Drug Information

THERAPEUTIC CLASS: CARDIOVASCULAR AGENT, SOLUBLE GUANYLATE CYCLASE STIMULATORS CLINICAL PHARMACOLOGY: SENSITIZES SOLUBLE GUANYLATE CYCLASE (SGC) TO ENDOGENOUS NITRIC OXIDE (NO) BY STABILIZING THE NO-SGC BINDING. IT ALSO DIRECTLY STIMULATES SGC INDEPENDENT OF NO. RIOCIGUAT STIMULATES THE NO-SGC–CYCLIC GUANOSINE MONOPHOSPHATE (CGMP)

PATHWAY AND LEADS TO INCREASED GENERATION OF CGMP WITH SUBSEQUENT VASODILATION Pharmacokinetics: Absorption: TIME TO PEAK, PLASMA: 1. 5 HOURS BIOAVAILABILITY: APPROXIMATELY 94% Distribution: VOLUME OF DISTRIBUTION IS APPROXIMATELY 30 L PROTEIN BINDING, PLASMA: APPROXIMATELY 95%.

Metabolism: MAINLY CLEARED BY METABOLISM BY CYP1A1, CYP3A, CYP2C8, AND CYP2J2. FORMATION OF THE MAJOR ACTIVE METABOLITE, M1, IS CATALYZED BY CYP1A1, WHICH IS INDUCIBLE BY POLYCYCLIC AROMATIC HYDROCARBONS SUCH AS THOSE PRESENT IN CIGARETTE SMOKE. M1 IS ONLY ONE-THIRD TO ONE-TENTH AS POTENT AS THE PARENT DRUG AND IS FURTHER METABOLIZED TO THE INACTIVE N-GLUCURONIDE.

PLASMA CONCENTRATIONS OF M1 IN PATIENTS WITH PAH ARE ABOUT HALF THOSE FOR RIOCIGUAT. Excretion: FECES (APPROXIMATELY 53%); URINE (APPROXIMATELY 40%) HALF-LIFE ELIMINATION: PATIENTS: 12 HOURS; HEALTHY SUBJECTS: 7 HOURS.

INDICATIONS AND USAGE: – CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION – PULMONARY ARTERIAL HYPERTENSION CLINICAL TRIAL: IDENTIFY ONE CLINICAL TRIAL. PRESENT MOST PERTINENT INFORMATION CONCISELY FOR THE STUDY USING THE TABLE FORMAT BELOW. THERE SHOULD BE 1 STUDY SUMMARIZED IN THE TABLE IN THE COMPLETED MONOGRAPH. Study design Methods Endpoint measures RESULTS (INCL. STATS;

P-VALUES, 95%CI) Conclusion/ Comments STUDY 1 (RANDOMIZATION, BLINDING, CONTROLS, PROSPECTIVE, ETC) TREATMENTS: (DOSE/ ROUTE/ FREQUENCY/ DURATION) SAMPLE SIZE: PRIMARY: SECONDARY: SAFETY: PRIMARY: SECONDARY: SAFETY: BASED ON.

SIGNIFICANT EFFICACY, SAFETY, CLINICAL RELEVANCE, GOOD STUDY DESIGN? 1 of 5 PT POPULATION: MET POWER? , LIMITATIONS. CONTRAINDICATIONS: – PREGNANCY – COADMINISTRATION WITH NITRATES OR NITRIC OXIDE DONORS IN ANY FORM – COADMINISTRATION WITH PHOSPHODIESTERASE (PDE) INHIBITORS (SILDENAFIL, TADALAFIL, VARDENAFIL, DIPYRIDAMOLE, OR THEOPHYLLINE) PREGNANCY AND LACTATION: PREGNANCY:

CATEGORY X LACTATION: IT IS NOT KNOWN IF THIS DRUG IS EXCRETED INTO BREAST MILK. DUE TO THE POTENTIAL FOR ADVERSE REACTIONS IN THE BREAST- FEEDING INFANT, IT IS NOT RECOMMENDED TO BREAST FEED WHILE TAKING THIS MEDICATION.

Warning/Precautions: – REMS PROGRAM: ALL FEMALE PATIENTS, REGARDLESS OF THEIR REPRODUCTIVE POTENTIAL, MUST BE ENROLLED IN THE REMS PROGRAM; PRESCRIBERS AND PHARMACIES MUST ALSO BE ENROLLED IN THE PROGRAM. FEMALE PATIENTS OF REPRODUCTIVE POTENTIAL MUST BE ABLE TO COMPLY WITH PREGNANCY TESTING AND CONTRACEPTION REQUIREMENTS – HYPOTENSION:

REDUCES BLOOD PRESSURE. USE WITH CAUTION IN PATIENTS AT INCREASED RISK FOR SYMPTOMATIC HYPOTENSION OR ISCHEMIA (EG, PATIENTS WITH HYPOVOLEMIA, SEVERE LEFT VENTRICULAR OUTFLOW OBSTRUCTION, RESTING HYPOTENSION, AUTONOMIC DYSFUNCTION)

OR CONCURRENT USE OF ANTIHYPERTENSIVES OR STRONG CYP-450 AND P-GLYCOPROTEIN/BREAST CANCER RESISTANCE PROTEIN INHIBITORS. CONSIDER INITIATING AT A LOWER DOSE FOR PATIENTS AT RISK OF HYPOTENSION AND/OR DOSE REDUCTION IF HYPOTENSION DEVELOPS. – BLEEDING: SERIOUS BLEEDING HAS BEEN OBSERVED. – PULMONARY VENO-OCCLUSIVE DISEASE:

USE IS NOT RECOMMENDED IN PATIENTS WITH PULMONARY VENO-OCCLUSIVE DISEASE. DISCONTINUE IN ANY PATIENT WITH PULMONARY EDEMA SUGGESTIVE OF PULMONARY VENO-OCCLUSIVE DISEASE. – CNS EFFECTS: PATIENTS MUST BE CAUTIONED ABOUT PERFORMING TASKS THAT REQUIRE MENTAL ALERTNESS (EG, OPERATING MACHINERY OR DRIVING).

– RENAL FUNCTION IMPAIRMENT: USE WITH CAUTION IN PATIENTS WITH RENAL IMPAIRMENT; USE IN PATIENTS WITH CREATININE CLEARANCE LESS THAN 15 ML/MIN OR RECEIVING DIALYSIS HAS NOT BEEN evaluated. – HEPATIC FUNCTION IMPAIRMENT: USE WITH CAUTION IN PATIENTS WITH HEPATIC IMPAIRMENT; USE IN PATIENTS WITH SEVERE HEPATIC IMPAIRMENT HAS NOT BEEN EVALUATED.

Drug Interactions: – NITRATES: MAY ENHANCE THE HYPOTENSIVE EFFECT OF RIOCIGUAT. AVOID COMBINATION – ANAGRELIDE: MAY ENHANCE THE HYPOTENSIVE EFFECT OF RIOCIGUAT. AVOID COMBINATION – ANTACIDS: MAY DECREASE THE SERUM CONCENTRATION OF RIOCIGUAT. MANAGEMENT: SEPARATE THE ADMINISTRATION OF ANTACIDS AND RIOCIGUAT BY AT LEAST 1 HOUR IN ORDER TO MINIMIZE ANY POTENTIAL INTERACTION.

CONSIDER THERAPY MODIFICATION. 2 of 5 – BOSENTAN: MAY DECREASE THE SERUM CONCENTRATION OF CYP3A4 SUBSTRATES. MONITOR THERAPY – CILOSTAZOL: MAY ENHANCE THE HYPOTENSIVE EFFECT OF RIOCIGUAT. AVOID COMBINATION – COBICISTAT: MAY INCREASE THE SERUM CONCENTRATION OF RIOCIGUAT. MANAGEMENT: CONSIDER STARTING WITH A REDUCED RIOCIGUAT DOSE OF 0.

5 MG THREE TIMES A DAY. PATIENTS RECEIVING SUCH A COMBINATION SHOULD ALSO BE MONITORED EXTRA CLOSELY FOR SIGNS OR SYMPTOMS OF HYPOTENSION. CONSIDER THERAPY MODIFICATION – CYP2C8 INDUCERS (STRONG): MAY INCREASE THE METABOLISM OF CYP2C8 SUBSTRATES.

MANAGEMENT: CONSIDER AN ALTERNATIVE FOR ONE OF THE INTERACTING DRUGS. SOME COMBINATIONS MAY BE SPECIFICALLY CONTRAINDICATED. CONSULT APPROPRIATE MANUFACTURER LABELING. CONSIDER THERAPY MODIFICATION – CYP3A4 INDUCERS (STRONG):

MAY INCREASE THE METABOLISM OF CYP3A4 SUBSTRATES. MANAGEMENT: CONSIDER AN ALTERNATIVE FOR ONE OF THE INTERACTING DRUGS. SOME COMBINATIONS MAY BE SPECIFICALLY CONTRAINDICATED. CONSULT APPROPRIATE MANUFACTURER LABELING. CONSIDER THERAPY MODIFICATION – DABRAFENIB: MAY DECREASE THE SERUM CONCENTRATION OF CYP3A4,2C8 SUBSTRATES. MANAGEMENT:

SEEK ALTERNATIVES TO THE CYP3A4,2C8 SUBSTRATE WHEN POSSIBLE. IF CONCOMITANT THERAPY CANNOT BE AVOIDED, MONITOR CLINICAL EFFECTS OF THE SUBSTRATE CLOSELY (PARTICULARLY THERAPEUTIC EFFECTS). CONSIDER THERAPY MODIFICATION. – PHOSPHODIESTERASE 5 INHIBITORS: MAY ENHANCE THE HYPOTENSIVE EFFECT OF RIOCIGUAT. AVOID COMBINATION – VASODILATORS (ORGANIC NITRATES):

MAY ENHANCE THE HYPOTENSIVE EFFECT OF RIOCIGUAT. AVOID COMBINATION Adverse Reactions: COMMON: – CARDIOVASCULAR: HYPOTENSION (3-10%) – CNS: DIZZINESS (20%), HEADACHE (27%) – GI: DIARRHEA (12%), DYSPEPSIA (13-19%), NAUSEA (14%), VOMITING (10%) Dosage and Administration:

-ADULTS: Chronic thromboembolic pulmonary hypertension: INITIAL DOSAGE: 1 MG THREE TIMES DAILY; 0. 5 MG THREE TIMES DAILY IN PATIENTS WHO MAY NOT TOLERATE THE HYPOTENSIVE EFFECTS. DOSAGE TITRATION: MAY INCREASE THE DOSE BY 0. 5 MG THREE TIMES DAILY IF SYSTOLIC BLOOD PRESSURE REMAINS GREATER THAN 95 MMHG AND THE PATIENT HAS NO SIGNS OR SYMPTOMS OF HYPOTENSION.

DOSE INCREASES SHOULD BE NO SOONER THAN 2 WEEKS APART. DOSAGE ADJUSTMENT: MAY DECREASE THE DOSE BY 0. 5 MG THREE TIMES DAILY IF THE HYPOTENSIVE EFFECTS ARE NOT TOLERATED. 3 of 5 Pulmonary arterial hypertension: INITIAL DOSAGE: 1 MG THREE TIMES DAILY; 0.

5 MG THREE TIMES DAILY IN PATIENTS WHO MAY NOT TOLERATE THE HYPOTENSIVE EFFECTS. DOSAGE TITRATION: MAY INCREASE THE DOSE BY 0. 5 MG THREE TIMES DAILY IF SYSTOLIC BLOOD PRESSURE REMAINS GREATER THAN 95 MMHG AND THE PATIENT HAS NO SIGNS OR SYMPTOMS OF HYPOTENSION. DOSE INCREASES SHOULD BE NO SOONER THAN 2 WEEKS APART. DOSAGE ADJUSTMENT: MAY DECREASE THE DOSE BY 0.

5 MG THREE TIMES DAILY IF THE HYPOTENSIVE EFFECTS ARE NOT TOLERATED. -SMOKERS: CONSIDER TITRATING TO GREATER THAN 2. 5 MG THREE TIMES DAILY, IF TOLERATED. A DECREASED DOSE MAY BE NECESSARY IN PATIENTS WHO STOP SMOKING DURING THERAPY -CONCOMITANT THERAPY:

STRONG CYTOCHROME P450 AND P-GLYCOPROTEIN/BREAST CANCER RESISTANCE PROTEIN INHIBITORS (EG, AZOLE ANTIFUNGALS [EG, KETOCONAZOLE, ITRACONAZOLE] OR PROTEASE INHIBITORS [EG, RITONAVIR]): CONSIDER A STARTING DOSE OF 0. 5 MG THREE TIMES DAILY. Pharmacoeconomics:

Drug Name Available asUsual DoseCost per week/ month/ treatment RIOCIGUAT (ADEMPAS) ORAL TABLETS: 0. 5 MG 1 MG 1. 5 MG 2 MG 2. 5 MG 1 MG PO TID $300/DAY $2100/WEEK $8400/MONTH CONCLUSION: COMPARE STRENGTHS AND WEAKNESSES OF YOUR DRUG COMPARED TO OTHER DRUGS IN THE SAME CLASS OR USED FOR THE SAME INDICATION, INCLUDING SUMMARY OF EFFICACY/SAFETY DEMONSTRATED IN CLINICAL TRIALS IF APPROPRIATE. CONSIDER ALL FACETS OF THE MONOGRAPH AS ARGUING POINTS TO ADD OR NOT TO ADD THIS DRUG TO THE FORMULARY.

RECOMMENDATION: MAKE A RECOMMENDATION WHETHER THE PROPOSED MEDICATION SHOULD BE ADDED TO THE FORMULARY, ADDED WITH RESTRICTIONS/LIMITATIONS FOR USE (E. G. , ONLY PRESCRIBED BY ATTENDING PHYSICIANS IN A PARTICULAR SPECIALTY, CAN ONLY BE USED IF CERTAIN CRITERIA ARE MET BY THE PATIENT, OR REVIEW USE IN 6 MONTHS), OR NOT ADDED (NON-FORMULARY STATUS) BECAUSE NO CLEAR BENEFIT OVER OTHER AVAILABLE MEDICATIONS.

FOR MANAGED CARE RECOMMENDATIONS, CONSIDER TIERS (I. E. FIRST TIER=NO CO-PAY; SECOND TIER=$5 CO-PAY; THIRD TIER=$10 CO-PAY; ETC).

4 of 5 REFERENCES: CITE REFERENCES THROUGHOUT MONOGRAPH AND IN THE BIBLIOGRAPHY USING AMA STYLE FORMATTING; SUPPLY COPIES OF ALL PRIMARY LITERATURE USED IN PREPARING THE MONOGRAPH. CONSIDER USING REFWORKS TO HELP YOU WITH THIS BIBLIOGRAPHY [ACCESSIBLE THROUGH LIU LIBRARY DATABASES UNDER R > REFWORKS; OFF-CAMPUS ACCESS REQUIRES YOU TO REGISTER FOR INDIVIDUAL SIGN-IN;

GOOGLE SCHOLAR LINK REQUIRES YOU TO USE GROUP LOGIN: RWLONGISLANDU (CASE SENSISTIVE! ); USE HELP LINK FOR MORE INFORMATION] PREPARED BY: MEGAN GEORGE DATE: COMPLETED DATE.