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Adempas Hospital Program Checklist

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CTEPH

We encourage you to visit CTEPH.com for comprehensive and current guidance on the disease state, diagnosis and current treatment.

Package Insert/ Full prescribing Information

Patient Subgroups

ADEMPAS CAN BE USED AS MONOTHERAPY AND IN COMBINATION WITH AN ERA OR PCA^1,3

ADEMPAS DEMONSTRATED IMPROMENTS IN 6MWD

Hemodynamics (PVR and NT-proBNP)

ADEMPAS IMPROVED PVR AND NT-proBNP AT WEEK 12^1,2*

PAH CLINICAL STUDY POPULATION AT WEEK 12

Right-heart catheterization was performed at the beginning and end of the study period in 339 patients.

Adempas, n=254; placebo, n=126

PCWP=pulmonary capillary wedge pressure
*Placebo corrected mean change from baseline.

WHO FC IMPROVEMENT
WHO Functional Class Improvement

50% MORE PATIENTS IMPROVED WHO FUNCTIONAL CLASS VS PLACEBO
CHANGE IN WHO FUNCTIONAL CLASS IN THE 12-WEEK TRIAL

Deteriorated:
4% for Adempas (n=9/254)
14% for placebo (n=18/125)

Stable:
76% for Adempas (n=192/254)
71% for placebo (n=89/125)

ITT=intention to treat

CLINICAL WORSENING

ADEMPAS SIGNIFICANTLY DELAYS TIME TO CLINICAL WORSENING¹

Time to clinical worsening was a combined endpoint defined as death (all-cause mortality), heart/lung transplantation, atrial septostomy, hospitalization due to persistent worsening of pulmonary hypertension, start of new PAH-specific treatment, persistent decrease in 6MWD and persistent worsening of WHO functional class.

ADVERSE EVENTS

Most Common Adverse Events

Other events that were seen more frequently in Adempas compared to placebo and potentially related to treatment were:

• Palpitations
• Nasal congestion
• Epistaxis
• Dysphagia
• Abdominal distention
• Peripheral edema

GERD=gastroesophageal reflux disease
†Pooled from PATENT-1 and CHEST-1.

CTEPH Results

Adempas demonstrated efficacy for CTEPH adult patients in both WHO functional class II and III by 3 parameters¹:

• EXERCISE CAPACITY (as measured by 6MWD)
• WHO FUNCTIONAL CLASS
• HEMODYNAMICS (PVR, NT-proBNP)

6MWD=6-minute walk distance; CTEPH=chronic thromboembolic pulmonary hypertension; NT-proBNP=N-terminal pro-brain natriuretic peptide; PVR=pulmonary vascular resistance; WHO=World Health Organization

CHEST STUDY DESIGN^1,2

Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase–Stimulator Trial 1 (CHEST-1) was a randomized, double-blind, multinational, multicenter, placebo-controlled, 16-week phase 3 study.

Baseline characteristics

Mean age: 59 years (range: 18-80)
CTEPH: Inoperable for PEA* with PVR >300 dyn-sec-cm-5, mPAP >25 mm Hg measured at least 90 days after the start of full anticoagulation, or recurrent/persisting PH with PVR >300 dyn-sec-cm-5 measured at least 180 days following PEA
Type of CTEPH: Inoperable (72%), recurrent or persisting PH following PEA (28%)
WHO functional class: II (31%); III (64%)
Mean 6MWD baseline: 347 m
Exclusions: Patients with SBP <95 mm Hg

ERA=endothelin receptor antagonist; FC=functional class; mPAP=mean pulmonary arterial pressure; NO=nitric oxide; PCA=prostacyclin analog; PDE-5=phosphodiesterase type 5; PH=pulmonary hypertension; SBP=systolic blood pressure
*PEA, also known as pulmonary thromboendarterectomy (PTE).

Treatment characteristics

Concomitant medications: Stable dosages of oral anticoagulants, diuretics, digitalis, calcium channel blockers, and oxygen were allowed, but not NO donors, ERAs, PCAs, specific PDE-5 inhibitors (such as sildenafil, tadalafil, or vardenafil), and nonspecific PDE inhibitors (for example, dipyridamole or theophylline)

ERA=endothelin receptor antagonist; FC=functional class; mPAP=mean pulmonary arterial pressure; NO=nitric oxide; PCA=prostacyclin analog; PDE-5=phosphodiesterase type 5; PH=pulmonary hypertension; SBP=systolic blood pressure
*PEA, also known as pulmonary thromboendarterectomy (PTE).

Dosing characteristics

Initiation: 1 mg 3x a day
Groups: Adempas @ 2.5 mg 3x a day; Adempas @ 1 mg 3x a day; placebo
Titration: 77% were titrated to 2.5 mg 3x day by Week 16

Adempas titrated every 2 weeks based on SBP and signs and symptoms of hypotension

ERA=endothelin receptor antagonist; FC=functional class; mPAP=mean pulmonary arterial pressure; NO=nitric oxide; PCA=prostacyclin analog; PDE-5=phosphodiesterase type 5; PH=pulmonary hypertension; SBP=systolic blood pressure
*PEA, also known as pulmonary thromboendarterectomy (PTE).

EXERCISE CAPACITY

Exercise Capacity (6MWD)

ADEMPAS SIGNIFICANTLY IMPROVED 6MWD AT WEEK 161

RESULTS IN CTEPH: 6MWD OVER 16 WEEKS

46 m improvement (mean) in 6-minute walk distance (6MWD) over placebo at Week 16 (95% confidence interval (CI): 25 m-67 m; p<0.0001) for adults with CTPH (WHO Group 4).

Patient Subgroups

CTEPH† PATIENTS WALKED FARTHER WITH ADEMPAS¹

PRESPECIFIED SUBGROUP:
MEAN CHANGE FROM BASELINE

†Inoperable and persistent/recurrent CTEPH after surgery in adults.

Hemodynamics (PVR and NT-proBNP)

ADEMPAS IMPROVED PVR AND NT-proBNP AT WEEK 161,2‡

CTEPH‡ CLINICAL STUDY POPULATION AT WEEK 16

Right-heart catheterization was performed at the beginning and end of the study period in 233 patients.
Adempas, n=173; placebo, n=88

PCWP=pulmonary capillary wedge pressure
‡Placebo corrected mean change from baseline.

WHO Functional Class Improvement

50% MORE PATIENTS IMPROVED WHO FUNCTIONAL CLASS VS PLACEBO¹

CHANGE IN WHO FUNCTIONAL CLASS IN THE 16-WEEK TRIAL

Deteriorated:
5% for Adempas (n=9/173)
7% for placebo (n=6/87)

Stable:
62% for Adempas (n=107/173)
78% for placebo (n=68/87)

ITT=intention to treat

Long-Term Data

MORE THAN 90% OF ADEMPAS PATIENTS SURVIVED AT 2 YEARS¹

PROBABILITY OF SURVIVAL DATA FOR CTEPH PATIENTS

An open-label extension CHEST-2 study included 237 patients who had completed CHEST-1. At the cut-off date in the CHEST-2 study, the mean treatment duration for the total population was 1077 days (±433). Without a control group, these data must be interpreted cautiously.

Most Common Adverse Events

ADVERSE REACTIONS, FROM POOLED DATA1§

Other events that were seen more frequently in Adempas compared to placebo and potentially related to treatment were:

• Palpitations
• Nasal congestion
• Epistaxis
• Dysphagia
• Abdominal distention
• Peripheral edema

GERD=gastroesophageal reflux disease
§Pooled from PATENT-1 and CHEST-1.

Help your patients take Adempas properly.

Learn more here.

Warnings and Precautions

Embryo-Fetal Toxicity. Based on data from animal reproduction studies, Adempas may cause embryo-fetal toxicity when administered to a pregnant female and is contraindicated in females who are pregnant. Advise females of reproductive potential of the potential risk to a fetus. Obtain a pregnancy test before the start of treatment, monthly during treatment, and for one month after stopping treatment. Advise females of reproductive potential to use effective contraception during treatment with Adempas and for at least one month after the last dose.

For females, Adempas is only available through a restricted program under the Adempas REMS Program.

Adempas REMS Program. Females can only receive Adempas through the Adempas REMS Program, a restricted distribution program.

Important requirements of the Adempas REMS Program include the following:

• Prescribers must be certified with the program by enrolling and completing training.
• All females, regardless of reproductive potential, must enroll in the Adempas REMS Program prior to initiating Adempas. Male patients are not enrolled in the Adempas REMS Program.
• Female patients of reproductive potential must comply with the pregnancy testing and contraception requirements.
• Pharmacies must be certified with the program and must only dispense to patients who are authorized to receive Adempas.

Further information, including a list of certified pharmacies, is available at www.AdempasREMS.com or 1-855-4ADEMPAS.

Hypotension. Adempas reduces blood pressure. Consider the potential for symptomatic hypotension or ischemia in patients with hypovolemia, severe left ventricular outflow obstruction, resting hypotension, autonomic dysfunction, or concomitant treatment with antihypertensives or strong CYP and P-gp/BCRP inhibitors. Consider a dose reduction if patient develops signs or symptoms of hypotension.

Bleeding. In the placebo-controlled clinical trials, serious bleeding occurred in 2.4% of patients taking Adempas compared to 0% of placebo patients. Serious hemoptysis occurred in 5 (1%) patients taking Adempas compared to 0 placebo patients, including one event with fatal outcome. Serious hemorrhagic events also included 2 patients with vaginal hemorrhage, 2 with catheter-site hemorrhage, and 1 each with subdural hematoma, hematemesis, and intra-abdominal hemorrhage.

Pulmonary Veno-Occlusive Disease. Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD). Therefore, administration of Adempas to such patients is not recommended. Should signs of pulmonary edema occur, the possibility of associated PVOD should be considered and if confirmed, discontinue treatment with Adempas.