иломедин

Overdose

Cases of overdose have been reported. Frequently observed symptoms following overdose are dizziness, headache, flushing, nausea, jaw pain or back pain. Hypotension, vomiting, and diarrhea are possible. A specific antidote is not known. Interruption of the inhalation session, monitoring, and symptomatic measures are recommended.

Contraindications

None

Pharmaceutical form

Undesirable effects

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

Table 1: Adverse Events in Phase 3 Clinical Trial

Pre-marketing serious adverse events reported with the use of inhaled Иломедин 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 Иломедин were consistent with those  observed in the larger experience of the Phase 3 study in patients receiving only Иломедин or bosentan.

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.

The following adverse reactions have been identified during the postapproval use of Иломедин. 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. Bleeding events most commonly reported as epistaxis and hemoptysis were observed on Иломедин treatment. Cases of thrombocytopenia, dizziness, diarrhea, mouth and tongue irritation, nasal congestion, dysgeusia, hypersensitivity, and rash have also been reported with the use of Иломедин.

Therapeutic indications

Иломедин® 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%).

Pharmacokinetic properties

In pharmacokinetic studies in animals, there was no evidence of interconversion of the two diastereoisomers of iloprost. In human pharmacokinetic studies, the two diastereoisomers were not individually assayed.

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.

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.

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 [3H]-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.

Name of the medicinal product

Qualitative and quantitative composition

Special warnings and precautions for use

Included as part of the PRECAUTIONS section.

Иломедин solution should not be allowed to come into contact with the skin or eyes; oral ingestion of Иломедин solution should be avoided.

Monitor vital signs while initiating Иломедин. Do not initiate Иломедин 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.

Should signs of pulmonary edema occur when inhaled Иломедин is administered in patients with pulmonary hypertension, stop treatment immediately, as this may be a sign of pulmonary venous hypertension.

Иломедин inhalation can induce bronchospasm. Bronchospasm may be more severe or frequent in patients with a history of hyperreactive airways. Иломедин has not been evaluated in patients with chronic obstructive pulmonary disease (COPD), severe asthma, or with acute pulmonary infections.

Patients receiving Иломедин should be advised to use the drug only as prescribed with the I-neb® AAD® System, following the manufacturer's instructions. Patients should be trained in proper administration techniques including dosing frequency, ampule dispensing, I-neb® AAD® System operation, and equipment cleaning.

Advise patients that they may have a fall in blood pressure with Иломедин, 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 Иломедин should be inhaled at intervals of not less than 2 hours and that the acute benefits of Иломедин may not last 2 hours. Thus patients may want to adjust times of administration to cover planned activities. See FDA-approved patient labeling.

Иломедин ampules may be opened with a rubber pad or with an ampule breaker.

When using a rubber pad:

1. With one hand, hold the bottom of the ampule with the blue dot facing away from your body.

2. With the other hand, wrap the included rubber pad around the entire ampule.

3. Using your thumbs, break open the neck of the ampule by snapping the top towards you and then carefully dispose of the top of the ampule into a sharps bin.

When using an ampule breaker:

1. Align the blue dot on the Иломедин ampule with the dot on the ampule breaker, if available, and then insert the top of the ampule into the ampule breaker.

2. Gently break open the neck of the ampule by levering away from the dot on the Иломедин ampule to snap off the ampule lid.

3. Carefully dispose of the top of the ampule into a sharps bin or appropriate storage container.

For either:

4. After opening the ampule, use the small tube (pipette) supplied with Иломедин, draw-up the entire amount of one ampule of Иломедин and transfer the entire contents of the ampule into the medication chamber of the I-neb® AAD® System.

5. Safely dispose of the open ampule and pipette as instructed by your healthcare practitioner. Keep ampules and pipettes out of the reach of children.

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:CD1®(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.

Иломедин has been shown to be teratogenic in rats as described below. There are no adequate and well controlled studies in pregnant women. Иломедин should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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.

It is not known whether Иломедин 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). 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. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Иломедин, a decision to discontinue nursing should be made, taking into account the importance of the drug to the mother.

Safety and efficacy in pediatric patients have not been established.

Clinical studies of Иломедин 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.

Иломедин 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.

Иломедин 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 requiring intermittent dialysis treatment (n=7), the mean AUC0-4h was 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.

Dosage (Posology) and method of administration

Иломедин 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. Иломедин 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 Иломедин 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.

Иломедин 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 Ineb®AAD® System will decrease treatment times to help maintain patient compliance.

For each inhalation session, the entire contents of each opened ampule of Иломедин should be transferred into the I-neb® AAD® System medication chamber immediately before use. 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.

Vital signs should be monitored while initiating Иломедин..

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.

Dose adjustment is not required in patients who are not on dialysis. The effect of dialysis on iloprost is unknown.