Adempas Tablets

Name: Adempas Tablets

Dosage Forms and Strengths

Tablets: film-coated, round, bi-convex:

• 0.5 mg, white, with “BAYER” cross on one side and “0.5” and “R” on the other side • 1 mg, pale-yellow, with “BAYER” cross on one side and “1” and “R” on the other side • 1.5 mg, yellow-orange, with “BAYER” cross on one side and “1.5” and “R” on the other side • 2 mg, pale orange, with “BAYER” cross on one side and “2” and “R” on the other side • 2.5 mg, red-orange, with “BAYER” cross on one side and “2.5” and “R” on the other side

Warnings and Precautions

Embryo-Fetal Toxicity

Adempas may cause fetal harm when administered during pregnancy and is contraindicated for use in women who are pregnant. In females of reproductive potential, exclude pregnancy prior to initiation of therapy, advise use of acceptable contraception and obtain monthly pregnancy tests. For females, Adempas is only available through a restricted program under the Adempas REMS Program [see Dosage and Administration (2.3), Warnings and Precautions (5.2) and Use in Specific Populations (8.1, 8.6)].

Adempas REMS Program

Females can only receive Adempas through the Adempas Risk Evaluation and Mitigation Strategy (REMS) Program, a restricted distribution program [see Warnings and Precautions (5.1)].

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 [see Use in Specific Populations (8.6)]. • 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 1-855-4 ADEMPAS.

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 [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)]. 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.

Adverse Reactions

The following serious adverse reactions are discussed elsewhere in the labeling:

• Embryo-Fetal Toxicity [see Warnings and Precautions (5.1)] • Hypotension [see Warnings and Precautions (5.3)] • Bleeding [see Warnings and Precautions (5.4)]

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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety data described below reflect exposure to Adempas in two, randomized, double blind, placebo-controlled trials in patients with inoperable or recurrent/persistent CTEPH (CHEST-1) and treatment naive or pre-treated PAH patients (PATENT-1). The population (Adempas: n = 490; Placebo: n = 214) was between the age of 18 and 80 years [see Clinical Studies (14.1, 14.2)].

The safety profile of Adempas in patients with inoperable or recurrent/persistent CTEPH (CHEST-1) and treatment naive or pre-treated PAH (PATENT-1) were similar. Therefore, adverse drug reactions (ADRs) identified from the 12 and 16 week placebo-controlled trials for PAH and CTEPH respectively were pooled, and those occurring more frequently on Adempas than placebo (≥3%) are displayed in Table 1 below. Most adverse reactions in Table 1 can be ascribed to the vasodilatory mechanism of action of Adempas.

The overall rates of discontinuation due to an adverse event in the pivotal placebo-controlled trials were 2.9% for Adempas and 5.1% for placebo (pooled data).

Table 1: Adverse Reactions Occurring More Frequently (≥3%) on Adempas than Placebo (Pooled from CHEST-1 and PATENT-1)

Adverse Reactions

Adempas %

(n=490)

Placebo %

(n=214)

Headache

27

18

Dyspepsia and Gastritis

21

8

Dizziness

20

13

Nausea

14

11

Diarrhea

12

8

Hypotension

10

4

Vomiting

10

7

Anemia
(including laboratory parameters)

7

2

Gastroesophageal reflux disease

5

2

Constipation

5

1

Other events that were seen more frequently in Adempas compared to placebo and potentially related to treatment were: palpitations, nasal congestion, epistaxis, dysphagia, abdominal distension and peripheral edema. With longer observation in uncontrolled long-term extension studies the safety profile was similar to that observed in the placebo controlled phase 3 trials.

Drug Interactions

Pharmacodynamic Interactions with Adempas

Nitrates: Co-administration of Adempas with nitrates or nitric oxide donors (such as amyl nitrite) in any form is contraindicated because of hypotension [see Contraindications (4.2) and Clinical Pharmacology (12.2)].

PDE Inhibitors: Co-administration of Adempas with specific PDE-5 inhibitors (such as sildenafil, tadalafil, or vardenafil) and nonspecific PDE inhibitors (such as dipyridamole or theophylline), is contraindicated because of hypotension. Do not administer within 24 hours of sildenafil. Do not administer 24 hours before or within 48 hours after tadalafil [see Dosage and Administration (2.6)]. Clinical experience with co-administration of Adempas and other phosphodiesterase inhibitors (for example, milrinone, cilostazole, roflumilast) is limited.

Pharmacokinetic Interactions with Adempas

Smoking: Plasma concentrations in smokers are reduced by 50% to 60% compared to nonsmokers. Based on pharmacokinetic modeling, for patients who are smokers, doses higher than 2.5 mg three times a day may be considered in order to match exposure seen in nonsmoking patients. Safety and effectiveness of Adempas doses higher than 2.5 mg three times a day have not been established. A dose reduction should be considered in patients who stop smoking [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].

Strong CYP and P-gp/BCRP inhibitors: Concomitant use of riociguat with strong cytochrome CYP inhibitors and P-gp/BCRP inhibitors such as azole antimycotics (for example, ketoconazole, itraconazole) or HIV protease inhibitors (such as ritonavir) increase riociguat exposure and may result in hypotension. Consider a starting dose of 0.5 mg 3 times a day when initiating Adempas in patients receiving strong CYP and P-gp/BCRP inhibitors. Monitor for signs and symptoms of hypotension on initiation and on treatment with strong CYP and P-gp/BCRP inhibitors. A dose reduction should be considered in patients who may not tolerate the hypotensive effect of riociguat [see Dosage and Administration (2.5), Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)].

Strong CYP3A inducers: Strong inducers of CYP3A (for example, rifampin, phenytoin, carbamazepine, phenobarbital or St. John’s Wort) may significantly reduce riociguat exposure. Data are not available to guide dosing of riociguat when strong CYP3A inducers are co-administered. [see Clinical Pharmacology (12.3)].

Antacids: Antacids such as aluminum hydroxide/magnesium hydroxide decrease riociguat absorption and should not be taken within 1 hour of taking Adempas [see Clinical Pharmacology (12.3)].

Clinical Studies

Chronic-Thromboembolic Pulmonary Hypertension

A double-blind, multi-national, multi-center, study (CHEST-1) was conducted in 261 patients with CTEPH. Patients were included if they:

• were technically inoperable for pulmonary endarterectomy, with PVR >300 dyn*sec*cm-5 and mean pulmonary artery pressure >25 mmHg measured at least 90 days after the start of full anticoagulation, or • had recurrent or persisting pulmonary hypertension defined as PVR > 300 dyn*sec*cm-5 measured at least 180 days following pulmonary endarterectomy.

Patients were randomized to Adempas titrated up to 2.5 mg three times a day (n=173) or placebo (n=88). All patients were initiated at 1 mg three times a day. Patients with systolic blood pressure < 95 mmHg were excluded from the study. The dose of riociguat was titrated every 2 weeks based on the patient’s systolic blood pressure and signs or symptoms of hypotension. Stable dosages of oral anticoagulants, diuretics, digitalis, calcium channel blockers and oxygen were allowed, but not concomitant therapy with NO donors, endothelin receptor antagonists, prostacyclin analogues (PCA), specific PDE-5 inhibitors (such as, sildenafil, tadalafil, or vardenafil), and nonspecific phosphodiesterase inhibitors (for example, dipyridamole or theophylline).

The primary endpoint of the study was change from baseline in six minute walking distance (6MWD) after 16 weeks. The mean age of the patients enrolled was 59 years (range 18–80 years). In the study, 72% of patients had inoperable CTEPH, 28% had recurrent or persisting pulmonary hypertension following pulmonary endarterectomy. The majority of patients had a World Health Organization (WHO) Functional Class II (31%) or III (64%) at baseline. The mean baseline 6MWD was 347 meters. In the study, 77% of patients were titrated to the maximum dose of 2.5 mg three times a day; 13%, 6%, 4%, and 1% of patients were titrated to riociguat doses of 2, 1.5, 1, and 0.5 mg three times a day, respectively.

Results of the 6MWD over 16 weeks for the CHEST-1 study are shown in Figure 3.

Figure 3: CHEST-1 Mean Change from Baseline in the 6-Minute Walk Distance

The pre-specified primary endpoint of the study was the change in 6MWD from baseline to week 16 and was based on imputed values. The imputation for missing values included last observed value, not including follow-up for patients who completed the study or withdrew. For deaths or clinical worsening without a termination visit or a measurement at that visit, the imputed worst value (zero) was used.

Improvements in walking distance were apparent from Week 2 onward. At Week 16, the placebo adjusted mean increase in 6MWD within the Adempas group was 46 m (95% confidence interval [CI]: 25 m to 67 m; p<0.0001). For CHEST-1, the median difference (Hodges-Lehmann non-parametric estimate) in 6MWD was 39 m (95% CI, 25 m to 54 m).

Figure 4 illustrates the results of the Adempas and placebo treatment groups displayed as a histogram summarizing the treatment effect on the 6MWD. The patients are grouped by change in 20 meters from baseline. Overall this figure shows that patients treated with Adempas benefit compared to those treated with placebo. As demonstrated in Figure 4, 143 patients receiving Adempas (83%) experienced an improvement in 6MWD compared to 50 patients (57%) on placebo.

Figure 4: CHEST-1 Distribution of Patients by Change from Baseline in 6-Minute Walk Distance

Placebo-adjusted changes in 6MWD at 16 weeks were evaluated in subgroups (see Figure 5).

Figure 5: Mean Treatment Difference in Change from Baseline to Last Visit in 6-Minute Walk Distance (meters) by Prespecified Subgroups

WHO Functional Class improvements in the CHEST-1 trial are shown in Table 4.

Table 4: Effects of Adempas on the Change in WHO Functional Class in CHEST-1 from Baseline to Week 16

Change in WHO Functional Class

Adempas (n=173)

Placebo (n=87)

Improved

57 (33%)

13 (15%)

Stable

107 (62%)

68 (78%)

Deteriorated

9 (5%)

6 (7%)

p-value=0.0026

Long Term Treatment of CTEPH

An open-label extension study (CHEST-2) 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 582 days (± 317). The probabilities of survival at 1 and 2 years were 97% and 94%, respectively. Without a control group, however, these data must be interpreted cautiously.

Pulmonary Arterial Hypertension

A double-blind, multi-national, multi-center study (PATENT-1) was conducted in 443 patients with PAH as defined by PVR >300 dyn*sec*cm-5 and a PAP mean >25 mmHg.

Patients were randomized to one of three treatment groups: Adempas titrated up to 1.5 mg (n=63), 2.5 mg (n=254) or placebo (n=126) three times a day. Patients with systolic blood pressure < 95 mmHg were excluded from the study. Patients assigned to Adempas were initiated at 1.0 mg three times a day. The dose of Adempas was up-titrated every 2 weeks based on the patient’s systolic blood pressure and signs or symptoms of hypotension. Oral anticoagulants, diuretics, digitalis, calcium channel blockers, and oxygen were allowed. In this study, 50% of the patients were treatment-naive with respect to PAH therapy, 44% were pre-treated with an endothelin receptor antagonist (ERA) and 6% were pre-treated with a PCA (inhaled, oral or subcutaneous). Pre-treated patients were defined as patients on stable treatment for 3 months with either an ERA or PCA; Adempas was added in combination to these background therapies.

The primary endpoint of the study was change from baseline and placebo in 6MWD after 12 weeks in the 2.5 mg group. The mean age of all patients was 51 years and approximately 80% were female. PAH etiologies were either idiopathic (61%) or familial PAH (2%), PAH associated with connective tissue disease (25%), congenital heart disease (8%), portal hypertension (3%), or anorexigen or amphetamine use (1%). The majority of patients had a WHO Functional Class II (42%) or III (54%) at baseline. The overall mean baseline 6MWD was 363 meters. Approximately 75% of patients were up-titrated to receive the maximum dose of 2.5 mg three times a day by week 12; 15%, 6%, 3%, and 2% were titrated to doses of 2, 1.5, 1, and 0.5 mg 3 times a day, respectively.

Results of the 6MWD over 12 weeks for the PATENT-1 study are shown in Figure 6.

Figure 6: PATENT-1 Mean Change from Baseline in the 6-Minute Walk Distance

The pre-specified primary endpoint of the study was the change in 6MWD from baseline to week 12 and was based on imputed values. The imputation for missing values included last observed value, not including follow-up for patients who completed the study or withdrew. In case of death or clinical worsening without a termination visit or a measurement at that termination visit, the imputed worst value (zero) was used.

Figure 7 illustrates the results of the Adempas and placebo treatment groups displayed as a histogram summarizing the treatment effect on the 6MWD. The patients are grouped by change in 20 meters from baseline. Overall this figure shows that patients treated with Adempas benefit compared to those treated with placebo. As demonstrated in Figure 7, 193 patients receiving Adempas (76%) experienced an improvement in 6MWD compared to 74 patients (59%) on placebo.

Figure 7: PATENT-1 Distribution of Patients by Change from Baseline in 6-Minute Walk Distance

Improvements 6MWD were apparent from Week 2 onward. At Week 12, the placebo-adjusted mean increase in 6MWD within the Adempas group was 36 m (95% CI: 20 m to 52 m; p<0.0001). For PATENT-1, the median difference (Hodges-Lehmann non-parametric estimate) in 6MWD was 29 m (95% CI, 17 m to 40 m). There was an exploratory 1.5 mg capped titration arm (n = 63). The data did not suggest incremental benefit from escalating dose from 1.5 mg three times a day to 2.5 mg three times a day.

Placebo-adjusted changes in 6MWD at 12 weeks were evaluated in subgroups (see Figure 8).

Figure 8: PATENT-1 Mean Treatment Difference in Change from Baseline to Last Visit in 6-Minute Walk Distance (meter) by Prespecified Subgroups

WHO Functional Class improvements in the IDT (individual dose titration) arm of the PATENT-1 trial are shown in Table 5

Table 5: Effects of Adempas on the Change in WHO Functional Class in PATENT-1 from Baseline to Week 12

Change in WHO Functional Class

Adempas (IDT) (n=254)

Placebo (n=125)

Improved

53 (21%)

18 (14%)

Stable

192 (76%)

89 (71%)

Deteriorated

9 (4%)

18 (14%)

p-value = 0.0033

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.

Effects of Adempas in PATENT-1 on events of clinical worsening are shown in Table 6.

Table 6: Effects of Adempas in PATENT-1 on Events of Clinical Worsening (ITT analysis set)

Clinical Worsening Events

Adempas (IDT) (n=254)

Placebo (n=126)

Patients with any clinical worsening*

3 (1.2%)

8 (6.3%)

• Death

2 (0.8%)

3 (2.4%)

• Hospitalizations due to PH

1 (0.4%)

4 (3.2%)

• Decrease in 6MWD due to PH

1 (0.4%)

2 (1.6%)

• Persistent worsening of FC due to PAH

0

1 (0.8%)

• Start of new PAH treatment

1 (0.4%)

5 (4.0%)

* p-value=0.0285 (Mantel-Haenszel estimate)

Note: Patients may have had more than one event of clinical worsening

Adempas-treated patients experienced a significant delay in time to clinical worsening versus placebo-treated patients (p=0.0046; Stratified log-rank test). Significantly fewer events of clinical worsening up to week 12 (last visit) were observed in patients treated with Adempas (1.2%) compared to placebo (6.3%) (p=0.0285, Mantel-Haenszel estimate).

The Kaplan-Meier plot of time to clinical worsening is presented in Figure 9.

Figure 9: PATENT-1 Time (in Days) to Clinical Worsening (ITT analysis set)

Long Term Treatment of PAH

An open label extension study (PATENT-2) included 363 patients who had completed PATENT-1. At the cut-off date in the PATENT-2 study, the mean treatment duration for the total population was 663 days (± 319). The probabilities of survival at 1 and 2 years were 97% and 93%, respectively. Without a control group, these data must be interpreted cautiously.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Embryo-Fetal Toxicity

Instruct patients on the risk of fetal harm when Adempas is used during pregnancy [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]. Instruct females of reproductive potential to use effective contraception and to contact her physician immediately if they suspect they may be pregnant. Female patients must enroll in the Adempas REMS Program.

Adempas REMS Program

For female patients, Adempas is available only through a restricted program called the Adempas REMS Program [see Warnings and Precautions (5.2)]. Male patients are not enrolled in the Adempas REMS Program.

Inform female patients (and their guardians, if applicable) of the following important requirements:

• All female patients must sign an enrollment form. • Advise female patients of reproductive potential that she must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.6)]. • Educate and counsel females of reproductive potential on the use of emergency contraception in the event of unprotected sex or contraceptive failure. • Advise pre-pubertal females to report any changes in their reproductive status immediately to her prescriber.

Review the Medication Guide and REMS educational materials with female patients.

Other Risks Associated with Adempas

• Inform patients of the contraindication of Adempas with nitrates or nitric oxide donors or PDE-5 inhibitors. • Advise patients about the potential risks/signs of hemoptysis and to report any potential signs of hemoptysis to their physicians. • Instruct patients on the dosing, titration, and maintenance of Adempas. • Advise patients regarding activities that may impact the pharmacology of Adempas (strong multi pathway CYP inhibitors and P-gp/BCRP inhibitors and smoking). Instruct patients to report all current medications and new medications to their physician. • Advise patients that antacids should not be taken within 1 hour of taking Adempas. • Inform patients that Adempas can cause dizziness, which can affect the ability to drive and use machines [see Adverse Reactions (6.1)]. Advise patients to be aware of how they react to Adempas, before driving or operating machinery and if needed, consult their physician. Patients should consult their physicians if dizziness gets worse with Adempas.

MEDICATION GUIDE

Adempas (a dem pahs)
(riociguat)

tablets

Read this Medication Guide before you start taking Adempas and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your doctor about your medical condition or your treatment.

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

• Serious birth defects. • Adempas can cause serious birth defects if taken during pregnancy. • Females must not be pregnant when they start taking Adempas or become pregnant during treatment with Adempas. • Females who are able to get pregnant must have a negative pregnancy test before beginning treatment with Adempas, each month during treatment, and 1 month after you stop treatment with Adempas. Talk to your doctor about your menstrual cycle. Your doctor will decide when to do the tests, and order the tests for you depending on your menstrual cycle. • Females who are able to get pregnant are females who: • Have entered puberty, even if they have not started their period, and • Have a uterus,and • Have not gone through menopause (have not had a period for at least 12 months for natural reasons, or who have had their ovaries removed) • Females who are not able to get pregnant are females who: • Have not yet entered puberty, or • Do not have a uterus, or • Have gone through menopause (have not had a period for at least 12 months for natural reasons, or who have had their ovaries removed)

Females who are able to get pregnant must use 2 acceptable forms of birth control, during treatment with Adempas and for 1 month after stopping Adempas because the medicine may still be in the body.

• If you have had a tubal sterilization, have a progesterone implant, or have an IUD (intrauterine device), these methods can be used alone and no other form of birth control is needed. • Talk with your doctor or gynecologist (a doctor who specializes in female reproduction) to find out about options for acceptable birth control that you may use to prevent pregnancy during treatment with Adempas. • If you decide that you want to change the form of birth control that you use, talk with your doctor or gynecologist to be sure that you choose another acceptable form of birth control.

See the chart below for Acceptable Birth Control Options during treatment with Adempas.

• Do not have unprotected sex. Talk to your doctor or pharmacist right away if you have unprotected sex or if you think your birth control has failed. Your doctor may talk with you about using emergency birth control. • Tell your doctor right away if you miss a menstrual period or think you may be pregnant for any reason.

If you are the parent or caregiver of a female child who started taking Adempas before reaching puberty, you should check your child regularly to see if she is developing signs of puberty. Tell your doctor right away if you notice that she is developing breast buds or any pubic hair. Your doctor should decide if your child has reached puberty. Your child may reach puberty before having her first menstrual period.

Females can only receive Adempas through a restricted program called the Adempas Risk Evaluation and Mitigation Strategies (REMS) Program. If you are a female who can become pregnant, you must talk to your doctor, understand the benefits and risks of Adempas, and agree to all of the instructions in the Adempas REMS Program.

Males can receive Adempas without taking part in the Adempas REMS Program.

What is Adempas?

Adempas is a prescription medicine used to treat adults with:

• chronic thromboembolic pulmonary hypertension (CTEPH) • treated with surgery but who continue to have high pulmonary blood pressure (persistent) or it comes back after surgery (recurrent), or • that cannot be treated with surgery. • CTEPH is a type of high blood pressure in the arteries of your lungs caused by blood clots that narrow or block blood flow. Adempas can improve your ability to exercise and can help to improve some of your symptoms. • pulmonary arterial hypertension (PAH) • PAH is a type of high blood pressure in the arteries of your lungs. Adempas can improve your ability to exercise, improve some of your symptoms, and help slow down the worsening of your physical condition. • It is unknown if Adempas is safe and effective in children.

Who should not take Adempas?

Do not take Adempas if:

• you are pregnant, plan to become pregnant, or become pregnant during treatment with Adempas. Adempas can cause serious birth defects. (See the Medication Guide section above called "What is the most important information I should know about Adempas?") • you take: • a nitrate medicine to treat high blood pressure or heart disease, such as nitroglycerin, or a medicine called a nitric oxide donor, such as amyl nitrite • certain other medicines that contain sildenafil (Revatio or Viagra), tadalafil (Adcirca or Cialis), vardenafil (Levitra or Staxyn), dipyridamole, or theophylline. Revatio and Adcirca are also used to treat PAH • you have pulmonary hypertension associated with idiopathic interstitial pneumonias (PH-IIP).

Ask your doctor or pharmacist if you are not sure if you take any of the medicines listed above.

What should I tell my doctor before taking Adempas?

Before you take Adempas, tell your doctor if you:

• smoke • have recently had serious bleeding from your lung, or if you have had a medical procedure called bronchial arterial embolization to stop you from coughing up blood • have problems with your heart or blood circulation • have low blood pressure • have liver problems • have kidney problems or are on dialysis • have narrowing of the pulmonary veins, a condition called pulmonary veno-occlusive disease or PVOD • have any other medical conditions

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Adempas and other medicines may affect each other causing side effects. Do not start any new medicine until you check with your doctor.

How should I take Adempas?

Adempas will be provided to you by a certified pharmacy. Your doctor will give you complete details.

• Do not take Adempas within 24 hours of sildenafil. Do not take Adempas 24 hours before or within 48 hours after tadalafil. • Take Adempas exactly as your doctor tells you. Do not stop taking Adempas or change your dose without talking to your doctor. • When you begin treatment with Adempas, your blood pressure should be monitored about every 2 weeks to help your doctor decide the correct dose of medicine for you. • Your doctor may change your dose during treatment, especially when you first start taking Adempas. It is important to tell your doctor if you have any symptoms of low blood pressure during this time, such as dizziness, lightheadedness, or fainting. • Take Adempas 3 times each day, about 6 to 8 hours apart. • Take Adempas with or without food. • Do not take more than a total of 7.5 mg of Adempas in 1 day unless your doctor tells you to. • If you take a heartburn medicine (antacid) that contains aluminum hydroxide or magnesium hydroxide, do not take it within 1 hour of taking Adempas. • If you take too much Adempas, call your doctor right away or go to the nearest hospital emergency room. • If you miss a dose, take your next dose of Adempas at the regular time. • If you miss 3 or more days of treatment with Adempas, call your doctor for instructions before you restart Adempas.

What should I avoid while taking Adempas?

• Do not get pregnant while taking Adempas. (See serious birth defects section of the Medication Guide above called "What is the most important information I should know about Adempas?") If you miss a menstrual period, or think you might be pregnant, call your doctor right away. • It is not known if Adempas passes into your breast milk. You should not breastfeed if you take Adempas. Talk to your doctor about the best way to feed your baby if you take Adempas. • Adempas may make you feel dizzy. Do not drive, operate machinery, or do other activities that require mental alertness or coordination until you know how Adempas affects you. Talk with your doctor if you are concerned about when it is safe for you to do these activities. • Smoking. Adempas may not work as well if you smoke during treatment. Tell your doctor if you stop smoking or start smoking during treatment with Adempas, because your dose of Adempas may need to be changed.

What are the possible side effects of Adempas?

Adempas can cause serious side effects including:

• Serious birth defects. (See "What is the most important information I should know about Adempas?") • Reduced blood pressure. Adempas reduces blood pressure. This may cause symptoms of low blood pressure, such as lightheadedness, chest pain, and dizziness especially in people who are dehydrated, or have a severe blockage of blood flow out of the heart, or have certain other medical problems. Your doctor will check you for these problems. • Increased risk of bleeding, including bleeding from the respiratory tract. Tell your doctor right away if you cough up blood during treatment with Adempas. • Worsening of symptoms in people with Pulmonary Veno-Occlusive Disease (PVOD). If you have PVOD, treatment with Adempas may cause a build-up of fluid in your lungs (pulmonary edema). This may cause you to feel short of breath. Your doctor may tell you to stop taking Adempas and switch you to a different medicine. • The most common side effects of Adempas are: • headache • dizziness • indigestion • swelling of your hands, legs, feet, and ankles (peripheral edema) • nausea, diarrhea, and vomiting

Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of Adempas.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Adempas?

• Store Adempas at room temperature between 59° F to 86° F (15° C to 30° C)

Keep Adempas and all medicines out of the reach of children.

General Information about Adempas

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Adempas for a condition for which it is not prescribed. Do not give Adempas to other people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about Adempas. If you would like more information about Adempas, talk with your doctor. You can ask your doctor or pharmacist for information about Adempas that is written for health professionals. For more information go to www.Adempas-us.com or call 1-888-842-2937.

What are the ingredients in Adempas?

Active ingredient: riociguat

Inactive ingredients: cellulose microcrystalline, crospovidone, hypromellose 5cP, lactose monohydrate, magnesium stearate, sodium laurylsulfate, hydroxypropylcellulose, hypromellose 3cP, propylene glycol, titanium dioxide. Adempas 1 mg, 1.5 mg, 2 mg and 2.5 mg tablets also contain ferric oxide yellow. Adempas 2 mg and 2.5 mg tablets also contain ferric oxide red.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Revised 1 2017

Manufactured for:

Bayer HealthCare Pharmaceuticals Inc.
Whippany, NJ 07981

Manufactured in Germany

©2013 Bayer HealthCare Pharmaceuticals Inc.

The following are representative examples of Adempas labeling. See the "How Supplied" section for a complete listing of all components.

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