Iloprost sandbox

## Pulmonary Arterial Hypertension
- Indication
- Iloprost 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%)
- Dosing information
- Iloprost 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.
- Frequency: 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 Iloprost 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-nebAAD System.
- Iloprost is supplied in 1 mL ampules in two concentrations: 10 mcg/mL and 20 mcg/mL.
Use in Patients with Pre-existing Hepatic Impairment
- Dosing information
- Because iloprost elimination is reduced in patients with impaired liver function , 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
- Dosing information
- Dose adjustment is not required in patients who are not on dialysis. The effect of dialysis on iloprost is unknown

## Risk of Syncope
Monitor vital signs while initiating Iloprost. Do not initiate Iloprost 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 Iloprost is administered in patients with pulmonary hypertension, stop treatment immediately, as this may be a sign of pulmonary venous hypertension.

## Bronchospasm
Iloprost inhalation can induce bronchospasm. Bronchospasm may be more severe or frequent in patients with a history of hyperreactive airways. Iloprost has not been evaluated in patients with chronic obstructive pulmonary disease (COPD), severe asthma, or with acute pulmonary infections.
Pre-marketing safety data on 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 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 Iloprost patients and reported at least 3% more frequently for Iloprost patients than placebo patients in the 12-week placebo-controlled study.
Pre-marketing serious adverse events reported with the use of inhaled 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 Iloprost were consistent with those observed in the larger experience of the Phase 3 study in patients receiving only Iloprost 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.
Cases of bronchospasm and wheezing have been reported, particularly in patients with a history of hyperreactive airways . Bleeding events most commonly reported as epistaxis and hemoptysis were observed on Iloprost treatment . Cases of thrombocytopenia, dizziness, diarrhea, mouth and tongue irritation, nasal congestion, dysgeusia, hypersensitivity, and rash have also been reported with the use of Iloprost.

# Cytochrome P450
Although clinical studies have not been conducted with Iloprost (inhaled iloprost), in vitro studies of iloprost indicate that no relevant inhibition of cytochrome P450 drug metabolism would be expected.

# Antihypertensives and Vasodilators
In studies in normal subjects, 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.

# Anticoagulants and Platelet Inhibitors
Since Iloprost inhibits platelet function, there is a potential for increased risk of bleeding, particularly in patients maintained on anticoagulants or platelet inhibitors.
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.
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)-(3aS, 4R, 5R, 6aS)-hexahydro-5-hydroxy-4--2(1H),-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 C22H32O4. Its relative molecular weight is 360.49. The structural formula is shown below:
Iloprost administered intravenously has linear pharmacokinetics over the dose range of 1 to 3 ng/kg/min. The half-life of iloprost is 20 to 30 minutes. Following inhalation of iloprost (5 mcg) patients with pulmonary hypertension have iloprost peak plasma levels of approximately 150 pg/mL. Iloprost was generally 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 -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 -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.
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.
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  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/m2, 8) CVP  22 mmHg despite adequate diuretic therapy, and 9) SVO2  45% despite nasal O2 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 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.
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)
Excursions permitted to 15  30C (59  86F)
Advise patients that they may have a fall in blood pressure with 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 Iloprost should be inhaled at intervals of not less than 2 hours and that the acute benefits of Iloprost may not last 2 hours. Thus patients may want to adjust times of administration to cover planned activities.