ion, stop treatment immediately, as this may be a sign of pulmonary venous hypertension. 5.3 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.

g 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.

ore 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 patients and reported at least 3% more frequently for ventavis patients than placebo patients in the 12-week placebo-controlled study. table 1: adverse events in phase 3 clinical trial adverse event ventavis n=101 placebo n=102 placebo subtracted % vasodilation (flushing) 27 9 18 cough increased 39 26 13 headache 30 20 10 trismus 12 3 9 insomnia 8 2 6 nausea 13 8 5 hypotension 11 6 5 vomiting 7 2 5 alk phos increased 6 1 5 flu syndrome 14 10 4 back pain 7 3 4 tongue pain 4 0 4 palpitations 7 4 3 syncope 8 5 3 ggt increased 6 3 3 muscle cramps 6 3 3 hemoptysis 5 2 3 pneumonia 4 1 3 pre-marketing serious adverse events reported with the use of inhaled ventavis 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) [see clinical studies (14) ] , safety trends in patients receiving concomitant bosentan and ventavis were consistent with those observed in the larger experience of the phase 3 study in patients receiving only ventavis or bosentan. adverse events with higher doses in a study in healthy subjects (n=160), inhaled doses of iloprost solution were given every 2 hours, beginning with 5 mcg and increasing up to 20 mcg for a total of 6 dose inhalations (total cumulative dose of 70 mcg) or up to the highest dose tolerated in a subgroup of 40 subjects. there were 13 subjects (32%) who failed to reach the highest scheduled dose (20 mcg). five were unable to increase the dose because of (mild to moderate) transient chest pain/discomfort/tightness, usually accompanied by headache, nausea, and dizziness. the remaining 8 subjects discontinued for other reasons. 6.2 postmarketing experience the following adverse reactions have been identified during the post-approval use of ventavis. 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 [see warnings and precautions (5.3) ] . bleeding events most commonly reported as epistaxis and hemoptysis were observed on ventavis treatment [see drug interactions (7.2) ] . cases of thrombocytopenia, dizziness, diarrhea, mouth and tongue irritation, nasal congestion, dysgeusia, hypersensitivity, and rash have also been reported with the use of ventavis.

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 (c max of 90 ng/ml), in pregnant rabbits at intravenous dosages of up to 0.5 mg/kg/day (c max 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. 8.2 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. 8.4 pediatric use safety and efficacy in pediatric patients have not been established. 8.5 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. 8.6 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 auc 0–8h 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 auc 0–8h was 639 pg*h/ml. although exposure increased with hepatic impairment, there was no effect on half-life. 8.7 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 auc 0–4h 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.

k 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 (c max of 90 ng/ml), in pregnant rabbits at intravenous dosages of up to 0.5 mg/kg/day (c max 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.

y not detectable in plasma 30 minutes to 1 hour after inhalation. absorption and distribution the absolute bioavailability of inhaled iloprost has not been determined. following intravenous infusion, the apparent steady-state volume of distribution was 0.7 to 0.8 l/kg in healthy subjects. iloprost is approximately 60% protein-bound, mainly to albumin, and this ratio is concentration-independent in the range of 30 to 3000 pg/ml. metabolism and excretion in vitro studies reveal that cytochrome p450-dependent metabolism plays only a minor role in the biotransformation of iloprost. iloprost is metabolized principally via β-oxidation of the carboxyl side chain. the main metabolite is tetranor-iloprost, which is found in the urine in free and conjugated form. in animal experiments, tetranor-iloprost was pharmacologically inactive. clearance in normal subjects was approximately 20 ml/min/kg. a mass-balance study using intravenously and orally administered [ 3 h]-iloprost in healthy subjects (n=8) showed recovery of 81% of total radioactivity over 14 hours post-dose, with 68% and 12% recoveries in urine and feces, respectively. 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.

excretion in vitro studies reveal that cytochrome p450-dependent metabolism plays only a minor role in the biotransformation of iloprost. iloprost is metabolized principally via β-oxidation of the carboxyl side chain. the main metabolite is tetranor-iloprost, which is found in the urine in free and conjugated form. in animal experiments, tetranor-iloprost was pharmacologically inactive. clearance in normal subjects was approximately 20 ml/min/kg. a mass-balance study using intravenously and orally administered [ 3 h]-iloprost in healthy subjects (n=8) showed recovery of 81% of total radioactivity over 14 hours post-dose, with 68% and 12% recoveries in urine and feces, respectively. 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.

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 2 , 8) cvp ≥22 mmhg despite adequate diuretic therapy, and 9) svo 2 ≤45% despite nasal o 2 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). figure 1: composite primary endpoint for pah patients (who group 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. figure 2: change (mean ± sem) in 6-minute walk distance 30 minutes post-inhalation in pah patients (who group 1). the effect of ventavis in various subgroups is shown in table 2. table 2: treatment effects by subgroup among pah patients (who group 1) composite clinical endpoint 6-minute walk (m) change from baseline to 12 weeks with measurement 30 minutes after dosing, based on all available data. n ventavis n (%) n placebo n (%) n ventavis (mean ±sd) n placebo (mean ±sd) all subjects with pah etiologies of pah, who group 1 included idiopathic in 62% (n=90), associated with connective tissue disease, including crest and scleroderma, in 17%, (n=25), associated with anorexigen use in 6% (n=9), heritable pah in 3% (n=5), other pph in 3% (n=5), sle in 1% (n=2), post-partum in 1% (n=2), and overlap/other in 5% (n=8). 68 13 (19%) 78 3 (4%) 64 31 ± 76 65 -9 ± 79 nyha iii 40 7 (18%) 47 2 (4%) 39 24 ± 72 43 -16 ± 86 nyha iv 28 6 (21%) 31 1 (3%) 25 43 ± 82 22 6 ± 63 male 23 5 (22%) 24 0 (0%) 21 37 ± 81 21 -22 ± 77 female 45 8 (18%) 54 3 (6%) 43 29 ± 74 44 -2 ± 81 age ≤55 41 6 (15%) 40 2 (5%) 39 24 ± 79 32 -5 ± 78 age >55 27 7 (26%) 38 1 (3%) 25 42 ± 71 33 -13 ± 81 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. table 3 hemodynamic parameters before and after iloprost inhalation: change from baseline to week 12 patients of all etiologies of pah, including cteph. baseline mean (± sd) change from baseline at week 12 parameter iloprost placebo iloprost placebo before inhalation after inhalation pvr (dyn∙s∙cm –5 ) 1029 ± 390 1041 ± 493 –9 ± 275 (n=76) –239 ± 279 (n=70) +96 ± 323 (n=77) mpap (mmhg) 53 ± 12 54 ± 14 –0.2 ± 7.3 (n=93) –4.6 ± 9.3 (n=90) –0.1 ± 6.9 (n=82) co (l/min) 3.8 ± 1.1 3.8 ± 0.9 +0.1 ± 0.9 (n=91) +0.5 ± 1.1 (n=89) –0.2 ± 0.8 (n=80) svo 2 (%) 60 ± 8 60± 8 –1.1 ± 7.6 (n=72) +1.8 ± 8.3 (n=70) –3.2 ± 6.7 (n=63) 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. figure 1 figure 2

ore taking ventavis, tell your doctor about all of your medical conditions, including if you: are pregnant, or plan to become pregnant. it is not known if ventavis can harm your unborn baby. ventavis should only be used during pregnancy if the benefit to you is worth the possible risk to your baby. are breast-feeding. it is not known if ventavis passes into your breast milk. you and your doctor should decide if you will take ventavis or breast feed. tell your doctor about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. ventavis and other medicines may affect each other causing side effects. ventavis may affect the way other medicines work, and other medicines may affect how ventavis works. especially tell your doctor if you take: medicines used to treat high blood pressure or heart problems medicines that lessen blood clotting (for example warfarin, coumadin ® , jantoven ® ) know the medicines you take. keep a list of your medicines and show it to your doctor and pharmacist when you get a new medicine. how should i take ventavis? see the end of this leaflet for detailed instructions for using ventavis. take ventavis exactly as your doctor tells you to take it. your doctor may change your dose if needed. you should not take ventavis more than every 2 hours. the benefits of ventavis may not last 2 hours, so you may adjust the times that you use it to cover planned activities. do not drink ventavis. do not let ventavis solution come into contact with your skin or eyes. if it does, rinse your skin or eyes with water right away. do not allow other people to be exposed to ventavis while you are breathing it, especially babies. if you take too much ventavis, you may have a headache, red face, dizziness, nausea, vomiting and diarrhea. if this happens stop taking ventavis. if your symptoms do not go away, call your doctor or get emergency help right away. what are the most common side effects of ventavis? ventavis may cause side effects, including feeling dizzy, lightheaded and faint. if you have any of these side effects, you should stand up slowly when you get out of chairs or bed. tell your doctor if your fainting gets worse during treatment with ventavis. your doctor may need to change your dose or your treatment. do not drive a car or operate any tools or machines if dizziness or fainting from low blood pressure is a problem for you. you may have trouble breathing after taking ventavis because it may cause the muscles around your airway to tighten (bronchospasm). get emergency help right away if you have trouble breathing. other important side effects of ventavis include: bleeding red face (flushing) increased cough low blood pressure headaches nausea spasm of your jaw muscles that makes it hard to open your mouth talk to your doctor if you have any side effect that bothers you or that does not go away. these are not all the possible side effects of ventavis. for more information, ask your doctor or pharmacist. call your doctor for medical advice about side effects. you may report side effects to fda at 1-800-fda-1088. how should i store ventavis? store ventavis between 68°f to 77°f (20°c to 25°c). safely throw away ventavis that is out of date or no longer needed. keep ventavis and all medicines out of the reach of children. general information about ventavis medicines are sometimes prescribed for conditions that are not listed in the patient leaflet. do not use ventavis for a condition for which it was not prescribed. do not give ventavis to other people, even if they have the same symptoms you have. it may harm them. this patient information leaflet summarizes the most important information about ventavis. if you would like more information about ventavis talk with your doctor. you can ask your doctor or pharmacist for information about ventavis that is written for health professionals. for more information go to www. ventavis.com or call 1-800-526-7736 (1-800-janssen). what are the ingredients of ventavis? active ingredient : iloprost inactive ingredients : ethanol, hydrochloric acid for ph adjustment, sodium chloride, tromethamine, and water for injection. ventavis is a clear, colorless solution. manufactured for: actelion pharmaceuticals us, inc. a janssen pharmaceutical company, titusville, nj 08560, usa made in germany © 2004 – 2019 actelion pharmaceuticals us, inc. jn20220302