RLS Training

T5GSL196_AnnotatedSA.qxd

1/26/06

12:45

Page 1

In the Treatment of Moderate-to-Severe Primary RLS

RESTLESS LEGS SYNDROME (RLS)—AN IRRESISTIBLE URGE TO MOVE ™

Help Relieve the Urge to Move

FOR TRAINING PURPOSES ONLY—NOT TO BE USED WITH HEALTHCARE PROFESSIONALS

T5GSL196_AnnotatedSA.qxd

1/26/06

Brand-Bonding Ladder for Requip

Regular User

Trial/Intermittent User

2

12:45

Page 2

Physician Profile

Doctor is aware of RLS and currently treats with L-dopa and other DAs (including Requip)

Doctor is aware of RLS and treats with benzodiazepines/sleep agents, gabapentin, and/or opioids.

Sometimes prescribes Requip or other DAs

Non-User Aware

Doctor is aware of RLS, but the condition is not top of mind and doctor is not treating

Non-User Unaware

Doctor is unaware of RLS and/or does not see any patients who present with RLS symptoms.

This doctor is currently not prescribing any treatment for RLS

Strategy

Detail Aid Page

When? For patients who present with a sleep disturbance as an initial complaint and/or report an irresistible urge to move the legs accompanied by uncomfortable sensations (eg, creepy, crawly) that often occur in the evening or when at rest

Pages 2-3

Why? Requip targets a proposed underlying cause and provides significant symptomatic relief of moderate-to-severe primary RLS. Requip provides onset of symptom improvement after 2 nights of therapy, with continued results at 9 months. Requip also significantly reduces involuntary leg movements that cause arousal

Page 5 Pages 6-9

How? Review the convenient, once-daily dosing with the easy-to-follow Sample Kit for Requip and ask the physician to write a 1-mg prescription for appropriate patients. Leave behind the TREAT 2 reprint, dosing card, and Prescribing Information

Page 11

When? For patients who present with a sleep disturbance as an initial complaint and/or report an irresistible urge to move the legs accompanied by uncomfortable sensations (eg, creepy, crawly) that often occur in the evening or when at rest

Pages 2-3

Why? RLS is believed to be related to dopaminergic dysfunction. Requip targets a proposed underlying cause and provides significant symptomatic relief of moderate-to-severe primary RLS. Requip provides onset of symptom improvement after 2 nights of therapy, with continued results at 9 months. Requip also significantly reduces involuntary leg movements that cause arousal

Page 5 Pages 6-9

How? Review the convenient, once-daily dosing with the easy-to-follow Sample Kit for Requip and ask the physician to write a 1-mg prescription for appropriate patients. Leave behind the TREAT 2 reprint, dosing card, and Prescribing Information

Page 11

When? For patients who present with a sleep disturbance as an initial complaint and/or report an irresistible urge to move the legs accompanied by uncomfortable sensations (eg, creepy, crawly) that often occur in the evening or when at rest

Pages 2-3

Why? RLS can greatly impact patients‘ daily activities and requires a treatment that targets a proposed underlying cause

Pages 4-5

How? Reinforce that Requip provides significant symptomatic relief of moderate-to-severe primary RLS. Focus on the 4 key diagnostic criteria and data that show Requip provides onset of symptom improvement after 2 nights of therapy, with continued results at 9 months. Review the convenient, once-daily dosing with the easy-to-follow Sample Kit for Requip and ask the physician to write a 1-mg prescription for appropriate patients. Leave behind the TREAT 2 reprint, dosing card, and Prescribing Information

Pages 6-9 Page 11

When? For patients who present with a sleep disturbance as an initial complaint and/or report an irresistible urge to move the legs accompanied by uncomfortable sensations (eg, creepy, crawly) that often occur in the evening or when at rest

Pages 2-3

Why? RLS is an established disease (ICD-9 code 333.99) and can greatly impact patients‘ daily activities, requiring treatment that targets a proposed underlying cause

Page 4 Pages 4-5

How? Reinforce that Requip provides significant symptomatic relief of moderate-to-severe primary RLS. Ask the physician to probe beyond patient‘s initial sleep complaints with the 4 key diagnostic criteria and review the convenient, once-daily dosing with the easy-to-follow Sample Kit. Leave behind the REST reprint, TREAT 2 reprint, dosing card, and Prescribing Information

Pages 6-9 Page 3 Page 11

T5GSL196_AnnotatedSA.qxd

1/26/06

12:45

Page 3

Notes

3

FOR TRAINING PURPOSES ONLY窶年OT TO BE USED WITH HEALTHCARE PROFESSIONALS

T5GSL196_AnnotatedSA.qxd

1/26/06

12:45

Page 4

HELP HELP

RELIEVE RELIEVE

HELP HELP

HELP

HELP

URGE URGE

THE

THE

RELIEVE RELIEVE THE

RELIEVE

RELIEVE

HELP 4

RELIEVE

RELIEVE

HELP

THE

RELIEVE

HELP

HELP

THE

RELIEVE

TO

URGE

URGE

THE THE

URGE

THE

TO

THE

MOVE TO

MOVE

MOVE TO

TO

MOVE MOVE

MOVE

URGE

URGE

MOVE

TO

URGE

URGE

THE

TO

TO

TO

URGE

MOVE

MOVE TO

MOVE

T5GSL196_AnnotatedSA.qxd

1/26/06

12:45

Page 5

RESTLESS LEGS SYNDROME (RLS)—AN IRRESISTIBLE URGE TO MOVE™

Key Messages: Core Message Requip provides significant symptomatic relief of moderate-to-severe primary Restless Legs Syndrome (RLS)

Help Relieve the Urge to Move In the Treatment of Moderate-to-Severe Primary RLS

Supporting Messages • Provides onset of symptom improvement after 2 nights of therapy, with long-term responses maintained at 9 months

• The first and only FDA-approved treatment that provides symptomatic relief of moderate-to-severe primary RLS

• Significantly reduces involuntary leg movements that cause arousal

• Demonstrated safety profile with a low rate of discontinuation

• Provides significant symptomatic improvement based on CGI-I Scale 5

FOR TRAINING PURPOSES ONLY—NOT TO BE USED WITH HEALTHCARE PROFESSIONALS

T5GSL196_AnnotatedSA.qxd

1/26/06

12:45

Page 6

Requip

IRLS/CGI-I Rating Scales WHY?

Help Relieve the Urge to Move

Requip reduced the mean IRLS Rating Scale score for patients with RLS.This reduction was statistically significant vs placebo at all time points, including initial assessment on Day 3.

Requip reduces Restless Legs Syndrome (RLS) disease severity10 Mean IRLS Rating Scale total score at each visit*† IRLS Rating Scale Total Score (Mean)

25

Benefit “Doctor, many patients with RLS suffer for years before a diagnosis is made, thereby emphasizing the importance of symptom improvement when treated with Requip.”

The Only FDA-Approved Treatment for Moderate-to-Severe Primary RLS

WEEK 12 LOCF P<0.0001 20

‡ 15

Placebo (n=193)

‡ 10

The IRLS Scale contains 10 items designed to assess the severity of sensory and motor symptoms, sleep disturbance, daytime somnolence, impact on activities of daily living, and mood associated with RLS.

‡ ‡

‡

‡

‡

‡

5

‡

‡

Requip (n=187)

0 Baseline

Day 3

Week 1

Week 2

Week 3

Week 4

Week 5

Week 6

Week 8

Week 10

Week 12

Assessment Point

IRLS=International Restless Legs Syndrome.

Patients feel better with Requip

73% of RLS patients improved with Requip.10

Significant improvement in RLS symptom severity was reported after 2 nights of therapy on Requip, with continued results through week 12.

Statistical significance was achieved at each assessment point.

•73% of RLS patients treated with Requip improved on the CGI-I Scale vs 57% with placebo (P=0.0006)*† •Similar results were reported in 2 additional clinical trials —60% vs 40% in patients treated with Requip and placebo, respectively (P=0.001)*§ —53% vs 41% in patients treated with Requip and placebo, respectively (P=0.0416)*

An additional clinical assessment further confirms efficacy with Requip.

Patients had significant improvement as 73% of patients on Requip were “very much improved” or “much improved” based on the CGI-I Scale at the week 12 assessment.

Two additional clinical trials showed similar significant improvement at 12 weeks on Requip based on the CGI-I and IRLS rating scales.

*A 12-week, randomized, double-blind, placebo-controlled trial to assess efficacy/safety of Requip vs placebo in the treatment of primary RLS. †TREAT RLS US (n=380). §TREAT RLS 2 (n=266). TREAT RLS 1 (n=284).

‡ Statistical

significance at each assessment point (P<0.001) except day 3 (P=0.003).

¶An

6

6

objective evaluation in a 12-week, randomized, double-blind trial (n=65) of Requip in RLS patients with involuntary leg movements/hour during sleep (PLMS index) and those that cause arousal (PLMA index).

Excludes patients who did not have postbaseline polysomnographic (PSG) assessment.

Note: Should physicians ask about any of the clinical trials described, please refer them to medical information.

T5GSL196_AnnotatedSA.qxd

1/26/06

12:45

Reduction in Involuntary Leg Movements WHY?

Benefit “Doctor, would you agree that a patient may have a more restful night if they experience fewer involuntary leg movements with arousal?”

Requip Significantly Reduces Involuntary Leg Movements Reduce involuntary leg movements that cause arousal associated with Restless Legs Syndrome (RLS)10,11 •Involuntary leg movements may cause arousal and further disrupt sleep12 •Involuntary leg movements are often a comorbid condition of RLS; however, patients may not be aware they are occurring1 Percentage reduction in mean involuntary leg movements with arousal per hour at week 1210¶ Requip (n=32)

Patients treated with Requip experienced a

Efficacy

Based on polysomnography tests, patients treated with Requip had significantly less involuntary leg movements with arousal than those given placebo.

Page 7

significant reduction in

22%

involuntary leg

Placebo (n=33)

A significant reduction in involuntary leg movements that cause arousal (PLMAs) associated with RLS was seen in 62% of patients on Requip at week 12 compared with a 22% increase of PLMAs for patients on placebo.

movements with arousal.10,13

62% P<0.0096

Requip has been associated with sedating effects, including somnolence, and the possibility of falling asleep while engaged in activities of daily living, including operation of a motor vehicle.

Syncope or symptomatic hypotension may occur, particularly during initial treatment or dose titration.

See Important Safety Information on page 10.

Please consult the complete Prescribing Information available from your representative.

7

Requip has been associated with sedating effects, including somnolence, and the possibility of falling asleep while engaged in activities of daily living, including operation of a motor vehicle. Syncope or symptomatic hypotension may occur, particularly during initial treatment or dose titration.

See Important Safety Information on page 10.

7

FOR TRAINING PURPOSES ONLY—NOT TO BE USED WITH HEALTHCARE PROFESSIONALS

T5GSL196_AnnotatedSA.qxd

1/26/06

12:45

Page 8

Requip

Improvement After 2 Nights WHY?

The Only FDA-Approved Treatment for Moderate-to-Severe Primary RLS

Improvement After 2 Nights...

Patients treated with Requip reported onset of symptom improvement based on the IRLS Scale after 2 nights of therapy.

Onset of symptom improvement seen after 2 nights10 Adjusted mean change from baseline in total IRLS Rating Scale score after 2 nights of a 12-week study (OC)*†

Patients treated with Requip reported improvement based on the IRLS Scale after 2 nights of therapy.

P=0.003

Benefit

6.8

-point improvement

4.6

-point improvement

“Doctor, do you agree your patients will be confident in a treatment that may provide them with onset of improvement after the first 2 doses?”

Requip (n=170)

Placebo (n=169)

•After 2 nights, 36% of Restless Legs Syndrome (RLS) patients treated with Requip improved, using the CGI-I Scale, vs 20% with placebo, with continued results through week 12 (P=0.0008)*† Symptom severity improved after

2 nights.10

•A similar analysis with the IRLS Scale in 2 additional pooled studies (TREAT RLS 1 and TREAT RLS 2) showed improvement after 2 nights with Requip vs placebo (improvement of 6.3 vs 3.9 points, respectively), with continued results through week 12 (P<0.001)*‡§ •An additional analysis with the CGI-I Scale in 2 additional pooled studies (TREAT RLS 1 and TREAT RLS 2) showed improvement after 2 nights with Requip vs placebo (24% vs 9%, respectively) at all points through week 12 (P<0.001)*‡§

*A 12-week, randomized, double-blind, placebo-controlled trial to assess efficacy/safety of Requip vs placebo in the treatment of primary RLS. †TREAT RLS US (n=380). ‡TREAT RLS 2 (n=266). §TREAT RLS 1 (n=284).

A

8

8

multicenter, double-blind, randomized, placebo-controlled study to evaluate the maintained efficacy and tolerability of Requip at a fixed dose vs placebo in the long-term treatment of primary RLS (n=92).

Maintenance of response was defined as those who did not relapse, where relapse was defined as a deterioration of at least 6 points on the IRLS Rating Scale score to a total score of at least 15 points or withdrawal due to lack of efficacy.

Results using the CGI-I Scale from the TREAT RLS US study also demonstrated improvement after 2 nights of therapy.

Two additional clinical trials showed improvement at 2 nights of therapy, with continued improvement through week 12, based on the IRLS and CGI-I rating scales.

T5GSL196_AnnotatedSA.qxd

1/26/06

12:45

Page 9

Continued Results at 9 Months WHY? The majority (67%) of patients treated with Requip maintained response to therapy at 9 months compared with placebo (42%).

Continued Results at 9 Months Long-term responses maintained at 9 months10

P=0.0156

67% 42%

Benefit “Doctor, once you establish an effective and tolerable dose for your patients, you can feel confident in knowing your patients may maintain response with long-term treatment with Requip.”

67% of patients maintained responses at 9 months with Requip in a long-term clinical trial.

Proportion of responders who maintained response with the IRLS Rating Scale in a 36-week study

Requip (n=43)

Placebo (n=45)

•During the 24-week, single-blind phase, 202 patients were treated with Requip •Responders from the single-blind phase (n=88) were placed into the second phase and were randomized to placebo or continuation of Requip for an additional 12 weeks (total of 36 weeks)

Long-term responses maintained at

9 months.10

Requip has been associated with sedating effects, including somnolence, and the possibility of falling asleep while engaged in activities of daily living, including operation of a motor vehicle. Syncope or symptomatic hypotension may occur, particularly during initial treatment or dose titration.

Requip has been associated with sedating effects, including somnolence, and the possibility of falling asleep while engaged in activities of daily living, including operation of a motor vehicle.

Syncope or symptomatic hypotension may occur, particularly during initial treatment or dose titration.

See Important Safety Information on page 10.

Please consult the complete Prescribing Information available from your representative.

9

See Important Safety Information on page 10.

9

FOR TRAINING PURPOSES ONLY—NOT TO BE USED WITH HEALTHCARE PROFESSIONALS

T5GSL196_AnnotatedSA.qxd

1/26/06

12:45

Page 10

Requip

Important Safety Information The most common adverse event in clinical trials was nausea, at 40%.

Nausea was generally dose dependent, mild to moderate in intensity, and not typically treatment limiting. Only 1.6% of patients on Requip withdrew from clinical trials due to nausea compared with 0.2% of patients treated with placebo.

The Only FDA-Approved Treatment for Moderate-to-Severe Primary RLS

Important Safety Information Adverse events (AEs) and withdrawal rates for Requip and placebo in 4 Restless Legs Syndrome (RLS) clinical trials10* AEs

Requip (n=496)

Placebo (n=500)

AEs

Withdrawal

AEs

Nausea

40%

1.6%

8%

Withdrawal

Somnolence

12%

0.4%

6%

0%

Vomiting

11%

0.6%

2%

0%

Dizziness

11%

0.8%

5%

0.2%

Fatigue

8%

0%

4%

0%

0.2%

Discuss with physicians the adverse events (AEs) and note the withdrawal rates for Requip. These AEs were seen in >5% of patients treated with Requip and were twice the rate for patients treated with placebo.

*AEs in >5% of patients treated with Requip and twice the rate for patients treated with placebo.

• Overall discontinuation rates due to AEs for Requip were similar to placebo (5% vs 4%, respectively)10 • Nausea was generally dose dependent, mild to moderate in intensity, and not typically treatment limiting10 _1 mg/day —Incidence of nausea in patients treated with doses < ranged from 4% to 9%10 —Requip may be taken with food, which may help reduce occurrence of nausea • Requip is metabolized by the liver. Hepatically impaired patients may have higher plasma levels and lower clearance of the drug.

Therefore, the drug should be titrated with caution in this population

Remind physicians of the warnings for Requip. Patients who experience sedating effects should discontinue treatment with Requip, and prescribers should reassess patients for somnolence throughout treatment.

Patients should be aware of the following: • Rising rapidly after sitting or lying down, particularly on initial dose or during dose titration • Patients with sleep disorders should avoid taking sedating medications, alcohol, CNS depressants, or medications that increase ropinirole plasma levels

10

• If Requip is used with estrogen or CYP450 1A2 inhibitors such as ciprofloxacin, then dosage adjustment may be required • No dosage adjustment is necessary for patients with mild-to-moderate renal impairment (creatinine clearance 30 to 50 mL/min). Requip has not been studied in patients with severe renal impairment and should be used with caution in this population

Requip has been associated with sedating effects, including somnolence, and the possibility of falling asleep while engaged in activities of daily living, including operation of a motor vehicle. Requip should be discontinued if these events occur; it is unknown if dose reduction will eliminate episodes of somnolence. Prescribers should reassess patients for somnolence throughout treatment.

10

Syncope or symptomatic hypotension may occur, particularly during initial treatment or dose titration. Patients should be cautioned against rising rapidly after sitting or lying down. Because of possible additive effects, caution should be exercised with patients who have sleep disorders or are taking sedating medications, alcohol, CNS depressants, or medications that increase ropinirole plasma levels.

Point out that nausea was generally dose dependent and mild to moderate in intensity. Only 1.6% of patients on Requip withdrew from the study because of nausea compared with 0.2% of patients treated with placebo. Note that Requip can be taken with food, which may reduce the occurrence of nausea.

Requip is metabolized by the liver and the drug should be titrated with caution in this population. If Requip is used with estrogen or CYP450 1A2 inhibitors, dose adjustments may be required.

No dosage adjustment is necessary for patients with mild-to-moderate renal impairment (creatinine clearance 30 to 50 mL/min). Requip has not been studied in patients with severe renal impairment and should be used with caution in this population.

T5GSL196_AnnotatedSA.qxd

1/26/06

12:45

Page 11

Easy-to-Follow Sample Kit HOW? Provide appropriate patients with a 2-week Sample Kit and a 1-mg prescription. Requip is not a controlled substance.

Start Patients With an Easy-to-Follow Sample Kit

+

Requip

1 mg #30 tabs Sig : 1 qd

1 to 3 hours before bedtime

Benefit Sample Kit

Titration schedule with Requip

Rx

“Doctor, do you agree that it is convenient for you to help your appropriate patients get started with this kit?”

Explain to physicians that when appropriate patients with moderate-to-severe primary RLS are ready to begin therapy with Requip, they can be given a 2-week Sample Kit and a 1-mg prescription.

2-Week Sample Kit

Dosing Steps

Daily Dose

Week 1 Days 1 and 2 Days 3 to 7

0.25 mg 0.5 mg

Week 2

1 mg

Week 3

1.5 mg

Week 4

2 mg

Week 5

2.5 mg

Week 6

3 mg

Week 7

Maximum Daily Dose

Provide appropriate patients with a 2-week Sample Kit and 1-mg prescription.

If necessary, titrate Requip to an effective dose with 0.5-mg tablets.

4 mg

Requip Safety Profile/Dosing

is not a The safety and effectiveness of Requip at >4 mg/day in patients with Restless Legs Syndrome (RLS) have not been established.

controlled substance.

Help your patients get off to a good start with Requip • Instruct patients to take their medication every day, 1 to 3 hours before bedtime, even if symptoms are not present

The Sample Kit provides the first 2 weeks of therapy. After 2 weeks, the dosage of Requip can be titrated as needed using 0.5-mg tablets, up to a maximum total daily dose of 4 mg/day based on adequate clinical response and tolerability.

Explain to physicians that keeping this important information in mind can help their patients get off to a good start with Requip.

• Continue dose titration as needed up to 4 mg/day based on adequate clinical response and tolerability • If a dose is missed, patients should be advised not to double their next dose • If a significant interruption in therapy with Requip has occurred, retitration of therapy may be warranted • If nausea occurs, advise patients that taking Requip with food may reduce the occurrence of nausea. However, this has not been established in controlled clinical trials • Occurrences of nausea in clinical trials were generally mild to moderate in intensity • When increasing the dosage of Requip, caution patients of the potential for feeling faint, dizzy, or nauseated when standing from a sitting position

Please consult the complete Prescribing Information available from your representative.

11

11

FOR TRAINING PURPOSES ONLY—NOT TO BE USED WITH HEALTHCARE PROFESSIONALS

T5GSL196_AnnotatedSA.qxd

1/26/06

12:45

Š2005 The GlaxoSmithKline Group of Companies

Page 12

All rights reserved.

Printed in USA.

November 2005