Ventavis
(iloprost)Dosage & Administration
VENTAVIS is intended to be inhaled using the I-neb® AAD® System. Patients should receive 6 to 9 doses (inhalations) per day (minimum of 2 hours between doses during waking hours) as follows:
| Delivered dose from ampule of: | ||
|---|---|---|
| Nebulizer | 10 mcg/mL | 20 mcg/mL |
| I-neb® AAD® | 2.5 or 5 mcg from one ampule | 5 mcg from one ampule |
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Ventavis Prescribing Information
Pulmonary Arterial Hypertension
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 diseases (23%) [see Clinical Studies (14)].
Recommended Dosing
VENTAVIS is intended to be inhaled using the I-neb® AAD® System. The recommended initial inhaled dose is 2.5 mcg (as delivered at the mouthpiece). If well tolerated, increase dosing to 5.0 mcg and maintain at that dose; otherwise maintain the dose at 2.5 mcg [see Warnings and Precautions (5.1)]. VENTAVIS 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 with other medications in the I-neb® 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.
For each inhalation session, only a mouthpiece should be used. Avoid skin or eye contact with VENTAVIS solution. Do not orally ingest VENTAVIS solution.
VENTAVIS is supplied in 1 mL ampules in two concentrations: 10 mcg/mL and 20 mcg/mL.
| Delivered dose from ampule of: | ||
|---|---|---|
| Nebulizer | 10 mcg/mL | 20 mcg/mL |
| I-neb® AAD® | 2.5 or 5 mcg from one ampule | 5 mcg from one ampule |
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-neb® AAD® System will decrease treatment times to help maintain patient compliance.
For each inhalation session, the entire contents of each opened ampule of VENTAVIS should be transferred into the I-neb® AAD® System medication chamber immediately before use. Discard any solution remaining in the medication chamber after each inhalation session. Patients should follow the manufacturer's instructions for cleaning the I-neb® AAD® System components after each dose administration.
1 mL ampules in two concentrations: 10 mcg/mL and 20 mcg/mL.
Pregnancy
Risk Summary
Limited published data from case series and case reports with VENTAVIS in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with pulmonary arterial hypertension (see Clinical Considerations). In animal reproductive studies, administration of continuous intravenous iloprost to pregnant Han-Wistar rats during organogenesis at doses 2-times the recommended human dose on a mg/m2 basis resulted in adverse developmental outcomes. However, there were no adverse developmental outcomes with intravenous administration of iloprost to pregnant Sprague-Dawley rats, rabbits and monkeys at doses 1200-, 180-, and 14-times, respectively, the recommended human dose on a mg/m2 basis (see Data).
The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Clinical Considerations
Disease-associated Maternal and/or Embryo/Fetal Risk
Pulmonary arterial hypertension in pregnancy increases the risk for maternal heart failure, stroke and death, miscarriage, preterm delivery, low birthweight infants, and stillbirth.
Data
Animal Data
In developmental toxicity studies in pregnant Han-Wistar rats, continuous intravenous administration of iloprost at a dosage of 0.01 mg/kg daily (serum levels not available) led to shortened digits of the thoracic extremity in fetuses and pups. In comparable studies in pregnant Sprague-Dawley rats which received iloprost clathrate (13% iloprost by weight) orally at dosages of up to 50 mg/kg/day (Cmax of 90 ng/mL), in pregnant rabbits at intravenous dosages of up to 0.5 mg/kg/day (Cmax of 86 ng/mL), and in pregnant monkeys at dosages of up to 0.04 mg/kg/day (serum levels of 1 ng/mL), no such digital anomalies or other gross-structural abnormalities were observed in the fetuses/pups. However, in gravid Sprague-Dawley rats, iloprost clathrate (13% iloprost) significantly increased the number of non-viable fetuses at a maternally toxic oral dosage of 250 mg/kg/day and in Han-Wistar rats was found to be embryolethal in 15 of 44 litters at an intravenous dosage of 1 mg/kg/day.
Lactation
Risk Summary
There are no data on the presence of iloprost in human milk, the effects on the breastfed infant, or the effects on milk production. Iloprost is present in rat milk (see Data). When a drug is present in animal milk, it is likely that the drug will be present in human milk.
Because of the potential for serious adverse reactions, advise women not to breastfeed during treatment with VENTAVIS [see Warnings and Precautions (5) and Adverse Reactions (6)].
Data
Animal Data
In studies with Han-Wistar rats, higher mortality was observed in pups of lactating dams receiving iloprost intravenously at 1 mg/kg daily. In Sprague-Dawley rats, higher mortality was also observed in nursing pups at a maternally toxic oral dose of 250 mg/kg/day of iloprost clathrate (13% iloprost by weight). In rats a passage of low levels of iloprost or metabolites in to the milk was observed (less than 1% of iloprost dose given intravenously). No disturbance of post-natal development and reproductive performance was seen in animals exposed during lactation.
Pediatric Use
Safety and efficacy in pediatric patients have not been established.
Geriatric Use
Clinical studies of VENTAVIS did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Hepatic Impairment
VENTAVIS has not been evaluated in subjects with impaired hepatic function. However, in an intravenous iloprost study in patients with liver cirrhosis, the mean clearance in Child- Pugh Class B subjects (n=5) was approximately 10 mL/min/kg (half that of healthy subjects). Following oral administration, the mean AUC0–8h in Child-Pugh Class B subjects (n=3) was 1725 pg*h/mL compared to 117 pg*h/mL in normal subjects (n=4) receiving the same oral iloprost dose. In Child-Pugh Class A subjects (n=5), the mean AUC0–8h was 639 pg*h/mL. Although exposure increased with hepatic impairment, there was no effect on half-life.
Renal Impairment
VENTAVIS has not been evaluated in subjects with impaired renal function. However, in a study with intravenous infusion of iloprost in patients with end-stage renal failure, patients requiring intermittent dialysis treatment (n=7) had a mean AUC0–4h of 230 pg*h/mL compared to 54 pg*h/mL in patients with renal failure (n=8) not requiring intermittent dialysis and 48 pg*h/mL in normals. The half-life was similar in both groups. The effect of dialysis on iloprost exposure has not been evaluated.
None.
Risk of Syncope
Monitor vital signs while initiating VENTAVIS. Do not initiate VENTAVIS in patients with systolic blood pressure below 85 mmHg. 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.
Pulmonary Venous Hypertension
Should signs of pulmonary edema occur when inhaled VENTAVIS is administered in patients with pulmonary hypertension, stop treatment immediately, as this may be a sign of pulmonary venous hypertension.
Bronchospasm
VENTAVIS inhalation can induce bronchospasm. Bronchospasm may be more severe or frequent in patients with a history of hyperreactive airways. VENTAVIS has not been evaluated in patients with chronic obstructive pulmonary disease (COPD), severe asthma, or with acute pulmonary infections.