or nonspecific PDE inhibitors (eg, dipyridamole, theophylline) because of additive hypotension Administration within 24 hr of sildenafil Concomitant use of other soluble guanylate cyclase (sGC) stimulators Tadalafil 24 hr before or within 48 hr after riociguat Patients with pulmonary hypertension associated with idiopathic interstitial pneumonia Cautions May cause fetal harm when administered during pregnancy and is contraindicated for use in women who are pregnant (see Black Box Warnings and Contraindications); because of this, females may only receive riociguat via a restricted access program Reduces blood pressure; consider the potential for symptomatic hypotension or ischemia in patients with hypovolemia, severe left ventricular outflow obstruction, resting hypotension, or autonomic dysfunction; dose reduction may be required Coadministration with strong CYP and P-gp/BCRP inhibitors increases riociguat systemic exposure and increases risk for hypotension; dose reduction may be required Serious bleeding reported including hemoptysis, vaginal bleeding, catheter site hemorrhage, subdural hematoma, hematemesis, and intra-abdominal hemorrhage Pulmonary vasodilators may significantly worsen cardiovascular status of patients with pulmonary veno-occlusive disease; avoid use in these patients and discontinue if signs of pulmonary edema occur and are confirmed Adempas REMS Program Females can only receive drug 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 program by enrolling and completing training. All females, regardless of reproductive potential, must enroll in Adempas REMS Program prior to initiating therapy 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 Further information, including a list of certified pharmacies, is available at www.AdempasREMS.com or 1-855-4 ADEMPAS Pregnancy Based on data from animal reproduction studies, therapy may cause embryo-fetal toxicity and miscarriage when administered to a pregnant woman and is contraindicated during pregnancy; in reproduction studies with pregnant rabbits, oral administration during organogenesis caused abortions and fetal toxicity at exposures approximately 4 times and 13 times, respectively, the maximum recommended human (MRHD); advise pregnant women of the potential risk to a fetus Females of reproductive potential must have a negative pregnancy test before initiation, monthly during, and 1 month after discontinuation of treatment; contraception must also be used during and for 1 month after treatment (see Boxed Warning) If pregnancy suspected, contact healthcare provider immediately Lactation There are no data on presence of riociguat in human milk, effects on breastfed infant, or on milk production; drug is present in rat milk; because of potential for serious adverse reactions, such as hypotension, in breastfed infants, advise women not to breastfeed during therapyPregnancy Categories A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk. B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available. Mechanism of Action Stimulates soluble guanylate cyclase (sGC), an enzyme in the cardiopulmonary system and the receptor for nitric oxide (NO) NO binds to sGC and catalyzes synthesis of cGMP, which in turn activates protein kinase G regulation of cytosolic calcium ion concentration; this cascade changes actin-myosin contractility resulting in vasodilation PAH is associated with endothelial dysfunction, impaired synthesis of NO and insufficient stimulation of the NO-sGC-cGMP pathway Elicits a dual mode of action; riociguat sensitizes sGC to endogenous NO by stabilizing the NO-sGC binding, and also directly stimulates sGC via a different binding site, independently of NO Absorption Bioavailability: 94% Peak plasma time: 1.5 hr Food does not affect bioavailability Distribution Protein bound: 95%; primarily to albumin and alpha-1-acidic glycoprotein Vd: 30 L Metabolism Mainly metabolized by CYP1A1, CYP3A, CYP2C8, and CYP2J2 Substrate of P-gp (ABCB1) and BCRP (ABCG2) efflux transporter proteins Active metabolite: Formation of the major active metabolite (M1) is catalyzed by CYP1A1; M1 is 10-33% as potent as riociguat; M1 is further metabolized to the inactive N-glucuronide Elimination Half-life: 12 hr ((patients with PAH); 7 hr (healthy individuals) Systemic clearance: 1.8 L/hr (patients with PAH); 3.4 L/hr (healthy individuals) Excretion: 40% urine; 53% feces Oral Administration Antacids (eg, aluminum hydroxide/magnesium hydroxide) decrease riociguat absorption and should not be taken within 1 hr of taking riociguat If a dose is missed, continue with next regularly scheduled dose If dosage interrupted for >3 days, retitrate dose Patients who are unable to swallow whole tablets, may crush them and mix them with water or soft foods (such as applesauce) immediately before administration BRAND FORM. UNIT PRICE PILL IMAGE Adempas oral- 1 mg tabletAdempas oral- 0.5 mg tabletCopyright © 2010 First DataBank, Inc.Print Patient Educationriociguat oral RIOCIGUAT - ORAL (RYE-oh-SIG-ue-at) COMMON BRAND NAME(S): Adempas WARNING: Riociguat must not be used during pregnancy. It may harm an unborn baby. It is important to prevent pregnancy while taking this medication and for 1 month after treatment. Female patients must use reliable birth control during treatment and for 1 month after the end of treatment. Ask your doctor which forms of birth control to use while taking this medication. Female patients must take a pregnancy test before starting treatment, take a monthly pregnancy test during treatment, and take a pregnancy test 1 month after the end of treatment. If you become pregnant or think you may be pregnant, tell your doctor right away.To receive this medication in the United States, you must understand, agree to, and carefully follow the requirements of the Riociguat REMS Program. If you live in Canada or any other country, consult your doctor and pharmacist for your country's regulations. USES: Riociguat is used to treat high blood pressure in the lungs (pulmonary hypertension). It can also be used to treat a certain type of high blood pressure in the lungs caused by blood clots (chronic thromboembolic pulmonary hypertension) when surgery has not been fully successful or is impossible. Riociguat works by relaxing and widening the blood vessels in your lungs so blood can flow more easily. Decreasing high blood pressure in the lungs allows your heart and lungs to work better and improves your ability to exercise. HOW TO USE: Read the Medication Guide and, if available, the Patient Information Leaflet provided by your pharmacist before you start taking riociguat and each time you get a refill. If you have any questions, ask your doctor or pharmacist.Take this medication by mouth with or without food as directed by your doctor, usually 3 times daily. The dosage is based on your medical condition, response to treatment, and other medications you may be taking. Be sure to tell your doctor and pharmacist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products).Take this medication 1 hour before or after taking antacids that contain aluminum or magnesium. These products prevent your body from fully absorbing riociguat.To reduce your risk of side effects (such as low blood pressure), your doctor may direct you to start this medication at a low dose and gradually increase your dose. Follow your doctor's instructions carefully.Use this medication regularly to get the most benefit from it. To help you remember, take it at the same times each day.Do not increase your dose or use this drug more often than prescribed. Your condition will not improve any faster, and your risk of side effects will increase.Tell your doctor if your condition does not improve or if it worsens. SIDE EFFECTS: Headache, dizziness, lightheadedness, fainting, unusual tiredness, heartburn, indigestion, nausea, vomiting, or diarrhea may occur. If any of these effects last or get worse, tell your doctor or pharmacist promptly.To reduce the risk of dizziness and lightheadedness, get up slowly when rising from a sitting or lying position.Remember that this medication has been prescribed because your doctor has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.This medication has rarely caused serious bleeding. If you notice any of the following unlikely but serious signs of bleeding, tell your doctor right away: unusual bleeding from the vagina, coughing up blood, bleeding around catheter site, signs of stomach/intestinal bleeding (such as black/bloody stools, vomit that contains blood or looks like coffee grounds), signs of bleeding in the brain (such as severe headache, weakness on one side of the body, vision problems, trouble speaking, confusion).A very serious allergic reaction to this drug is rare. However, get medical help right away if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.In the US -Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or at www.fda.gov/medwatch.In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345. PRECAUTIONS: Before taking riociguat, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.Before using this medication, tell your doctor or pharmacist your medical history, especially of: smoking or history of smoking, low or high blood pressure, other lung conditions (such as pulmonary veno-occlusive disease, idiopathic interstitial pneumonia), dehydration, a severe blockage of blood flow out of the heart.This drug may make you dizzy. Alcohol or marijuana (cannabis) can make you more dizzy. Do not drive, use machinery, or do anything that needs alertness until you can do it safely. Limit alcoholic beverages. Talk to your doctor if you are using marijuana (cannabis).Before having surgery, tell your doctor or dentist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products).This medication must not be used during pregnancy. It may harm an unborn baby. See also Warning section.It is unknown if this medication passes into breast milk. Consult your doctor before breast-feeding. DRUG INTERACTIONS: See also How To Use section.Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor's approval.Some products that may interact with this drug include: aminophylline, certain drugs used to treat chest pain/angina or high blood pressure (nitrates such as nitroglycerin, isosorbide), dipyridamole, drugs to treat erectile dysfunction-ED/pulmonary hypertension (such as sildenafil, tadalafil, vardenafil), recreational drugs called "poppers" containing amyl or butyl nitrite, theophylline, vericiguat.Cigarette smoking decreases blood levels of this medication. Tell your doctor if you smoke or if you have recently stopped smoking. OVERDOSE: If someone has overdosed and has serious symptoms such as passing out or trouble breathing, call 911. Otherwise, call a poison control center right away. US residents can call their local poison control center at 1-800-222-1222. Canada residents can call a provincial poison control center. NOTES: Do not share this medication with others.Lab and/or medical tests (such as blood pressure, pregnancy tests) must be done while you are taking this medication. Keep all medical and lab appointments. Consult your doctor for more details. MISSED DOSE: If you miss a dose, skip the missed dose. Take your next dose at the regular time. Do not double the dose to catch up. Check with your doctor if you miss doses for more than 3 days in a row. STORAGE: Store at room temperature away from light and moisture. Do not store in the bathroom. Keep all medications away from children and pets.Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard