Ventavis Information
Ventavis (Iloprost) . Dosage And Administration
Ventavis (Iloprost) is intended to be inhaled using either of two pulmonary drug delivery devices: the I-neb® AAD® System or the Prodose® AAD® System. The first inhaled dose should be 2.5 mcg (as delivered at the mouthpiece). If this dose is well tolerated, dosing should be increased to 5.0 mcg and maintained at that dose; otherwise maintain the dose at 2.5 mcg. Ventavis (Iloprost) should be taken 6 to 9 times per day (no more than once every 2 hours) during waking hours, according to individual need and tolerability. The maximum daily dose evaluated in clinical studies was 45 mcg (5 mcg 9 times per day).
Direct mixing of Ventavis (Iloprost) with other medications in the I-neb® AAD® System or the Prodose® AAD® System has not been evaluated; do not mix with other medications. To avoid potential interruptions in drug delivery due to equipment malfunctions, the patient should have easy access to a back-up I-neb®AAD® System or Prodose® AAD® System.
Ventavis (Iloprost) is supplied in 1 mL ampules in two concentrations: 10 mcg/mL and 20 mcg/mL.
The 20 mcg/mL concentration is intended for patients who are maintained at the 5 mcg dose and who have repeatedly experienced extended treatment times which could result in incomplete dosing. Transitioning patients to the 20 mcg/mL concentration using the I-nebAAD System will decrease treatment times to help maintain patient compliance.
For each inhalation session, the entire contents of each opened ampule of Ventavis (Iloprost) should be transferred into either the I-neb® AAD® System or the Prodose® AAD® System medication chamber immediately before use . After each inhalation session, any solution remaining in the medication chamber should be discarded. Use of the remaining solution will result in unpredictable dosing. Patients should follow the manufacturer's instructions for cleaning the I-neb® AAD® System or the Prodose® AAD® System components after each dose administration.
Ventavis (Iloprost) . Dosage Forms And Strengths
1 mL ampules in two concentrations: 10 mcg/mL and 20 mcg/mL.
Ventavis (Iloprost) . Warnings And Precautions
Ventavis (Iloprost) solution should not be allowed to come into contact with the skin or eyes; oral ingestion of Ventavis (Iloprost) solution should be avoided.
Ventavis (Iloprost) . Adverse Reactions
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Pre-marketing safety data on Ventavis (Iloprost) were obtained from 215 patients with pulmonary arterial hypertension receiving iloprost in two 12-week clinical trials and two long-term extensions. Patients received inhaled Ventavis (Iloprost) for periods of from 1 day to more than 3 years. The median number of weeks of exposure was 15. Forty patients completed 12 months of open-label treatment with iloprost.
The following table shows adverse events reported by at least 4 Ventavis (Iloprost) patients and reported at least 3% more frequently for Ventavis (Iloprost) patients than placebo patients in the 12-week placebo-controlled study.
Pre-marketing serious adverse events reported with the use of inhaled Ventavis (Iloprost) and not shown in Table 1 include congestive heart failure, chest pain, supraventricular tachycardia, dyspnea, peripheral edema, and kidney failure.
In a small clinical trial (the STEP trial) , safety trends in patients receiving concomitant bosentan and Ventavis (Iloprost) were consistent with those observed in the larger experience of the Phase 3 study in patients receiving only Ventavis (Iloprost) or bosentan.
The following adverse reactions have been identified during the postapproval use of Ventavis (Iloprost) . Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Cases of bronchospasm and wheezing have been reported, particularly in patients with a history of hyperreactive airways . Cases of epistaxis and gingival bleeding have been reported within one month of starting Ventavis (Iloprost) treatment. Cases of dizziness, diarrhea, mouth and tongue irritation, dysgeusia, hypersensitivity, and rash have also been reported with the use of Ventavis (Iloprost) .
Ventavis (Iloprost) . Drug Interactions
During clinical trials, iloprost was used concurrently with anticoagulants, diuretics, cardiac glycosides, calcium channel blockers, analgesics, antipyretics, nonsteroidal anti-inflammatory drugs, 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.
Ventavis (Iloprost) . Overdosage
In clinical trials of Ventavis (Iloprost) , no case of overdose was reported. Signs and symptoms to be anticipated are extensions of the dose-limiting pharmacological effects, including hypotension, headache, flushing, nausea, vomiting, and diarrhea. A specific antidote is not known. Interruption of the inhalation session, monitoring, and symptomatic measures are recommended.
Ventavis (Iloprost) . Description
Ventavis (Iloprost) Inhalation Solution is a clear, colorless, sterile solution containing iloprost formulated for inhalation via either of two pulmonary drug delivery devices: the I-neb® AAD® (Adaptive Aerosol Delivery) System or the Prodose® AAD® System. Ventavis (Iloprost) is supplied in 1 mL single-use glass ampules containing either 10 mcg/mL or 20 mcg/mL.
For the 10 mcg/mL solution, one mL of the solution contains 0.01 mg iloprost, 0.81 mg ethanol, 0.121 mg tromethamine, 9.0 mg sodium chloride, and approximately 0.51 mg hydrochloric acid (for pH adjustment to 8.1) in water for injection.
For the 20 mcg/mL solution, one mL of the solution contains 0.02 mg iloprost, 1.62 mg ethanol, 0.242 mg tromethamine, 9.0 mg sodium chloride, and approximately 0.76 mg hydrochloric acid (for pH adjustment to 8.4) in water for injection.
The solution contains no preservatives.
The chemical name for iloprost is (E)-(3a, 4, 5, 6a)-hexahydro-5-hydroxy-4-[()-(3,4)-3-hydroxy-4-methyl-1-octen-6-ynyl]-Δ-pentalenevaleric acid. Iloprost consists of a mixture of the 4R and 4S diastereoisomers at a ratio of approximately 53:47. Iloprost is an oily substance, which is soluble in methanol, ethanol, ethyl acetate, acetone, and pH 7 buffer, sparingly soluble in buffer pH 9, and very slightly soluble in distilled water, buffer pH 3, and buffer pH 5. The molecular formula of iloprost is CHO. Its relative molecular weight is 360.49. The structural formula is shown below:
Ventavis (Iloprost) . Clinical Studies
A randomized, double-blind, multi-center, placebo-controlled trial was conducted in 203 adult patients (inhaled iloprost: n=101; placebo: n=102) with NYHA Class III or IV pulmonary arterial hypertension (PAH, WHO Group 1; idiopathic in 53%, associated with connective tissue disease, including CREST and scleroderma, in 17%, or associated with anorexigen use in 2%) or PAH related to chronic thromboembolic disease (WHO Group 4; 28%). Inhaled iloprost (or placebo) was added to patients' current therapy, which could have included anticoagulants, vasodilators (e.g., calcium channel blockers), diuretics, oxygen, and digoxin, but not PGI (prostacyclin or its analogs) or endothelin receptor antagonists. Patients received 2.5 or 5.0 mcg of iloprost by repeated inhalations 6 to 9 times per day during waking hours. The mean age of the entire study population was 52 years and 68% of the patients were female. The majority of patients (59%) were NYHA Class III. The baseline 6-minute walk test values reflected a moderate exercise limitation (the mean was 332 meters for the iloprost group and 315 meters for the placebo group). In the iloprost group, the median daily inhaled dose was 30 mcg (range of 12.5 to 45 mcg/day). The mean number of inhalations per day was 7.3. Ninety percent of patients in the iloprost group never inhaled study medication during the nighttime.
The primary efficacy endpoint was clinical response at 12 weeks, a composite endpoint defined by: a) improvement in exercise ability (6-minute walk test) by at least 10% versus baseline evaluated 30 minutes after dosing, b) improvement by at least one NYHA class versus baseline, and c) no death or deterioration of pulmonary hypertension. Deterioration required two or more of the following criteria: 1) refractory systolic blood pressure < 85 mmHg, 2) worsening of right heart failure with cardiac edema, ascites, or pleural effusion despite adequate background therapy, 3) rapidly progressive cardiogenic hepatic failure (e.g., leading to an increase of GOT or GPT to > 100 U/L, or total bilirubin ≥ 5 mg/dL), 4) rapidly progressive cardiogenic renal failure (e.g., decrease of estimated creatinine clearance to ≤ 50% of baseline), 5) decrease in 6-minute walking distance by ≥ 30% of baseline value, 6) new long-term need for i.v. catecholamines or diuretics, 7) cardiac index ≤ 1.3 L/min/m, 8) CVP ≥ 22 mmHg despite adequate diuretic therapy, and 9) SVO ≤ 45% despite nasal O therapy.
Although effectiveness was seen in the full population (response rates for the primary composite endpoint of 17% and 5%; p=0.007), there was inadequate evidence of benefit in patients with pulmonary hypertension associated with chronic thromboembolic disease (WHO Group 4); the results presented are therefore those related to patients with PAH (WHO Group 1). The response rate for the primary efficacy endpoint among PAH patients was 19% for the iloprost group, compared with 4% for the placebo group (p=0.0033). All three components of the composite endpoint favored iloprost (Figure 1).
The absolute change in 6-minute walk distance (Figure 2) measured (using all available data and no imputation) 30 minutes after inhalation among patients with PAH was greater in the iloprost group compared to the placebo group at all time points. At Week 12, the placebo-corrected difference was 40 meters (p<0.01). 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 effect of Ventavis (Iloprost) in various subgroups is shown in Table 2.
Hemodynamic assessments obtained at week 12 before inhalation in both groups (at least 2 hours after a previous dose, trough) and after inhalation in the iloprost group (approximately 15 minutes after a dose, peak), are shown in Table 3. The relationship between hemodynamic changes and clinical effects is unknown.
In a small, randomized, double-blind, placebo-controlled study (the STEP trial), 34 patients treated with bosentan 125 mg bid for at least 16 weeks tolerated the addition of inhaled iloprost (up to 5 mcg 6 to 9 times per day during waking hours). The mean daily inhaled dose was 27 mcg and the mean number of inhalations per day was 5.6.
Ventavis (Iloprost) . How Supplied/storage And Handling
Ventavis (Iloprost) Inhalation Solution is supplied in cartons of 30 × 1 mL clear glass single-use ampules as follows:
1 mL ampule containing iloprost 10 mcg per mL, carton of 30 (NDC 66215-302-30)
1 mL ampule containing iloprost 20 mcg per mL, carton of 30 (NDC 66215-303-30)
Ventavis (Iloprost) . Patient Counseling Information
Patients receiving Ventavis (Iloprost) should be advised to use the drug only as prescribed with either of two pulmonary drug delivery devices: the I-neb® AAD® System or the Prodose® AAD® System, following the manufacturer's instructions. Patients should be trained in proper administration techniques including dosing frequency, ampule dispensing, I-neb® AAD® System or the Prodose® AAD® System operation, and equipment cleaning.
Advise patients that they may have a fall in blood pressure with Ventavis (Iloprost) , so they may become dizzy or even faint. They should stand up slowly when they get out of a chair or bed. If fainting gets worse, patients should consult their physicians about dose adjustment.
Advise patients that Ventavis (Iloprost) should be inhaled at intervals of not less than 2 hours and that the acute benefits of Ventavis (Iloprost) may not last 2 hours. Thus patients may want to adjust times of administration to cover planned activities.
Ventavis (Iloprost)
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