Kaptivated

eled

Patients with ADHD are lab

Hyperactive, Impulsive, and

Inattentive...

With KAPVAY , ÂŽ

there may be a different word to describe them—

Please see inside for Important Safety Information and enclosed full Prescribing Information.

Up to 30% of patients with ADHD do not respond (eg, inadequate symptom relief) to stimulant monotherapy alone1,2

ADD-ON

KAPVAY ® add-on—achieve significant symptom improvement3,4 In the add-on trial, KAPVAY® demonstrated efficacy at week 5 (primary end point as measured by the ADHD RS-IV Total Score) with statistically significant symptom improvement seen as early as week 23,4 Mean Change in ADHD RS-IV Total Score Over Time* KAPVAY® + stimulant (n=102) Placebo + stimulant (n=95)

Reduction in Mean ADHD RS-IV Total Score Change From Baseline

40 38 36 34 32 30 †

28 26

†

24 22 20

†

†

‡

P<0.05

P=0.0091

Baseline Week 1

Week 2

Week 3

Dose Escalation and Maintenance

40 %

IMPROVEMENT IN ADHD SYMPTOMS at week 5 (primary end point as measured by the ADHD RS-IV Total Score) in the KAPVAY® + stimulant group compared with a 29% improvement for patients taking a stimulant alone (P<0.01)3

† †

‡

Week 4

Week 5

Week 6

Primary End Point

Week 8

Dose Taper

* Eight-week, multicenter, randomized, double-blind, placebo-controlled flexible-dose study, with primary efficacy end point measured at 5 weeks. A total of 198 children and adolescents (6-17 years of age) who met DSM-IV criteria for ADHD hyperactive or combined inattentive/hyperactive subtypes were randomized to 1 of 2 treatment groups: KAPVAY® as adjunctive therapy to a psychostimulant (n=102) or a placebo added to a psychostimulant (n=96). The KAPVAY ® dose was initiated at 0.1 mg/day and titrated up to 0.4 mg/day over a 3-week period. The dose was maintained at this level for a period of 2 weeks before being gradually tapered to 0.1 mg/day at the last week of treatment.

One patient in the placebo + stimulant group was omitted from the ITT population because of a lack of study assessment after baseline.

Indication KAPVAY® (clonidine hydrochloride) extended-release tablets are indicated for the treatment of attention deficit/hyperactivity disorder (ADHD) as monotherapy or as adjunctive therapy to stimulant medications in children and adolescents ages 6-17. The efficacy of KAPVAY® is based on the results of 2 clinical trials in children and adolescents.

KAPVAY ® is indicated as an integral part of a total treatment program for ADHD that may include other measures (psychological, educational, and social) for patients with this syndrome.

Please see additional Important Safety Information throughout and enclosed full Prescribing Information.

2

Week 7

SUBSCALES

ADD-ON EFFICACY

Get your patients closer to their individualized treatment goals Adding KAPVAY® to a stimulant demonstrated significant improvement in both the Inattention and Hyperactivity/Impulsivity subscales of the ADHD RS-IV 3

ADHD RS-IV Total and Subscale Scores (mean change from baseline)*

Mean Change in ADHD RS-IV Subscale Score From Baseline to Week 5

Primary End Point 0

Total Score

Secondary End Points Inattention

–2

–5.8

–4

–7.8

–6 –8

–11.5

–10 –12 –14

–5.8 –7.9

P=0.0169

P=0.0143

P=0.0091

≈

40 % SYMPTOM

IMPROVEMENT

–15.7

–16 –18

Hyperactivity/Impulsivity

achieved in Total Score and both Subscale Scores

KAPVAY® + stimulant (n=102) Placebo + stimulant (n=95)

(at week 5—the primary end point as measured by the ADHD RS-IV)3

Indication (continued) The effectiveness of KAPVAY® for longer-term use (more than 5 weeks) has not been systematically evaluated in controlled trials; therefore, the physician electing to use KAPVAY® for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

Important Safety Information KAPVAY® should not be used in patients with known hypersensitivity to clonidine.

KAPVAY® can cause dose-related decreases in blood pressure and heart rate.

Use caution in treating patients who have a history of syncope or may have a condition that predisposes them to syncope, such as hypotension, orthostatic hypotension, bradycardia, or dehydration. Use with caution in patients treated concomitantly with antihypertensives or other drugs that can reduce blood pressure or heart rate or increase the risk of syncope.

3

Adverse reactions were generally mild to moderate in the add-on trial Most Common Adverse Reactions (≥5%) in Add-on Trial—Treatment Period5 KAPVAY® + Stimulant

Placebo + Stimulant

% Patients Reporting Reaction

% Patients Reporting Reaction

Somnolence

19%

8%

Fatigue

16%

4%

Abdominal Pain Upper

12%

7%

Nasal Congestion

6%

5%

Throat Pain

6%

3%

Decreased Appetite

5%

4%

• T he adverse events reported in the KAPVAY® add-on trial were generally mild to moderate and were unaffected by the concomitant stimulant (amphetamine or methylphenidate)4 •M ore patients in the stimulant alone group (n=102) discontinued treatment than in the KAPVAY® + stimulant group (n=96) (4.2% vs 1%)4 —O nly 1 patient taking KAPVAY® + stimulant discontinued the KAPVAY® add-on clinical trial due to a treatment emergent adverse event 4

Important Safety Information (continued) Clonidine may potentiate the CNS-depressive effects of alcohol, barbiturates or other sedating drugs.

Use caution when KAPVAY® is administered concomitantly with antihypertensive drugs, due to the additive pharmacodynamic effects (e.g., hypotension, syncope).

In patients who have developed localized contact sensitization or other allergic reaction to clonidine in a transdermal system, substitution of oral clonidine hydrochloride therapy may be associated with the development of a generalized skin rash, urticaria, or angioedema. Use cautiously in patients with vascular disease, cardiac conduction disease, or chronic renal failure: Monitor carefully and uptitrate slowly.

Please see additional Important Safety Information throughout and enclosed full Prescribing Information.

4

MONO

KAPVAY® monotherapy—achieve significant symptom improvement4,6 In the monotherapy trial,* KAPVAY® demonstrated efficacy at week 5 (primary end point as measured by the ADHD RS-IV Total Score) with statistically significant symptom improvement seen as early as week 24,6

36% IMPROVEMENT 37% IMPROVEMENT

In ADHD symptoms for patients in the KAPVAY® 0.4 mg/day group at week 5 (vs 17% in placebo group; P<0.0001)6

SAFETY

* Eight-week, multicenter, randomized, double-blind, placebo-controlled, fixed-dose study, with primary efficacy end point measured at 5 weeks. A total of 236 children and adolescents (6-17 years of age) who met DSM-IV criteria for ADHD hyperactive or combined inattentive/hyperactive subtypes were randomized to 1 of 3 treatment groups: KAPVAY® 0.2 mg/day (n=78), KAPVAY® 0.4 mg/day (n=80), or placebo (n=78).

Dosing for the KAPVAY® groups started at 0.1 mg/day and a weekly titration schedule was used to escalate patients to their respective fixed dose. Patients were maintained at their dose levels for a minimum period of 2 weeks before being gradually tapered down to 0.1 mg/day at the last week of treatment.

KAPVAY safety—assessed in a well-controlled trial ®

5

• Most common adverse reactions (≥5%) include: somnolence, headache, upper abdominal pain, fatigue, upper respiratory tract infection, irritability, throat pain, nausea, nightmare, dizziness, insomnia, emotional disorder, constipation, dry mouth, nasal congestion, increased body temperature, gastrointestinal viral, and ear pain

STATISTICALLY

SIGNIFICANT

SYMPTOM IMPROVEMENT

• Most common adverse reactions reported during the dose-tapering phase in the KAPVAY® 0.2 mg/day-treatment group were headache (5%), somnolence (2%), and otitis media acute (3%). In the KAPVAY® 0.4 mg/day-treatment group, the most common adverse reactions were abdominal pain upper (6%), headache (2%), gastrointestinal viral (5%), somnolence (3%), and heart rate increased (3%)

5

ADD-ON SAFETY/MONO EFFICACY AND SAFETY

In ADHD symptoms for patients in the KAPVAY® 0.2 mg/day group at week 5 (vs 17% in placebo group; P<0.0001)6

FLEXIBLE

Offer convenient flexibility to your patients KAPVAY® can be administered with or without food5 KAPVAY® Pharmacokinetic Profile in the Fed and Fasted State* 400

Mean Concentration (pg/mL)

350 300 250 200 150 100 50

KAPVAY ®—Fasted KAPVAY ®—Fed

0 0

6

12

18

Time (hr)

* Open-label, 3-period, randomized, crossover study of 15 healthy adult subjects receiving 3 single-dose regimens of clonidine: 0.1 mg of KAPVAY® under fasted conditions, 0.1 mg of KAPVAY® following a high-fat meal, and 0.1 mg of Catapres® under fasted conditions (not shown). Each treatment was separated by a 1-week washout period.4

Important Safety Information (continued)

NO FOOD

EFFECT

KAPVAY® should not be used during pregnancy unless clearly needed. Since clonidine hydrochloride is excreted in human milk, caution should be exercised when KAPVAY® is administered to a nursing woman.

Caution is warranted in patients receiving clonidine concomitantly with agents known to affect sinus node function or AV nodal conduction (e.g., digitalis, calcium-channel blockers and beta-blockers) due to a potential for additive effects such as bradycardia and AV block.

Please see additional Important Safety Information throughout and enclosed full Prescribing Information.

6

Catapres® is a registered trademark of Boehringer Ingelheim.

24

Prescribe KAPVAY ® —See if your patients become

KAPVAY® add-on—

achieve significant symptom improvement3,4 • I n the add-on trial, KAPVAY ® demonstrated efficacy at week 5 (primary end point as measured by the ADHD RS-IV Total Score) with statistically significant symptom improvement seen as early as week 2 3,4 — ≈ 40% improvement achieved in Total Score and both Subscale Scores3

KAPVAY® monotherapy—

achieve significant symptom improvement 4,6 • I n the monotherapy trial, KAPVAY® demonstrated efficacy at week 5 (primary end point as measured by the ADHD RS-IV Total Score) with statistically significant symptom improvement seen as early as week 24,6 — 36% improvement in ADHD symptoms for patients in the KAPVAY ® 0.2 mg/day group at week 5 6 — 37% improvement in ADHD symptoms for patients in the KAPVAY ® 0.4 mg/day group at week 5 6

KAPVAY® offers

convenient flexibility to your patients •K APVAY ® can be administered with or without food5 •K APVAY ® should be dosed based on a patient’s response to treatment, so titrate only to the dose necessary to achieve desired results5 •W hen KAPVAY ® is added to a stimulant, the dose of the stimulant can be adjusted/reduced depending on the patient’s response5 •U nlike other non-stimulants, adjustments in the KAPVAY ® dose for a patient’s body weight are not necessary to achieve optimal efficacy 7,8

Important Safety Information (continued) Somnolence/Sedation were commonly reported adverse reactions in clinical studies with KAPVAY®. Potential for additive sedative effects with CNS-depressant drugs. Advise patients to avoid use with alcohol. Caution patients against operating heavy equipment or driving until they know how they respond to KAPVAY®.

Patients should be instructed not to discontinue KAPVAY® therapy without consulting their physician due to the potential risk of withdrawal effects. KAPVAY® should be discontinued slowly in decrements of no more than 0.1 mg every 3 to 7 days.

Clonidine, the active ingredient in KAPVAY®, is also approved as an antihypertensive. Do not use KAPVAY® in patients concomitantly taking other clonidine-containing products, (e.g., Catapres®, JENLOGA).

Common adverse reactions (incidence at least 5% and twice the rate of placebo) include: somnolence, fatigue, upper respiratory tract infection, irritability, throat pain, insomnia, nightmares, emotional disorder, constipation, nasal congestion, increased body temperature, dry mouth, and ear pain.

Please see additional Important Safety Information throughout and enclosed full Prescribing Information. © 2012 Shionogi Inc. Florham Park, NJ. All rights reserved. KAP12-PSA-001A-00 04/12

PK/DOSING

7

•K APVAY® is an extended-release tablet; therefore, it should not be crushed, chewed, or broken before swallowing5 • T he effectiveness of KAPVAY® for longer-term use (more than 5 weeks) has not been systematically evaluated in controlled trials; therefore, the physician electing to use KAPVAY® for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient 5 •D ue to the lack of controlled clinical trial data and differentiating pharmacokinetic profiles, substitution of KAPVAY® for other clonidine products on a mg-per-mg basis is not recommended5 •K APVAY® is not to be used interchangeably with the immediate-release formulation5 •W hen discontinuing KAPVAY®, the total daily dose should be tapered in decrements of no more than 0.1 mg every 3 to 7 days5 •D oses should be taken twice a day, with either an equal or higher split dosage being given at bedtime5 •U nlike other non-stimulants, adjustments in the KAPVAY® dose for a patient’s body weight are not necessary to achieve optimal efficacy7,8 FACTS

KAPVAY® dosing—important facts

Dosing should be initiated with one 0.1 mg tablet at bedtime. Doses of KAPVAY® higher than 0.4 mg/day (0.2 mg twice daily) were not evaluated in clinical trials for ADHD and are not recommended.

†

Total Daily Dose

Morning Dose

Bedtime Dose

0.1 mg/day

---

0.1 mg

0.2 mg/day

0.1 mg

0.1 mg

0.3 mg/day

0.1 mg

0.2 mg

0.4 mg/day

0.2 mg

0.2 mg

depending on the patient’s response5

be adjusted/reduced

When KAPVAY® is added to a stimulant, the dose of the stimulant can

KAPVAY® Dosing Guide† DOSING

KAPVAY® should be dosed based on a patient’s needs and response to treatment, so titrate only to the dose necessary to achieve desired results5

KAPVAY® dosing offers a personalized approach

Prescribe KAPVAY ® —See if your patients become

KAPVAY® add-on—

achieve significant symptom improvement3,4 • I n the add-on trial, KAPVAY ® demonstrated efficacy at week 5 (primary end point as measured by the ADHD RS-IV Total Score) with statistically significant symptom improvement seen as early as week 2 3,4 — ≈ 40% improvement achieved in Total Score and both Subscale Scores3

KAPVAY® monotherapy—

achieve significant symptom improvement 4,6 • I n the monotherapy trial, KAPVAY® demonstrated efficacy at week 5 (primary end point as measured by the ADHD RS-IV Total Score) with statistically significant symptom improvement seen as early as week 24,6 — 36% improvement in ADHD symptoms for patients in the KAPVAY ® 0.2 mg/day group at week 5 6 — 37% improvement in ADHD symptoms for patients in the KAPVAY ® 0.4 mg/day group at week 5 6

KAPVAY® offers

convenient flexibility to your patients •K APVAY ® can be administered with or without food5 •K APVAY ® should be dosed based on a patient’s response to treatment, so titrate only to the dose necessary to achieve desired results5 •W hen KAPVAY ® is added to a stimulant, the dose of the stimulant can be adjusted/reduced depending on the patient’s response5 •U nlike other non-stimulants, adjustments in the KAPVAY ® dose for a patient’s body weight are not necessary to achieve optimal efficacy 7,8

Important Safety Information (continued) Somnolence/Sedation were commonly reported adverse reactions in clinical studies with KAPVAY®. Potential for additive sedative effects with CNS-depressant drugs. Advise patients to avoid use with alcohol. Caution patients against operating heavy equipment or driving until they know how they respond to KAPVAY®.

Patients should be instructed not to discontinue KAPVAY® therapy without consulting their physician due to the potential risk of withdrawal effects. KAPVAY® should be discontinued slowly in decrements of no more than 0.1 mg every 3 to 7 days.

Clonidine, the active ingredient in KAPVAY®, is also approved as an antihypertensive. Do not use KAPVAY® in patients concomitantly taking other clonidine-containing products, (e.g., Catapres®, JENLOGA).

Common adverse reactions (incidence at least 5% and twice the rate of placebo) include: somnolence, fatigue, upper respiratory tract infection, irritability, throat pain, insomnia, nightmares, emotional disorder, constipation, nasal congestion, increased body temperature, dry mouth, and ear pain.

Please see additional Important Safety Information throughout and enclosed full Prescribing Information. © 2012 Shionogi Inc. Florham Park, NJ. All rights reserved. KAP12-PSA-001A-00 04/12

•K APVAY® is an extended-release tablet; therefore, it should not be crushed, chewed, or broken before swallowing5 • T he effectiveness of KAPVAY® for longer-term use (more than 5 weeks) has not been systematically evaluated in controlled trials; therefore, the physician electing to use KAPVAY® for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient 5 •D ue to the lack of controlled clinical trial data and differentiating pharmacokinetic profiles, substitution of KAPVAY® for other clonidine products on a mg-per-mg basis is not recommended5 •K APVAY® is not to be used interchangeably with the immediate-release formulation5 •W hen discontinuing KAPVAY®, the total daily dose should be tapered in decrements of no more than 0.1 mg every 3 to 7 days5 •D oses should be taken twice a day, with either an equal or higher split dosage being given at bedtime5 •U nlike other non-stimulants, adjustments in the KAPVAY® dose for a patient’s body weight are not necessary to achieve optimal efficacy7,8

KAPVAY® dosing—important facts

Dosing should be initiated with one 0.1 mg tablet at bedtime. Doses of KAPVAY® higher than 0.4 mg/day (0.2 mg twice daily) were not evaluated in clinical trials for ADHD and are not recommended.

†

0.2 mg

0.4 mg/day

0.1 mg

0.3 mg/day

0.1 mg

0.2 mg/day

---

0.1 mg/day

Morning Dose

Total Daily Dose

0.2 mg 0.2 mg 0.1 mg 0.1 mg

depending on the patient’s response5

be adjusted/reduced

When KAPVAY® is added to a stimulant, the dose of the stimulant can

Bedtime Dose

KAPVAY® Dosing Guide† DOSING

KAPVAY® should be dosed based on a patient’s needs and response to treatment, so titrate only to the dose necessary to achieve desired results5

KAPVAY® dosing offers a personalized approach

PK/DOSING

7

FACTS