Bolesi

Bolesi® (alprostadil for injection) is indicated for the treatment of erectile dysfunction due to neurogenic, vasculogenic, psychogenic, or mixed etiology.

Treatment of erectile dysfunction of primarily organic etiology.

Adjunct to other tests in the diagnosis and management of erectile dysfunction.

Bolesi is indicated for the treatment of erectile dysfunction in adult males due to neurogenic, vasculogenic, psychogenic or mixed aetiology.

Bolesi may be a useful adjunct to other diagnostic tests in the diagnosis of erectile dysfunction.

Bolesi is not indicated for paediatric use.

Prostin VR is indicated to temporarily maintain the patency of the ductus arteriosus until corrective or palliative surgery can be performed in infants who have congenital defects and who depend upon the patent ductus for survival. Such congenital heart defects include pulmonary atresia, pulmonary stenosis, tricuspid atresia, tetralogy of Fallot, interruption of the aortic arch, co-arctation of the aorta, aortic stenosis, aortic atresia, mitral atresia, or transposition of the great vessels with or without other defects.

Bolesi® (alprostadil for injection) in the Treatment of Erectile Dysfunction

The dosage range of Bolesi® (alprostadil for injection) for the treatment of erectile dysfunction is 1 to 40 mcg. The intracavernous injection should be given over a 5 to 10 second interval. In a study with a dose range of 1 to 20 mcg of Bolesi® (alprostadil for injection) , the mean dose was 10.7 mcg at the end of the dose titration period. In two studies with a dose range of 1 to 40 mcg of Bolesi® (alprostadil for injection) , the mean dose was 21.9 mcg at the end of the dose titration period. Doses greater than 40 mcg have not been studied. A ½ inch, 27 to 30 gauge needle is generally recommended for the intracavernous injection. The patient is advised not to exceed the optimum Bolesi® (alprostadil for injection) dose which was determined in the doctor's office. The lowest possible effective dose should always be used.

Initial Titration in Physician's Office

Erectile Dysfunction of Vasculogenic, Psychogenic, or Mixed Etiology: Dosage titration should be initiated at 2.5 micrograms of alprostadil. If there is a partial response, the dose may be increased by 2.5 micrograms to a dose of 5 micrograms and then in increments of 5 to 10 micrograms, depending upon erectile response, until the dose that produces an erection suitable for intercourse and not exceeding a duration of 1 hour is reached. If there is no response to the initial 2.5-microgram dose, the second dose may be increased to 7.5 micrograms, followed by increments of 5 to 10 micrograms. The patient must stay in the physician's office until complete detumescence occurs. It there is no response, then the next higher dose may be given within 1 hour. If there is a response, then there should be at least a 1-day interval before the next dose is given.

Erectile Dysfunction of Pure Neurogenic Etiology (Spinal Cord Injury): Dosage titration should be initiated at 1.25 micrograms of alprostadil. The dose may be increased by 1.25 micrograms to a dose of 2.5 micrograms, followed by an increment of 2.5 micrograms to a dose of 5 micrograms, and then in 5-microgram increments until the dose that produces an erection suitable for intercourse and not exceeding a duration of 1 hour is reached. The patient must stay in the physician's office until complete detumescence occurs. If there is no response, then the next higher dose may be given within 1 hour. If there is a response, then there should be at least a 1-day interval before the next dose is given.

At-Home (Maintenance Therapy) Dosing Instructions

The first injections of Bolesi® (alprostadil for injection) must be done at the physician's office by medically trained personnel. Self-injection therapy by the patient can be started only after the patient is properly instructed and well trained in the self-injection technique. The physician should instruct the patient to discard any needles which become bent during the self-injection procedure as these needles may break. The physician should make a careful assessment of the patient's skills and competence with the self-injection procedure. The intracavernous injection must be done under sterile conditions. The site of injection is usually along the lateral aspect of the proximal third of the penis. Visible veins should be avoided. The side of the penis that is injected and the site of injection must be alternated. The injection site must be cleansed with an alcohol swab before injection.

The dose of Bolesi® (alprostadil for injection) that is selected for self-injection treatment should provide the patient with an erection that is satisfactory for sexual intercourse and that is maintained for no longer than 1 hour. If the duration of erection is longer than 1 hour, the dose of Bolesi® (alprostadil for injection) should be reduced. The lowest effective dose should be used at home. Self-injection therapy for use at home should be initiated at the dose that was determined in the physician's office. Dose adjustment may be required and should be made only after consultation with the physician.

Careful and continuous follow-up of the patient while in the self-injection program must be exercised. This is especially true for the initial self-injections, since adjustments in the dose of Bolesi® (alprostadil for injection) may be needed. The recommended frequency of injection is no more than 3 times weekly, with at least 24 hours between each dose. The reconstituted Bolesi® (alprostadil for injection) cartridge and needle are intended for single use only and should be discarded after use. The user should be instructed in the proper disposal of the needles and cartridges.

While on self-injection treatment, it is recommended that the patient visit the prescribing physician's office every 3 months. At that time, the efficacy and safety of the therapy should be assessed, and the dose of Bolesi® (alprostadil for injection) should be adjusted, if needed.

The patient is instructed to follow the enclosed PATIENT INFORMATION pamphlet.

Preparation of Solution

The Bolesi® (alprostadil for injection) injection device is used to reconstitute the single-dose, dual-chamber cartridge. The plunger is used to force the sterile 0.9% sodium chloride (1.075 mL) in one chamber into the chamber containing alprostadil. After reconstitution, the Bolesi® (alprostadil for injection) injection device is used to administer the intracavernous injection of alprostadil. The reusable Bolesi® (alprostadil for injection) injection device is for use only with the cartridges and needles included in the Bolesi® (alprostadil for injection) Cartridge Packs.

Prepare the Bolesi® (alprostadil for injection) solution immediately before use. Do not administer unless solution is clear. Do not add any drugs or solutions to the Bolesi® (alprostadil for injection) solution. Discard any unused solution remaining in the cartridge. The reconstituted solution should not be stored.

The Bolesi® (alprostadil for injection) cartridge contains a solid layer or lyophilized cake of dry white powder approximately 3/8” in thickness. A normal cake may appear cracked or crumbled. If the cartridge is damaged, the cake may shrink in size. Do not use the cartridge if it appears damaged or the cake is substantially reduced in size.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. The reconstituted solution may initially appear cloudy due to small air bubbles. Do not use the solution if it remains cloudy, contains precipitates, or is discolored.

CAUTION: Do not reuse any solution remaining in the cartridge due to the possibility of bacterial contamination.

Administration

Bolesi® (alprostadil for injection) is given as an intracavernous injection over a 5 to 10 second interval. See PATIENT INFORMATION for Bolesi® (alprostadil for injection).

Stability

The single-dose, dual-chamber cartridge should be reconstituted only when it is certain that the patient is ready to administer the drug. The reconstituted drug solution should be used immediately after reconstitution. Any solution remaining in the cartridge should be discarded.

Use in Adults

Treatment of erectile dysfunction

Initiation of therapy: a medical professional should instruct each patient on the correct use of Bolesi. The recommended starting dose is 500 micrograms.

Dosage may be increased in a stepwise manner (to 1000 micrograms), or decreased (to 250 or 125 micrograms) under medical supervision until the patient achieves a satisfactory response. After an assessment of the patient's skill and competence with the procedure, the chosen dose may then be prescribed for home use.

It is important for the patient to urinate before administration since a moist urethra makes administration of Bolesi easier and is essential to dissolve the drug. To administer Bolesi, remove the protective cover from the Bolesi applicator, stretch the penis upward to its full length, and insert the applicator stem into the urethra. Depress the applicator button to release the medication from the applicator and remove the applicator from the urethra, (rocking the applicator gently prior to removal will ensure that the medication is separated from the applicator stem). Roll the penis between the hands for at least 10 seconds to ensure that the medication is adequately distributed along the wall of the urethra. If the patient feels a burning sensation it may help to roll the penis for an additional 30 to 60 seconds or until the burning subsides. The erection will develop within 5-10 minutes after administration and lasts approximately 30-60 minutes. After administration of Bolesi, it is important to sit, or preferably, stand or walk for about 10 minutes while the erection is developing. More detailed information is given in the patient information leaflet. During home use, periodic checks of efficacy and safety are recommended.

Not more than 2 doses are recommended to be used in any 24-hour period, and not more than 7 doses are recommended to be used in a 7-day period. The prescribed dosage should not be exceeded.

Adjunct to other tests in the diagnosis and management of erectile dysfunction.

Bolesi can be used as an adjunct in evaluating penile vascular function using Doppler duplex ultrasonography. It has been shown that a 500 microgram dose of Bolesi has a comparable effect on penile arterial dilatation and peak systolic velocity flow to 10 microgram of alprostadil given by intracavernosal injection. At the time of discharge from the clinic, the erection should have subsided.

Use in the elderly

No adjustment for age is required.

Bolesi is administered by direct intracavernous injection. A half inch, 27 to 30 gauge needle is generally recommended. The dose of Bolesi should be individualised for each patient by careful titration under supervision by a physician.

The intracavernosal injection must be done under sterile conditions. The site of injection is usually along the dorsolateral aspect of the proximal third of the penis. Visible veins should be avoided. Both the side of the penis that is injected and the site of injection must be alternated; prior to the injection, the injection site must be cleansed with an alcohol swab.

To reconstitute Bolesi using the prefilled diluent syringe: flip off the plastic cap from the vial, and use one of the swabs to wipe the rubber cap. Fit the 22 gauge needle to the syringe.

Inject the 1 ml of diluent into the vial, and shake to dissolve the powder entirely. Withdraw slightly more than the required dose of Bolesi solution, remove the 22 gauge needle, and fit the 30 gauge needle. Adjust volume to the required dose for injection. Following administration, any unused contents of the vial or syringe should be discarded.

A. As an aid to aetiologic diagnosis.

Over 80% of subjects may be expected to respond to a single 20 micrograms dose of alprostadil. At the time of discharge from the clinic, the erection should have subsided entirely and the penis must be in a completely flaccid state.

B. Treatment

The initial dose of alprostadil in patients with erectile dysfunction of neurogenic origin secondary to spinal cord injury is 1.25 micrograms, with a second dose of 2.5 micrograms, a third of 5 micrograms, and subsequent incremental increases of 5 micrograms until an optimal dose is achieved. For erectile dysfunction of vasculogenic, psychogenic, or mixed aetiology, the initial dose is 2.5 micrograms. The second dose should be 5 micrograms if there is a partial response, and 7.5 micrograms if there is no response. Subsequent incremental increases of 5-10 micrograms should be given until an optimal dose is achieved. If there is no response to the administered dose, then the next higher dose may be given within 1 hour. If there is a response, there should be at least a 1-day interval before the next dose is given. The usual maximum recommended frequency of injection is no more than once daily and no more than three times weekly.

The first injections of alprostadil must be done by medically trained personnel. After proper training and instruction, alprostadil may be injected at home. If self-administration is planned, the physician should make an assessment of the patient's skill and competence with the procedure. It is recommended that patients are regularly monitored (e.g. every 3 months) particularly in the initial stages of self injection therapy when dose adjustments may be needed.

The dose that is selected for self-injection treatment should provide the patient with an erection that is satisfactory for sexual intercourse. It is recommended that the dose administered produces a duration of the erection not exceeding one hour. If the duration is longer, the dose should be reduced. The majority of patients achieve a satisfactory response with doses in the range of 5 to 20 micrograms. Doses of greater than 60 micrograms of alprostadil are not recommended. The lowest effective dose should be used.

Posology

The infusion is generally initiated at a rate of 0.05-0.1 micrograms/kg/min. The most experience has been with 0.1 micrograms/kg/min. After a therapeutic response (an increase in pO₂ in neonates with restricted pulmonary blood flow or an increase in systemic blood pressure and blood pH in neonates with restricted systemic blood flow) has been obtained, the infusion rate should be reduced to the lowest possible dosage that will maintain the desired response.

Doses lower than 0.05 microgram/kg/min (as low as 0.005 microgram/kg/min) alprostadil have been used successfully in neonates, specifically when transport of the infant is necessary. No comparative trials exist and the efficacy and safety of this approach when compared to the generally initiated dosage rate of 0.05-0.1 micrograms/kg/min is currently unclear.

Method of administration

For administration by intravenous drip or constant rate infusion pump.

In infants with lesions restricting pulmonary blood flow (blood is flowing through the ductus arteriosus from the aorta to the pulmonary artery), Prostin VR may be administered by continuous infusion through an umbilical artery catheter placed at or just above the junction of the descending aorta and the ductus arteriosus, or intravenously. The diluted solution should contain no more than 20 micrograms/ml alprostadil.

PARTICULAR CARE SHOULD BE TAKEN IN CALCULATING AND PREPARING DILUTIONS OF PROSTIN VR.

Bolesi® (alprostadil for injection) should not be used in patients who have a known hypersensitivity to alprostadil or other prostaglandins, in patients who have conditions that might predispose them to priapism, such as sickle cell anemia or trait, multiple myeloma, or leukemia, or in patients with anatomical deformation of the penis, such as angulation, cavernosal fibrosis, or Peyronie's disease. Patients with penile implants should not be treated with Bolesi® (alprostadil for injection).

Bolesi® (alprostadil for injection) should not be used in men for whom sexual activity is inadvisable or contraindicated.

Bolesi® (alprostadil for injection) should not be used in women and children and is not for use in newborns.

Bolesi is contraindicated in the following patients:

- Patients who have a known hypersensitivity to the active substance or to any of the excipients.

- Patients with anatomical deformation of the penis, such as stenosis of the distal urethra, severe hypospadias, severe curvature, balanitis, acute or chronic urethritis, angulation, cavernosal fibrosis or Peyronie's disease.

- Patients who have conditions that might predispose them to priapism, such assickle cell anaemia or trait, thrombocythaemia, polycythaemia, multiple myeloma or leukemia; predisposition to venous thrombosis, or a history of recurrent priapism.

- Patients for whom sexual activity is inadvisable or contraindicated, such as men with unstable cardiovascular or unstable cerebrovascular conditions.

Bolesi should not be used if the female partner is or may be pregnant unless the couple uses a condom barrier.

Bolesi is contraindicated in women and children.

Alprostadil should not be used in men for whom sexual activity is inadvisable or contraindicated.

WARNINGS

Prolonged erections greater than four hours in duration occurred in 4% of all patients treated up to 24 months. The incidence of priapism (erections greater than 6 hours in duration) was < 1% with long-term use for up to 24 months. In the majority of cases, spontaneous detumescence occurred. Pharmacologic intervention and/or aspiration of blood from the corpora was necessary in 1.6% of 311 patients with prolonged erections/priapism. To minimize the chances of prolonged erection or priapism, Bolesi® (alprostadil for injection) should be titrated slowly to the lowest effective dose (see DOSAGE AND ADMINISTRATION). The patient must be instructed to immediately report to his prescribing physician or, if unavailable, to seek immediate medical assistance for any erection that persists longer than six hours. If priapism is not treated immediately, penile tissue damage and permanent loss of potency may result.

PRECAUTIONS

General

1. Intracavernous injections of Bolesi® (alprostadil for injection) can lead to increased peripheral blood levels of PGE₁ and its metabolites, especially in those patients with significant corpora cavernosa venous leakage. Increased peripheral blood levels of PGE₁ and its metabolites may lead to hypotension and/or dizziness.
2. Regular follow-up of patients, with careful examination of the penis at the start of therapy and at regular intervals (e.g. 3 months), is strongly recommended to identify any penile changes. The overall incidence of penile fibrosis, including Peyronie's disease, reported in clinical studies up to 24 months with Bolesi® (alprostadil for injection) was 7.8%. Treatment with Bolesi® (alprostadil for injection) should be discontinued in patients who develop penile angulation, cavernosal fibrosis, or Peyronie's disease. Treatment can be resumed if the penile abnormality subsides.
3. The safety and efficacy of combinations of Bolesi® (alprostadil for injection) and other vasoactive agents have not been systematically studied. Therefore, the use of such combinations is not recommended.
4. After injection of the Bolesi® (alprostadil for injection) solution, compression of the injection site for five minutes, or until bleeding stops, is necessary. Patients on anticoagulants, such as warfarin or heparin, may have increased propensity for bleeding after intracavernous injection.
5. Underlying treatable medical causes of erectile dysfunction should be diagnosed and treated prior to initiation of therapy with Bolesi® (alprostadil for injection).
6. Bolesi® (alprostadil for injection) uses a superfine (29 gauge) needle. As with all superfine needles, the possibility of needle breakage exists. Careful instruction in proper patient handling and injection techniques may minimize the potential for needle breakage.
7. The patient should be instructed not to reuse or to share needles or cartridges. As with all prescription medicines, the patient should not allow anyone else to use his medicine.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term carcinogenicity studies have not been conducted. Alprostadil showed no evidence of mutagenicity in three in vitroassays including the AMES bacterial reverse mutation assay, a forward gene mutation assay in Chinese hamster lung (V79) cells, and a chromosome aberration assay in human peripheral lymphocytes. Alprostadil did not produce damage to chromosomes or the mitotic apparatus in the in vivorat micronucleus test.

Alprostadil did not cause any adverse effects on fertility or general reproductive performance when administered intraperitoneally to male or female rats at dose levels from 2 to 200 mcg/kg/day. The high dose of 200 mcg/kg/day is about 300 times the maximum recommended human dose (MRHD) on a body weight basis. The human dose of Bolesi® (alprostadil for injection) is < 1 mcg/kg (MRHD is 40 mcg and the calculation assumes a 60 kg subject).

Pregnancy, Nursing Mothers and Pediatric Use

Bolesi® (alprostadil for injection) is not indicated for use in women or pediatric patients.

Geriatric Use

Of the approximately 1,065 patients who entered the in-office dose-titration period in clinical studies, 25% were 65 years or older. In clinical studies, geriatric patients required, on average, higher minimally effective doses and had a higher rate of lack of effect (optimum dose not determined). Overall differences in safety were not observed between these geriatric patients and younger patients. Geriatric patients should be dosed and titrated according to the same DOSAGE AND ADMINISTRATION recommendations as younger patients, and the lowest possible effective dose should always be used.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Underlying treatable medical causes of erectile dysfunction should be diagnosed and treated prior to initiation of treatment with Bolesi.

Painful erection is more likely to occur in patients with anatomical deformations of the penis, such as angulation, phimosis, cavernosal fibrosis, Peyronie's disease or plaques.

Incorrect insertion of Bolesi may cause urethral abrasion and minor urethral bleeding.). Instruct patients to immediately report to their prescribing physician, or, if unavailable, seek immediate medical assistance for any erection that persists longer than 4 hours. Treatment of priapism should be according to established medical practice.

In clinical trials of Bolesi, priapism (rigid erections lasting >6 hours) and prolonged erection (rigid erection lasting 4 hours and <6 hours) were reported infrequently (<0.1% and 0.3% of patients, respectively). To minimize the risk, select the lowest effective dose. It may be necessary to reduce the dose or discontinue treatment in any patient who develops priapism.

Penile fibrosis, including angulation, cavernosal fibrosis, fibrotic nodules and Peyronie's disease may occur following the administration of Bolesi. The occurrence of fibrosis may increase with increased duration of use. Regular follow-up of patients, with careful examination of the penis, is strongly recommended to detect signs of penile fibrosis or Peyronie's disease. Treatment with Bolesi should be discontinued in patients who develop penile angulation, cavernosal fibrosis, or Peyronie's disease.

Bolesi should be used with caution in patients who have experienced transient ischaemic attacks or those with unstable cardiovascular disorders.

Bolesi is not intended for co-administration with any other agent for the treatment of erectile dysfunction (see also 4.5).

The potential for abuse of Bolesi should be considered in patients with a history of psychiatric disorder or addiction.

Sexual stimulation and intercourse can lead to cardiac and pulmonary events in patients with coronary heart disease, congestive heart failure or pulmonary disease. These patients when using Bolesi should engage in sexual activity with caution.

Patients and their partners should be advised that Bolesi offers no protection from transmission of sexually transmitted diseases. They should be counselled about the protective measures that are necessary to guard against the spread of sexually transmitted agents, including the human immunodeficiency virus (HIV). The use of Bolesi will not affect the integrity of condoms. Since Bolesi may add small amounts of alprostadil to the naturally occurring PGE₁ already present in the semen, it is recommended that adequate contraception is used if the woman is of child-bearing potential.

The use of Bolesi in patients with penile implants has been reported in a limited number of cases in the literature. However no conclusions can be drawn regarding the safety or efficacy of this combination.

Painful erection is more likely to occur in patients with anatomical deformations of the penis, such as angulation, phimosis, cavernosal fibrosis, Peyronie's disease or plaques. Penile fibrosis, including angulation, cavernosal fibrosis, fibrotic nodules and Peyronie's disease may occur following the intracavernosal administration of alprostadil. The occurrence of fibrosis may increase with increased duration of use. Regular follow-up of patients, with careful examination of the penis, is strongly recommended to detect signs of penile fibrosis or Peyronie's disease. Treatment with alprostadil should be discontinued in patients who develop penile angulation, cavernosal fibrosis, or Peyronie's disease.

Patients on anticoagulants such as warfarin or heparin may have increased propensity for bleeding after the intracavernosal injection.

Underlying treatable medical causes of erectile dysfunction should be diagnosed and treated prior to initiation of therapy with alprostadil.

Use of intracavernosal alprostadil offers no protection from the transmission of sexually transmitted diseases. Individuals who use alprostadil should be counselled about the protective measures that are necessary to guard against the spread of sexually transmitted diseases, including the human immunodeficiency virus (HIV). In some patients, injection of alprostadil can induce a small amount of bleeding at the site of injection. In patients infected with blood-borne diseases, this could increase the transmission of such diseases to their partner.

Alprostadil should be used with caution in patients with cardiovascular and cerebrovascular risk factors. Alprostadil should be used with caution in patients who have experienced transient ischaemic attacks or those with unstable cardiovascular disorders.

Sexual stimulation and intercourse can lead to cardiac and pulmonary events in patients with coronary heart disease, congestive heart failure or pulmonary disease. These patients when using alprostadil should engage in sexual activity with caution.

Alprostadil is not intended for co-administration with any other agent for the treatment of erectile dysfunction.

The potential for abuse of alprostadil should be considered in patients with a history of psychiatric disorder or addiction.

Bolesi uses a superfine needle for administration. As with all superfine needles, the possibility of needle breakage exists.

Needle breakage, with a portion of the needle remaining in the penis, has been reported and, in some cases, required hospitalisation and surgical removal.

Careful patient instruction in proper handling and injection techniques may minimise the potential for needle breakage.

The patient should be instructed that, if the needle is bent, it must not be used; they should also not attempt to straighten a bent needle. They should remove the needle from the syringe, discard it, and attach a new, unused sterile needle to the syringe.

Reconstituted solutions of alprostadil are intended for single use only, they should be used immediately and not stored. The syringe and any remaining solution should be properly discarded.

The solvent contains benzyl alcohol, which may cause hypersensitivity reactions and has been associated with serious adverse events, including the “gasping syndrome”, and death in paediatric patients. The minimum amount of benzyl alcohol at which toxicity may occur is not known. The risk of benzyl alcohol toxicity depends on the quantity administered and the hepatic capacity to detoxify the chemical. Premature and low-birth weight infants may be more likely to develop toxicity.

Prostin VR should be administered only by well trained healthcare professionals and in facilities with immediate access to paediatric intensive care.

Apnoea may occur in about 10-12% of neonates with congenital heart defects treated with alprostadil. There is some evidence that apnoea is dose related. Apnoea is most often seen in neonates weighing less than 2 kg at birth and usually appears during the first hour of drug infusion. Therefore Prostin VR should be used where ventilatory assistance is immediately available.

Prostin VR should be infused for the shortest time possible and at the lowest dose that will produce the desired effects. The risk of long-term infusion of Prostin VR should be weighed against the possible benefits that critically ill infants may derive from its administration.

Pathologic studies of the ductus arteriosus and pulmonary arteries of infants treated with prostaglandin E1 have disclosed histologic changes related with the weakening effect upon these structures. The specificity or clinical relevance of these results is not known.

Cortical proliferation of the long bones has followed long-term infusions of alprostadil in infants and dogs. The proliferation in infants regressed after withdrawal of the drug.

Since prostaglandin E1 is a potent inhibitor of platelet aggregation, use Prostin VR cautiously in neonates with histories of bleeding tendencies.

Alprostadil should not be used in neonates (or infants) with respiratory distress syndrome (hyaline membrane disease). A differential diagnosis should always be made between respiratory distress syndrome and cyanotic heart disease (restricted pulmonary blood flow). In the event that full diagnostic facilities are not immediately available, the diagnosis should be based on the presence of cyanosis (pO2 less than 40 torr) and x-ray evidence of a restricted pulmonary blood flow.

Arterial pressure should be monitored by umbilical artery catheter, auscultation or with a Doppler transducer. Should arterial pressure fall significantly, the rate of infusion should be immediately decreased.

Weakening of the ductus arteriosus wall and pulmonary artery has been reported, particularly during prolonged administration.

The administration of alprostadil to neonates may result in gastric outlet obstruction secondary to antral hyperplasia. This effect appears to be related to duration of therapy and cumulative dose of the drug. Neonates receiving alprostadil at recommended doses for more than 120 hours should be closely monitored for evidence of antral hyperplasia and gastric outlet obstruction.

In neonates (or infants) with decreased pulmonary blood flow, the oxygenation increase is inversely proportional to the previous pO2 values; i.e., better responses are obtained in patients with low pO2 values (less than 40 mmHg), whereas patients with high pO2 values (more than 40 mmHg) have usually a minimal response.

In neonates (or infants) with decreased pulmonary blood flow, alprostadil efficacy is measured by monitoring blood oxygenation increase. In neonates (or infants) with decreased systemic blood flow, the efficacy is determined by monitoring the increase in systemic blood pressure and blood pH.

Patients should be cautioned to avoid activities, such as driving or hazardous tasks, where injury could result if hypotension or syncope were to occur after Bolesi administration. In patients experiencing hypotension and/or syncope, these events have usually occurred during initial titration and within one hour of drug administration.

Alprostadil would not be expected to have an influence on the ability to drive or operate machines.

Not relevant.

Bolesi® (alprostadil for injection) , administered by intracavernous injection in doses ranging from 1 to 40 mcg per injection for periods up to 24 months, has been evaluated in clinical trials for safety in over 1,065 patients with erectile dysfunction. Discontinuation of therapy due to a side effect in clinical trials was required in approximately 9% of patients treated with Bolesi® (alprostadil for injection) and in < 1% of patients treated with placebo.

Local Adverse Reactions

The following local adverse reactions were reported in studies including 1,065 patients treated with Bolesi® (alprostadil for injection) for up to two years.

Penile Pain: With use of up to 24 months, penile pain was reported at least once by 29% of patients during injection, 35% of patients during erection, and by 30% of patients after erection. On a per injection basis, 15% of injections were associated with penile pain. Penile pain was judged by patients to be mild in intensity for 80% of painful injections, moderate in intensity for 16% of painful injections, and severe in intensity for 4% of painful injections. The frequency of penile pain reports decreased over time; forty-one percent of the patients experienced pain during the first 2 months and 3% of the patients experienced pain during months 21-24. In placebo-controlled studies, penile pain was reported by 31% of patients after Bolesi® (alprostadil for injection) and by 9% of patients after placebo injection.

Prolonged Erection/Priapism: Prolonged erections greater than four hours in duration occurred in 4% of all patients treated up to 24 months. In placebo-controlled studies, 3% of patients treated with Bolesi® (alprostadil for injection) and < 1% of patients treated with placebo reported prolonged erections greater than four hours. The incidence of priapism (erections greater than 6 hours in duration) was < 1% with long-term use for up to 24 months. In the majority of cases, spontaneous detumescence occurred. A higher incidence of prolonged erections was found in younger patients ( < 40 years), non-diabetic patients, and patients with psychogenic etiology of erectile dysfunction. (See WARNINGS.)

Hematoma/Ecchymosis: In patients treated with Bolesi® (alprostadil for injection) for up to 24 months, local bleeding, hematoma and ecchymosis were observed in 15%, 5% and 4% of patients, respectively. In placebo-controlled studies, the frequency of local bleeding was 6% with injection of Bolesi® (alprostadil for injection) and 3% with injection of placebo. In most cases, these reactions were attributed to faulty injection technique.

Local Adverse Reactions Reported by ≥ 1% of Patients All Study Periods*

Systemic Adverse Experiences

The following systemic adverse experiences were reported in controlled and uncontrolled studies in ≥ 1% of patients treated for up to 24 months with Bolesi® (alprostadil for injection).

Systemic Adverse Experiences Reported by ≥ 1% of Patients*

Hemodynamic changes, manifested as increases or decreases in blood pressure and pulse rate, were observed during clinical studies but did not appear to be dose-dependent. Four patients ( < 1%) reported clinical symptoms of hypotension such as dizziness or syncope.

Bolesi® (alprostadil for injection) had no clinically important effect on serum or urine laboratory tests.

Post-Marketing Adverse Experiences

Needle breakage.

The most frequently reported adverse effect following treatment with Bolesi was pain in the penis. In most cases, pain was assessed as mild or moderate.

Penile fibrosis, including angulation, fibrotic nodules, and Peyronie's disease, was reported in 3% of clinical trial patients overall.

Adverse drug reactions reported during treatment with Bolesi are presented in the table below. Frequencies are Very common (> 1/10); Common (> 1/100 to <1/10); Uncommon (>1/1000 to <1/100); Rare (>1/10,000 to <1/1,000); Very rare (<1/10,000); not known (cannot be estimated from the available data).

Vaginal burning/itching was reported by approximately 6% of partners of patients on active treatment. This may be due to resuming sexual intercourse or due to the use of Bolesi.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

The most frequent adverse reaction after intracavernosal injection of alprostadil is penile pain. Thirty percent of the patients reported penile pain at least once; however, this event was associated with only 11% of the administered injections. In the majority of the cases, penile pain was rated mild or moderate in intensity. 3% of patients discontinued treatment because of penile pain.

Prolonged erection (defined as an erection that lasts for 4 to 6 hours) after intracavernosal administration of alprostadil was reported in 4% of patients. The frequency of priapism (defined as an erection that lasts 6 hours or longer) was 0.4%. In the majority of cases, spontaneous detumescence occurred.

Penile fibrosis, including angulation, fibrotic nodules and Peyronie's disease was reported in 3% of clinical trial patients overall, however, in one self-injection study in which the duration of use was up to 18 months, the incidence of penile fibrosis was higher, approximately 8%.

Haematoma and ecchymosis at the site of injection, which is related to the injection technique rather than to the effects of alprostadil, occurred in 3% and 2% of patients, respectively. Penile oedema or rash was reported by 1% of alprostadil treated patients.

Adverse drug reactions reported during clinical trials and post marketing experience are presented in the table below, frequencies are very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); not known (cannot be estimated from the available data). The adverse drug reactions are listed in order of decreasing medical seriousness within each frequency category and system organ class.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.

The most frequent adverse reactions observed with Prostin VR infusion in neonates with ductal-dependent congenital heart defects are related to the drug's known pharmacological effects.

The following undesirable effects have been observed and reported during treatment with alprostadil (436 neonates treated) with the following frequencies: Very common (>1/10); Common (>1/100 to <1/10); Uncommon (>1/1,000 to <1/100); Rare (>1/10,000 to <1/1,000); Very rare (<1/10,000).

*This is the only adverse event directly related to the route of administration, being more frequent with intra-arterial administration.

The relationship of the following adverse events to the drug, in decreasing frequency, is unknown: sepsis, cardiac arrest, disseminated intravascular coagulation, hypokalaemia, and oedema.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme: www.mhra.gov.uk/yellowcard.

Limited data are available in regard to Bolesi® (alprostadil for injection) overdose in humans. Systemic reactions are uncommon with intracavernous injection of Bolesi® (alprostadil for injection). Hypotension occurred in less than 1% of patients treated with Bolesi® (alprostadil for injection). A single dose rising tolerance study in healthy volunteers indicated that single intravenous doses of alprostadil from 1 to 120 mcg were well tolerated. Beginning with a 40 mcg bolus intravenous dose, the frequency of drug-related systemic adverse events increased in a dose-dependent manner, characterized mainly by facial flushing.

The primary symptom of an Bolesi® (alprostadil for injection) overdose is a prolonged erection or priapism. Because of the potential for tissue hypoxia and possible necrosis, it is strongly recommended to treat an erection lasting more than 6 hours. The patient is strongly encouraged to go to the nearest emergency room if his personal physician is not available.

In the event of an overdose, supportive therapy according to the presence of other symptoms is recommended.

Overdosage has not been reported with Bolesi.

Symptomatic hypotension, persistent penile pain and in rare instances, priapism may occur with alprostadil overdosage. Patients should be kept under medical supervision until systemic or local symptoms have resolved.

Should a prolonged erection lasting 4 or more hours occur, the patient should be advised to seek medical help. The following actions can be taken:

- The patient should be supine or lying on his side. Apply an ice pack alternately for two minutes to each upper inner thigh (this may cause a reflex opening of the venous valves). If there is no response after 10 minutes, discontinue treatment.

- If this treatment is ineffective and a rigid erection has lasted for more than 6 hours, penile aspiration should be performed. Using aseptic technique, insert a 19-21 gauge butterfly needle into the corpus cavernosum and aspirate 20-50 ml of blood. This may detumesce the penis. If necessary, the procedure may be repeated on the opposite side of the penis.

- If still unsuccessful, intracavernous injection of α-adrenergic medication is recommended. Although the usual contraindication to intrapenile administration of a vasoconstrictor does not apply in the treatment of priapism, caution is advised when this option is exercised. Blood pressure and pulse should be continuously monitored during the procedure. Extreme caution is required in patients with coronary heart disease, uncontrolled hypertension, cerebral ischaemia, and in subjects taking monoamine oxidase inhibitors. In the latter case, facilities should be available to manage a hypertensive crisis.

- A 200 microgram/ml solution of phenylephrine should be prepared, and 0.5 to 1.0 ml of the solution injected every 5-10 minutes. Alternatively, a 20 microgram/ml solution of adrenaline should be used. If necessary, this may be followed by further aspiration of blood through the same butterfly needle. The maximum dose of phenylephrine should be 1 mg, or adrenaline 100 micrograms (5ml of the solution).

- As an alternative metaraminol may be used, but it should be noted that fatal hypertensive crises have been reported. If this still fails to resolve the priapism, the patient should immediately be referred for surgical management.

The pharmacotoxic signs of alprostadil are similar in all animal species and include depression, soft stools or diarrhoea and rapid breathing. In animals, the lowest acute LD₅₀ was 12 mg/kg which is 12,000 times greater than the maximum recommended human dose of 60 micrograms.

In man, prolonged erection and/or priapism are known to occur following intracavernous administration of vasoactive substances, including alprostadil. Patients should be instructed to report to a physician any erection lasting for a prolonged time period, such as 4 hours or longer.

Overdosage was not observed in clinical trials with alprostadil. If intracavernous overdose of alprostadil occurs, the patient should be placed under medical supervision until any systemic effects have resolved and/or until penile detumescence has occurred. Symptomatic treatment of any systemic symptoms would be appropriate.

The treatment of priapism (prolonged erection) should not be delayed more than 6 hours. Initial therapy should be by penile aspiration. Using aseptic technique, insert a 19-21 gauge butterfly needle into the corpus cavernosum and aspirate 20-50 ml of blood. This may detumesce the penis. If necessary, the procedure may be repeated on the opposite side of the penis until a total of up to 100 ml blood has been aspirated. If still unsuccessful, intracavernous injection of alpha-adrenergic medication is recommended. Although the usual contra-indication to intrapenile administration of a vasoconstrictor does not apply in the treatment of priapism, caution is advised when this option is exercised. Blood pressure and pulse should be continuously monitored during the procedure. Extreme caution is required in patients with coronary heart disease, uncontrolled hypertension, cerebral ischaemia, and in subjects taking monoamine oxidase inhibitors. In the latter case, facilities should be available to manage a hypertensive crisis. A 200 microgram/ml solution of phenylephrine should be prepared, and 0.5 to 1.0 ml of the solution injected every 5 to 10 minutes. Alternatively, a 20 microgram/ml solution of adrenaline should be used. If necessary, this may be followed by further aspiration of blood through the same butterfly needle. The maximum dose of phenylephrine should be 1 mg, or adrenaline 100 micrograms (5 ml of the solution). As an alternative metaraminol may be used, but it should be noted that fatal hypertensive crises have been reported. If this still fails to resolve the priapism, urgent surgical referral for further management, which may include a shunt procedure, is required.

Apnoea, bradycardia, pyrexia, hypotension and flushing may be signs of drug overdose. If apnoea or bradycardia occur, the infusion should be discontinued and the appropriate medical treatment initiated. Caution should be used if the infusion is restarted. If pyrexia or hypotension occur, the infusion rate should be reduced until these symptoms subside. Flushing is usually attributed to incorrect intra-arterial catheter placement and is usually alleviated by repositioning the tip of the catheter.

ATC Code: G04B E01 (Drugs used in erectile dysfunction).

Alprostadil is chemically identical to prostaglandin E₁, the actions of which include vasodilatation of blood vessels in the erectile tissues of the corpora cavernosa and increase in cavernosal artery blood flow, causing penile rigidity.

Pharmacotherapeutic group: Drugs used in erectile dysfunction

ATC code: G04B E01

Alprostadil is present in various mammalian tissues and fluids. It has a diverse pharmacologic profile, among which some of its more important effects are vasodilation, inhibition of platelet aggregation, inhibition of gastric secretion, and stimulation of intestinal and uterine smooth muscle. The pharmacologic effect of alprostadil in the treatment of erectile dysfunction is presumed to be mediated by inhibition of alpha₁-adrenergic activity in penile tissue and by its relaxing effect on cavernosal smooth muscle.

Pharmacotherapeutic group: Prostaglandins, ATC code: C01EA01

Prostaglandins are potent vasoactive derivatives of arachidonic acid that exert vasomotor, metabolic and cellular effects on the pulmonary and coronary circulation. The E series of prostaglandins produces vasodilation of the systemic and coronary circulation in most species: these prostaglandins have been used for maintaining the patency of the ductus arteriosus in children.

Information for Patients

To ensure safe and effective use of Bolesi® (alprostadil for injection) , the patient should be thoroughly instructed and trained in the self-injection technique before he begins intracavernous treatment with Bolesi® (alprostadil for injection) at home. The desirable dose should be established in the physician's office. The instructions for preparation of the Bolesi® (alprostadil for injection) solution should be carefully followed. The reconstituted solution may initially appear cloudy due to small air bubbles. Do not use the solution if it remains cloudy, contains precipitates, or is discolored. The reconstituted solution should be gently mixed, not shaken. A PATIENT INFORMATION pamphlet is included in each package of Bolesi® (alprostadil for injection) cartridges.

Bolesi® (alprostadil for injection) should be used immediately after reconstitution. The patient should follow the instructions in the patient information pamphlet to limit the possibility of bacterial contamination. The reconstituted cartridge is designed for one use only and should be discarded after use. The Bolesi® (alprostadil for injection) cartridge contains a solid layer or Iyophilized cake of dry white powder approximately 3/8” in thickness. A normal cake may appear cracked or crumbled. If the cartridge is damaged, the cake may shrink in size. Do not use the cartridge if it appears damaged or the cake is substantially reduced in size.

If the dosage prescribed is less than 1 mL of Bolesi® (alprostadil for injection) solution, excess solution will be expelled through the needle as the plunger is pushed and the upper rim of the top stopper reaches the correct volume mark for the prescribed dose. The needle must be properly discarded after use; it must not be reused or shared with other persons.

The dose of Bolesi® (alprostadil for injection) that is established in the physician's office should not be changed by the patient without consulting the physician. The patient may expect an erection to occur within 5 to 20 minutes. A standard treatment goal is to produce an erection lasting no longer than 1 hour. Bolesi® (alprostadil for injection) should be used no more than 3 times per week, with at least 24 hours between each use.

Patients should be aware of possible side effects of therapy with Bolesi® (alprostadil for injection) ; the most frequently occurring is penile pain during and/or after injection, usually mild to moderate in severity. A potentially serious adverse reaction with intracavernous therapy is priapism. Accordingly, the patient should be instructed to contact the physician's office immediately or, if unavailable, to seek immediate medical assistance if an erection persists for longer than 6 hours.

The patient should report any penile pain that was not present before or that increased in intensity, as well as the occurrence of nodules or hard tissue in the penis to his physician as soon as possible. As with any injection, infection is possible. Patients should be instructed to report to the physician any penile redness, swelling, tenderness or curvature of the erect penis. The patient must visit the physician's office for regular checkups for assessment of the therapeutic benefit and safety of treatment with Bolesi® (alprostadil for injection).

Note: Individuals who are sexually active should be counseled about the protective measures that are necessary to guard against the spread of sexually transmitted diseases, including the human immunodeficiency virus (HIV). Use of intracavernous Bolesi® (alprostadil for injection) offers no protection from the transmission of sexually transmitted or blood-borne diseases. The injection of Bolesi® (alprostadil for injection) can induce a small amount of bleeding at the site of injection. In patients infected with blood-borne diseases, this could increase the risk of transmission of blood-borne diseases between partners.

WARNINGS

Prolonged erections greater than four hours in duration occurred in 4% of all patients treated up to 24 months. The incidence of priapism (erections greater than 6 hours in duration) was < 1% with long-term use for up to 24 months. In the majority of cases, spontaneous detumescence occurred. Pharmacologic intervention and/or aspiration of blood from the corpora was necessary in 1.6% of 311 patients with prolonged erections/priapism. To minimize the chances of prolonged erection or priapism, Bolesi® (alprostadil for injection) should be titrated slowly to the lowest effective dose (see DOSAGE AND ADMINISTRATION). The patient must be instructed to immediately report to his prescribing physician or, if unavailable, to seek immediate medical assistance for any erection that persists longer than six hours. If priapism is not treated immediately, penile tissue damage and permanent loss of potency may result.

PRECAUTIONS

General

1. Intracavernous injections of Bolesi® (alprostadil for injection) can lead to increased peripheral blood levels of PGE₁ and its metabolites, especially in those patients with significant corpora cavernosa venous leakage. Increased peripheral blood levels of PGE₁ and its metabolites may lead to hypotension and/or dizziness.
2. Regular follow-up of patients, with careful examination of the penis at the start of therapy and at regular intervals (e.g. 3 months), is strongly recommended to identify any penile changes. The overall incidence of penile fibrosis, including Peyronie's disease, reported in clinical studies up to 24 months with Bolesi® (alprostadil for injection) was 7.8%. Treatment with Bolesi® (alprostadil for injection) should be discontinued in patients who develop penile angulation, cavernosal fibrosis, or Peyronie's disease. Treatment can be resumed if the penile abnormality subsides.
3. The safety and efficacy of combinations of Bolesi® (alprostadil for injection) and other vasoactive agents have not been systematically studied. Therefore, the use of such combinations is not recommended.
4. After injection of the Bolesi® (alprostadil for injection) solution, compression of the injection site for five minutes, or until bleeding stops, is necessary. Patients on anticoagulants, such as warfarin or heparin, may have increased propensity for bleeding after intracavernous injection.
5. Underlying treatable medical causes of erectile dysfunction should be diagnosed and treated prior to initiation of therapy with Bolesi® (alprostadil for injection).
6. Bolesi® (alprostadil for injection) uses a superfine (29 gauge) needle. As with all superfine needles, the possibility of needle breakage exists. Careful instruction in proper patient handling and injection techniques may minimize the potential for needle breakage.
7. The patient should be instructed not to reuse or to share needles or cartridges. As with all prescription medicines, the patient should not allow anyone else to use his medicine.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term carcinogenicity studies have not been conducted. Alprostadil showed no evidence of mutagenicity in three in vitroassays including the AMES bacterial reverse mutation assay, a forward gene mutation assay in Chinese hamster lung (V79) cells, and a chromosome aberration assay in human peripheral lymphocytes. Alprostadil did not produce damage to chromosomes or the mitotic apparatus in the in vivorat micronucleus test.

Alprostadil did not cause any adverse effects on fertility or general reproductive performance when administered intraperitoneally to male or female rats at dose levels from 2 to 200 mcg/kg/day. The high dose of 200 mcg/kg/day is about 300 times the maximum recommended human dose (MRHD) on a body weight basis. The human dose of Bolesi® (alprostadil for injection) is < 1 mcg/kg (MRHD is 40 mcg and the calculation assumes a 60 kg subject).

Pregnancy, Nursing Mothers and Pediatric Use

Bolesi® (alprostadil for injection) is not indicated for use in women or pediatric patients.

Geriatric Use

Of the approximately 1,065 patients who entered the in-office dose-titration period in clinical studies, 25% were 65 years or older. In clinical studies, geriatric patients required, on average, higher minimally effective doses and had a higher rate of lack of effect (optimum dose not determined). Overall differences in safety were not observed between these geriatric patients and younger patients. Geriatric patients should be dosed and titrated according to the same DOSAGE AND ADMINISTRATION recommendations as younger patients, and the lowest possible effective dose should always be used.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

OVERDOSE

Limited data are available in regard to Bolesi® (alprostadil for injection) overdose in humans. Systemic reactions are uncommon with intracavernous injection of Bolesi® (alprostadil for injection). Hypotension occurred in less than 1% of patients treated with Bolesi® (alprostadil for injection). A single dose rising tolerance study in healthy volunteers indicated that single intravenous doses of alprostadil from 1 to 120 mcg were well tolerated. Beginning with a 40 mcg bolus intravenous dose, the frequency of drug-related systemic adverse events increased in a dose-dependent manner, characterized mainly by facial flushing.

The primary symptom of an Bolesi® (alprostadil for injection) overdose is a prolonged erection or priapism. Because of the potential for tissue hypoxia and possible necrosis, it is strongly recommended to treat an erection lasting more than 6 hours. The patient is strongly encouraged to go to the nearest emergency room if his personal physician is not available.

In the event of an overdose, supportive therapy according to the presence of other symptoms is recommended.

CONTRAINDICATIONS

Bolesi® (alprostadil for injection) should not be used in patients who have a known hypersensitivity to alprostadil or other prostaglandins, in patients who have conditions that might predispose them to priapism, such as sickle cell anemia or trait, multiple myeloma, or leukemia, or in patients with anatomical deformation of the penis, such as angulation, cavernosal fibrosis, or Peyronie's disease. Patients with penile implants should not be treated with Bolesi® (alprostadil for injection).

Bolesi® (alprostadil for injection) should not be used in men for whom sexual activity is inadvisable or contraindicated.

Bolesi® (alprostadil for injection) should not be used in women and children and is not for use in newborns.

CLINICAL PHARMACOLOGY

Alprostadil (PGE₁ ) is one of the prostaglandins, a family of naturally occurring acidic lipids with various pharmacological effects. Endogenous PGE₁ is derived from dihomo-gamma-linolenic acid, a fatty acid found within the phospholipids of cellular membranes. As an endogenous substance, PGE₁ exerts its biological effects either directly or indirectly by regulating and modifying the synthesis and effects of other hormones and mediators.

Mode of Action

Alprostadil is a smooth muscle relaxant. Precontracted isolated preparations of the human corpus cavernosum, corpus spongiosum and cavernous artery are relaxed by alprostadil. Alprostadil has been shown to bind to specific receptors in human penile tissue. Two types of receptors that differ in their PGE₁ binding affinity have been identified. The binding of alprostadil to its receptors is accompanied by an increase in intracellular cAMP levels. Human cavernous smooth muscle cells respond to alprostadil by releasing intracellular calcium into the surrounding medium. Smooth muscle relaxation is associated with a reduction of the cytoplasmic free calcium concentration. Alprostadil also attenuates presynaptic noradrenaline release in the corpus cavernosum which is essential for the maintenance of a flaccid and non-erect penis.

Alprostadil induces erection by relaxation of trabecular smooth muscle and by dilation of cavernous arteries. This leads to expansion of lacunar spaces and entrapment of blood by compressing the venules against the tunica albuginea, a process referred to as the corporal veno-occlusive mechanism.

Pharmacokinetics

Alpha-Cyclodextrin

After reconstitution, PGE₁ immediately dissociates from the α-cyclodextrin inclusion complex; the in vivodisposition of both components occurs independently after administration. After intravenous infusion of radiolabeled α-cyclodextrin to healthy volunteers, the radiolabeled components were rapidly eliminated within 24-hours, urine accounting for 81-83% of radioactivity and feces for 0.1%. There was no evidence of significant accumulation of radiolabeled α-cyclodextrin in the body even after 7 days of repeated intravenous injection. After intracavernous administration in monkeys, radiolabeled α-cyclodextrin was rapidly distributed from the injection site with less than 0.1% of the dose remaining in the penis 1 hour after administration. There was no evidence of tissue retention of radiolabeled α-cyclodextrin in monkeys.

Alprostadil Absorption: After intracavernous injection of 20 mcg of Bolesi® (alprostadil for injection) in 24 patients with erectile dysfunction, mean systemic plasma concentrations of PGE₁ increased from baseline of 0.8 ± 0.6 pg/mL to a peak (Cmax) of 16.8 ± 18.9 pg/mL (corrected for baseline) within 2 to 5 minutes and dropped to endogenous plasma levels within 2 hours (Table 1). The absolute bioavailability of alprostadil estimated from systemic exposure was about 98% as compared to the same dose given by a short-term intravenous infusion.

Distribution: The volume of distribution for PGE₁ was not estimated. Approximately 93% of PGE₁ found in plasma is protein-bound.

Metabolism: PGE₁ is metabolized in the corpus cavernosum after intracavernous administration. PGE₁ entering the systemic circulation is rapidly and extensively metabolized in the lungs with a first-pass pulmonary elimination of 60 to 90% of PGE₁. Enzymatic oxidation of the C15-hydroxy group followed by reduction of the C13, 14-double bond produces the primary metabolites, 15-keto-PGE₁ , 15-keto-PGE₀ , and PGE₀. 15-keto-PGE₁ has only been detected in vitroin homogenized lung preparations, whereas 15-keto-PGE₀ and PGE₀ have been measured in plasma. Unlike the 15-keto metabolites which are less pharmacologically active than the parent compound, PGE₀ is similar in potency to PGE₁ in vitrousing isolated animal organs.

After intracavernous injection of 20 mcg of Bolesi® (alprostadil for injection) to 24 patients with erectile dysfunction, mean systemic plasma 15-keto-PGE₀ levels increased within 7 minutes from endogenous levels of 12.9 ± 11.8 pg/mL to a Cmax of 421 ± 337 pg/mL (corrected for baseline) followed by a decrease to baseline levels in several hours. Mean systemic plasma PGE₀ levels increased within 20 minutes from endogenous levels of 0.6 ± 0.5 pg/mL to a Cmax of 3.9 ± 2.3 pg/mL (corrected for baseline) followed by a decrease to baseline levels in several hours.

Excretion: After further degradation of PGE₁ by beta and omega oxidation, the main metabolites are excreted primarily in urine (88%) and feces (12%) over 72 hours, and total excretion is essentially complete (92%) within 24 hours after administration. No unchanged PGE₁ has been found in the urine and there is no evidence of tissue retention of PGE₁ and its metabolites. After intracavernous injection of 20 mcg of Bolesi® (alprostadil for injection) in patients with erectile dysfunction, the terminal half-lives (t½) of 15-keto-PGE₀ and PGE₀ were calculated to be 40.9 ± 16.5 minutes and 63.2 ± 31.1 minutes, respectively. The terminal half-life of PGE₁ in healthy volunteers was calculated to be around 9-11 minutes which is consistent with that reported in the literature (8 minutes).

Mean total body clearance of PGE₁ in patients with erectile dysfunction was calculated to be around 115 L/min after an intravenous infusion of 20 mcg alprostadil. The above value exceeded cardiac output indicating extensive and rapid elimination of PGE₁ in the lungs and/or blood.

Special Populations

Geriatric: The potential effect of age on the pharmacokinetics of alprostadil has not been formally evaluated.

Race: The potential influence of race on the pharmacokinetics of alprostadil has not been formally evaluated.

Hepatic Insufficiency: In a study in symptomatic subjects with impaired hepatic function and age/weight/sex-matched healthy volunteers, 120 mcg of alprostadil was administered by intravenous infusion over 2 hours. The mean Cmax value of PGE₁ in hepatically impaired patients was 96% higher than in healthy volunteers. Mean Cmax values of both 15-keto-PGE₀ and PGE₀ increased 65% as compared to those in healthy volunteers. The terminal half-lives of PGE₁ , PGE₀ , and 15-keto-PGE₀ and plasma albumin levels were similar in patients compared to healthy volunteers. Due to the fact that PGE₁ is primarily metabolized in the lung, the observed differences between hepatically impaired subjects and healthy volunteers were not anticipated; the mechanism responsible for the observed discrepancies is not known.

Renal Impairment: In a study in symptomatic subjects with end-stage renal disease undergoing hemodialysis and age/weight/sex-matched healthy volunteers, 120 mcg of alprostadil was administered by intravenous infusion over 2 hours. The mean Cmax value of PGE₁ in renally impaired patients was 37% lower as compared to that in healthy volunteers whereas mean Cmax values of 15-keto-PGE₀ and PGE₀ in these patients increased 104% and 145%, respectively as compared to those in healthy volunteers. The terminal half-lives of PGE₁ , PGE₀ and 15-keto-PGE₀ and plasma albumin levels were similar in these patients vs healthy volunteers. The mechanism responsible for the observed discrepancies between renally impaired subjects and healthy volunteers is not known.

Pulmonary Disease: The pulmonary extraction of alprostadil following intravascular administration was reduced by 15% (66 ± 3.6% vs 78 ± 2.3%) in patients with acute respiratory distress syndrome (ARDS) compared with a group of patients with normal respiratory function who were undergoing cardiopulmonary bypass surgery. Pulmonary clearance was found to vary as a function of cardiac output and pulmonary intrinsic clearance in a group of 14 patients with ARDS or at risk of developing ARDS following trauma or sepsis. In this study, the pulmonary extraction efficiency of alprostadil ranged from subnormal (11%) to normal (90%), with an overall mean of 67%.

Drug-Drug Interactions: In clinical trials, concomitant use of agents such as antihypertensive drugs, diuretics, antidiabetic agents (including insulin), or nonsteroidal anti-inflammatory drugs had no apparent effect on the efficacy or safety of Bolesi® (alprostadil for injection).

Aspirin, Warfarin, Digoxin, Glyburide: Several drug-drug interaction studies have been conducted with alprostadil alone or in combination with aspirin, digoxin or warfarin in healthy volunteers and with glyburide in subjects with stable, non-insulin dependent diabetes mellitus. The pharmacokinetic profiles of aspirin, warfarin, digoxin, and glyburide were not affected by concomitant administration of alprostadil. There were no clinically important changes or trends in pharmacodynamic parameters for these drugs.

Heparin: The pharmacokinetic and pharmacodynamic interaction between alprostadil intravenous infusion, 90 mcg over 3 hours, and heparin (5,000 IU) was evaluated in 12 healthy volunteers. Alprostadil had a significant effect on the pharmacodynamics of heparin resulting in a 140% increase in partial thromboplastin time and a 120% increase in thrombin time. Therefore, caution should be exercised with concomitant administration of heparin and Bolesi® (alprostadil for injection).

TABLE 1

Clinical Studies

In two studies [Protocol numbers KU-620-001 (Study 1) and KU-620-002 (Study 2)], the safety and efficacy of Bolesi® (alprostadil for injection) were evaluated in 347 men with a diagnosis of erectile dysfunction due to vasculogenic, neurogenic and/or mixed etiology. Each study consisted of three phases: an in-office dose-titration phase, a two-week double-blind cross-over phase at home, and an open-label at home treatment phase that lasted for 12 months (Study 1) or six months (Study 2).

During the dose-titration phase, individualized optimum doses of Bolesi® (alprostadil for injection) were established. Erectile response was measured by the Buckling Test to assess axial penile rigidity. A positive Buckling Test was achieved if the erect penis was able to support an axial load of 1.0 kg without buckling of the penile shaft. During the subsequent two-week double-blind, cross-over phase, patients self-injected Bolesi® (alprostadil for injection) or placebo at home. Thereafter, patients continued to perform self-injections of open-label Bolesi® (alprostadil for injection) for six or 12 months, and the occurrence of an erection sufficient for sexual intercourse was documented following each injection.

Results

Study 1: One hundred fourteen men with a mean age of 53 years (range 22 to 65 years) were enrolled in the first phase. The mean optimum dose was 13.8 mcg (range 1 to 20 mcg). Seventy-six percent (87/114) of patients had an erection with a positive penile Buckling Test. Among the 71% (81/114) of patients who entered the placebo-controlled phase, an erection sufficient for sexual intercourse was achieved in 74% (60/81) of patients following Bolesi® (alprostadil for injection) injection compared to 7% (6/81) of patients following placebo injection. The mean duration of erection following Bolesi® (alprostadil for injection) was 56.9 minutes compared to 4.0 minutes following placebo. Among the 65% (74/114) of patients who entered the open-label treatment phase, the mean rate of response with an erection sufficient for sexual intercourse was 88.9% through 12 months. The average dose of Bolesi® (alprostadil for injection) remained essentially unchanged throughout the study duration.

Study 2: Two hundred thirty-three men with a mean age of 59.8 years (range 23 to 74 years) were enrolled in the first phase. The mean optimum dose was 25.9 mcg (range 1 to 40 mcg). Seventy-three percent (17½33) of patients had an erection with a positive penile Buckling Test. Among the 60% (14½33) of patients who entered the placebo-controlled phase, an erection sufficient for sexual intercourse was achieved in 73% (103/141) of patients following Bolesi® (alprostadil for injection) injection compared to 13% (18/141) of patients following placebo injection. The mean duration of erection following Bolesi® (alprostadil for injection) was 59.0 minutes compared to 7.6 minutes following placebo. Among the 60% (139/233) of patients who entered the open-label treatment phase, the mean rate of response with an erection sufficient for intercourse was 85.3% through six months. The average dose of Bolesi® (alprostadil for injection) remained essentially unchanged throughout the study duration.

Approximately 80% of the alprostadil delivered by Bolesi is absorbed through the urethral mucosa within 10 minutes. The half-life is less than 10 minutes and peripheral venous plasma concentrations are low or undetectable. Alprostadil is rapidly metabolised, both locally and in the pulmonary capillary bed; metabolites are excreted in the urine (90% within 24 hours) and the faeces. There is no evidence of tissue retention of alprostadil or its metabolites.

Following intracavernous injection of 20 micrograms of alprostadil, mean peripheral levels of alprostadil at 30 and 60 minutes after injection are not significantly greater than baseline levels of endogenous PGE₁. Peripheral levels of the major circulating metabolite, 15-oxo-13,14-dihydro-PGE₁, increase to reach a peak 30 minutes after injection and return to pre-dose levels by 60 minutes after injection. Any alprostadil entering the systemic circulation from the corpus cavernosum will be rapidly metabolised. Following intravenous administration, approximately 80% of the circulating alprostadil is metabolised in one pass through the lungs, primarily by beta- and omega-oxidation. The metabolites are excreted primarily by the kidney and excretion is essentially complete within 24 hours. There is no evidence of tissue retention of alprostadil or its metabolites following intravenous administration.

Distribution

Based on studies in several animal species, intravenous or arterially administered prostaglandin E1 is very rapidly distributed throughout the entire body, with the exception of the central nervous system, where distribution, though detectable, is markedly reduced.

Biotransformation

Prostaglandin E1 is very rapidly metabolised. The primary organs for metabolism and inactivation of prostaglandin E1 are probably the lung, liver and kidney which remove and metabolise 40-95% of the prostaglandin E1 in a single pass through the organ. A number of other tissues possess lesser, but significant, capacity to metabolise prostaglandin E1. The predominant metabolites found in plasma, 15-oxo-prostaglandin E1 and 13, 14-dihydro-15 oxo-prostaglandin E1 are extensively metabolised by β- and ω-oxidation prior to excretion, primarily by the kidney. Few urinary metabolites of prostaglandin E1 have been characterised, but are widely believed to be analogous to those reported in detail for prostaglandin E2 and prostaglandin F2.

Elimination

Excretion is essentially complete within 24 hours after dosing, with no intact prostaglandin E1 being found in urine and no evidence of tissue retention of prostaglandin E1 or metabolites. In three species (rat, rabbit and lamb), the prostaglandin metabolising activity of lung from near-term fetal animals has been shown to be at least as effective as that of adults.

In rats, high doses of prostaglandin E₁ increased foetal resorption, presumably due to maternal stress. High concentrations of alprostadil (400 microgram/ml) had no effect on human sperm motility or viability in vitro. In rabbits, there was no foetal damage or effect on reproductive function at the maximum tested intravaginal dose of 4mg.

In the majority of in vitro and in vivo genotoxicity test systems in which alprostadil has been evaluated it produced negative results. These tests include the bacterial reversion test using Salmonella typhimurium, unscheduled DNA synthesis in rat primary hepatocytes, forward mutation assay at the hprt locus in cultured ovary cells from Chinese hamsters, alkaline elution test, sister chromatid exchange assay (all in vitro tests) and the micronucleus test in both mice and rats (in vivo tests). In two other in vitro tests, the mouse lymphoma forward mutation assay and the Chinese hamster ovary chromosomal aberration assay, alprostadil produced borderline positive and positive evidence, respectively, for chromosomal damage. In view of the number of negative in vitro results and the lack of evidence for genotoxicity in two in vivo tests, it is considered that the positive results obtained in these two in vitro tests are of doubtful biological significance. Overall the presently available evidence cannot fully exclude the risk of genotoxic activity in humans.

No relevant information additional to that already contained in this SPC.

Long-term carcinogenicity and fertility studies have not been done. The Ames and Alkaline Elution assays reveal no potential for mutagenesis.

Not applicable.

Bolesi is not intended to be mixed or coadministered with any other products.

Diluted solutions of Prostin VR should be infused from glass or hard plastic containers, or PVC infusion bags.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

No special requirements.

The presence of benzyl alcohol in the reconstitution vehicle decreases the degree of binding to package surfaces. Therefore, a more consistent product delivery is produced when Bacteriostatic Water for Injection containing benzyl alcohol is used.

Use immediately after reconstitution.

Dilution instructions

To prepare infusion solutions, dilute 1 ml of Prostin VR with sterile 0.9% sodium chloride intravenous infusion or sterile 5% dextrose intravenous infusion.

If undiluted Prostin VR comes in direct contact with a plastic container, plasticisers are leached from the side walls. The solution may turn hazy and the appearance of the container may change. Should this occur, the solution should be discarded and the plastic container should be replaced. This appears to be a concentration-dependent phenomenon. To minimise the possibility of haze formation, Prostin VR should be added directly to the intravenous infusion solution, avoiding contact with the walls of plastic containers. Dilute to volumes appropriate for the delivery system available. Prepare fresh infusion solutions every 24 hours. Discard any solution more than 24 hours old.

No special requirements for disposal. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.