Pharmacia & Upjohn
Action And Clinical Pharmacology: Alprostadil is a prostaglandin with various pharmacological actions that include vasodilatation and inhibition of platelet aggregation, inhibition of gastric secretion, stimulation of intestinal smooth muscle and stimulation of uterine smooth muscle.
Alprostadil, when given to impotent men by intracavernous injection, induces erections within 5 to 20 minutes after administration. The duration of erection is dose-dependent. The mechanism of penile erection involves a complex series of neurovascular events. Alprostadil injected intracavernosally causes tumescence by increasing cavernous blood flow through relaxation of trabecular smooth muscle and dilation of cavernosal arteries.
With regards to the action of alprostadil on penile structures, in most animal species tested, alprostadil had relaxant effects on retractor penis and corpus cavernosum urethra in vitro. Alprostadil also relaxed isolated preparations of human corpus cavernosum and spongiosum as well as cavernous arterial segments previously contracted by either norepinephrine or PGF2 . In pigtail monkeys (Macaca nemestrina), alprostadil increased cavernous arterial blood flow in vivo. The degree and duration of cavernous smooth muscle relaxation in this animal model was dose-dependent.
Other actions of PGE1 involve the cardiovascular system, CNS, autonomic nervous system, respiratory system, gastrointestinal system and hematopoietic system.
Pharmacokinetics: Absorption: The absolute bioavailability of alprostadil following intracavernosal injection has not been determined.
Distribution: Following a 20 g intracavernosal injection of alprostadil, mean peripheral plasma concentrations of alprostadil were 89 pg/mL and 102 pg/mL at 30 and 60 minutes post-injection respectively, which were not significantly greater than baseline levels of endogenous alprostadil at 96 pg/mL. Alprostadil is bound primarily to plasma albumin (81%) and to a lesser degree to g-globulin IV-4 fraction (55%). No significant binding could be demonstrated with erythrocytes or white cells.
Metabolism: Alprostadil is rapidly converted to compounds, which are further metabolized prior to excretion. In man, a single pass through the lung effectively metabolizes approximately 80% of the available PGE1 primarily by beta- and omega-oxidation. Therefore, any alprostadil that may enter the systemic circulation following intracavernosal injection is rapidly metabolized. However, pulmonary clearance of PGE1 can be affected by disease states such as acute respiratory distress syndrome (ARDS), with a resultant reduction in the pulmonary extraction ratio.
After intracavernosal administration of 20 g of alprostadil, peripheral levels of the primary metabolite 15-oxo-13,14-dihydro-PGE1 increased, reaching a peak at 30 minutes and falling to predose levels by 60 minutes postinjection.
Excretion: The major route of elimination of the metabolites of alprostadil is through the kidney. Urinary excretion of an i.v. dose is essentially complete (90%) within 24 hours of administration. The remainder of the dose is excreted in the feces. There is no evidence to suggest any tissue retention of PGE1 or its metabolites after an i.v. administration.
Pharmacokinetics in Special Populations: Geriatrics: The potential effect of age on the pharmacokinetics of alprostadil has not been formally evaluated. In patients with ARDS, the mean (±SD) pulmonary extraction of alprostadil was 72%±15% in 11 elderly patients aged 65 years or older (mean 71±6 years) and 65%±20% in 6 young patients aged 35 years or younger (mean 28±5 years).
Children: Plasma alprostadil concentrations were evaluated in 10 neonates (gestational age 34 weeks in 2 infants and 38 to 40 weeks in 8 infants) receiving steady-state i.v. infusions of alprostadil to treat underlying cardiac malformations. Alprostadil infusion rates ranged from 5 to 50 ng/kg/min (median 45 ng/kg/min), with resultant plasma concentrations in the range of 22 to 530 pg/mL (median 56 pg/mL). The individual clearance of alprostadil in neonates is highly variable as reflected by the wide range of plasma concentrations observed.
Gender: The influence of gender on the pharmacokinetics of alprostadil has not been formally studied. Two studies evaluated pulmonary extraction in 23 patients with ARDS following i.v. administration of alprostadil. The 17 males had a pulmonary extraction of 66% compared to 69% in the 6 female patients, suggesting no gender influence.
Race: The influence of race on the pharmacokinetics of alprostadil have not been formally studied.
Renal and Hepatic Insufficiency: The effects of renal and hepatic insufficiency on the pharmacokinetics of alprostadil have not been formally studied. Since systemic clearance of alprostadil is primarily by first-pass metabolism through the lungs, it is not expected that altered renal or hepatic function will have a major influence on the pharmacokinetics of alprostadil.
Pulmonary Disease: In one study, pulmonary extraction of alprostadil given i.v. was found to be reduced by 15% in patients with ARDS (66%) compared to patients with normal respiratory function (78%). In a second study of 14 patients with ARDS or at risk of developing ARDS, the mean extraction efficiency of alprostadil was 67% ranging from subnormal (11%) to normal (90%).
Indications And Clinical Uses: For the intracavernosal treatment of erectile dysfunction due to neurogenic, vasculogenic, psychogenic, or mixed etiology. Intracavernosal alprostadil may also be useful as an adjunct to diagnostic tests in the diagnosis of erectile dysfunction.
Contra-Indications: Patients with a known hypersensitivity to the drug. Patients who have any condition that may predispose them to priapism such as sickle cell anemia or trait, multiple myeloma or leukemia. Patients with anatomical deformations of the penis, such as angulation, cavernosal fibrosis, Peyronie’s disease. Patients with penile implants.
Caverject should not be used in women or children and is not for use in newborns.
Alprostadil should not be used in men for whom sexual activity is inadvisable or contraindicated.
Manufacturers’ Warnings In Clinical States: Prolonged erection (4 to 6 hours) and/or priapism (>6 hours) are known to occur following intracavernosal administration of vasoactive substances, including alprostadil. In clinical studies, prolonged erection occurred in 4% of patients and 0.4% experienced priapism.
The patient should be instructed to immediately report to his physician, or if unavailable, to seek immediate medical assistance for an erection persisting for more than 3 hours. Treatment of prolonged erection/priapism should be according to established medical practice (see Overdose: Symptoms and Treatment). If priapism is not treated immediately, penile tissue damage and permanent loss of potency may result.
In the majority of cases, spontaneous detumescence occurred. To minimize the chances of prolonged erection or priapism, alprostadil should be titrated slowly to the lowest effective dose (see Dosage).
Precautions: General: Underlying treatable medical causes of erectile dysfunction must be diagnosed and treated prior to initiating therapy with alprostadil.
The results of clinical studies with alprostadil indicate an overall incidence of penile fibrosis, including Peyronie’s disease, of 3% (55/1 861). In one long-term (up to 18 months duration) self-injection study, the incidence of fibrosis reported was 7.8% (53/683). Regular follow-up of patients, with careful examination of the penis, is strongly recommended to detect signs of penile fibrosis. 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 an increased propensity for bleeding after intracavernosal injection.
An injection of alprostadil can induce a small amount of bleeding at the injection site (see Adverse Effects, Hematoma Ecchymosis, Hemorrhage). In patients infected with blood-borne diseases, this may increase the transmission of blood-borne diseases between partners.
The safety and efficacy of combinations of alprostadil and other vasoactive agents have not been systematically studied. Therefore, the use of such combinations is not recommended.
Drug Interactions: The potential for pharmacokinetic drug-drug interactions between alprostadil and other agents has not been formally studied.
Information for the Patient: Patients using a self-injection program of therapy should receive proper instruction in both intracavernosal injection and aseptic technique (see Blue Section – Information for the Patient). Physicians should ensure that patients are able to demonstrate competence and skill with the injection procedure prior to initiating self-injection.
The initial treatment dose is established in the physicians office. The lowest effective dose sufficient to induce an erection lasting up to 1 hour should be used. The patient may expect an erection to occur within 5 to 20 minutes. Patients who require dosage adjustments and are self-injecting alprostadil, should not increase or decrease their dose without the advice of their physician. Generally, patients should not use alprostadil more than once a day and not more than 3 times a week, with at least 24 hours between each use.
Alprostadil is labelled for “single use only”, patients should discard any unused solution after withdrawing the proper volume for their dose. The vial should not be shaken once reconstituted.
Reconstituted vials of alprostadil that on visual inspection appear cloudy, colored or contain particulate matter, should be discarded.
Patients who experience an erection lasting longer than 2 hours should attempt to detumesce using methods prescribed by their physician.
Patients should be advised on the possible adverse effects associated with the use of alprostadil; the most frequent being mild to moderate penile pain after injection. A patient should report to his physician if he complains of: any penile pain not previously present, an increased intensity of pain, nodules or hard tissue appearing in the penis, or curvature of the erect penis. There is the potential for infection with any type of injection, therefore patients should also report any occurrences of penile redness, swelling, or tenderness. The importance of regular physician visits to assess the continued safety and efficacy of alprostadil treatment should be stressed to the patient.
A potentially serious adverse reaction with intracavernosal 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 3 hours.
In clinical trials, the use of concomitant medicines such as antihypertensives, diuretics, antidiabetic agents (including insulin) or NSAIDs, did not affect the safety or efficacy of alprostadil.
The use of alprostadil intracavernosally does not offer any protection from the spread of sexually transmitted diseases. Individuals using alprostadil should be properly counselled with regards to protective measures to safeguard against the spread of sexually transmitted diseases, including human immunodeficiency virus (HIV) infection.
Patients should be instructed not to reuse or share needles or syringes. The patient should not allow anyone else to use this medicine. Patients should dispose of used needles, syringes, and vials, safely and properly (see Blue Section – Information for the Patient).
A patient administration guide, found in every package, provides a step-by-step method for proper preparation and administration of alprostadil. Patients should be instructed to carefully follow this guide for self-injection.
Carcinogenesis, Mutagenesis and Impairment of Fertility: Long-term carcinogenicity studies have not been conducted. Reproductive studies in the rat with alprostadil at doses of up to 0.2 mg/kg/day did not adversely affect or alter spermatogenesis, conferring a 200-fold margin of safety at usual human doses. A battery of mutagenicity assays including, bacterial mutation (Ames), alkaline elution, rat micronucleus, sister chromatid exchange, CHO/HGPRT mammalian cell forward gene mutation and unscheduled DNA synthesis (UDS), revealed no potential for mutagenesis.
A one-year irritancy study was conducted in male Cynomolgus monkeys. Three groups of 5 animals received twice weekly intracavernosal injections of either 3 or 8.25 g alprostadil or vehicle. A further 2 groups of 6 animals were given 8.25 Âµg alprostadil or vehicle twice weekly, as above, and in addition, multiple doses during weeks 44, 48 and 52. Three monkeys receiving vehicle and 3 monkeys receiving 8.25 g alprostadil were held for evaluation following a 4-week recovery period. No evidence of alprostadil-related penile or systemic tissue lesions were found. Local irritation noted in control and treated monkeys was considered to be related to the injection procedure itself and any penile lesions found were reversible. After the 4-week recovery period, a regression in histological changes in the penis was observed.
Adverse Reactions: Local Adverse Events: The following local adverse events were reported from controlled and uncontrolled clinical trials, including an uncontrolled 18-month safety study.
Penile Pain: Penile pain after intracavernosal administration of alprostadil was reported at least once by 37% of patients in clinical studies up to 18 months in duration. The intensity of pain was rated mild or moderate in the majority of cases. Three percent of patients discontinued treatment because of penile pain. The frequency of penile pain was 2% in 294 patients who received 1 to 3 injections of placebo.
Prolonged Erection/Priapism: In clinical trials, prolonged erection was defined as an erection that lasted for 4 to 6 hours; priapism was defined as an erection that lasted 6 hours or longer (see Warnings).
Hematoma/Ecchymosis: The frequency of hematoma and ecchymosis was 3 and 2 % respectively. In most cases, hematoma/ecchymosis was judged to be a complication of a faulty injection technique. Accordingly, proper instruction of the patient in self-injection is of importance to minimize the potential of hematoma/ecchymosis (see Dosage).
Local events observed in 6 h), numbness, yeast infection, irritation, sensitivity, phimosis, pruritus, erythema, venous leak, painful erection and abnormal ejaculation.
Systemic Adverse Events: The following systemic adverse event information was derived from controlled and uncontrolled studies, including an uncontrolled 18-month safety study.
Systemic events reported in 1% of patients and judged by investigators to be possibly related to the use of alprostadil include: testicular pain, scrotal disorder, scrotal edema, hematuria, testicular disorder, impaired urination, urinary frequency, pelvic pain, hypotension, vasodilation, peripheral vascular disorder, supraventricular extrasystole, vasovagal reactions, hypesthesia, nongeneralized weakness, diaphoresis, rash, nonapplication site pruritus, skin neoplasm, nausea, dry mouth, increased serum creatinine, leg cramps and mydriasis.
Hemodynamic changes, manifested as decreases in blood pressure and increases in pulse rate, were observed during clinical studies, principally at doses above 20 Âµg and above 30 Âµg of alprostadil respectively, and appeared to be dose-dependent. However, these changes were clinically unimportant; only 3 patients discontinued the treatment because of symptomatic hypotension.
Alprostadil had no clinically important effect on serum or urine laboratory tests.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: The pharmacotoxic signs of alprostadil are similar in all animal species and include depression, soft stool or diarrhea and rapid breathing. In mice, the lowest acute LD50 was 12 mg/kg which is 12 000 times greater than the maximum recommended human dose of 60 g.
In man, prolonged erection and/or priapism are known to occur following intracavernosal administration of vasoactive substances. Given the dose-response relationship of alprostadil with erection duration, the therapeutic dose range should be determined individually for each patient by his physician during the initial office instruction. Inadvertent or intentional overdosing is the most common cause of prolonged pharmacological erection. In clinical trials with alprostadil, overdosage was not observed. If intracavernous overdose of alprostadil occurs, the patient should be 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.
Patients should be instructed to report any erections persisting for more than 3 hours to a physician. The treatment of priapism/prolonged erection should be according to established medical practice. Physicians may refer to 2 suggested protocols for detumescence presented below.
Detumescence Protocols: 1. Aspirate 40 to 60 mL from either right or left corpora using vacutainer and holder as for drawing blood. Use landmarks as for intracavernosal injection. Patient will often detumesce while aspirating. Apply ice for 20 minutes post-aspiration if erection remains. If 1) unsuccessful then, 2. Have patient lie in supine postion. Dilute 10 mg phenylephrine into 20 mL water for injection (0.05%). With an insulin syringe, inject 0.1 to 0.2 mL (50 to 100 g) into the corpora every 2 to 5 minutes, until detumescence occurs. The occasional patient may experience very transient bradycardia and hypertension when given phenylephrine injections, therefore monitor patient’s blood pressure and pulse every 10 minutes. Patients at risk include those with cardiac arrhythmias and diabetics. Refer to the prescribing information for phenylephrine before use. Do not give to patients on MAOIs. When phenylephrine is used within the first 12 hours of erection, the majority of patients will respond. 3. If the above measures fail to detumesce the patient, a urologist should be consulted as soon as possible, especially if the erection has been present for many hours. If priapism is not treated immediately, penile tissue damage and/or permanent loss of potency may result.
Dosage And Administration: Administration: Alprostadil is administered by direct intracavernosal injection. A 0.5-inch 27- to 30-gauge needle is generally recommended. Alprostadil is injected into either of two corpora cavernosum along the dorso-lateral aspects of the proximal third of the penis. Avoid any area where there are visible veins. The injection site should be changed for each injection (i.e., alternate sides of penis). Within either area, the point of injection should also be changed each time and the injection site must be cleansed with an alcohol swab.
Therapeutic/Effective Dose: Appropriate initial doses and maintenance doses are recommended based on the etiology of the erectile dysfunction. In all cases, the dose should be titrated on an individual basis by the physician, and the lowest effective dose always employed as the therapeutic dose. An effective dose is defined as one that produces an erection sufficient for intercourse with an erection duration not exceeding 1 hour. The following guidelines for dose titration are recommended.
Initial Titration in Physician’s Office: Erectile Dysfunction of Vasculogenic, Psychogenic or Mixed Etiology: Dosage titration should be initiated at 2.5 g of alprostadil. If there is a partial response, the dose may be increased by 2.5 g to a dose of 5 g and then in increments of 5 to 10 g, depending upon erectile response, until the effective dose is reached (see Therapeutic/Effective Dose). If there is no response to the initial 2.5 g dose, the second dose may be increased to 7.5 g, followed by increments of 5 to 10 g. The patient must remain in the physician’s office until complete detumescence is achieved. 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 24-hour interval before the next dose is given.
Erectile Dysfunction of Pure Neurogenic Etiology: Dosage titration should be initiated at 1.25 g of alprostadil. The dose may be increased by 1.25 g to a dose of 2.5 g, followed by an increment of 2.5 g to a dose of 5 g and then in 5 g increments until the effective dose is reached (see Therapeutic/Effective Dose). The patient must remain in the physician’s office until complete detumescence is achieved. 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 24-hour interval before the next dose is given.
In one clinical study involving 579 patients, the majority of patients (56%) were titrated to doses of >5 g but 20 g. The mean dose at the end of the titration phase was 17.8 g of alprostadil.
Maintenance Therapy: The initial injection of alprostadil must be delivered by a medically trained health care professional. Before beginning a self-injection program of therapy, the physician must ensure that the patient (or his partner) aptly demonstrates skill and competence with the injection procedure, and uses appropriate sterile technique. A patient package insert is available to patients for referral (see Blue Section – Information for the Patient).
The dose selected for self-injection therapy is established during dose titration in the physician’s office. The correct dose is the lowest effective dose. The dose should be reduced if the erection persists for longer than 1 hour, however, the physician should take into consideration the patient’s preferences when defining the dose for self-injection. An erection lasting >3 hours is to be treated as a medical emergency. A physician should be consulted for any dose adjustments, if required. The dose should be adjusted in accordance with the titration guidelines described above. Regular follow-up visits, at least every 3 months, are recommended in order to assess the safety and efficacy of the therapy.
Maximum Recommended Dose Limits: Daily dose should not exceed 60 g. Not more than once daily and not more than 3 times weekly, with at least 24 hours between each dose. Do not inject alprostadil into an erect penis.
There is no evidence that tolerance to the effects of alprostadil develops with continued use. The long-term use of alprostadil has been documented for up to 6 months in an uncontrolled self-injection study. The mean dose after 6 months was 20.7 g.
A vial of Caverject delivers 1 dose only and is labelled “single dose vial”. Instructions for proper disposal of the syringe, needle and vial should be followed (see Blue Section – Information for the Patient).
Diagnostic Dose: Pharmacologic Testing: An initial dose of 2.5 g is employed with subsequent upward titration in 2.5 g increments. Patients are monitored for the occurrence of an erection following an intracavernosal injection of alprostadil.
Adjunct to Laboratory Investigations: A single dose of alprostadil sufficient to induce a rigid erection is used. For use with Doppler imaging/Duplex Ultrasonography, 33enon washout tests, Radionuclide Phallography and Penile Arteriography for the visualization and assessment of the penile vasculature.
Reconstituted Solutions: Alprostadil is reconstituted with the addition of 1 mL bacteriostatic water for injection (BWFI). Vial content after reconstitution is approximately 1.13 mL which allows 1.0 mL to be delivered to the patient. Approximately 0.5 g/mL of alprostadil is lost due to adsorption to the vial and syringe. The resultant solution contains 10 or 20 g/mL of alprostadil, 172 mg/mL lactose, 47 g/mL sodium citrate, and 8.4 mg/mL benzyl alcohol. Once reconstituted, no additional substances should be injected into the vial.
Once reconstituted, the alprostadil solution must be used immediately. Do not freeze the reconstituted solution. A solution that appears cloudy, colored or contains particles should be discarded.
Availability And Storage: 10 g: Each case contains: a single dose vial of alprostadil 10 g sterile powder, 1 mL prefilled syringe of BWFI diluent, a 27-gauge (0.5 inch) needle, 2 alcohol swabs and Patient Administration Leaflet. These cases are fitted with a lock designed for safe and convenient disposal of the contents after use. Diagnostic vials of 10 g. Cartons of 5.
20 g: Each case contains: a single dose vial of alprostadil 20 g sterile powder, 1 mL prefilled syringe of BWFI diluent, a 27-gauge (0.5 inch) needle, 2 alcohol swabs and Patient Administration Leaflet. These cases are fitted with a lock designed for safe and convenient disposal of the contents after use. Cartons of 5.
The unreconstituted lyophilized sterile powder (10 and 20 g vials) should be stored between 2 to 30°C.
CAVERJECT Pharmacia & Upjohn Alprostadil Prostaglandin