Pulmonary Arterial Hypertension Flashcards
Riociguat
- Adempas®
- therapeutic calss: sGC stimulator; sensitize NO to cause vasodilation
- tablet
Riociguat adverse effects
- Fetal harm
- Hypotension
- Headache
- Dizziness
- Dyspepsia
- Bleeding
Riociguat dosing
- 1 mg PO three times daily; may initiate dose at 0.5 mg PO three times daily who become intolerable to hypotension
- If SBP remains >95 mm Hg and the patient has no signs or symptoms of hypotension, increase the dose by 0.5 mg PO three times daily at intervals of ≥2 weeks to the highest tolerated dosage.
Riociguat Clinical Pearls/Counseling Points
- Restricted through REMS program in females
- Metabolized via BCRP, CYP2C8/3A4; eliminated via P-gp
- Dose adjustment in: smokers & patients with strong multi-pathway CYP and P-gp/BCRP inhibitors
- Contraindicated: pregnancy; co-administration of nitrates, specific/non-specific PDE5 inhibitors
- No dose adjustments provided for CrCl ≥ 15 mL/min or mild-moderate hepatic impairment
PDE5 Inhibitors
- NO -> guanylate cyclase -> ↑cGMP = vasodilation
- Sildenafil Citrate (Revatio®)
- Tadalafil (Adcirca®)
- Vardenafil (not approved for treatment of PAH)
Sildenafil Citrate (Revatio®) dosing
5 - 40 mg PO three times daily (240 mg/day)
Sildenafil Citrate (Revatio®) Clinical Pearls/Counseling Points
- Primarily metabolized via CYP 3A4
- Avoid grapefruit juice
- Contraindicated in patients concomitantly receiving nitrates or riociguat; use with protease inhibitors
- Priapism
Sildenafil Citrate (Revatio®) adverse effects
- Flushing
- Headache
- Hypotension*
- Diarrhea
- Visual disturbances
- Reports of hearing loss
Tadalafil (Adcirca®) dosing
40 mg once daily (40 mg)
Tadalafil (Adcirca®) Clinical Pearls/Counseling Points
- Metabolized via CYP 3A4
- Avoid grapefruit juice
- Contraindicated in patients concomitantly receiving nitrates or riociguat; use with protease inhibitors
- Priapism
- Dose adjust with ritonavir
- CrCl 31-80 mL/min: initiate 20 mg once daily
- Mild-moderate hepatic impairment: initiate 20 mg once daily
Tadalafil (Adcirca®) adverse effects
- Flushing
- Headache
- Hypotension*
- Nausea
- Myalgia
- Visual disturbances
Endothelin Receptor Antagonists (ERAs)
- Competitively inhibit endothelin-1 receptors
- ETa located primarily in pulmonary vascular smooth muscle and is responsible for vasoconstriction; difficult to target this only
- Ambrisentan (Letairis®)
- Bosentan (Tracleer®)
- Macitentan (Opsumit®)
- all FDA approved for PAH and all restricted through REMS
Why are the ERA’s restricted via REMS?
- all cause birth defects
- Bosentan causes hepatotoxicity
ERA’s agents’ affinity for receptors
- Ambrisentan more affinity for ETa but associated with more adverse effects
- Bosentan more affinity for A but dual antagonism
- Macitentan more affinity for A but dual antagonism but tissue selective
Endothelin Receptor Antagonists (ERAs) adverse effects
▪ Headache ▪ Anemia ▪ Fluid retention/peripheral edema ▪ Respiratory complications ▪ Decrease in spermatogenesis ▪ Hepatic impairment ▪ Flushing & dyspepsia ▪ Ambrisentan ▪ ALL are contraindicated in pregnancy!!
Ambrisentan (Letairis®) dosing
5 mg once daily (10 mg/day)
Ambrisentan (Letairis®) Clinical Pearls/Counseling Points
- Minor metabolism via CYP2C19/3A4; eliminated via P-gp
- Do not exceed 5 mg/day if using concomitantly with cyclosporine
- Dose adjustment in hepatic impairment that develops during therapy
- Do not crush, split, or chew tablets
Bosentan (Tracleer®) dosing
<40 kg: Initial and maintenance: 62.5 mg twice daily ≥40 kg: Initial: 62.5 mg twice daily for 4 weeks; increase to maintenance dose of 125 mg twice daily
Bosentan (Tracleer®) Clinical Pearls/Counseling Points
- Minor metabolism via CYP 2C9/3A4; induces CYP2C9 (weak/moderate)/3A4 (moderate)
- Avoid grapefruit juice
- Dose adjust in patients currently receiving ritonavir
- Dose adjust in patients that develop hepatic dysfunction during treatment & in patients with pre-existing moderate-severe hepatic impairment
- Contraindicated: concurrent use of cyclosporine or glyburide
Macitentan (Opsumit®) dosing
10 mg once daily (10 mg/day)
Macitentan (Opsumit®) Clinical Pearls/Counseling Points
- Metabolized by CYP3A4
* Do not crush, split, or chew tablets
Prostacyclin Analogs
▪ Vasodilate pulmonary arteries
▪ Impair platelet aggregation
▪ Anti-proliferative effect on pulmonary endothelial cells
▪ All agents are FDA-approved for the treatment of PAH
▪ IV and SQ formulas
Prostacyclin Analogs drugs and dosage forms
▪ Intravenous (IV) - Epoprostenol (Flolan®, Veletri®) - Treprostonil (Remodulin®) ▪ Subcutaneous (SQ) - Treprostonil (Remodulin®) ▪ Inhaled - Treprostonil (Tyvaso®) - Iloprost (Ventavis®) ▪ Oral - Treprostonil (Orenitram®)
Epoprostenol (Flolan®, Veletri®) dosing
- Delivered by continuous IV infusion
- Started in the hospital at 2 ng/kg/min via a central venous catheter
- Dose adjusted based on PAH symptoms and tolerability to side effects
- Maintenance dose: 25-40 ng/kg/min
Epoprostenol (Flolan®, Veletri®) clinical pearls
- Special ambulatory infusion pumps
- Veletri® is stable at room temperature
- Flolan® must be kept on ice packs
- Drug only available via two distributors
- Use with caution in patients with other risk factors for bleeding
- Chronic continuous IV infusion of epoprostenol via a chronic indwelling central venous catheter has been associated with local infections and serious blood stream infections
- Discontinue and do not re-administer if patient develops pulmonary edema on epoprostenol
Epoprostenol (Flolan®, Veletri®) adverse effects
▪ Flushing ▪ Headache ▪ Nausea/vomiting ▪ Hypotension ▪ Anxiety/agitation ▪ Chest pain ▪ Jaw pain ▪ Contraindications - Heart failure due to severe left ventricular dysfunction
Treprostonil (Remodulin®) SQ dosing
- Administered via an ambulatory pump
- 1.25 ng/kg/minute
- Can decrease to 0.625 ng/kg/min if experience adverse effects
- Can be administered up to 72 hours at > 98 degrees Fahrenheit
Treprostonil (Remodulin®) IV dosing
- Infused via a central venous catheter use an infusion pump
- 1.25 ng/kg/minute
- Can decrease to 0.625 ng/kg/min if experience adverse effects
- Can be administered up to 48 hours at > 98 degrees Fahrenheit
- Significantly greater increased risk of catheter-related gram (-) bloodstream infections compared to epoprostenol
Treprostonil (Remodulin®) adverse effects
- Infusion site pain/reaction in ~85% of patients
- Headache*
- Nausea/diarrhea*
- Jaw pain*
- Rash
Treprostonil (Tyvaso®) inhaled dosing
- 18 mcg (or 3 inhalations) every 4 hours 4 times/day
- If tolerated, increase dose by an additional 3 inhalations at approximately 1to 2-week intervals; target dose and maximum dose: 54 mcg (or 9 inhalations) 4 times/day
- Safety and efficacy have not been established in patients with underlying pulmonary disease (e.g., asthma, COPD).
Treprostonil (Tyvaso®) adverse effects
- Headache*
- Dizziness*
- Nausea/diarrhea*
- Flushing*
- Cough/throat irritation
Treprostonil (Tyvaso®) clinical pearls
▪ Avoid abrupt discontinuation
▪ Metabolized through CYP2C8
▪ Concomitant diuretics, antihypertensives or other vasodilators may increase the risk of systemic hypotension.
▪ May inhibit platelet aggregation and increases the risk of bleeding
▪ IV/SQ: available via prescribing access restrictions
- dose adjust in hepatic impairment: 0.625 ng/kg/minute (ideal body weight)
Iloprost (Ventavis®) dosing
- 2.5 mcg inhaled specific inhalation system
- If tolerated increase to 5 mcg inhaled 6-9 times per day (no more than q. 2 hours {45 mcg}) during waking hours
- Do not initiate therapy if SBP < 85 mmHg
Iloprost (Ventavis®) adverse effects
▪ Cough ▪ Influenza-like symptoms ▪ Nausea* ▪ Headache* ▪ Hypotension* ▪ syncope ▪ Flushing* ▪ Jaw pain*
Iloprost (Ventavis®) clinical pearls
▪ Do not initiate therapy is SBP < 85 mmHg
▪ Maximum daily dose: 45 mcg (5 mcg/dose 9 times daily)
▪ Safety and efficacy have not been established in patients with other concurrent pulmonary diseases (COPD, severe asthma, or acute pulmonary infections): may induce bronchospasm in patients with hyper-reactive airways
▪ May inhibit platelet aggregation and increases the risk of bleeding
▪ Hepatic impairment: Consider increasing dosing interval (every 3-4 hours)
Prostacyclin IP-receptor agonists: what is an IP receptor?
▪ One of 4 different types of prostanoid receptors found in the lungs
▪ Regulates vascular tone, platelet activation, and immunologic cell responses
▪ Expressed in vascular smooth muscle cells (SMC) and platelets
▪ Activation of the IP receptor triggers SMC vasodilation and inhibition of SMC proliferation and platelet aggregation
Prostacyclin IP-receptor agonist drugs
- Selexipag (Uptravi®)
▪ Oral, non-prostanoid, selective agonist of the prostacyclin IP receptor
Selexipag (Uptravi®) dosing
Initial: 200 mcg PO twice daily; increase by 200 mcg PO twice daily, usually at weekly intervals, to the highest tolerated dose (1,600 mcg twice daily)
Selexipag (Uptravi®) Clinical Pearls/Counseling Points
- Major substrate of BCRP & CPY 2C8
- Take with food
- Avoid use in severe hepatic impairment
- Discontinue if patient develops pulmonary edema
Selexipag (Uptravi®) adverse effects
- Flushing
- Headache
- GI (n/v/d)
- Myalgia
- Jaw pain
- Pulmonary edema
What is the role of the pharmacist in the care of patients with pulmonary arterial hypertension (PAH)?
▪ Formulary management ▪ Medication Safety ▪ Regulatory Compliance (REMS) ▪ Patient/Provider Education ▪ Medication Access (only available via 2 carriers) ▪ Adverse Effect Management
What is the endorsing organization for guidelines to treat PAH?
Journal of the American College of Cardiology (JACC)
Which medications are restricted via REMS?
- Riociguat (Adempas®)
- Ambrisentan (Letairis®)
- Bosentan (Tracleer®)
- Macitentan (Opsumit®)
Which aspects of drug administration can pharmacy intervene on?
▪ Accidental bolus dosing
▪ Incorrect dosing
▪ Pump-related errors
▪ these are epoprostenol-related errors
Drugs or toxins that may cause PAH
▪ Cocaine ▪ Phenylpropanolamine ▪ St. John’s Wort ▪ SSRIs in newborns ▪ Amphetamine-like drugs ▪ Interferon alpha & beta
General Considerations in Patients with PAH
▪ Avoid heavy lifting: Can cause syncope
▪ Participate in low level graded aerobic activity to improve peak oxygen consumption
▪ Avoid high altitudes: May need supplemental O2 on aircraft
▪ Salt restriction to < 2,400 mg/day: don’t want to increase preload on L ventricle that is already failing
▪ Women should avoid pregnancy: 60% mortality in pregnant women
▪ Immunizations: Influenza, Pneumococcal
