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FDA Approves Actelion Pharmaceuticals US, Inc. (ATLN.VX)'s SNDA for Second Generation VELETRI for Injection


6/29/2012 7:06:20 AM

SOUTH SAN FRANCISCO, CA--(Marketwire - June 29, 2012) - Actelion Pharmaceuticals US, Inc. (SIX: ATLN) announced today that the U.S. Food and Drug Administration (FDA) approved their supplemental new drug application (sNDA) for second generation VELETRI, 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).

Second generation VELETRI will offer patients an expanded stability profile and prolonged storage capacity. "This is one example of our continued and long-term commitment to patients with pulmonary arterial hypertension," said Shal Jacobovitz, President of Actelion Pharmaceuticals US, Inc. "Second generation VELETRI provides patients and their caregivers a treatment option that allows patients to have more flexibility in their daily lives."

In addition, Actelion will make VELETRI available in 2 vial strengths, 0.5 mg and 1.5 mg. The new 0.5 mg vial is recommended for patients using final concentrations of VELETRI < 15,000 ng/mL. Until the newly approved formulation and vial strength become available, patients should continue to use VELETRI according to the current package insert, which can be found at www.veletri.com.

About VELETRI®

INDICATION
VELETRI 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).

CONTRAINDICATIONS
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 develop pulmonary edema during dose initiation which may be associated with pulmonary veno-occlusive disease. VELETRI is contraindicated in patients with known hypersensitivity to the drug or to structurally related compounds.

WARNINGS AND PRECAUTIONS
General
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. VELETRI should be used only by clinicians experienced in the diagnosis and treatment of pulmonary hypertension.

Dose Initiation
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.

Withdrawal Effects
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.

ADVERSE EVENTS
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.
Potential adverse events from postmarketing evaluations include anemia, hypersplenism, pancytopenia, splenomegaly, and hyperthyroidism.

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.

DRUG INTERACTIONS
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.

Accredo Health Group, Inc. is the sole specialty pharmacy provider of VELETRI. Accredo offers an enhanced level of personalized service to patients with chronic and complex disease, and will provide call center, nursing and reimbursement support services for patients using VELETRI and their healthcare providers. Patients and their physicians can call 1-866-FIGHTPH (1-866-344-4874), a hotline maintained by Accredo, to obtain benefit information available for VELETRI.

About Accredo® Health Group
Accredo Health Group, Inc., an Express Scripts company, is one of the nation's largest specialty pharmacies dedicated to providing an enhanced level of personalized service to patients with chronic and complex disease. Drugs dispensed by Accredo frequently require special handling and clinical services to ensure the drugs are properly administered to promote patient safety and health.

About Pulmonary Arterial Hypertension
Pulmonary arterial hypertension (PAH) is a chronic, life-threatening disorder characterized by abnormally high blood pressure in the arteries between the heart and lungs of an affected individual. The symptoms of PAH are non-specific and can range from mild breathlessness and fatigue during normal daily activity to symptoms of right heart failure and severe restrictions on exercise capacity and ultimately reduced life expectancy.

PAH is one group within the classification of pulmonary hypertension (PH). This group includes idiopathic PAH, heritable PAH and PAH caused by factors which include connective tissue disease, HIV infection and congenital heart disease.

The last decade has seen significant advances in the understanding of the pathophysiology of PAH, which has been paralleled with developments of treatment guidelines and new therapies. Drugs targeting the 3 pathways that have been established in the pathogenesis of PAH are endothelin receptor antagonists (ERAs), prostacyclins and phosphodiesterase-5 inhibitors. PAH treatments have transformed the prognosis for PAH patients from symptomatic improvements in exercise tolerance 10 years ago to delayed disease progression today. Improved disease awareness and evidence-based guidelines developed from randomized clinical trial data have highlighted the need for early intervention, goal-oriented treatment and combination therapy.

Despite these advances in PAH, survival rates are unacceptably low and PAH remains incurable.

References

1. For a general discussion of a clinically meaningful outcome end-point, please see: Proceedings of the 4th world symposium on pulmonary hypertension. J Am Coll Cardiol 2009;54(1 Suppl).

2. Sidharta PN et al. Macitentan: Entry-into-humans study with a new endothelin receptor antagonist. Eur J Clin Pharmacol. 2011;67(10):977-84

3. Bruderer S et al. Effect of cyclosporine A and rifampin on the pharmacokinetics of macitentan, a tissue-targeting dual endothelin receptor antagonist. AAPS J. 2012;14(1):68-78.

4. Bruderer S et al. Absorption, distribution, metabolism, and excretion of macitentan, a dual endothelin receptor antagonist, in humans. Epub Mar 30, 2012

For more information on Actelion's offerings in the area of PAH, please refer to www.actelion.com

Actelion Ltd.
Actelion Ltd is a biopharmaceutical company with its corporate headquarters in Allschwil/Basel, Switzerland. Actelion's first drug Tracleer®, an orally available dual endothelin receptor antagonist, has been approved as a therapy for pulmonary arterial hypertension. Actelion markets Tracleer through its own subsidiaries in key markets worldwide, including the United States (based in South San Francisco), the European Union, Japan, Canada, Australia and Switzerland. Actelion, founded in late 1997, is a leading player in innovative science related to the endothelium -- the single layer of cells separating every blood vessel from the blood stream. Actelion's over 2,500 employees focus on the discovery, development and marketing of innovative drugs for significant unmet medical needs. Actelion shares are traded on the SIX Swiss Exchange (SIX: ATLN) as part of the Swiss blue-chip index SMI (Swiss Market Index SMI®).


For further information please contact:
Roland Haefeli
Senior Vice President, Head of Investor Relations & Public Affairs
Actelion Pharmaceuticals Ltd
Gewerbestrasse 16, CH-4123 Allschwil
+41 61 565 62 62
+1 650 624 69 36
www.actelion.com




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