*Indication

Ventavis 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 predominately patients with NYHA Functional Class III-IV symptoms and etiologies of idiopathic or heritable PAH (65%) or PAH associated with connective tissue disease (23%).

• About Ventavis

•      Indications

•      Clinical Trials

•      Efficacy

•           Clinical Improvement

•           Improved Exercise
            Capacity

•           Functional Class
            Improvement

•           Improved
            Hemodynamics

•      Safety Profile

•      Dosage & Administration

•      Ventavis Support

• About the I-neb AAD
  System

• Services for Your Patients

• Resources

• Prescribing Information

• For Patients and
  Caregivers

FAQs

Q. Is it safe to use Ventavis^® (iloprost) Inhalation Solution in combination with other PAH* therapies?
A. Safety in combination has only been established to date in combination with an endothelin receptor antagonist. In a small clinical trial (the STEP trial—Safety and Pilot efficacy in combination with [an ERA] for Evaluation of Pulmonary arterial hypertension*), safety trends in patients receiving concomitant bosentan and iloprost were consistent with those observed in the larger experience of the Phase 3 study in patients receiving only iloprost.¹

During clinical trials, iloprost was used concurrently with anticoagulants, diuretics, cardiac glycosides, calcium channel blockers, analgesics, antipyretics, nonsteroidal anti-inflammatories, corticosteroids, and other medications. Intravenous infusion of iloprost had no effect on the pharmacokinetics of digoxin. Acetylsalicylic acid did not alter the clearance (pharmacokinetics) of iloprost.

Q. What is the STEP trial?
A. The STEP study is the largest randomized, double-blind, placebo controlled trial completed to date that explores the use of incremental therapy for PAH*.

• In this study, 67 patients with PAH* treated with [an endothelin receptor antagonist, or ERA] for at least 4 months were randomized to receive inhaled iloprost or placebo
• No patient discontinued or reduced the dose of [the ERA] during the study. The 34 patients treated with an ERA for at least 16 weeks tolerated the addition of inhaled iloprost.
• Therapy with inhaled iloprost in addition to [an ERA] was well tolerated, and appeared safe, with an adverse event profile typical of the prostanoid class
• There were no clinically important changes in laboratory tests (chemistry, hematology, urinalysis), and no patient had significant liver function test elevation
• One patient in the iloprost group and two patients in the placebo group reported syncope that did not require treatment and was without sequelae

The STEP study was intended to test primarily safety of combination therapy, although efficacy data was also assessed as a secondary endpoint. The AIR study, by contrast, compared the efficacy and safety of standalone inhaled iloprost versus placebo alone.

Q. What is the pharmacodynamic profile of iloprost?
A. A single dose of inhaled iloprost 5 mcg was administered via 3 different pulmonary drug delivery devices in a Phase I, single-dose, crossover pharmacokinetic and pharmacodynamic trial to 13 patients with various forms of PAH*.

Increased serum concentrations of iloprost appeared within 10 to 20 minutes of beginning inhalation with all 3 devices, and peak concentrations were achieved at the end of the inhalation (i.e., 9 to12 minutes) or within 5 minutes after inhalation.

This same trial provided information about the hemodynamic effects of inhaled iloprost. Immediately after inhalation, iloprost reduced mean PVR by approximately 37% (p<0.001), with PVR returning to baseline within 60 to 120 minutes. Inhaled iloprost also decreased mean PAP and slightly increased mean cardiac output over pre-inhalation values. Systemic heart rate and blood pressure remained unchanged. These pharmacodynamic effects of inhaled iloprost were observed for 60 to 90 minutes, but plasma concentrations were undetectable 30 minutes after inhalation.²

Pulmonary vasodilation, persisting after disappearance of the drug from the systemic circulation, supports the hypothesis that local drug deposition largely contributes to the preferential pulmonary vasodilation in response to iloprost.

Q. Can any significant drug interactions be expected with Ventavis?
A. In studies in normal volunteers, there was no pharmacodynamic interaction between intravenous iloprost and either nifedipine, diltiazem, or captopril. However, iloprost has the potential to increase the hypotensive effect of vasodilators and antihypertensive agents. Since iloprost inhibits platelet function, there is a potential for increased risk of bleeding, particularly in patients maintained on anticoagulants.

Q. Are there any trough efficacy data available for the effect of Ventavis?
A. The AIR trial compared the effect of 3 months of inhaled iloprost versus placebo and evaluated changes in walk distance at peak and trough levels. When walk distance was measured immediately prior to inhalation, the improvement compared to placebo was approximately 60% of the effect seen at 30 minutes after inhalation. The improvement in NYHA Functional Class was significant (p=0.03) and was not dependent upon peak/trough levels.^1,3 To assess "long-term" effects, hemodynamics before inhalation (expected trough condition) and at the end of inhalation (expected peak condition) at week 12 were compared with the pre-inhalation values obtained at baseline. A significant improvement was observed for mPAP, PVR, and SvO2 at the peak measurement in the iloprost group (p < 0.05). At 12 weeks, patients were stable compared with baseline for trough values.

Q. What are the most common adverse reactions with Ventavis?
A. In clinical studies, common adverse reactions due to Ventavis included: vasodilation (flushing, 27%), cough (39%), headache (30%), flu syndrome (14%), nausea (13%), trismus (12%), hypotension (11%), insomnia (8%), and syncope (8%). Other pre-marketing serious adverse events reported with the use of Ventavis included congestive heart failure, chest pain, supraventricular tachycardia, dyspnea, peripheral edema, and kidney failure.

Q. How can I manage the risk of syncope when starting treatment with Ventavis?
A. Vital signs should be monitored while initiating Ventavis. In patients with low systemic blood pressure, care should be taken to avoid further hypotension. Ventavis should not be initiated in patients with systolic blood pressure less than 85 mm Hg. Physicians should be aware of the presence of concomitant conditions or drugs that might increase the risk of syncope. Syncope can also occur in association with pulmonary arterial hypertension*, particularly in association with physical exertion. The occurrence of exertional syncope may reflect a therapeutic gap or insufficient efficacy, and the need to adjust dose or change therapy should be considered.

Q. How many times a day should patients inhale Ventavis, and do they need to take it during sleeping hours?
A. Ventavis should be taken 6 to 9 times per day during waking hours, according to individual need and tolerability (but not more than once every 2 hours). In the randomized, placebo-controlled, Phase 3 clinical trial, the mean number of inhalations per day was 7.3 and 90% of patients in the iloprost group never inhaled study medication during sleeping hours.

Q. What makes the I-neb AAD System unique?
A. The I-neb AAD System uses Adaptive Aerosol Delivery (AAD) technology to precisely and reproducibly deliver Ventavis to every patient, at either dose (2.5 mcg or 5.0 mcg), using a single ampule of medication.

The I-neb AAD System monitors a patient's unique breathing pattern and continually adapts to breathing changes during treatment to deliver a precise dose. The I-neb AAD System delivers aerosolized Ventavis during the first 80% of inhalation, ensuring no medication is wasted in the deadspace on inhalation or lost to the environment on exhalation. With the I-neb AAD System, a medication chamber controls the dose and a control disc operates the I-neb AAD System. Once a patient receives a complete dose, the I-neb AAD System stops delivering aerosol and signals the user with visual and audible indicators.

Q. Why must Ventavis be administered with the I-neb AAD System?
A. Although there are many aerosol devices approved in the U.S., it is important that Ventavis be dosed only via the I-neb AAD System. Only the I-neb AAD System is currently available and has been FDA approved to deliver safe and accurate dosing of Ventavis.

Standard airjet nebulizers/compressors or ultrasonic nebulizer systems, such as those used to deliver inhalation solutions for asthma, are continuous flow systems that constantly generate aerosol. Patients typically have a 40:60 inhalation:exhalation ratio; therefore, about 60% of the drug is wasted to the environment with such devices during exhalation. Additionally, a variable amount of drug is inhaled by each patient because individual breathing patterns differ (e.g., short, shallow breaths to long, deep breaths).

In contrast, Ventavis is a potent prostacyclin analogue which requires precise, reproducible dosing of Ventavis to every patient for the safety and efficacy of the drug. The I-neb AAD System only delivers the drug during the patient's inhalation and adapts for each patient's unique breathing pattern.

Q. How large is the I-neb AAD device?
A. The I-neb AAD device is a compact, lightweight, battery-powered system that is approximately 6 inches high and weighs less than 8 ounces. Each patient is provided with one I-neb AAD System and a convenient carrying bag, complete with room for supplies.

I-neb AAD System User Guide
Respironics and I-neb are trademarks of or belonging to Koninklijke Philips Electronics N.V.

Q. Does cytochrome P450 play a role in the biotransformation of iloprost?
A. In vitro studies reveal that cyctochrome P450-dependent pathways play only a minor role in the metabolism of iloprost.

IMPORTANT SAFETY INFORMATION

Hypotension leading to syncope has been observed; Ventavis should therefore not be initiated in patients with systolic blood pressure less than 85 mmHG. Stop Ventavis immediately if signs of pulmonary edema occur; this may be a sign of pulmonary venous hypertension. Ventavis inhalation may cause brochospasm and patients with a history of hyperreactive airway disease may be more sensitive. Serious adverse events reported at a rate of less than 3% included congestive heart failure, chest pain, supraventricular tachycardia, dyspnea, peripheral edema, and kidney failure. Vital signs should be monitored while initiating Ventavis. In clinical studies, common adverse reactions due to Ventavis included vasodilation (flushing), cough, headache, trismus, and insomnia. Ventavis has the potential to increase risk of bleeding, particularly in patients maintained on anticoagulants.

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