Dosing and uses of Adempas (riociguat)
Adult dosage forms and strengths
tablet
- 0.5mg
- 1mg
- 1.5mg
- 2mg
- 2.5mg
Pulmonary Hypertension
Initial dose: 1 mg PO TID; consider 0.5 mg PO TID if patient may not tolerate hypotensive effect
If systolic blood pressure >95 mmHg and no symptoms of hypotension, up-titrate dose by 0.5 mg PO TID with dose increases no sooner than 2 weeks apart to highest tolerated dose (not to exceed 2.5 mg PO TID)
If symptoms of hypotension occur, decrease dose by 0.5 mg TId
Indications
- Chronic-thromboembolic pulmonary hypertension (CTEPH): Indicated for the treatment of adults with persistent/recurrent CTEPH, (WHO Group 4) after surgical treatment, or inoperable CTEPH, to improve exercise capacity and WHO functional class
- Pulmonary arterial hypertension (PAH): Indicated for the treatment of adults with PAH, (WHO Group 1), to improve exercise capacity, WHO functional class and to delay clinical worsening
Dosage modifications
Smoking: Consider titrating to dosage higher than 2.5 mg PO TID if tolerated
Coadministration with strong CYP and P-gp/BCRP inhibitors: Consider lower initial dose of 0.5 mg PO TId
CrCl <15 mL/min or dialysis: Safety and efficacy have not been demonstrated
Severe hepatic impairment (Child Pugh C): Safety and efficacy have not been demonstrated
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
Systemic Sclerosis (Orphan)
Orphan designation for treatment of systemic sclerosis
Sponsor
- Bayer HealthCare Pharmaceuticals; 100 Bayer Blvd, P. O. Box 915; Whippany, NJ 07981-0915
Pediatric dosage forms and strengths
Safety and efficacy not established
Adempas (riociguat) adverse (side) effects
>10%
Headache (27%)
Dyspepsia and gastritis (21%)
Dizziness (20%)
Nausea (14%)
Diarrhea (12%)
1-10%
Hypotension (10%)
Vomiting (10%)
Anemia (7%)
GERD (5%)
Constipation (5%)
Serious bleeding (2.4%)
Hemoptysis (1%)
Warnings
Black box warnings
Contraindicated in pregnant females because it may cause fetal harm
In females of reproductive potential, exclude pregnancy before the start of treatment, monthly during treatment, and 1 month after stopping treatment
Prevent pregnancy during treatment and for 1 month after stopping treatment by using acceptable methods of contraception (ie, 1 highly effective form of contraception [IUD, contraceptive implants, or tubal sterilization] or a combination of methods (hormone method with a barrier method or 2 barrier methods)
Available to females only through a restricted program called the Adempas Risk Evaluation and Mitigation Strategy (REMS) Program
Contraindications
Pregnancy (see Black box warnings)
Coadministration with nitrates or nitric oxide donors (eg, amyl nitrite), PDE inhibitors (eg, avanafil, sildenafil, tadalafil, vardenafil), or nonspecific PDE inhibitors (eg, dipyridamole, theophylline) because of additive hypotension
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
Pregnancy and lactation
Pregnancy category: X; Contraindicated in pregnancy due to consistent teratogenic effects shown in animal studies
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: Unknown if distributed in human breast milk; due to potential for serious adverse effects in infants and studies showing distribution into milk of rats, do not recommend nursing during treatment
Pregnancy 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.
Pharmacology of Adempas (riociguat)
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
