` HIGHLIGHTS OF PRESCRIBING INFORMATION
` These highlights do not include all the information needed to use
`
`
`
` ADEMPAS safely and effectively. See full prescribing information for
`
` ADEMPAS.
`
`
`
` ADEMPAS (riociguat) tablets, for oral use
`
`
`
` Initial U.S. Approval: 2013
`
`
`
`
`
`
`
` WARNING: EMBRYO-FETAL TOXICITY
` See full prescribing information for complete boxed warning
`
`
`
`
`
`
` Do not administer Adempas to a pregnant female because it may
`
` cause fetal harm. (4.1, 5.1, 8.1)
`
`
` Females of reproductive potential: Exclude pregnancy before start
`
` of treatment, monthly during treatment, and 1 month after
`
` treatment discontinuation. Prevent pregnancy during treatment and
`
` for one month after treatment discontinuation by use of acceptable
`
`
` methods of contraception. (2.3, 5.1, 5.2, 8.6)
`
`
`
`
`
`
`
`For females, Adempas is available only through a restricted
` program called the Adempas REMS Program. (5.1, 5.2)
`
`
`
`
`
`
`
`•
`
`
`•
`
`
`•
`
`
`
`
`
`
`---------------------------RECENT MAJOR CHANGES --------------------------­
`
`
`Dosage and Administration
`
`
`
`
`Recommended Dosage in Adult Patients (2.1)
`2/2017
`
`
`
`
`Transitioning to and from Adempas (2.6)
`1/2017
`
`
`Contraindications (4.4)
`1/2017
`
`
`
`
`
`--------------------------- INDICATIONS AND USAGE --------------------------
`
`
`Adempas is a soluble guanylate cyclase (sGC) stimulator indicated for the
`
`treatment of adults with:
`
`• Persistent/recurrent Chronic Thromboembolic Pulmonary Hypertension
`
`
`
`
`(CTEPH) (WHO Group 4) after surgical treatment or inoperable CTEPH to
`
`improve exercise capacity and WHO functional class. (1.1)
`
`
`• Pulmonary Arterial Hypertension (PAH) (WHO Group 1) to improve
`
`
`
`
`
`exercise capacity, improve WHO functional class and to delay clinical
`
`
`worsening. (1.2)
`
`
`---------------------- DOSAGE AND ADMINISTRATION ---------------------­
`
`
`
`
`• Initiate treatment at 1 mg taken three times a day. (2.1)
`
`
`
`
`
`
`
`• For patients who may not tolerate the hypotensive effect of Adempas,
`
`
`
`
`consider a starting dose of 0.5 mg, three times a day. (2.1)
`
`
`• Increase dosage by 0.5 mg at intervals of no sooner than 2-weeks as
`
`
`
`
`tolerated to a maximum of 2.5 mg three times a day. (2.1)
`
`
`
`• Tablets may be crushed and mixed with water or soft foods for patients
`
`
`
`
`who have difficulty swallowing. (2.1)
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING: EMBRYO-FETAL TOXICITY
`
`
`1 INDICATIONS AND USAGE
`
`
`1.1 Chronic-Thromboembolic Pulmonary Hypertension
`
`
`1.2 Pulmonary Arterial Hypertension
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Recommended Dosage in Adult Patients
`
`
`2.2 Dosage Interruption
`
`2.3 Pregnancy Testing in Females of Reproductive Potential
`
`
`2.4 Use in Patients who Smoke
`
`2.5 Strong CYP and P-gp/BCRP inhibitors
`
`
`2.6 Transitioning to and from Adempas
`
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`4 CONTRAINDICATIONS
`
`4.1 Pregnancy
`4.2 Nitrates and Nitric Oxide Donors
`
`
`4.3 Phosphodiesterase Inhibitors
`
`4.4 Pulmonary Hypertension Associated with Idiopathic Interstitial
`
`
`
`Pneumonias (PH-IIP)
`
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Embryo-Fetal Toxicity
`
`5.2 Adempas REMS Program
`
`5.3 Hypotension
`5.4 Bleeding
`
`
`5.5 Pulmonary Veno-Occlusive Disease
`
`6 ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`
`
`7 DRUG INTERACTIONS
`
`Reference ID: 4059997
`
`--------------------- DOSAGE FORMS AND STRENGTHS -------------------­
`
`
`
`
`Tablets: 0.5 mg, 1 mg, 1.5 mg, 2 mg and 2.5 mg (3)
`
`
`
`
`
`
`------------------------------ CONTRAINDICATIONS ----------------------------­
`
`
`
`
`• Pregnancy (4.1)
`
`
`• Use with nitrates or nitric oxide donors in any form (4.2, 7.1)
`
`
`
`
`
`• Use with PDE inhibitors (2.6, 4.3, 7.1)
`
`
`
`• Pulmonary hypertension associated with idiopathic interstitial pneumonias
`
`
`
`
`
`
`(PH-IIP) (4.4)
`
`----------------------- WARNINGS AND PRECAUTIONS ----------------------­
`
`
`
`
`• Symptomatic hypotension (5.3)
`
`
`
`• Bleeding (5.4)
`
`
`• Pulmonary edema in patients with pulmonary veno-occlusive disease. If
`
`
`
`confirmed, discontinue treatment (5.5)
`
`
`------------------------------ ADVERSE REACTIONS ----------------------------­
`
`
`
`
`Adverse reactions occurring more frequently (≥3%) on Adempas compared to
`
`placebo are headache, dyspepsia/gastritis, dizziness, nausea, diarrhea,
`
`
`
`hypotension, vomiting, anemia, gastroesophageal reflux, and constipation.
`
`(6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Bayer
`
`HealthCare Pharmaceuticals Inc. at 1-888-842-2937 or FDA at 1-800­
`
`FDA-1088 or www.fda.gov/medwatch.
`
`
`------------------------------ DRUG INTERACTIONS ----------------------------­
`
`
`
`
`• Strong CYP and P-gp/BCRP inhibitors: For patients receiving strong CYP
`
`
`
`and P-gp/BCRP inhibitors, consider a starting dose of 0.5 mg three times a
`
`
`
`
`day. Monitor for hypotension. (7.2)
`
`• Antacids: Separate administration by at least 1 hour. (7.2)
`
`
`
`----------------------- USE IN SPECIFIC POPULATIONS ---------------------­
`
`
`
`
`• Nursing mothers: Discontinue drug or breastfeeding. (8.3)
`
`
`• Renal impairment: Not recommended in patients with creatinine clearance
`
`
`<15 mL/min or on dialysis. (8.7)
`
`
`
`• Hepatic impairment: Not recommended in patients with severe (Child Pugh
`
`
`
`
`C) hepatic impairment. (8.8)
`
`
`• Smoking: May require dosages higher than 2.5 mg three times a day if
`
`
`
`
`tolerated. Dose decrease may be required in patients who stop smoking.
`
`(2.4, 7.2)
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`
`
`Guide
`
`
`Revised: 02/2017
`
`
`
`
`
`7.1 Pharmacodynamic Interactions with Adempas
`
`7.2 Pharmacokinetic Interactions with Adempas
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`8.3 Nursing Mothers
`
`8.4 Pediatric Use
`
`8.5 Geriatric Use
`
`8.6 Females and Males of Reproductive Potential
`
`
`8.7 Renal Impairment
`
`
`8.8 Hepatic Impairment
`
`10 OVERDOSAGE
`
`11 DESCRIPTION
`
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`12.2 Pharmacodynamics
`
`12.3 Pharmacokinetics
`
`13 NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`
`13.2 Animal Toxicology
`
`14 CLINICAL STUDIES
`
`14.1 Chronic-Thromboembolic Pulmonary Hypertension
` 14.2 Pulmonary Arterial Hypertension
`
`
` 16 HOW SUPPLIED/STORAGE AND HANDLING
`
` 16.1 How Supplied
`
` 16.2 Storage and Handling
`
` 17 PATIENT COUNSELING INFORMATION
`
`
`
`
`
`
`
`
`
`
`*Sections or subsections omitted from the full prescribing information are not listed.
`
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`

`

`
`
` FULL PRESCRIBING INFORMATION
`
`
`
`
`WARNING: EMBRYO-FETAL TOXICITY
`
`Do not administer Adempas to a pregnant female because it may cause fetal harm [see Contraindications (4.1),
`
`
`
`
`Warnings and Precautions (5.1) and Use in Specific Populations (8.1)].
`
`
`
`Females of reproductive potential: Exclude pregnancy before the start of treatment, monthly during treatment,
`
`and 1 month after stopping treatment. Prevent pregnancy during treatment and for one month after stopping
`
`
`treatment by using acceptable methods of contraception [see Dosage and Administration (2.3), Warnings and
`
`
`
`Precautions (5.1, 5.2),and Use in Specific Populations (8.6)].
`
`
`For all female patients, Adempas is available only through a restricted program called the Adempas Risk
`
`
`
`Evaluation and Mitigation Strategy (REMS) Program [see Warnings and Precautions (5.1, 5.2)].
`
`
`
`
`
`
`1 INDICATIONS AND USAGE
`
`
`1.1 Chronic-Thromboembolic Pulmonary Hypertension
`
`
`
`Adempas is indicated for the treatment of adults with persistent/recurrent chronic thromboembolic pulmonary
`
`
`
`hypertension (CTEPH), (WHO Group 4) after surgical treatment, or inoperable CTEPH, to improve exercise capacity and
`
`
`
`WHO functional class [see Clinical Studies (14.1)].
`
`
`
`1.2 Pulmonary Arterial Hypertension
`
`
`Adempas is indicated for the treatment of adults with pulmonary arterial hypertension (PAH), (WHO Group 1), to
`
`
`improve exercise capacity, WHO functional class and to delay clinical worsening.
`
`
`
`Efficacy was shown in patients on Adempas monotherapy or in combination with endothelin receptor antagonists or
`
`
`prostanoids. Studies establishing effectiveness included predominately patients with WHO functional class II–III and
`
`
`etiologies of idiopathic or heritable PAH (61%) or PAH associated with connective tissue diseases (25%) [see Clinical
`
`
`
`
`Studies (14.2)].
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`2.1 Recommended Dosage in Adult Patients
`
`
`The recommended starting dosage is 1 mg taken 3 times a day. For patients who may not tolerate the hypotensive effect of
`
`Adempas, consider a starting dose of 0.5 mg taken three times a day. If systolic blood pressure remains greater than 95
`
`
`mmHg and the patient has no signs or symptoms of hypotension, up-titrate the dose by 0.5 mg taken three times a day.
`
`
`Dose increases should be no sooner than 2 weeks apart. The dose can be increased to the highest tolerated dosage, up to a
`
`
`
`maximum of 2.5 mg taken three times a day. If at any time, the patient has symptoms of hypotension, decrease the dosage
`
`
`by 0.5 mg taken three times a day.
`
`
`Crushed Tablets
`
`For patients who are unable to swallow whole tablets, Adempas may be crushed and mixed with water or soft foods (such
`
`
`
`as applesauce) immediately before administration [see Clinical Pharmacology (12.3)].
`
`
`
`
`
`2.2 Dosage Interruption
`
`If a dose is missed, advise patients to continue with the next regularly scheduled dose.
`
`
`
`In case Adempas is interrupted for 3 days or more, re-titrate Adempas.
`
`
`
`
`2.3 Pregnancy Testing in Females of Reproductive Potential
`
`
`
`Obtain pregnancy tests prior to initiation and monthly during treatment [see Use in Specific Populations (8.6)].
`
`
`
`
`2.4 Use in Patients who Smoke
`
`Consider titrating to dosages higher than 2.5 mg three times a day, if tolerated, in patients who smoke. A dose decrease
`
`
`
`
`
`may be required in patients who stop smoking [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)].
`
`
`
`
`Reference ID: 4059997
`
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`

`

`
`
` 2.5 Strong CYP and P-gp/BCRP Inhibitors
` Consider a starting dose of 0.5 mg, three times a day when initiating Adempas in patients receiving strong cytochrome
`
`
` P450 (CYP) and P-glycoprotein/breast cancer resistance protein (P-gp/BCRP) inhibitors such as azole antimycotics (for
`
`
`
` example, ketoconazole, itraconazole) or HIV protease inhibitors (for example, ritonavir). Monitor for signs and symptoms
`
`
` of hypotension on initiation and on treatment with strong CYP and P-gp/BCRP inhibitors [see Warnings and Precautions
`
`
`
` (5.3), Drug Interactions (7.2) and Clinical Pharmacology (12.3)].
`
` 2.6 Transitioning to and from Adempas
`
`
` • Discontinue sildenafil at least 24 hours prior to administering Adempas [see Contraindications (4.3) and Drug
`
`
` Interactions (7)].
`
`
`
`
` • Discontinue tadalafil at least 48 hours prior to administering Adempas [see Contraindications (4.3) and Drug
`
`
`
`
`
` Interactions (7)]. Consider initiating Adempas at a starting dose of 0.5 mg in patients at risk of hypotension [see
`
`
`
`
` Dosage and Administration (2.1)]. It is recommended to monitor for signs and symptoms of hypotension on initiation.
`
`
`
`
` • Discontinue Adempas at least 24 hours prior to administering a PDE5-inhibitor [see Dosage and Administration (2.1),
`
`
`
` Contraindications (4.3), and Drug Interactions (7)]. It is recommended to monitor for signs and symptoms of
`
`
`
`
`
`
` hypotension on initiation.
`
`
`
`
`
`
`
`
`
` 3 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
`
`
`
`
`
`
`
`
`
` 4 CONTRAINDICATIONS
`
` 4.1 Pregnancy
`
`
`
`
`
` Adempas may cause fetal harm when administered to a pregnant woman. Adempas is contraindicated in females who are
` pregnant. Adempas was consistently shown to have teratogenic effects when administered to animals. If this drug is used
`
`
`
`
`
`
`
`
`
`
` during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential
` hazard to the fetus [see Use in Specific Populations (8.1)].
`
`
`
`
`
`
`
` 4.2 Nitrates and Nitric Oxide Donors
`
`
`Co-administration of Adempas with nitrates or nitric oxide donors (such as amyl nitrite) in any form is contraindicated
`
`
` [see Drug Interactions (7.1) and Clinical Pharmacology (12.2)].
`
`
`
`
` 4.3 Phosphodiesterase Inhibitors
`
`
` Concomitant administration of Adempas with specific PDE-5 inhibitors (such as sildenafil, tadalafil, or vardenafil) or
`
`
` nonspecific PDE 5 inhibitors (such as dipyridamole or theophylline) is contraindicated [see Dosage and Administration
`
`
`
`
` (2.6), Drug Interactions (7.1) and Clinical Pharmacology (12.2)]. Do not administer within 24 hours of sildenafil. Do not
`
`
`
` administer 24 hours before or within 48 hours after tadalafil.
`
`
`
`
`
`
`
`
`
`.4 Pulmonary Hypertension Associated with Idiopathic Interstitial Pneumonias (PH-IIP)
`
`
`dempas is contraindicated in patients with pulmonary hypertension associated with idiopathic interstitial pneumonias
`PH-IIP).
`
`
`4 A(
`
`Reference ID: 4059997
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`

`

`5 WARNINGS AND PRECAUTIONS
`
`
`5.1 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)].
`
`
`5.2 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.
`
`
`5.3 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.
`
`
`
`5.4 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.
`
`
`5.5 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.
`
`
`6 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)]
`
`
`
`Reference ID: 4059997
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`

`

` 6.1 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
`
`
`
`
`
` Headache
`
` Dyspepsia and Gastritis
`
` Dizziness
`Nausea
`
` Diarrhea
`
`Hypotension
`
` Vomiting
`
`Anemia
`
` (including laboratory parameters)
`
` Gastroesophageal reflux disease
`
` Constipation
`
`
`
` Adempas %
`
`
` (n=490)
`
` 27
`
` 21
`
` 20
`
` 14
`
` 12
`
` 10
`
` 10
`
` 7
`
`
` Placebo %
`
` (n=214)
`
` 18
`
` 8
`
` 13
`11
`
`
` 8
`
` 4
`
` 7
`
` 2
`
`
` 5
`
` 5
`
`
` 2
`
` 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.
`
`
`
` 7 DRUG INTERACTIONS
`
` 7.1 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.
`
`
`
`
`Reference ID: 4059997
`
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`

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`
`
`
`7.2 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)].
`
`
`
`
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`Pregnancy Category X
`
`Risk Summary
`
`Adempas may cause fetal harm when administered to a pregnant woman and is contraindicated during pregnancy.
`
`
`
`Adempas was teratogenic and embryotoxic in rats at doses with exposures to unbound drug that were approximately 8
`
`
`
`
`
`times and 2 times, respectively, the human exposure. In rabbits, riociguat led to abortions at 4 times the human exposure
`
`and fetal toxicity with exposures approximately 13 times the human exposure. If Adempas is used in pregnancy, or if the
`patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus [see Boxed
`
`
`Warning and Contraindications (4.1)].
`
`
`Animal Data
`
`In rats administered riociguat orally (1, 5, and 25 mg/kg/day) throughout organogenesis, an increased rate of cardiac
`
`
`
`
`ventricular-septal defect was observed at the highest dose tested. The highest dose produced evidence of maternal toxicity
`(reduced body weight). Post-implantation loss was statistically significantly increased from the mid-dose of 5 mg/kg/day.
`Plasma exposure at the lowest dose in which no adverse effects were observed is approximately 0.4 times that in humans
`
`
`at the maximally recommended human dose (MRHD) of 2.5 mg three times a day based on area under the time-
`
`
`
`
`concentration curve (AUC) for unbound drug in rat and humans. Plasma exposure at the highest dose (25 mg/kg/day) is
`
`approximately 8 times that in humans at the MRHD while exposure at the mid-dose (5 mg/kg/day) is approximately 2
`
`
`
`
`times that in humans at the MRHD. In rabbits given doses of 0.5, 1.5 and 5 mg/kg/day, an increase in spontaneous
`
`
`
`
`abortions was observed starting at the middle dose of 1.5 mg/kg, and an increase in resorptions was observed at 5
`
`
`
`
`mg/kg/day. Plasma exposures at these doses were 4 times and 13 times, respectively, the human exposure at the MRHD.
`
`
`8.3 Nursing Mothers
`
`
`
`It is not known if Adempas is present in human milk. Riociguat or its metabolites were present in the milk of rats.
`
`
`
`Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing
`
`infants from riociguat, discontinue nursing or Adempas.
`
`
`8.4 Pediatric Use
`Safety and effectiveness of Adempas in pediatric patients have not been established [see Nonclinical Toxicology (13.2)].
`
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`8.5 Geriatric Use
`
`Of the total number of subjects in clinical studies of Adempas, 23% were 65 and over, and 6% were 75 and over [see
`
`
`
`Clinical Studies (14)]. No overall differences in safety or effectiveness were observed between these subjects and younger
`
`
`
`
`
`
`
`
`
`
`subjects, and other reported clinical experience has not identified differences in responses between the elderly and
`
`younger patients, but greater sensitivity of some older individuals cannot be ruled out.
`
`
`Elderly patients showed a higher exposure to Adempas [see Clinical Pharmacology (12.3)].
`
`
`
`
`
`8.6 Females and Males of Reproductive Potential
`
`Pregnancy Testing: Female patients of reproductive potential must have a negative pregnancy test prior to starting
`
`
`treatment with Adempas, monthly during treatment, and one month after discontinuation of treatment with Adempas.
`
`
`
`
`Advise patients to contact their healthcare provider if they become pregnant or suspect they may be pregnant. Counsel
`
`
`
`patients on the risk to the fetus [see Boxed Warning, Dosage and Administration (2.3) and Use in Specific Populations
`
`
`(8.1)].
`
`Contraception: Female patients of reproductive potential must use acceptable methods of contraception during treatment
`
`
`
`
`with Adempas and for 1 month after treatment with Adempas. Patients may choose one highly effective form of
`
`
`
`
`contraception (intrauterine devices [IUD], contraceptive implants or tubal sterilization) or a combination of methods
`
`
`
`
`(hormone method with a barrier method or two barrier methods). If a partner’s vasectomy is the chosen method of
`
`contraception, a hormone or barrier method must be used along with this method. Counsel patients on pregnancy planning
`and prevention, including emergency contraception, or designate counseling by another healthcare provider trained in
`contraceptive counseling [see Boxed Warning].
`
`
`
`
`8.7 Renal Impairment
`Safety and efficacy have not been demonstrated in patients with creatinine clearance <15 mL/min or on dialysis [see
`
`Clinical Pharmacology (12.3)].
`
`
`
`8.8 Hepatic Impairment
`
`Safety and efficacy have not been demonstrated in patients with severe hepatic impairment (Child Pugh C) [see Clinical
`
`
`Pharmacology (12.3)].
`
`
`
`10 OVERDOSAGE
`
`In cases of overdose, blood pressure should be closely monitored and supported as appropriate. Based on extensive
`
`
`
`plasma protein binding, riociguat is not expected to be dialyzable.
`
`
`11 DESCRIPTION
`
`
`Adempas (riociguat) is a tablet for oral administration. Riociguat is methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H­
`
`pyrazolo [3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate with the following structural formula:
`O
`
`CH3
`
`O
`NH2
`
`N
`
`N
`
`H3C
`
`NH2
`
`N
`
`N
`N
`
`N
`
`F
` C20H19FN8O2
`
`
` Riociguat is a white to yellowish, crystalline, non-hygroscopic substance with a molecular weight of 422.42 g/mol. In
` solid form it is stable to temperature, light, and humidity.
`
`
`
`
`
` The solubility at 25°C in water: 4 mg/L, in ethanol: 800 mg/L, in 0.1 HCl (pH 1): 250 mg/L and in buffer (phosphate) pH
`
` 7: 3 mg/L. In the pH range of 2 to 4 the solubility showed strong pH-dependency. Solubility increases at lower pH values.
`
`
`
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`Each round film-coated tablet contains 0.5 mg (1.0, 1.5, 2.0, 2.5 mg) riociguat. The inactive ingredients are cellulose
`
`
`
`
`microcrystalline, crospovidone, hypromellose 5cP, lactose monohydrate, magnesium stearate, sodium laurylsulfate,
`hydroxypropylcellulose, hypromellose 3cP, propylene glycol, and titanium dioxide. Adempas 1, 1.5, 2, and 2.5 mg tablets
`
`
`contain, in addition, ferric oxide yellow. Adempas 2 and 2.5 mg tablets contain, in addition, ferric oxide red.
`
`
`
`
`
`12 CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`Riociguat is a stimulator of soluble guanylate cyclase (sGC), an enzyme in the cardiopulmonary system and the receptor
`
`
`for nitric oxide (NO).
`
`
`When NO binds to sGC, the enzyme catalyzes synthesis of the signaling molecule cyclic guanosine monophosphate
`
`(cGMP). Intracellular cGMP plays an important role in regulating processes that influence vascular tone, proliferation,
`
`
`
`
`fibrosis and inflammation.
`
`
`Pulmonary hypertension is associated with endothelial dysfunction, impaired synthesis of nitric oxide and insufficient
`
`
`
`
`
`stimulation of the NO-sGC-cGMP pathway.
`
`
`Riociguat has a dual mode of action. It sensitizes sGC to endogenous NO by stabilizing the NO-sGC binding. Riociguat
`
`
`
`also directly stimulates sGC via a different binding site, independently of NO.
`
`
`Riociguat stimulates the NO-sGC-cGMP pathway and leads to increased generation of cGMP with subsequent
`
`vasodilation.
`
`The active metabolite (M1) of riociguat is 1/3 to 1/10 as potent as riociguat.
`
`
`
`
`
`12.2 Pharmacodynamics
`
`There is a direct relationship between riociguat plasma concentration and hemodynamic parameters such as systemic
`
`
`vascular resistance, systolic blood pressure, pulmonary vascular resistance (PVR), and cardiac output [see Clinical Studies
`
`
`
`
`
`
`(14)].
`
`Hemodynamic parameters were assessed in CTEPH patients in CHEST-1 [see Clinical Studies (14.1)]. Right heart
`
`catheterization was performed at the beginning and the end of the study period in 233 patients. A statistically significant
`
`
`
`
`
`reduction of PVR (-246 dyn*s*cm-5) was shown in the Adempas group vs. placebo. Improvements in other hemodynamic
`
`
`
`
`
`
`
`parameters (not pre-specified as endpoints) are displayed in Table 2 below.
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`Table 2: CHEST-1, Change In Hemodynamic Parameters from Baseline to Last Visit (Individual Dose
`Titration to Maximum 2.5 mg Three Times a Day versus placebo)
`
`
`
`Parameter (unit)
`
`
`Mean change
`
`
`Adempas
`
`
`Placebo
`
`
`LS mean
`difference
`
`
`
`95% CI
`
`
`
`
`
`Pulmonary Capillary Wedge Pressure
`(mmHg)
`
`
` Right Atrial Pressure (mmHg)
`
` Pulmonary Arterial Pressure
`
` Systolic (mmHg)
` Pulmonary Arterial Pressure
`
` Diastolic (mmHg)
` Pulmonary Arterial Pressure
`
`
` Mean (mmHg)
` Mean Arterial Pressure (mmHg)
`
`
` Mixed Venous Oxygen Saturation (%)
` Cardiac Output (L/min)
`
`
` Cardiac Index (L/min/m2)
`
` Pulmonary Vascular Resistance
`
`
` (dyn*s*cm-5)
` Pulmonary Vascular Resistance Index
`
` (dyn*s*cm-5*m2)
` Systemic Vascular Resistance
`
` (dyn*s*cm-5)
` Systemic Vascular Resistance Index
`
` (dyn*s*cm-5*m2)
`
`
`Hemodynamic parameters were assessed in PAH patients in PATENT-1 [see Clinical Studies (14.2)]. Right heart
`
`
`catheterization was performed at the beginning and the end of the study period in 339 patients.
`
`
`
`
`
`
`A statistically significant reduction of PVR (-226 dyn*sec*cm-5) was shown in the Adempas individual titration group (to
`
`
`maximum dose of 2.5 mg three times a day) vs. placebo. Improvement in other relevant hemodynamic parameters (not
`
`
`pre-specified as endpoints) for the individual dose titration group versus placebo are displayed in Table 3.
`
`
`
`
`
`
`0.18
`
`
`
`
` –0.55
`
`
`0.95
`
`
`0.67
`
`
`0.76
`
`
` –0.29
`
` –0.44
`
` –0.03
`
` –0.01
`
`
`23.1
`
`
`48.3
`
`
`16.6
`
`
`53.7
`
`0.58
`
`
`
`
` –0.55
`
`
`–7.52
`
`
`–3.62
`
`
`–4.96
`
`
` –9.15
` 3.85
`
`
` 0.86
`
` 0.47
`
`
`–246
`
`
`–449
`
`
`–478
`
`
`–914
`
`–0.36 to 1.53
`
`
`
`
` –1.72 to 0.62
`
`
`–10.88 to –4.16
`
`
`–5.30 to –1.95
`
`
`–6.75 to –3.16
`
`
` –11.83 to –6.46
`
` 1.46 to 6.25
`
` 0.59