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Black Box Warning
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.
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.
For all female patients, Adempas is available only through a restricted program called the Adempas Risk Evaluation and Mitigation Strategy (REMS) Program.
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.
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%).
Dosage
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.
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.
Pregnancy Testing in Females of Reproductive Potential
Obtain pregnancy tests prior to initiation and monthly during treatment.
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.
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.
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
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Riociguat in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Riociguat in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Riociguat in pediatric patients.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Riociguat in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Riociguat in pediatric patients.
Contraindications
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 .
Nitrates and Nitric Oxide Donors
Co-administration of Adempas with nitrates or nitric oxide donors (such as amyl nitrite) in any form is contraindicated.
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 .
Warnings
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.
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.
For all female patients, Adempas is available only through a restricted program called the Adempas Risk Evaluation and Mitigation Strategy (REMS) Program.
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 Female, Adempas is only available through a restricted program under the Adempas REMS Program.
Adempas REMS Program
Females can only receive Adempas through the Adempas Risk Evaluation and Mitigation Strategy (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.
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.
Adverse Reactions
Clinical Trials Experience
The following serious adverse reactions are discussed elsewhere in the labeling:
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.
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).
This image is provided by the National Library of Medicine.
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.
Postmarketing Experience
There is limited information regarding Postmarketing Experience of Riociguat in the drug label.
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.
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. 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 50-60% 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.
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.
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.
Antacids: Antacids such as aluminum hydroxide/magnesium hydroxide decrease riociguat absorption and should not be taken within 1 hour of taking Adempas.
