Limited data are available in regard to Prostavasin® (alprostadil for injection) overdose in humans. Systemic reactions are uncommon with intracavernous injection of Prostavasin® (alprostadil for injection). Hypotension occurred in less than 1% of patients treated with Prostavasin® (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 Prostavasin® (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 Prostavasin.
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.
Not applicable.
Prostavasin 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.
Prostavasin® (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 Prostavasin® (alprostadil for injection) and in < 1% of patients treated with placebo.
Local Adverse ReactionsThe following local adverse reactions were reported in studies including 1,065 patients treated with Prostavasin® (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 Prostavasin® (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 Prostavasin® (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 Prostavasin® (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 Prostavasin® (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*
| Local Reaction | Prostavasin® (alprostadil for injection) N = 1065 n (%) | Local Reaction | Prostavasin® (alprostadil for injection) N = 1065 n (%) |
| Penile pain during injection | 305 (29) | Ecchymosis | 44 (4) |
| Penile pain during erection | 368 (35) | Penile angulation | 72 (7) |
| Penile pain after erection | 317 (30) | Penile fibrosis | 52 (5) |
| Penile pain (other)** | 116 (11) | Cavernous body fibrosis | 20 (2) |
| Prolonged erection | Peyronie's disease | 11 (1) | |
| > 4 ≤ 6 Hours | 44 (4) | Faulty injection technique*** | 59 (6) |
| > 6 Hours | 6 ( < 1) | Penis disorder | 28 (3) |
| Bleeding | 158 (15) | Erythema | 17 (2) |
| Hematoma | 56 (5) | ||
| * Protocol Numbers KU-620-001, KU-620-002, KU-620-003, F-8653. ** Penile pain reported without an association to injection site or erection, such as pain in penis and scrotum, pain in glans penis, and burning penile pain. *** Examples include injection into glans penis, urethra or subcutaneously. |
The following systemic adverse experiences were reported in controlled and uncontrolled studies in ≥ 1% of patients treated for up to 24 months with Prostavasin® (alprostadil for injection).
Systemic Adverse Experiences Reported by ≥ 1% of Patients*
| BODY SYSTEM Adverse Experience | Prostavasin® (alprostadil for injection) N = 1065 n (%) | BODY SYSTEM Adverse Experience | Prostavasin® (alprostadil for injection) N = 1065 n (%) | BODY SYSTEM Adverse Experience | Prostavasin® (alprostadil for injection) N = 1065 n (%) |
| RESPIRATORY | CARDIOVASCULAR | UROGENITAL | |||
| Upper respiratory tract | Hypertension | 17 (2) | Prostate disorder | 15 (1) | |
| infection | 58 (5) | Myocardial infarction | 13 (1) | Testicular pain | 13 (1) |
| Sinusitis | 14 (1) | Abnormal ECG | 12 (1) | Inguinal hernia | 11 (1) |
| BODY AS A WHOLE | METABOLIC/NURITIONAL | DERMATOLOGIC | |||
| Influenza-like symptoms | 35 (3) | Hypertriglyceridemia | 17 (2) | Skin disorder | 14 (1) |
| Headache | 20 (2) | Hypercholesterolemia | 12 (1) | SPECIAL SENSES | |
| Infection | 18 (2) | Hyperglycemia | 12 (1) | Abnormal vision | 11 (1) |
| Pain | 16 (2) | ||||
| MUSCULOSKELETAL | |||||
| Back pain | 23 (2) | ||||
| Leg pain | 13 (1) | ||||
| * Protocol Numbers KU-620-001, KU-620-002, KU-620-003, F-8653. | |||||
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.
Prostavasin® (alprostadil for injection) had no clinically important effect on serum or urine laboratory tests.
Post-Marketing Adverse ExperiencesNeedle breakage.
The most frequently reported adverse effect following treatment with Prostavasin 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 Prostavasin 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).
| System Organ Class | Frequency | Adverse Reaction |
| Infections and infestations | Uncommon | Common cold |
| Nervous system disorders | Common | Headache, dizziness |
| Uncommon | Syncope, pre-syncope, hypoaesthesia, hyperaesthesia | |
| Vascular disorders | Common | Symptomatic hypotension, haematoma |
| Uncommon | Vein disorder, peripheral vascular disorder, vasodilatation | |
| Gastrointestinal disorders | Uncommon | Nausea |
| Skin and subcutaneous disorders | Uncommon | Swelling of the leg veins, erythema, hyperhidrosis, rash, pruritus, scrotal erythema |
| Very rare | Urticaria | |
| Musculoskeletal, connective tissue and bone disorders | Common | Muscle spasms |
| Uncommon | Leg pain | |
| Renal and Urinary disorders | Very common | Urethral burning |
| Common | Minor urethral bleeding | |
| Uncommon | Dysuria, pollakiuria, micturition urgency, urethral haemorrhage | |
| Rare | Urinary tract infection | |
| Reproductive system | Very common | Penile pain |
| Common | Erection increased, Peyronie's disease, penis disorder, vaginal burning/itching (in partners) | |
| Uncommon | Perineal pain, erectile dysfunction, ejaculation disorder, balanitis, painful erection, phimosis, priapism, testicular pain, scrotal disorder, scrotal erythema, scrotal pain, spermatocele, scrotal oedema, testicular disorder, testicular swelling, testicular oedema, testicular mass, pelvic pain | |
| Rare | Penile fibrosis | |
| Investigations | Uncommon | Blood pressure decreased, heart rate increased, blood creatinine increased |
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 Prostavasin.
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.
| System Organ Class | Frequency | Undesirable effects |
| Infections and Infestations | Uncommon | Fungal infection, Common cold |
| Nervous System Disorders | Uncommon | Presyncope, Hypoaesthesia, Hyperaesthesia |
| Not known | Cerebrovascular accident | |
| Eye Disorders | Uncommon | Mydriasis |
| Cardiac Disorders | Uncommon | Supraventricular extrasystoles |
| Not known | Myocardial ischaemia | |
| Vascular Disorders | Uncommon | Venous haemorrhage, Hypotension, Vasodilatation, Peripheral vascular disorder, Vein disorder |
| Gastrointestinal Disorders | Uncommon | Nausea, Dry mouth |
| Skin and Subcutaneous Tissue Disorders | Uncommon | Erythema, Rash, Hyperhidrosis, Pruritus |
| Musculoskeletal and Connective Tissue Disorders | Common | Muscle spasms |
| Renal and Urinary Disorders | Uncommon | Urethral haemorrhage, Haematuria, Dysuria, Pollakiuria, Micturition urgency |
| Reproductive System and Breast Disorders | Very common | Penile pain |
| Common | Peyronie's disease, Penis disorder, Erection increased | |
| Uncommon | Priapism, Pelvic pain, Testicular mass, Spermatocele, Testicular swelling, Testicular oedema, Testicular disorder, Scrotal pain, Scrotal erythema, Scrotal oedema, Testicular pain, Scrotal disorder, Painful erection, Balanitis, Phimosis, Erectile dysfunction, Ejaculation disorder | |
| General Disorders and Administration Site Conditions | Common | Injection site haematoma, Haematoma, Ecchymosis |
| Uncommon | Haemorrhage, Injection site haemorrhage, Inflammation, Injection site inflammation, Injection site warmth, Injection site oedema, Injection site swelling, Injection site pain, Injection site irritation, Asthenia, Injection site anaesthesia, Oedema, Oedema peripheral, Injection site pruritus | |
| Investigations | Uncommon | Blood creatinine increased, Blood pressure decreased, Heart rate increased |
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).
| System Organ Class | Frequency | Undesirable effects |
| Nervous system disorders | Common | Seizures |
| Cardiac disorders | Common | Bradycardia, hypotension, tachycardia |
| Vascular disorders | Uncommon | Vascular fragility |
| Respiratory, thoracic and mediastinal disorders | Very common | Apnoea |
| Gastrointestinal disorders | Common | Diarrhoea |
| Uncommon | Gastric obstruction, gastric mucosal hypertrophy | |
| Musculoskeletal and connective tissue disorders | Uncommon | Exostosis |
| General disorders and administration site conditions | Very common | Transient pyrexia |
| Common | Cutaneous vasodilatation (flushing)* |
*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.
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.
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.
To ensure safe and effective use of Prostavasin® (alprostadil for injection) , the patient should be thoroughly instructed and trained in the self-injection technique before he begins intracavernous treatment with Prostavasin® (alprostadil for injection) at home. The desirable dose should be established in the physician's office. The instructions for preparation of the Prostavasin® (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 Prostavasin® (alprostadil for injection) cartridges.
Prostavasin® (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 Prostavasin® (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 Prostavasin® (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 Prostavasin® (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. Prostavasin® (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 Prostavasin® (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 Prostavasin® (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 Prostavasin® (alprostadil for injection) offers no protection from the transmission of sexually transmitted or blood-borne diseases. The injection of Prostavasin® (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 & Precautions WARNINGSProlonged 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, Prostavasin® (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 GeneralLong-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 Prostavasin® (alprostadil for injection) is < 1 mcg/kg (MRHD is 40 mcg and the calculation assumes a 60 kg subject).
Pregnancy, Nursing Mothers and Pediatric UseProstavasin® (alprostadil for injection) is not indicated for use in women or pediatric patients.
Geriatric UseOf 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.
Overdosage & Contraindications OVERDOSELimited data are available in regard to Prostavasin® (alprostadil for injection) overdose in humans. Systemic reactions are uncommon with intracavernous injection of Prostavasin® (alprostadil for injection). Hypotension occurred in less than 1% of patients treated with Prostavasin® (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 Prostavasin® (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.
CONTRAINDICATIONSProstavasin® (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 Prostavasin® (alprostadil for injection).
Prostavasin® (alprostadil for injection) should not be used in men for whom sexual activity is inadvisable or contraindicated.
Prostavasin® (alprostadil for injection) should not be used in women and children and is not for use in newborns.
Clinical Pharmacology CLINICAL PHARMACOLOGYAlprostadil (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 ActionAlprostadil 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-CyclodextrinAfter 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 Prostavasin® (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 Prostavasin® (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 Prostavasin® (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 PopulationsGeriatric: 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 Prostavasin® (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 Prostavasin® (alprostadil for injection).
TABLE 1
| Study No. | Participants | Route and Dose Administration | Drug/Metabolites | Cmax1[pg/mL] | Tmax[min] | AUC2 [pg•min/mL] | Total Clearance3 [L/min] | t½4 [min] |
| PHAKI 848 | Erectile Dysfunction Patients | 20 mcg/0.5 hr IV | PGE1 | 7.09 ± 3.12 | 25.5 ± 4.8 | 174 ± 101 | 115 | - |
| 15-keto-PGE0 | 471 ± 88 | 30.0 ± 1.2 | 13705 ± 2559 | - | 15.6 ± 5.6 | |||
| PGE0 | 7.10 ± 2.19 | 32.2 ± 2.4 | 380 ± 115 | - | 39.8 ± 26.3 | |||
| 20 mcg/IC | PGE1 | 16.8 ± 18.9 | 4.8 ± 3.3 | 173 ± 115 | - | - | ||
| 15-keto-PGE0 | 421 ± 337 | 9.7 ± 7.7 | 10500 ± 4101 | - | 40.9 ± 16.5 | |||
| PGE0 | 3.9 ± 2.3 | 20.3 ± 12.6 | 252 ± 134 | - | 63.2 ± 31.1 | |||
| 1 Baseline-corrected data. 2 AUC0-150 for IV infusion and AUC0-120 for IC injection. 3 Calculated as IV dose/AUC0-150 (IV). 4 Apparent terminal half-life. |
In two studies [Protocol numbers KU-620-001 (Study 1) and KU-620-002 (Study 2)], the safety and efficacy of Prostavasin® (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 Prostavasin® (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 Prostavasin® (alprostadil for injection) or placebo at home. Thereafter, patients continued to perform self-injections of open-label Prostavasin® (alprostadil for injection) for six or 12 months, and the occurrence of an erection sufficient for sexual intercourse was documented following each injection.
ResultsStudy 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 Prostavasin® (alprostadil for injection) injection compared to 7% (6/81) of patients following placebo injection. The mean duration of erection following Prostavasin® (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 Prostavasin® (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 Prostavasin® (alprostadil for injection) injection compared to 13% (18/141) of patients following placebo injection. The mean duration of erection following Prostavasin® (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 Prostavasin® (alprostadil for injection) remained essentially unchanged throughout the study duration.
Approximately 80% of the alprostadil delivered by Prostavasin 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.
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, Prostavasin® (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 GeneralLong-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 Prostavasin® (alprostadil for injection) is < 1 mcg/kg (MRHD is 40 mcg and the calculation assumes a 60 kg subject).
Pregnancy, Nursing Mothers and Pediatric UseProstavasin® (alprostadil for injection) is not indicated for use in women or pediatric patients.
Geriatric UseOf 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 Prostavasin.
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 Prostavasin 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 Prostavasin, 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 Prostavasin. 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 Prostavasin should be discontinued in patients who develop penile angulation, cavernosal fibrosis, or Peyronie's disease.
Prostavasin should be used with caution in patients who have experienced transient ischaemic attacks or those with unstable cardiovascular disorders.
Prostavasin 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 Prostavasin 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 Prostavasin should engage in sexual activity with caution.
Patients and their partners should be advised that Prostavasin 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 Prostavasin will not affect the integrity of condoms. Since Prostavasin 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 Prostavasin 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.
) and should be according to established medical practice.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.
Prostavasin 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 syndromeâ€, 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 Prostavasin 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.
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.
