MOBILE VIEW  | 

RIOCIGUAT

Classification   |    Detailed evidence-based information

Therapeutic Toxic Class

    A) Riociguat is a soluble guanylate cyclase stimulator used to treat patients with pulmonary hypertension.

Specific Substances

    1) 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo [3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate
    2) BAY 63-2521
    3) CAS 625115-55-1
    1.2.1) MOLECULAR FORMULA
    1) C20H19FN8O2 (Prod Info Adempas oral tablets, 2013)

Available Forms Sources

    A) FORMS
    1) Riociguat is available as round, film coated tablets of 0.5 mg, 1 mg, 1.5 mg, 2 mg, and 2.5 mg (Prod Info Adempas oral tablets, 2013)
    B) USES
    1) Riociguat is used in the treatment of pulmonary arterial hypertension and in persistent/recurrent chronic thromboembolic pulmonary hypertension that is either inoperable or post surgical treatment (Prod Info Adempas oral tablets, 2013).

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Riociguat is used in the treatment of pulmonary hypertension.
    B) PHARMACOLOGY: Riociguat stimulates soluble guanylate cyclase (sGC), which is a nitric oxide receptor and an enzyme found in the cardiopulmonary system. Nitric oxide binds sGC and it catalyzes the synthesis of cyclic guanosine monophosphate (cGMP). Riociguat stimulates the nitric oxide-sGC-cGMP pathway, which leads to increased generation of cGMP and subsequent vasodilation.
    C) TOXICOLOGY: Increased intracellular cGMP can cause vasodilation of the systemic vasculature and hypotension.
    D) EPIDEMIOLOGY: Exposure is rare and overdose has not been reported.
    E) WITH THERAPEUTIC USE
    1) Headache, dyspepsia, dizziness, nausea and vomiting, diarrhea, hypotension, anemia, hemorrhage, gastroesophageal reflux and constipation have been reported.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Little data available. Hypotension, headache, nausea and vomiting would be expected.
    2) SEVERE TOXICITY: Has not been reported. Severe hypotension with end organ effects such as syncope or acute kidney injury, and severe hemorrhage are theoretically possible.
    0.2.20) REPRODUCTIVE
    A) Riociguat is classified as FDA pregnancy category X. It is teratogenic and embryotoxic in rats, and induced abortion and fetal toxicity in rabbits.

Laboratory Monitoring

    A) Monitor vital signs, particularly blood pressure.
    B) Monitor CBC. In patients who develop hypotension, monitor serum electrolytes and renal function.
    C) Institute continuous cardiac monitoring and obtain an ECG.
    D) Obtain a pregnancy test on any exposed woman of childbearing potential.
    E) Riociguat concentrations are not widely available or useful to guide therapy.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Care is symptomatic and supportive. Administer antiemetics for nausea/vomiting. Treat mild hypotension with intravenous fluids.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treat hypotension with intravenous fluids; add vasopressors if necessary.
    C) DECONTAMINATION
    1) Consider activated charcoal in patients with recent, substantial ingestions who are alert and can protect their airway.
    D) HYPOTENSIVE EPISODE
    1) Treat with intravenous fluids. Add vasopressors (dopamine, norepinephrine, phenylephrine) if hypotension persists.
    E) ENHANCED ELIMINATION
    1) Hemodialysis is unlikely to be of benefit because of the high degree of protein binding (95%). Hemoperfusion or plasmapheresis might be useful as riociguat has a small volume of distribution (30 L), but this has not been described. These modalities may be considered in patients with severe overdose not responding to supportive care.
    F) PATIENT DISPOSITION
    1) HOME CRITERIA: Asymptomatic adults with inadvertent ingestion of a single extra dose can be monitored at home.
    2) OBSERVATION CRITERIA: All children, symptomatic patients, deliberate ingestions and adults ingesting more than a single extra dose should be referred to a healthcare facility for evaluation and treatment.
    3) ADMISSION CRITERIA: Patients who develop hypotension or other persistent signs or symptoms of toxicity should be admitted.
    4) CONSULT CRITERIA: Consult a medical toxicologist or poison center for patients with severe toxicity or in whom the diagnosis is unclear. Exposed pregnant women should be referred to a specialist in teratogenesis.
    G) PITFALLS
    1) Treatment of hypotension with vasopressors may temporarily worsen pulmonary hypertension.
    H) PHARMACOKINETICS
    1) Well absorbed; protein binding: 95%; Vd: 30 L. Undergoes hepatic metabolism, renal (about 40%) and fecal (about 53%) excretion. Elimination half-life: 12 hours in patients, 7 hours in healthy subjects.
    I) DIFFERENTIAL DIAGNOSIS
    1) Overdose with other vasodilators such as nitrates, diazoxide, hydralazine, minoxidil. Sepsis.

Range Of Toxicity

    A) TOXICITY: Toxic dose is unknown. THERAPEUTIC DOSE: ADULT: Usual range is from 1 mg to 2.5 mg orally 3 times daily. CHILD: The safety and efficacy of riociguat have not been established in pediatric patients.

Summary Of Exposure

    A) USES: Riociguat is used in the treatment of pulmonary hypertension.
    B) PHARMACOLOGY: Riociguat stimulates soluble guanylate cyclase (sGC), which is a nitric oxide receptor and an enzyme found in the cardiopulmonary system. Nitric oxide binds sGC and it catalyzes the synthesis of cyclic guanosine monophosphate (cGMP). Riociguat stimulates the nitric oxide-sGC-cGMP pathway, which leads to increased generation of cGMP and subsequent vasodilation.
    C) TOXICOLOGY: Increased intracellular cGMP can cause vasodilation of the systemic vasculature and hypotension.
    D) EPIDEMIOLOGY: Exposure is rare and overdose has not been reported.
    E) WITH THERAPEUTIC USE
    1) Headache, dyspepsia, dizziness, nausea and vomiting, diarrhea, hypotension, anemia, hemorrhage, gastroesophageal reflux and constipation have been reported.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Little data available. Hypotension, headache, nausea and vomiting would be expected.
    2) SEVERE TOXICITY: Has not been reported. Severe hypotension with end organ effects such as syncope or acute kidney injury, and severe hemorrhage are theoretically possible.

Heent

    3.4.5) NOSE
    A) WITH THERAPEUTIC USE
    1) Nasal congestion and epistaxis were more common in riociguat treated patients than placebo treated patients (Prod Info Adempas oral tablets, 2013).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) In clinical trials involving 704 patients (490 treated with riociguat and 214 with placebo), 10% of riociguat treated subjects developed hypotension compared with 4% of placebo treated subjects (Prod Info Adempas oral tablets, 2013).
    B) SYNCOPE
    1) WITH THERAPEUTIC USE
    a) Syncope has been reported in patients receiving riociguat in clinical trials, although it is not clear that the effect is drug related as it was also reported in placebo treated patients (Hoeper et al, 2013; Bonderman et al, 2013).
    C) VENTRICULAR TACHYCARDIA
    1) WITH THERAPEUTIC USE
    a) Ventricular tachycardia has been reported in patients receiving riociguat in clinical trials, although it is not clear that the effect is drug related as it was also reported in placebo treated patients (Bonderman et al, 2013).
    D) PERIPHERAL EDEMA
    1) WITH THERAPEUTIC USE
    a) In a randomized, double-blind, placebo controlled trial of patients with pulmonary hypertension, peripheral edema was more common in patients treated with riociguat than placebo treated patients. Peripheral edema was reported in 44 out of 254 patients (17%) who received a maximum riociguat dose up to 2.5 mg 3 times daily, 14 out of 63 patients (22%) who received a maximum dose of riociguat up to 1.5 mg 3 times daily, and 14 of 126 (11%) of placebo treated patients (Ghofrani et al, 2013).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) HEMOPTYSIS
    1) WITH THERAPEUTIC USE
    a) In a randomized, double blind, placebo controlled trial involving 261 patients with pulmonary hypertension, hemoptysis was reported in 2% of the riociguat treated patients and none of the placebo treated patients (Ghofrani et al, 2013a).
    b) In clinical trials involving 704 patients (490 treated with riociguat and 214 with placebo), serious hemoptysis developed in 5 (1%) riociguat treated patients, with one fatality (Prod Info Adempas oral tablets, 2013).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) In clinical trials involving 704 patients (490 treated with riociguat and 214 with placebo), 27% of riociguat treated subjects developed headache compared with 18% of placebo treated subjects (Prod Info Adempas oral tablets, 2013).
    B) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) In clinical trials involving 704 patients (490 treated with riociguat and 214 with placebo), 20% of riociguat treated subjects complained of dizziness headache compared with 13% of placebo treated subjects (Prod Info Adempas oral tablets, 2013).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) In clinical trials involving 704 patients (490 treated with riociguat and 214 with placebo), 14% of riociguat treated subjects developed nausea and 10% had vomiting compared with 11% and 7%, respectively, of placebo treated subjects (Prod Info Adempas oral tablets, 2013).
    B) INDIGESTION
    1) WITH THERAPEUTIC USE
    a) In clinical trials involving 704 patients (490 treated with riociguat and 214 with placebo), 21% of riociguat treated subjects developed dyspepsia/gastritis compared with 8% of placebo treated subjects (Prod Info Adempas oral tablets, 2013).
    C) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) In clinical trials involving 704 patients (490 treated with riociguat and 214 with placebo), 12% of riociguat treated subjects developed diarrhea compared with 8% of placebo treated subjects (Prod Info Adempas oral tablets, 2013).
    D) GASTROESOPHAGEAL REFLUX DISEASE
    1) WITH THERAPEUTIC USE
    a) In clinical trials involving 704 patients (490 treated with riociguat and 214 with placebo), 5% of riociguat treated subjects complained of gastroesophageal reflux compared with 2% of placebo treated subjects (Prod Info Adempas oral tablets, 2013).
    E) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) In clinical trials involving 704 patients (490 treated with riociguat and 214 with placebo), 5% of riociguat treated subjects developed constipation compared with 1% of placebo treated subjects (Prod Info Adempas oral tablets, 2013).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) BLEEDING
    1) WITH THERAPEUTIC USE
    a) In clinical trials involving 704 patients (490 treated with riociguat and 214 with placebo), 2.4% of riociguat treated subjects developed serious bleeding compared with 0 placebo treated subjects. Serious hemoptysis developed in 5 (1%) riociguat treated patients, with one fatality. Among the riociguat treated patients, 2 developed vaginal hemorrhage, 2 had hemorrhage at the site of a catheter, and there was one patient each with subdural hematoma, hematemesis, and intra-abdominal hemorrhage (Prod Info Adempas oral tablets, 2013).
    B) ANEMIA
    1) WITH THERAPEUTIC USE
    a) In clinical trials involving 704 patients (490 treated with riociguat and 214 with placebo), 7% of riociguat treated subjects developed anemia compared with 2% of placebo treated subjects (Prod Info Adempas oral tablets, 2013).

Reproductive

    3.20.1) SUMMARY
    A) Riociguat is classified as FDA pregnancy category X. It is teratogenic and embryotoxic in rats, and induced abortion and fetal toxicity in rabbits.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) RATS: In pregnant rats receiving riociguat (1, 5 and 25 mg/kg/day) throughout organogenesis, an increase in the rate of ventricular-septal defects of the heart was seen in offspring at the highest doses, which was also associated with maternal toxicity (reduced body weight). Rats receiving the 5 mg/kg/day dose had increased post-implantation loss. The doses of 1, 5 and 25 mg/kg/day resulted in plasma concentrations of approximately 0.4, 2 and 8 times, respectively, that found in humans receiving the maximum recommended dose of 2.5 mg 3 times daily (Prod Info ADEMPAS oral tablets, 2014).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Riociguat is classified as US FDA pregnancy category X (Prod Info ADEMPAS oral tablets, 2014).
    2) Use of riociguat is contraindicated during pregnancy, as it may cause fetal harm when administered to a pregnant woman. While there are no adequate and well-controlled studies of riociguat in pregnant women, teratogenicity and embryotoxicity were evident in animal studies of rats given doses with exposures approximately 3 times the human exposure. In addition, riociguat led to abortions in rabbits at 5 times the human exposure and fetal toxicity at doses with exposures approximately 15 times the human exposure. Women of childbearing potential must have a negative pregnancy test prior to initiating treatment, monthly during treatment, and 1 month after discontinuation. Effective contraception is required in women of childbearing potential using riociguat. Where exposure is unavoidable or unanticipated, the pregnant mother should be advised of possible consequences to the fetus (Prod Info ADEMPAS oral tablets, 2014).
    B) ANIMAL STUDIES
    1) RABBITS: In pregnant rabbits receiving riociguat (0.5, 1.5 and 5 mg/kg/day), an increase in spontaneous abortions was seen at the 1.5 mg/kg dose and an increase in resorptions at the 5 mg/kg/day dose. These doses resulted in plasma concentrations that were 4 and 13 times, respectively, those seen in humans receiving the maximum recommended dose of 2.5 mg 3 times daily (Prod Info ADEMPAS oral tablets, 2014).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) It is not known if riociguat is excreted in human milk, but riociguat or its metabolites are excreted in rat milk. Because of potential for adverse effects to the infant, the manufacturer recommends that women either discontinue nursing or riociguat therapy (Prod Info ADEMPAS oral tablets, 2014).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) RATS: No effects on male or female fertility were seen with doses up to 37 times the human exposure before and during the mating period in males and before mating through gestation day 7 in females (Prod Info ADEMPAS oral tablets, 2014).

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs, particularly blood pressure.
    B) Monitor CBC. In patients who develop hypotension, monitor serum electrolytes and renal function.
    C) Institute continuous cardiac monitoring and obtain an ECG.
    D) Obtain a pregnancy test on any exposed woman of childbearing potential.
    E) Riociguat concentrations are not widely available or useful to guide therapy.
    4.1.2) SERUM/BLOOD
    A) Monitor CBC. In patients who develop hypotension monitor serum electrolytes and renal function.
    B) Obtain a pregnancy test on any exposed woman of childbearing potential. Riociguat is classified as FDA pregnancy category X and is considered teratogenic.
    4.1.4) OTHER
    A) OTHER
    1) Monitor vital signs, particularly blood pressure.
    2) Institute continuous cardiac monitoring and obtain an ECG.

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients who develop hypotension or other persistent signs or symptoms of toxicity should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Asymptomatic adults with inadvertent ingestion of a single extra dose can be monitored at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a medical toxicologist or poison center for patients with severe toxicity or in whom the diagnosis is unclear. Exposed pregnant women should be referred to a specialist in teratogenesis.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) All children, symptomatic patients, deliberate ingestions and adults ingesting more than a single extra dose should be referred to a healthcare facility for evaluation and treatment.

Monitoring

    A) Monitor vital signs, particularly blood pressure.
    B) Monitor CBC. In patients who develop hypotension, monitor serum electrolytes and renal function.
    C) Institute continuous cardiac monitoring and obtain an ECG.
    D) Obtain a pregnancy test on any exposed woman of childbearing potential.
    E) Riociguat concentrations are not widely available or useful to guide therapy.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY: Consider activated charcoal in patients with recent, substantial ingestions who are alert and can protect their airway.
    B) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY: Consider activated charcoal in patients with recent, substantial ingestions who are alert and can protect their airway.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Care is symptomatic and supportive. Administer antiemetics for nausea/vomiting. Treat mild hypotension with intravenous fluids.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treat hypotension with intravenous fluids; add vasopressors if necessary.
    B) MONITORING OF PATIENT
    1) Monitor vital signs, particularly blood pressure.
    2) Monitor CBC. In patients who develop hypotension, monitor serum electrolytes and renal function.
    3) Institute continuous cardiac monitoring and obtain an ECG.
    4) Obtain a pregnancy test on any exposed woman of childbearing potential.
    5) Riociguat concentrations are not widely available or useful to guide therapy.
    C) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    4) PHENYLEPHRINE
    a) MILD OR MODERATE HYPOTENSION
    1) INTRAVENOUS: ADULT: Usual dose: 0.2 mg; range: 0.1 mg to 0.5 mg. Maximum initial dose is 0.5 mg. A 0.5 mg IV dose can elevate the blood pressure for approximately 15 min (Prod Info phenylephrine HCl subcutaneous injection, intramuscular injection, intravenous injection, 2011). PEDIATRIC: Usual bolus dose: 5 to 20 mcg/kg IV repeated every 10 to 15 min as needed (Taketomo et al, 1997).
    b) CONTINUOUS INFUSION
    1) PREPARATION: Add 10 mg (1 mL of a 1% solution) to 500 mL of normal saline or dextrose 5% in water to produce a final concentration of 0.2 mg/mL.
    2) ADULT DOSE: To raise blood pressure rapidly; start an initial infusion of 100 to 180 mcg/min until blood pressure stabilizes; then reduce infusion to 40 to 60 mcg/min titrated to desired effect. If necessary, additional doses in increments of 10 mg or more may be added to the infusion solution and the rate of flow titrated to the desired effect (Prod Info phenylephrine HCl subcutaneous injection, intramuscular injection, intravenous injection, 2011).
    3) PEDIATRIC DOSE: Intravenous infusion should begin at 0.1 to 0.5 mcg/kg/min; titrate to the desired effect (Taketomo et al, 1997).
    c) ADVERSE EFFECTS
    1) Headache, reflex bradycardia, excitability, restlessness and rarely dysrhythmias may develop (Prod Info phenylephrine HCl subcutaneous injection, intramuscular injection, intravenous injection, 2011).

Enhanced Elimination

    A) SUMMARY
    1) Riociguat is highly protein bound (95%), so hemodialysis is unlikely to be of benefit. Riociguat has a small volume of distribution (30 L) (Prod Info Adempas oral tablets, 2013), so hemoperfusion or plasmapheresis might be useful in severe overdose, but this has never been reported. These modalities may be considered in patients with severe overdose not responding to supportive care.

Summary

    A) TOXICITY: Toxic dose is unknown. THERAPEUTIC DOSE: ADULT: Usual range is from 1 mg to 2.5 mg orally 3 times daily. CHILD: The safety and efficacy of riociguat have not been established in pediatric patients.

Therapeutic Dose

    7.2.1) ADULT
    A) Initial treatment is 1 mg orally 3 times daily. Patients who may not tolerate the hypotensive effects may receive a starting dose of 0.5 mg 3 times daily. In patients with systolic blood pressure greater than 95 mmHg without signs or symptoms of hypotension, the dose may be increased by 0.5 mg orally 3 times daily every 2 weeks as needed to a maximum of 2.5 mg orally 3 times daily (Prod Info Adempas oral tablets, 2013).
    7.2.2) PEDIATRIC
    A) The safety and efficacy of riociguat have not been established in pediatric patients (Prod Info Adempas oral tablets, 2013).

Maximum Tolerated Exposure

    A) Healthy volunteers tolerated a riociguat 2.5 mg orally 3 times daily for 10 days. The most common adverse effects reported were dyspepsia, flatulence, headache, nausea and vomiting. Clinically significant hypotension was not reported in any of the volunteers (Frey et al, 2011).

Pharmacologic Mechanism

    A) Riociguat stimulates soluble guanylate cyclase (sGC), which is a nitric oxide receptor and an enzyme found in the cardiopulmonary system. Nitric oxide binds sGC and it catalyzes the synthesis of cyclic guanosine monophosphate (cGMP). Riociguat stimulates the nitric oxide-sGC-cGMP pathway, which leads to increased generation of cGMP and subsequent vasodilation (Prod Info Adempas oral tablets, 2013). In the pulmonary vasculature, vasodilation reduces pulmonary hypertension.

Toxicologic Mechanism

    A) Increased intracellular cGMP can cause vasodilation of the systemic vasculature and hypotension.

Physical Characteristics

    A) White to yellowish crystalline, non-hygroscopic substance (Prod Info Adempas oral tablets, 2013).

Molecular Weight

    A) 422.42 g/mol (Prod Info Adempas oral tablets, 2013)

General Bibliography

    1) Alaspaa AO, Kuisma MJ, Hoppu K, et al: Out-of-hospital administration of activated charcoal by emergency medical services. Ann Emerg Med 2005; 45:207-12.
    2) Bonderman D, Ghio S, Felix SB, et al: Riociguat for patients with pulmonary hypertension caused by systolic left ventricular dysfunction: a phase IIb double-blind, randomized, placebo-controlled, dose-ranging hemodynamic study. Circulation 2013; 128(5):502-511.
    3) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    4) Dagnone D, Matsui D, & Rieder MJ: Assessment of the palatability of vehicles for activated charcoal in pediatric volunteers. Pediatr Emerg Care 2002; 18:19-21.
    5) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    6) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    7) Frey R, Muck W, Kirschbaum N, et al: Riociguat (BAY 63-2521) and warfarin: a pharmacodynamic and pharmacokinetic interaction study. J Clin Pharmacol 2011; 51(7):1051-1060.
    8) Ghofrani HA , D'Armini AM , Grimminger F , et al: Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med 2013a; 369(4):319-329.
    9) Ghofrani HA , Galie N , Grimminger F , et al: Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med 2013; 369(4):330-340.
    10) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    11) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    12) Guenther Skokan E, Junkins EP, & Corneli HM: Taste test: children rate flavoring agents used with activated charcoal. Arch Pediatr Adolesc Med 2001; 155:683-686.
    13) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    14) Hoeper MM, Halank M, Wilkens H, et al: Riociguat for interstitial lung disease and pulmonary hypertension: a pilot trial. Eur Respir J 2013; 41(4):853-860.
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    16) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
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    19) Product Information: ADEMPAS oral tablets, riociguat oral tablets. Bayer HealthCare Pharmaceuticals Inc. (per manufacturer), Whippany, NJ, 2014.
    20) Product Information: Adempas oral tablets, riociguat oral tablets. Bayer HealthCare Pharmaceuticals Inc. (per manufacturer), Whippany, NJ, 2013.
    21) Product Information: dopamine hcl, 5% dextrose IV injection, dopamine hcl, 5% dextrose IV injection. Hospira,Inc, Lake Forest, IL, 2004.
    22) Product Information: norepinephrine bitartrate injection, norepinephrine bitartrate injection. Sicor Pharmaceuticals,Inc, Irvine, CA, 2005.
    23) Product Information: phenylephrine HCl subcutaneous injection, intramuscular injection, intravenous injection, phenylephrine HCl subcutaneous injection, intramuscular injection, intravenous injection. West-Ward Pharmaceuticals (per DailyMed), Eatontown, NJ, 2011.
    24) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    25) Spiller HA & Rogers GC: Evaluation of administration of activated charcoal in the home. Pediatrics 2002; 108:E100.
    26) Taketomo CK, Hodding JH, & Kraus DM (Eds): Pediatric Dosage Handbook, 4th. Lexi-Comp, Inc, Cleveland, OH, 1997.
    27) Thakore S & Murphy N: The potential role of prehospital administration of activated charcoal. Emerg Med J 2002; 19:63-65.