Adempas Drug Information

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.

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

Exclude pregnancy before initiating Adempas.

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.

Transitioning to and from Adempas •

Discontinue sildenafil at least 24 hours prior to administering Adempas. • Discontinue tadalafil at least 48 hours prior to administering Adempas. Consider initiating Adempas at a starting dose of 0.5 mg in patients at risk of hypotension. Monitor for signs and symptoms of hypotension on initiation. • Discontinue Adempas at least 24 hours prior to administering a PDE5-inhibitor.

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 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) 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.

• Pharmacodynamic Interactions with Adempas Other Soluble Guanylate Cyclase Stimulators: Co-administration of Adempas is contraindicated in patients with use of other soluble guanylate cyclase (sGC) stimulators.
• 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. Do not administer within 24 hours of sildenafil. Do not administer 24 hours before or within 48 hours after tadalafil. 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. 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.

Pregnancy Risk Summary Based on data from animal reproduction studies, Adempas may cause fetal harm, including birth defects and fetal death, and miscarriage when administered to a pregnant patient and is contraindicated during pregnancy. Available data from published literature and post-marketing surveillance over a decade of use with riociguat have not identified an increased risk of major birth defects. However, these data are limited and do not establish the presence or absence of a drug-associated risk of major birth defects or miscarriage.

Methodological limitations of these postmarketing reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and missing data. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal riociguat use. In animal reproduction studies, oral administration of riociguat to pregnant rats during organogenesis was teratogenic and embryotoxic at exposures approximately 8 times and 2 times, respectively, the human exposure.

In reproduction studies with pregnant rabbits, oral administration of riociguat during organogenesis caused abortions and fetal toxicity at exposures approximately 4 times and 13 times, respectively, the maximum recommended human dose (MRHD). Advise pregnant patients of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. Data 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. Plasma exposures at these doses were 4 times and 13 times, respectively, the human exposure at the MRHD.

Pediatric Use Safety and effectiveness of Adempas in pediatric patients have not been established.

Pregnancy Use of Adempas is contraindicated in patients who are pregnant.

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-5 inhibitors (such as dipyridamole or theophylline) is contraindicated. Do not administer within 24 hours of sildenafil. Do not administer 24 hours before or within 48 hours after tadalafil.

Soluble Guanylate Cyclase Stimulators Adempas is contraindicated in patients with concomitant use of other soluble guanylate cyclase (sGC) stimulators.

Pulmonary Hypertension Associated with Idiopathic Interstitial Pneumonias (PH-IIP) Adempas is contraindicated in patients with pulmonary hypertension associated with idiopathic interstitial pneumonias (PH-IIP).

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.