ADEMPAS (riociguat) tablets, for oral use
Initial U.S. Approval: 2013
BRIEF SUMMARY of PRESCRIBING INFORMATION
For additional information, please see the full Prescribing Information at
www.adempas-us.com.
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: Ex clude 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).
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)].
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 inhibitors (such as
dipyridamole or theophylline) is contraindicated [see Drug Interactions (7.1)
and Clinical Pharmacology (12.2)].
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)]
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
Adempas % Placebo %
(n=490)
(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.
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 [see Contraindications (4.3) and Clinical Pharmacology
(12.2)]. Clinical experience with co-administration of Adempas and