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OPSUMIT® is an endothelin receptor antagonist (ERA) indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to reduce the risks of disease progression and hospitalization for PAH.
Effectiveness was established in a long-term study in PAH patients with predominantly WHO Functional Class II-III symptoms treated for an average of 2 years. Patients had idiopathic and heritable PAH (57%), PAH caused by connective tissue disorders (31%), and PAH caused by congenital heart disease with repaired shunts (8%).
BOXED WARNING: EMBRYO-FETAL TOXICITY
- Do not administer OPSUMIT® to a pregnant female because it may cause fetal harm.
- 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 one month after stopping treatment by using acceptable methods of contraception.
- For all female patients, OPSUMIT® is available only through a restricted program called the OPSUMIT® Risk Evaluation and Mitigation Strategy (REMS).
Pregnancy: OPSUMIT® may cause fetal harm when administered to a pregnant woman. OPSUMIT® is contraindicated in females who are pregnant. If OPSUMIT® is used during pregnancy, advise the patient of the potential risk to a fetus.
WARNINGS AND PRECAUTIONS
Embryo-fetal Toxicity and OPSUMIT® REMS Program
Due to the risk of embryo-fetal toxicity, OPSUMIT® is available for females only through a restricted program called the OPSUMIT® REMS Program. For females of reproductive potential, exclude pregnancy prior to initiation of therapy, ensure use of acceptable contraceptive methods, and obtain monthly pregnancy tests.
Notable requirements of the OPSUMIT® REMS Program include:
- Prescribers must be certified with the program by enrolling and completing training.
- All females, regardless of reproductive potential, must enroll in the OPSUMIT® REMS Program prior to initiating OPSUMIT®. Male patients are not enrolled in the REMS.
- Females 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 OPSUMIT®.
- ERAs have caused elevations of aminotransferases, hepatotoxicity, and liver failure. The incidence of elevated aminotransferases in the SERAPHIN study >3 x ULN was 3.4% for OPSUMIT® vs 4.5% for placebo, and >8 x ULN was 2.1% vs 0.4%, respectively. Discontinuations for hepatic adverse events were 3.3% for OPSUMIT® vs 1.6% for placebo.
- Obtain liver enzyme tests prior to initiation of OPSUMIT® and repeat during treatment as clinically indicated.
- Advise patients to report symptoms suggesting hepatic injury (nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, fever, or itching).
- If clinically relevant aminotransferase elevations occur, or if elevations are accompanied by an increase in bilirubin >2 x ULN, or by clinical symptoms of hepatotoxicity, discontinue OPSUMIT®. Consider re-initiation of OPSUMIT® when hepatic enzyme levels normalize in patients who have not experienced clinical symptoms of hepatotoxicity.
- Peripheral edema and fluid retention are known consequences of PAH and ERAs. In the pivotal PAH study SERAPHIN, edema was reported in 21.9% of the OPSUMIT® group vs 20.5% for placebo.
- Patients with underlying left ventricular dysfunction may be at particular risk for developing significant fluid retention after initiation of ERA treatment. In a small study of pulmonary hypertension due to left ventricular dysfunction, more patients in the OPSUMIT® group developed significant fluid retention and had more hospitalizations due to worsening heart failure compared to placebo. Postmarketing cases of edema and fluid retention occurring within weeks of starting OPSUMIT®, some requiring intervention with a diuretic or hospitalization for decompensated heart failure, have been reported.
- Monitor for signs of fluid retention after OPSUMIT® initiation. If clinically significant fluid retention develops, evaluate the patient to determine the cause and the possible need to discontinue OPSUMIT®.
- Decreases in hemoglobin concentration and hematocrit have occurred following administration of other ERAs and in clinical studies with OPSUMIT®. These decreases occurred early and stabilized thereafter.
- In the SERAPHIN study, OPSUMIT® caused a mean decrease in hemoglobin (from baseline to 18 months) of about 1.0 g/dL vs no change in the placebo group. A decrease in hemoglobin to below 10.0 g/dL was reported in 8.7% of the OPSUMIT® group vs 3.4% for placebo. Decreases in hemoglobin seldom require transfusion.
- Initiation of OPSUMIT® is not recommended in patients with severe anemia. Measure hemoglobin prior to initiation of treatment and repeat during treatment as clinically indicated.
Pulmonary Edema with Pulmonary Veno-occlusive Disease (PVOD)
Should signs of pulmonary edema occur, consider the possibility of associated PVOD. If confirmed, discontinue OPSUMIT®.
Decreased Sperm Counts
OPSUMIT®, like other ERAs, may have an adverse effect on spermatogenesis. Counsel men about potential effects on fertility.
Most common adverse reactions (more frequent than placebo by ≥3%) were anemia (13% vs 3%), nasopharyngitis/pharyngitis (20% vs 13%), bronchitis (12% vs 6%), headache (14% vs 9%), influenza (6% vs 2%), and urinary tract infection (9% vs 6%).
- Strong inducers of CYP3A4 such as rifampin significantly reduce macitentan exposure. Concomitant use of OPSUMIT® with strong CYP3A4 inducers should be avoided.
- Strong inhibitors of CYP3A4 like ketoconazole approximately double macitentan exposure. Many HIV drugs like ritonavir are strong inhibitors of CYP3A4. Avoid concomitant use of OPSUMIT® with strong CYP3A4 inhibitors. Use other PAH treatment options when strong CYP3A4 inhibitors are needed as part of HIV treatment.
- Moderate dual inhibitors of CYP3A4 and CYP2C9 such as fluconazole and amiodarone are predicted to increase macitentan exposure. Avoid concomitant use of OPSUMIT® with moderate dual inhibitors of CYP3A4 and CYP2C9.
- Concomitant treatment of both a moderate CYP3A4 inhibitor and moderate CYP2C9 inhibitor with OPSUMIT® should also be avoided.
Please see accompanying full Prescribing Information, including BOXED WARNING.
TRACLEER® (bosentan) is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1):
- in adults to improve exercise ability and to decrease clinical worsening. Studies establishing effectiveness included predominantly patients with WHO Functional Class II-IV symptoms and etiologies of idiopathic or heritable PAH (60%), PAH associated with connective tissue diseases (21%), and PAH associated with congenital heart disease with left-to-right shunts (18%).
- in pediatric patients aged 3 years and older with idiopathic or congenital PAH to improve pulmonary vascular resistance (PVR), which is expected to result in an improvement in exercise ability.
Because of the risks of hepatotoxicity and birth defects, TRACLEER® is available only through a restricted program called the Bosentan REMS Program. Under the Bosentan REMS, prescribers, patients, and pharmacies must enroll in the program.
Elevations of liver aminotransferases (ALT, AST) and liver failure have been reported with TRACLEER®. In a setting of close monitoring, rare cases of liver failure and unexplained hepatic cirrhosis were observed after prolonged (>12 months) treatment. In general, avoid using TRACLEER® in patients with elevated aminotransferases (>3 x ULN) at baseline. Measure liver aminotransferases prior to initiation of treatment and then monthly. Discontinue TRACLEER® if aminotransferase elevations are accompanied by signs or symptoms of liver dysfunction or injury or increases in bilirubin ≥2 x ULN.
Based on animal data, TRACLEER® is likely to cause major birth defects if used during pregnancy. Exclude pregnancy before and during treatment. To prevent pregnancy, females of reproductive potential must use 2 reliable forms of contraception during treatment and for 1 month after stopping TRACLEER® unless the patient has an intrauterine device (IUD) or tubal sterilization, in which case no other contraception is needed. Obtain monthly pregnancy tests.
TRACLEER® is contraindicated:
- In females who are or may become pregnant
- With cyclosporine A
- With glyburide
- In patients who are hypersensitive to bosentan or any component of TRACLEER®. Observed reactions include Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), anaphylaxis, rash and angioedema.
WARNINGS AND PRECAUTIONS
In clinical trials, ALT/AST elevations (>3 x ULN) were observed in 11% of patients treated with TRACLEER®, accompanied by elevated bilirubin in a few cases. In a pooled analysis of pediatric studies conducted in PAH, elevations in liver aminotransferases ≥3 x ULN were observed in 2% of patients. The combination of hepatocellular injury (increases in aminotransferases of >3 x ULN) and increases in total bilirubin (≥2 x ULN) is a marker for potential serious hepatotoxicity. Liver aminotransferase levels must be measured prior to initiation of treatment and then monthly. Avoid using TRACLEER® in patients with moderate or severe liver impairment or elevated ALT/AST >3 x ULN prior to drug initiation.
If clinically significant fluid retention develops, with or without associated weight gain, the cause, such as TRACLEER® or underlying heart failure, must be determined. Patients may require treatment or TRACLEER® therapy may need to be discontinued.
Should signs of pulmonary edema occur, consider the possibility of associated pulmonary veno-occlusive disease and consider whether TRACLEER® should be discontinued.
Decreased sperm counts have been observed in patients receiving TRACLEER®. Preclinical data also suggest that TRACLEER®, like other endothelin receptor antagonists, may have an adverse effect on spermatogenesis.
Treatment with TRACLEER® can cause a dose-related decrease in hemoglobin (Hgb) and hematocrit. Hgb should be checked after 1 and 3 months, and then every 3 months. Upon marked decrease in Hgb, determine the cause and need for specific treatment.
In TRACLEER® pivotal trials, the most common adverse events occurring more often in TRACLEER®-treated patients than in patients taking placebo were respiratory tract infection (22% vs 17%), headache (15% vs 14%), edema (11% vs 9%), chest pain (5% vs 5%), syncope (5% vs 4%), flushing (4% vs 3%), hypotension (4% vs 2%), sinusitis (4% vs 2%), arthralgia (4% vs 2%), abnormal serum aminotransferases (4% vs 2%), palpitations (4% vs 2%), and anemia (3% vs 0%). TRACLEER® was evaluated for safety in pediatric patients in uncontrolled studies. The safety profile was similar to that observed in adult patients with PAH.
- TRACLEER® is contraindicated for use with cyclosporine A and with glyburide.
TRACLEER® is metabolized by CYP2C9 and CYP3A.
- Co-administration with agents that are metabolized by these pathways may affect plasma concentrations of one or both agents.
- Hormonal contraceptives, including oral, injectable, transdermal, and implantable forms, may not be reliable when TRACLEER® is co-administered.
- When initiating lopinavir/ritonavir and other ritonavir-containing HIV regimens, dosage adjustment of TRACLEER® is necessary.
- When co-administered with simvastatin, or other statins that are CYP3A substrates, dosage adjustment of such statins may need to be considered.
- When co-administered with rifampin, a CYP3A inducer, liver function should be monitored weekly.
- When co-administered with ketoconazole, a potent CYP3A inhibitor, no dose adjustment of TRACLEER® is necessary, but increased effects of TRACLEER® may need to be considered.
There are no clinically relevant interactions between TRACLEER® and warfarin, digoxin, nimodipine, losartan, sildenafil, or tadalafil.
- Dose adjustments are not necessary when TRACLEER® and sildenafil or tadalafil are co-administered.
LIVER ENZYME ELEVATIONS
- Measure liver aminotransferases prior to initiation of treatment and then monthly.
- Use of TRACLEER® should generally be avoided in patients with elevated aminotransferases (>3 x ULN) at baseline because monitoring for hepatotoxicity may be more difficult.
It is important to adhere strictly to the monthly monitoring schedule for the duration of treatment.
- Changes in aminotransferases may occur early or late in treatment.
- There have been rare postmarketing reports of liver failure and unexplained hepatic cirrhosis in a setting of close monitoring; the contribution of TRACLEER® could not be excluded.
- For patients whose monthly LFTs are ≤3 x ULN, no change in monitoring schedule or dosage is required.
- For patients whose monthly LFTs are >3 x ULN, close monitoring and either dose reduction or treatment cessation are necessary.
It is important to adhere strictly to the monthly monitoring schedule for LFTs and, if applicable, pregnancy for the duration of treatment.
Please see full Prescribing Information and Medication Guide for TRACLEER®, including BOXED WARNING about liver injury and birth defects. Provide the Medication Guide to your patients and encourage discussion.
UPTRAVI® (selexipag) is indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to delay disease progression and reduce the risk of hospitalization for PAH.
Effectiveness was established in a long-term study in PAH patients with WHO Functional Class II-III symptoms.
Patients had idiopathic and heritable PAH (58%), PAH associated with connective tissue disease (29%), and PAH associated with congenital heart disease with repaired shunts (10%).
Concomitant use of strong inhibitors of CYP2C8 (eg, gemfibrozil) with UPTRAVI® is contraindicated.
WARNINGS AND PRECAUTIONS
Pulmonary Veno-Occlusive Disease (PVOD)
Should signs of pulmonary edema occur, consider the possibility of associated PVOD. If confirmed, discontinue UPTRAVI®.
Adverse reactions more frequent compared to placebo (≥3%) are headache (65% vs 32%), diarrhea (42% vs 18%), jaw pain (26% vs 6%), nausea (33% vs 18%), myalgia (16% vs 6%), vomiting (18% vs 9%), pain in extremity (17% vs 8%), flushing (12% vs 5%), arthralgia (11% vs 8%), anemia (8% vs 5%), decreased appetite (6% vs 3%), and rash (11% vs 8%).
These adverse reactions are more frequent during the dose titration phase.
Hyperthyroidism was observed in 1% (n=8) of patients on UPTRAVI® and in none of the patients on placebo.
Concomitant administration with gemfibrozil, a strong inhibitor of CYP2C8, doubled exposure to selexipag and increased exposure to the active metabolite by approximately 11-fold. Concomitant use of UPTRAVI® with strong inhibitors of CYP2C8 is contraindicated.
Concomitant administration of UPTRAVI® with clopidogrel, a moderate inhibitor of CYP2C8, had no relevant effect on the exposure to selexipag and increased the exposure to the active metabolite by approximately 2.7-fold. Reduce the dosing of UPTRAVI® to once daily in patients on a moderate CYP2C8 inhibitor.
Concomitant administration with an inducer of CYP2C8 and UGT 1A3 and 2B7 enzymes (rifampin) halved exposure to the active metabolite. Increase UPTRAVI® dose, up to twice, when co-administered with rifampin. Reduce UPTRAVI® when rifampin is stopped.
DOSAGE AND ADMINISTRATION
Recommended starting dose is
Patients With Hepatic Impairment
For patients with moderate hepatic impairment (Child-Pugh class B), the starting dose is
Co-administration With Moderate CYP2C8 Inhibitors
When co-administered with moderate CYP2C8 inhibitors (eg, clopidogrel, deferasirox and teriflunomide), reduce the dosing of UPTRAVI® to once daily. Revert back to twice daily dosing frequency of UPTRAVI® when co-administration of moderate CYP2C8 inhibitor is stopped.
UPTRAVI® tablet strengths:
200, 400, 600, 800, 1000, 1200, 1400, and 1600 mcg.
VELETRI® (epoprostenol) for Injection is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise capacity. Studies establishing effectiveness included predominantly patients with NYHA Functional Class III-IV symptoms and etiologies of idiopathic or heritable PAH or PAH associated with connective tissue diseases (CTD).
VELETRI® is contraindicated in patients with congestive heart failure due to severe left ventricular systolic dysfunction.
VELETRI® should not be used chronically in patients who during dose initiation develop pulmonary edema, which may be associated with pulmonary veno-occlusive disease.
VELETRI® is also contraindicated in patients with known hypersensitivity to the drug or to structurally related compounds.
WARNINGS AND PRECAUTIONS
Reconstitute VELETRI® only as directed using Sterile Water for Injection, USP, or Sodium Chloride 0.9% Injection, USP. Do not mix VELETRI® with any other parenteral medications or solutions prior to or during administration. Each vial is for single use only; discard any unused solution. Use after reconstitution and immediate dilution to final concentration. Use at room temperature (77°F/25°C). Do not expose VELETRI® to direct sunlight.
VELETRI® should be used only by clinicians experienced in the diagnosis and treatment of pulmonary hypertension.
VELETRI® is a potent pulmonary and systemic vasodilator. Initiate VELETRI® in a setting with adequate personnel and equipment for physiologic monitoring and emergency care. During dose initiation, asymptomatic increases in pulmonary artery pressure coincident with increases in cardiac output occurred rarely. In such cases, consider dose reduction, but such an increase does not imply that chronic treatment is contraindicated.
Chronic Use and Dose Adjustment
During chronic use, deliver VELETRI® continuously on an ambulatory basis through a permanent indwelling central venous catheter. Unless contraindicated, administer anticoagulant therapy to patients receiving VELETRI® to reduce the risk of pulmonary thromboembolism or systemic embolism through a patent foramen ovale. To reduce the risk of infection, use aseptic technique in the reconstitution and administration of VELETRI® and in routine catheter care.
Because epoprostenol is metabolized rapidly, even brief interruptions in the delivery of VELETRI® may result in symptoms associated with rebound pulmonary hypertension including dyspnea, dizziness, and asthenia. Intravenous therapy with VELETRI® will likely be needed for prolonged periods, possibly years, so consider the patient’s capacity to accept and care for a permanent intravenous catheter and infusion pump.
Dosage of VELETRI® during chronic use should be adjusted at the first sign of recurrence or worsening of symptoms attributable to pulmonary hypertension or the occurrence of adverse events associated with epoprostenol. Following dosage adjustments, monitor standing and supine blood pressure and heart rate closely for several hours.
Abrupt withdrawal (including interruptions in drug delivery) or sudden large reductions in dosage of VELETRI® may result in symptoms associated with rebound pulmonary hypertension, including dyspnea, dizziness, and asthenia. Abrupt withdrawal should be avoided.
The most common and dose-limiting adverse events during dose initiation and escalation (≥1%) were flushing (58%), headache (49%), nausea/vomiting (32%), hypotension (16%), anxiety/nervousness/agitation (11%), chest pain (11%), dizziness (8%), bradycardia (5%), abdominal pain (5%), musculoskeletal pain (3%), dyspnea (2%), back pain (2%), sweating (1%), dyspepsia (1%), hypesthesia/paresthesia (1%), and tachycardia (1%).
Adverse events occurring in patients with idiopathic or heritable PAH with ≥10% difference between epoprostenol and conventional therapy alone were chills/fever/sepsis/flu-like symptoms (25% vs 11%), tachycardia (35% vs 24%), flushing (42% vs 2%), diarrhea (37% vs 6%), nausea/vomiting (67% vs 48%), jaw pain (54% vs 0%), myalgia (44% vs 31%), nonspecific musculoskeletal pain (35% vs 15%), anxiety/nervousness/tremor (21% vs 9%), dizziness (83% vs 70%), headache (83% vs 33%), and hypesthesia/hyperesthesia/paresthesia (12% vs 2%).
Adverse events occurring in patients with PAH/CTD with ≥10% difference between epoprostenol and conventional therapy alone were flushing (23% vs 0%), hypotension (13% vs 0%), anorexia (66% vs 47%), nausea/vomiting (41% vs 16%), diarrhea (50% vs 5%), jaw pain (75% vs 0%), pain/neck pain/arthralgia (84% vs 65%), headache (46% vs 5%), skin ulcer (39% vs 24%), and eczema/rash/urticaria (25% vs 4%).
Thrombocytopenia has been reported during uncontrolled clinical trials in patients receiving epoprostenol.
Although the relationship to epoprostenol administration has not been established, pulmonary embolism has been reported in several patients taking epoprostenol and there have been reports of hepatic failure.
Additional reductions in blood pressure may occur when VELETRI® is administered with diuretics, antihypertensive agents, or other vasodilators. When other antiplatelet agents or anticoagulants are used concomitantly, there is the potential for VELETRI® to increase the risk of bleeding. However, patients receiving infusions of epoprostenol in clinical trials were maintained on anticoagulants without evidence of increased bleeding. In clinical trials, epoprostenol was used with digoxin, diuretics, anticoagulants, oral vasodilators, and supplemental oxygen.
Please see full Prescribing Information for VELETRI®. Provide to your patients and encourage discussion.
VENTAVIS® (iloprost) Inhalation Solution is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve a composite endpoint consisting of exercise tolerance, symptoms (NYHA Class), and lack of deterioration. Studies establishing effectiveness included predominantly patients with NYHA Functional Class III-IV symptoms and etiologies of idiopathic or heritable PAH (65%) or PAH associated with connective tissue disease (23%).
WARNINGS AND PRECAUTIONS
Risk of Syncope
- Vital signs should be monitored while initiating VENTAVIS®. Hypotension leading to syncope has been observed; VENTAVIS® should therefore not be initiated in patients with systolic blood pressure less than 85 mmHg.
Pulmonary Venous Hypertension
- Stop VENTAVIS® immediately if signs of pulmonary edema occur; this may be a sign of pulmonary venous hypertension.
- VENTAVIS® inhalation may cause bronchospasm and patients with a history of hyperreactive airway disease may be more sensitive.
Serious Adverse Events
- Serious adverse events reported include congestive heart failure, chest pain, supraventricular tachycardia, dyspnea, peripheral edema, and kidney failure.
- Adverse events reported in a Phase 3 clinical trial occurring with a ≥3% difference between VENTAVIS® patients and placebo patients were vasodilation (flushing) (27% vs 9%), increased cough (39% vs 26%), headache (30% vs 20%), trismus (12% vs 3%), insomnia (8% vs 2%), nausea (13% vs 8%), hypotension (11% vs 6%), vomiting (7% vs 2%), alkaline phosphatase increased (6% vs 1%), flu syndrome (14% vs 10%), back pain (7% vs 3%), tongue pain (4% vs 0%), palpitations (7% vs 4%), syncope (8% vs 5%), GGT increased (6% vs 3%), muscle cramps (6% vs 3%), hemoptysis (5% vs 2%), and pneumonia (4% vs 1%).
Antihypertensives and Vasodilators
- VENTAVIS® has the potential to increase the hypotensive effect of vasodilators and antihypertensive agents.
Anticoagulants and Platelet Inhibitors
- VENTAVIS® also has the potential to increase risk of bleeding, particularly in patients maintained on anticoagulants or platelet inhibitors.
- Advise not to breastfeed during treatment with VENTAVIS®.
Please see full Prescribing Information for VENTAVIS®. Provide to your patients and encourage discussion.