Sandbox Riociguat

{{DrugProjectFormSinglePage |genericName=Riociguat |aOrAn=a |drugClass=Soluble Guanylate Cyclase Stimulator |indicationType=treatment |indication=Chronic Thromboembolic Pulmonary Hypertension (CTEPH) and Pulmonary Arterial Hypertension |hasBlackBoxWarning=Yes |adverseReactions=fetal harm (teratogenic effects) |blackBoxWarningTitle=WARNING: EMBRYO-FETAL TOXICITY |blackBoxWarningBody=*Do not administer Adempas to a pregnant female because it may cause fetal harm.

• 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.
• For females, Adempas is available only through a restricted program called the Adempas REMS Program.

|fdaLIADAdult=The recommended starting dosage is 1 mg taken 3 times a day. For patients who may not tolerate the hypotensive effect of Riociguat, 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. |offLabelAdultGuideSupport=There is limited information regarding Off-Label Guideline-Supported Use of Sandbox Riociguat in adult patients. |offLabelAdultNoGuideSupport=There is limited information regarding Off-Label Non–Guideline-Supported Use of Sandbox Riociguat in adult patients. |fdaLIADPed=The safety and effectiveness of Adempas in pediatric patients have not been established. |offLabelPedGuideSupport=There is limited information regarding Off-Label Guideline-Supported Use of Sandbox Riociguat in pediatric patients. |offLabelPedNoGuideSupport=There is limited information regarding Off-Label Non–Guideline-Supported Use of Sandbox Riociguat in pediatric patients. |contraindications=====Pregnant Women====

• 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

• Co-administration of Adempas with nitrates or nitric oxide donors (such as amyl nitrite) in any form is contraindicated.

PDE-5 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=====Fetal Harm====

• 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.

Low Blood Pressure

• Adempas reduces blood pressure. Consider the potential for symptomatic hypotension or ischemia in patients with hypovolemia, left ventricular outflow tract obstruction, resting hypotension, autonomic dysfunction, or concomitant treatment with antihypertensives or strong CYP and P-gp/BCRP inhibitors

|clinicalTrials=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.

This image is provided by the National Library of Medicine.

|postmarketing=No postmarketing experience is currently available because Adempas was only recently approved by the FDA in 2013. |drugInteractions=====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.

|FDAPregCat=X |useInPregnancyFDA=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. |AUSPregCat=D

|useInPregnancyAUS=

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While no increase in malformation rate was observed in the rabbit embryofetal development study, exaggerated pharmacological effects of riociguat on the F1 dams at ≥ 1.5 mg/kg/day led to an increased rate of abortion and total resorption. At the maternal and fetal NOAEL of 0.5 mg/kg/day the ERAUCU was similar to that expected clinically. Riociguat prolonged the mean gestation time and reduced maternal bodyweight gain at the high dose (HD) of 15 mg/kg/day in the pre and postnatal development studies in rats (maternal NOAEL of 5 mg/kg/day, ERAUCU of about 1). A reduced number of live births were observed at doses ≥ 5 mg/kg/day but there were no notable effects on the development of the surviving pups including on their reproductive performance (NOAEL for pup development of 15 mg/kg/day, ERAUCU approximately 2 to 3). The M1 metabolite BAY 60-4552 was not well tolerated in reproductive studies and the NOAEL for maternal and fetal toxicity was 2 mg/kg/day (ERAUCU <0.1). Doses of 5 mg/kg/day in rabbits resulted in increased rates of abortion. There was, however, no evidence of a direct teratogenic effect in either species.

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