarrhea	3	2
Dry mouth	2	<1
General disorders
Edema peripheral	4	1
Injury, poisoning, and procedural complications
Fallb	2	1
Musculoskeletal and connective tissue disorders
Back pain	3	2
Nervous system disorders
Dyskinesiab	13	3
Dizziness	8	3
Somnolence	7	4
Psychiatric disorders
Hallucination	8	2
Anxiety	2	1
Vascular disorders
Orthostatic hypotension	5	1
Hypertensionb	3	2
Hypotension	2	0

  a Patients may have reported multiple adverse reactions during the trial or at discontinuation; thus, patients may be included in more than one category.   b Dose-related.

Although this trial was not designed for optimally characterizing dose-related adverse reactions, there was a suggestion (based upon comparison of incidence of adverse reactions across dose ranges for REQUIP XL and placebo) that the incidence for dyskinesia, hypertension, and fall was dose-related to REQUIP XL.

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. Some adverse reactions developing in the titration phase persisted (≥7 days) into the maintenance phase. These “persistent” adverse reactions included dyskinesia, hallucination, orthostatic hypotension, and dry mouth.

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 [see Warnings and Precautions (5.2, 5.5)]. 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 ≥5% of Patients Treated with any Dose of REQUIP XL and More Common than on Placebo)

Adverse Reaction	Placebo N = 74 %	REQUIP XL
		4 mg N = 25 %	8 mg N = 76 %	12 mg N = 75 %	16 mg N = 75 %	24 mg N = 25 %	All Doses N = 276 %
Nervous system disorders
Somnolence	5	4	5	12	11	0	8
Dyskinesia	1	4	4	7	11	4	7
Dizziness	3	8	4	8	5	4	6
Sudden onset of sleep	3	8	5	4	1	0	4
Vascular disorders		8	1	1	4
Hypertension	1					8	3
Infections and infestations			3	3	0
Nasopharyngitis	1	0				8	2
Musculoskeletal and connective tissue disorders			3	0	3
Arthralgia	0	0				8	2
Psychiatric disorders
Insomnia	0	0	0	1	5	0	2

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 (≥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 ≥10% of Patients Treated with any Dose of REQUIP XL and Greater % than on Placebo)

	Placebo			REQUIP XL
Adverse Reactions	N = 40 %	2 mg N = 13 %	4 mg N = 41 %	8 mg N = 40 %	12 mg N = 39 %	24 mg N = 13 %	All Doses N = 146 %
Gastrointestinal disorders    Nausea    Vomiting	8 5	8 0	15 5	33 10	10 0	15 0	18 4
Nervous system disorders    Somnolence    Headache    Dizziness    Sudden onset of sleep	5 3 5 0	15 8 0 0	12 10 5 5	10 8 10 0	8 5 8 10	8 15 8 8	10 8 7 5
Vascular disorders    Hypertension	0	0	5	5	3	15	5
Musculoskeletal and connective tissue disorders    Back pain	3	0	5	3	3	15	4

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.

Adverse Reactions Observed during the Clinical Development of the Immediate-Release Formulation of REQUIP for Parkinson’s Disease (Advanced and Early)

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug (or of another development program of a different formulation of the same drug) and may not reflect the rates observed in practice.

In patients with advanced Parkinson’s disease who were treated with the immediate-release formulation of REQUIP, the most common adverse reactions (≥5% treatment difference from placebo presented in order of decreasing treatment difference frequency) were dyskinesia (21%), somnolence (12%), nausea (12%), dizziness (10%), confusion (7%), hallucinations (6%), headache (5%), and increased sweating (5%). In patients with early Parkinson’s disease who were treated with the immediate-release formulation of REQUIP, the most common adverse reactions (≥5% treatment difference from placebo presented in order of decreasing treatment difference frequency) were nausea (38%), somnolence (34%), dizziness (18%), syncope (11%), asthenic condition (11%), viral infection (8%), leg edema (6%), vomiting (5%), and dyspepsia (5%).

CYP1A2 Inhibitors and Inducers

In vitro metabolism studies showed that 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)].

Estrogens

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

Dopamine Antagonists

Because ropinirole is a dopamine agonist, it is possible that dopamine antagonists such as neuroleptics (e.g., phenothiazines, butyrophenones, thioxanthenes) or metoclopramide may reduce the efficacy of REQUIP XL.