Ventavis

Take this medication exactly as prescribed by your doctor. Follow the directions on your prescription label carefully.

The dose your doctor recommends may be based on the following:

• how you tolerate this medication.
• if you have liver problems

The recommended starting dose of Ventavis is 2.5 mcg. If this dose is well-tolerated, further doses are increased to 5.0 mcg per dose. Ventavis is typically taken 6 to 9 times per day (no more than once every 2 hours) during waking hours.

The amount of doses of Ventavis you will need to take per day will be determined by your individual need and how you tolerate this medication.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include severe forms of some of the side effects listed in this medication guide.

Contraindications

• No known contraindications.1 3

Warnings/Precautions

Administration Precautions

For oral inhalation use only using the I-neb AAD system nebulizer.1 2

Do not take inhalation solution orally or allow it to come in contact with skin or eyes.1

Hypotensive Effects

Monitor vital signs during initiation of iloprost therapy.1 3 Take precautions to avoid additional decreases in BP in patients with low SBP.1 3

Do not initiate in patients with SBP <85 mm Hg.1 3

Be alert for the presence of underlying conditions or concomitant drugs that predispose to syncope.1 (See Specific Drugs under Interactions.)

In patients who develop exertional syncope during iloprost therapy, consider the need for adjustment of iloprost dosage or initiation of alternative therapy.1

Risk of Pulmonary Edema

If signs of pulmonary edema occur, stop iloprost immediately, as these manifestations may indicate the presence of pulmonary venous hypertension.1

Other Pulmonary Effects

Risk of bronchospasm; may be more severe or frequent in patients with history of hyperreactive airways.1

Safety and efficacy not established in patients with COPD, severe asthma, or acute pulmonary infections.1

Specific Populations

Category C.1

Distributed into milk in rats; not known whether distributed into human milk.1 Discontinue nursing or the drug.1

Safety and efficacy not established in patients <18 years of age.1 2 11

Studies did not include sufficient numbers of patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.1 Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1 (See Geriatric Patients under Dosage and Administration.)

Elimination of iloprost is reduced and/or systemic exposure is increased after oral or IV administration in patients with impaired hepatic function.1 11 Orally inhaled iloprost has not been evaluated in patients with hepatic impairment.1 11

Systemic exposure is increased after IV administration in patients with severe renal impairment requiring intermittent dialysis.1 11 Orally inhaled iloprost has not been evaluated in patients with renal impairment, including those undergoing dialysis.1 11 (See Special Populations under Pharmacokinetics and see Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Cough,1 4 headache,1 4 vasodilation (flushing),1 4 influenza-like syndrome,1 4 nausea,1 4 trismus,1 4 hypotension,1 4 insomnia,1 syncope,1 4 vomiting,1 palpitations,1 back pain,1 increased alkaline phosphatase,1 increased γ-glutamyl transferase (γ-glutamyl transpeptidase, GGT, GGTP),1 muscle cramps,1 hemoptysis,1 tongue pain,1 pneumonia.1 4

Absorption

Bioavailability

Absolute bioavailability not determined.1

Distribution

Extent

Generally not detectable in plasma 0.5–1 hour after inhalation.1

Plasma Protein Binding

60% (mainly albumin).1

Elimination

Metabolism

Undergoes β-oxidation of the carboxyl side chain.1 5 Main metabolite (tetranor-iloprost; pharmacologically inactive) found in urine in free and conjugated form.1 5 CYP isoenzymes play minor role in metabolism of iloprost.1

Elimination Route

Following oral and IV administration, 81% of radiolabeled dose recovered in urine (68%) and feces (12%) within 14 hours.1

Half-life

20–30 minutes.1

Special Populations

In patients with hepatic impairment, elimination reduced and/or systemic exposure increased after oral or IV administration.1 11

In patients with severe renal impairment, systemic exposure increased after IV administration in individuals requiring dialysis; AUC not substantially increased after IV administration in those not requiring dialysis.1

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Available only through specialty pharmacies.3 (See Restricted Distribution under Dosage and Administration.)

• Store at room temperature.
• Store in a dry place. Do not store in a bathroom.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

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 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 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.

Ventavis 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-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 [see Patient Counseling Information (17.1)]. 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 components after each dose administration.

Monitoring

Vital signs should be monitored while initiating Ventavis. [see Warnings and Precautions (5.1)].

Use in Patients with Pre-existing Hepatic Impairment

Because iloprost elimination is reduced in patients with impaired liver function [see Special Populations (8.6)], consider increasing the dosing interval (e.g., 3-4 hours between doses depending on the patient's response at the end of the dose interval) in patients with Child-Pugh Class B or C hepatic impairment.

Use in Patients with Pre-existing Renal Impairment

Dose adjustment is not required in patients who are not on dialysis. The effect of dialysis on iloprost is unknown [see Special Populations (8.7)].

None

Clinical Studies Experience

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 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 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 patients and reported at least 3% more frequently for Ventavis patients than placebo patients in the 12-week placebo-controlled study.

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.

Postmarketing Experience

The following adverse reactions have been identified during the postapproval 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 (7.3)]. Cases of thrombocytopenia, dizziness, diarrhea, mouth and tongue irritation, nasal congestion, dysgeusia, hypersensitivity, and rash have also been reported with the use of Ventavis.

Use Ventavis inhalation exactly as prescribed by your doctor. Do not use in larger or smaller amounts or for longer than recommended. Ventavis is usually given 6 to 9 times per day. Follow the directions on your prescription label.

Your doses should not be spaced less than 2 hours apart, even if you feel like the effects of the medicine have worn off in less than 2 hours.

Your doctor may occasionally change your dose of Ventavis or daily dosing schedule to make sure you get the best results.

Ventavis is an inhaled medicine that should be used only with the I-neb ADD System, or the Prodose AAD System. Do not use Ventavis inhalation with any other type of nebulizers.

You will be shown how to use your nebulizer at home. Your nebulizer system comes with patient instructions for safe and effective use, and for cleaning and care. Follow these directions carefully. Ask your doctor or pharmacist if you have any questions.

Each single-use ampule (bottle) of this medicine is for one use only. Throw away after one use, even if there is still some medicine left in it after empyting the entire contents into your nebulizer.

Store Ventavis at room temperature away from moisture and heat.

Get emergency medical help if you have any of these signs of an allergic reaction to Ventavis: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have a serious side effect such as:

• feeling like you might pass out;

• pounding heartbeats or fluttering in your chest;

• coughing up blood;

• unusual bleeding (nosebleeds, bleeding gums);

• fever, chills, cough with yellow or green mucus;

• chest tightness, stabbing chest pain, wheezing, feeling short of breath; or

• anxiety, sweating, pale skin, severe shortness of breath, wheezing, gasping for breath, cough with foamy mucus, chest pain, fast or uneven heart rate.

Less serious Ventavis side effects may include:

• flushing (warmth, redness, or tingly feeling);

• increased cough;

• nausea, vomiting, diarrhea;

• headache, dizziness;

• muscle cramps, back pain;

• sleep problems (insomnia);

• tongue pain, jaw tightness or pain, trouble chewing or speaking; or

• altered sense of taste.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Tell your doctor about all other medicines you use, especially:

• blood pressure medication;

• a blood thinner such as warfarin (Coumadin, Jantoven); or

• medication used to prevent blood clots, such as abciximab (ReoPro), anagrelide (Agrylin), cilostazol (Pletal), clopidogrel (Plavix), dipyridamole (Persantine, Aggrenox), eptifibatide (Integrilin), prasugrel (Effient), rivaroxaban (Xarelto), ticlopidine (Ticlid), or tirofiban (Aggrastat).

This list is not complete and other drugs may interact with Ventavis. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

Applies to iloprost: inhalation solution

Along with its needed effects, iloprost (the active ingredient contained in Ventavis) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking iloprost:

• Black, tarry stools
• chest pain
• cough
• difficult or labored breathing
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• extreme fatigue
• fast, pounding, or irregular heartbeat or pulse
• fever
• hives or rash
• irregular breathing
• itching
• noisy breathing
• pinpoint red spots on the skin
• swelling of the eyelids, face, lips, fingers, feet, or lower legs
• tightness in the chest
• troubled breathing or swallowing
• unusual bleeding or bruising

Some side effects of iloprost may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Back pain
• chills
• cough increased
• coughing or spitting up blood
• difficulty opening the mouth
• feeling of warmth
• headache
• lockjaw
• nausea
• redness of the face, neck, arms, and occasionally, upper chest
• sweating
• trouble sleeping

• Change in taste
• mouth irritation
• tongue irritation or pain

• Nosebleeds
• stuffy nose