Usual Adult Dose for Pulmonary Hypertension

Initial dose: 1 mg orally 3 times a day
Maximum dose: 2.5 mg orally 3 times a day

Comments:

• For patients who cannot tolerate the hypotensive effect, consider a starting dose of 0.5 mg orally 3 times a day. If systolic blood pressure remains greater than 95 mmHg and the patient has no signs of hypotension, the dose may be titrated up by 0.5 mg orally 3 times a day.
• Dose increases should be no more frequent than every 2 weeks.

• Persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) (WHO group 4) after surgical treatment or inoperable CTEPH to improve exercise capacity and WHO functional class.
• As monotherapy or in combination with endothelin receptor antagonists or prostanoids to treat pulmonary arterial hypertension (PAH) (WHO group 1) to improve exercise capacity, improve WHO functional class and to delay clinical worsening.

Renal Dose Adjustments

CrCl less than 15 mL/min: Safety and efficacy have not been established.

Liver Dose Adjustments

Severe liver dysfunction (Child-Pugh C): Safety and efficacy have not been established.

Dose Adjustments

Hypotension: If the patient has symptoms of hypotension during treatment, the dosage should be decreased by 0.5 mg orally 3 times a day.

Patients receiving strong CYP450 and P-gp/BCRP inhibitors (e.g., azole antifungals [ketoconazole, itraconazole] or protease inhibitors [ritonavir]): Consider a starting dose of 0.5 mg 3 times daily. Monitor for hypotension with strong CYP450 and P-gp/BCRP inhibitors.

Patients who smoke: Consider titrating to doses higher than 2.5 mg 3 times daily, if tolerated. A decreased dose may be necessary in patients who stop smoking.

Transitioning to riociguat in patients receiving a phosphodiesterase type-5 (PDE-5) inhibitor: Discontinue sildenafil at least 24 hours prior to administering riociguat. Discontinue tadalafil at least 48 hours prior to administering riociguat; consider initiating riociguat at 0.5 mg orally in patients at risk for hypotension and monitor for signs/symptoms of hypotension on initiation

Transitioning from riociguat to a PDE-5 inhibitor: Discontinue riociguat at least 24 hours prior to administering a PDE-5 inhibitor; monitor for signs/symptoms of hypotension on initiation

Precautions

The US FDA requires a Risk Evaluation and Mitigation Strategy (REMS) for riociguat. It includes elements to assure safe use and an implementation system. For additional information: http://www.accessdata.fda.gov/scripts/cder/rems/index.cfm

US BOXED WARNING:

• EMBRYOFETAL TOXICITY: This drug is contraindicated in pregnant women because it may cause fetal harm.

• Female patients of reproductive potential must have a negative pregnancy test prior to starting treatment, monthly during treatment, and for 1 month after discontinuation of treatment. Patients should be instructed to contact their provider if they become pregnant or suspect they may be pregnant.
• Female patients of reproductive potential must use acceptable methods of contraception during treatment and for 1 month after discontinuation of treatment. 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 vasectomy is the chosen method, a hormone or barrier method must be used also.
• Patients should be counseled on pregnancy planning and prevention, including emergency contraception.
• Patients should be counseled on the risk to the fetus.
• Females can only receive this drug through the Adempas REMS Program.

Dialysis

Due to its high protein binding, this drug is not expected to be dialyzable.

Other Comments

Administration advice:

• May be taken without regard to meals.
• If a dose is missed, continue with the next regularly scheduled dose. If therapy is interrupted for 3 days or more, retitration is required.
• May crush tablets and mix with water or soft foods (such as applesauce) immediately before administration in patients unable to swallow whole tablets.

• Cardiovascular: Monitor for hypotension
• Female patients: Pregnancy tests should be obtained prior to initiation and monthly during treatment.