WARNINGS
Ventavis is intended for inhalation administration only via either of two pulmonary drug delivery devices: the I-neb™ AAD® System or the Prodose® AAD® System (See DOSAGE AND ADMINISTRATION). It has not been studied with any other nebulizers.
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 mmHg. Physicians should be alert to 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.
Should signs of pulmonary edema occur when inhaled iloprost is administered in patients with pulmonary hypertension, the treatment should be stopped immediately. This may be a sign of pulmonary venous hypertension.
PRECAUTIONS
General
Ventavis solution should not be allowed to come into contact with the skin or eyes; oral ingestion of Ventavis solution should be avoided.
Direct mixing of Ventavis with other medications in the I-neb™ AAD® System or the Prodose® AAD® System has not been evaluated.
Ventavis has not been evaluated in patients with chronic obstructive pulmonary disease (COPD), severe asthma, or with acute pulmonary infections.
Information for Patients
Patients receiving Ventavis 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 (see DOSAGE AND ADMINISTRATION). Patients should be trained in proper administration techniques including dosing frequency, ampule dispensing, I-neb™ AAD® System or Prodose® AAD® System operation, and equipment cleaning.
Patients should be advised that they may have a fall in blood pressure with Ventavis, 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.
Patients should be advised that Ventavis should be inhaled at intervals of not less than 2 hours and that the acute benefits of Ventavis may not last 2 hours.
Drug Interactions
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. 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. Although clinical studies have not been conducted, in vitro studies of iloprost indicate that no relevant inhibition of cytochrome P450 drug metabolism would be expected.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Iloprost was not mutagenic in bacterial and mammalian cells in the presence or absence of extrinsic metabolic activation. Iloprost did not cause chromosomal aberrations in vitro in human lymphocytes and was not clastogenic in vivo in NMRI/SPF mice. There was no evidence of a tumorigenic effect of iloprost clathrate (13% iloprost by weight) in Sprague-Dawley rats dosed orally for up to 8 months at doses of up to 125 mg/kg/day (Cmax of 45 ng/mL serum), followed by 16 months at 100 mg/kg/day, or in Crl:CD-1®(ICR)BR albino mice dosed orally for up to 24 months at doses of up to 125 mg/kg/day (Cmax of 156 ng/mL serum). The recommended clinical dosage regimen for iloprost (5 mcg) affords a serum Cmax of 0.16 ng/mL. Fertility of males or females was not impaired in Han-Wistar rats at intravenous doses up to 1 mg/kg/day.
Pregnancy
Pregnancy Category C. 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. There are no adequate and well-controlled studies in pregnant women. Ventavis should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers
It is not known whether Ventavis is excreted in human milk. 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). It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Ventavis, a decision to discontinue nursing should be made, taking into account the importance of the drug to the mother.
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 age 65 and older to determine whether they respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between the 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 or Renal Impairment
Ventavis has not been studied in patients with pulmonary hypertension and hepatic or renal impairment, both of which increase mean AUC in otherwise normal subjects (see CLINICAL PHARMACOLOCY, Special Populations).
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