Page 63 - Remedial Andrology

5.6.2.7.1 Alprostadil
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Alprostadil (Caverject , Edex/Viridal ) was the first and only drug approved for intracavernous treatment of
ED [503, 552]. Intracavernous alprostadil is most efficacious as a monotherapy at a dose of 5-40 μg (40 μg may
be offered off label in some European countries). The erection appears after 5-15 minutes and lasts according
to the dose injected, but with significant heterogeneity among patients. An office-training programme is
required for patients to learn the injection technique. In men with limited manual dexterity, the technique may
be taught to their partners. The use of an automatic pen that avoids a view of the needle may be useful to
resolve fear of penile puncture and simplifies the technique.

Efficacy rates for intracavernous alprostadil of > 70% have been found in the general ED population, as well
as in patient subgroups (e.g., men with diabetes or CVD), with reported satisfaction rates of 87-93.5% in
patients and 86-90.3% in partners after the injections [503, 550]. Complications of intracavernous alprostadil
include penile pain (50% of patients reported pain only after 11% of total injections), excessively-prolonged
undesired erections (5%), priapism (1%), and fibrosis (2%) [503, 550, 553]. Pain is usually self-limited after
prolonged use and it can be alleviated with the addition of sodium bicarbonate or local anaesthesia [503,
550, 554]. Cavernosal fibrosis (from a small haematoma) usually clears within a few months after temporary
discontinuation of the injection programme. However, tunical fibrosis suggests early onset of Peyronie’s
disease and may indicate stopping intracavernous injections indefinitely. Systemic adverse effects are
uncommon. The most common is mild hypotension, especially when using higher doses. Contraindications
include men with a history of hypersensitivity to alprostadil, men at risk of priapism, and men with bleeding
disorders. Despite these favourable data, drop-out rates of 41-68% have been reported for intracavernous
pharmacotherapy [503, 550, 555, 556], with most drop-outs occurring within the first 2-3 three months. In
a comparative study, alprostadil monotherapy had the lowest discontinuation rate (27.5%) compared to
overall drug combinations (37.6%), with an attrition rate after the first few months of therapy of 10% per year
[557]. Reasons for discontinuation included desire for a permanent mode of therapy (29%), lack of a suitable
partner (26%), poor response (23%) (especially among early drop-out patients), fear of needles (23%), fear of
complications (22%), and lack of spontaneity (21%). Careful counselling of patients during the office-training
phase as well as close follow-up are important in addressing patient withdrawal from an intracavernous
injection programme [558-560].

5.6.2.8 Combination therapy
Table 16 details the available intracavernous injection therapies (compounds and characteristics). Combination
therapy enables a patient to take advantage of the different modes of action of the drugs being used, as well as
alleviating adverse effects by using lower doses of each drug.
• Papaverine (20-80 mg) was the first oral drug used for intracavernous injections. It is most commonly
used in combination therapy because of its high incidence of adverse effects as monotherapy.
Papaverine is currently not licensed for treatment of ED.
• Phentolamine has been used in combination therapy to increase efficacy. As monotherapy, it produces a
poor erectile response.
• Sparse data in the literature support the use of other drugs, such as vasoactive intestinal peptide (VIP),
NO donors (linsidomine), forskolin, potassium channel openers, moxisylyte or calcitonin gene-related
peptide, usually combined with the main drugs [561, 562]. Most combinations are not standardised and
some drugs have limited availability worldwide.
• Bimix, Trimix: papaverine (7.5-45 mg) plus phentolamine (0.25-1.5 mg) (also known as Bimix), and
papaverine (8-16 mg) plus phentolamine (0.2-0.4 mg) plus alprostadil (10-20 μg) (also known as Trimix),
have been widely used with improved efficacy rates, although they have never been licensed for ED [563,
564]. Trimix has the highest efficacy rates, reaching 92%; this combination has similar adverse effects as
alprostadil monotherapy, but a lower incidence of penile pain due to lower doses of alprostadil. However,
fibrosis is more common (5-10%) when papaverine is used (depending on total dose).
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• Invicorp : Vasoactive intestinal peptide (25 μg) plus phentolamine mesylate (1-2 mg Invicorp), currently
licensed in Scandinavia, is a combination of two active components with complementary modes of action.
Clinical studies have shown that the combination is effective for intracavernous injections in > 80% of men
with ED, including those who have failed to respond to other therapies and, unlike existing intracavernous
therapies, is associated with a low incidence of penile pain and a virtually negligible risk of priapism [565].

Despite high efficacy rates, 5-10% of patients do not respond to combination intracavernous injections. The
combination of sildenafil with intracavernous injection of the triple combination regimen may salvage as many
as 31% of patients who do not respond to the triple combination alone [566]. However, combination therapy
is associated with an increased incidence of adverse effects in 33% of patients, including dizziness in 20% of
patients. This strategy can be considered in carefully selected patients before proceeding to a penile implant.

62 SEXUAL AND REPRODUCTIVE HEALTH - MARCH 2021