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.
2 years. Reconstituted solutions should be used immediately and not stored.
Alprostadil should not be used in men for whom sexual activity is inadvisable or contraindicated.
Caverject is not intended to be mixed or coadministered with any other products.
lactose monohydrate
sodium citrate
α-cyclodextrine
hydrochloric acid for pH adjustment
sodium hydroxide for pH adjustment
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.
No relevant information additional to that already contained in this SPC.
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.
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.
03/2017
Pfizer Limited
Ramsgate Road
Sandwich
Kent
CT13 9NJ
United Kingdom
Do not store above 25°C. Reconstituted solutions are intended for single use only, they should be used immediately and not stored.
Single pack containing a 5 ml clear, colourless, glass vial of Caverject 10 micrograms powder with a bromobutyl rubber stopper and an aluminium overseal with polypropylene flip-off cap
Packs also each contain a syringe of solvent, a sterile 22G and a 30G needle plus pre-injection swab.
PL 00057/0941
Not applicable.
High doses of alprostadil (0.5 to 2.0 mg/kg subcutaneously) had an adverse effect on the reproductive potential of male rats, although this was not seen with lower doses (0.05 to 0.2 mg/kg). Alprostadil did not affect rat spermatogenesis at doses 200 times greater than the proposed human intrapenile dose.
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.
Caverject 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.
Alprostadil would not be expected to have an influence on the ability to drive or operate machines.
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.
4 August 2010
The effects of combinations of alprostadil with other treatments for erectile dysfunction (e.g. sildenafil) or other drugs inducing erection (e.g. papaverine) have not been formally studied. Such agents should not be used in combination with alprostadil due to the potential for inducing prolonged erections.
Sympathomimetics may reduce the effect of alprostadil. Alprostadil may enhance the effects of antihypertensives, vasodilative agents, anticoagulants and platelet aggregation inhibitors.
