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4.4 Special warnings and precautions for use
A thorough medical history and physical examination should be undertaken to diagnose erectile dysfunction, determine
potential underlying causes, and identify appropriate treatment.
There is a degree of cardiac risk associated with sexual activity; therefore, physicians may wish to consider the
cardiovascular status of their patients prior to initiating any treatment for erectile dysfunction.
Agents for the treatment of erectile dysfunction should not be used in men for whom sexual activity is inadvisable.
Serious cardiovascular events, including myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage and transient ischemic attack have been reported post-marketing in temporal association
with the use of sildenafil for erectile dysfunction. Most, but not all, of these patients had pre-existing cardiovascular risk
factors. Many of these events were reported to occur during or shortly after sexual activity, and a few were reported
to occur shortly after the use of sildenafil without sexual activity. Others were reported to have occurred hours to days
after the use of sildenafil and sexual activity. It is not possible to determine whether these events are related directly
to sildenafil, to sexual activity, to the patient's underlying cardiovascular disease, to a combination of these factors,
or to other factors.
In clinical trials, sildenafil has been shown to have systemic vasodilator properties that result in transient decreases in
blood pressure (see Section 5.4 Clinical Studies). This is of little or no consequence in most patients. However, prior
to prescribing sildenafil, physicians should carefully consider whether their patients with certain underlying conditions
could be adversely affected by such vasodilatory effects, especially in combination with sexual activity. Patients with
increased susceptibility to vasodilators include those with left ventricular outflow obstruction (e.g., aortic stenosis,
hypertrophic obstructive cardiomyopathy), or those with the rare syndrome of multiple system atrophy manifesting as
severely impaired autonomic control of blood pressure.
Non-arteritic anterior ischemic optic neuropathy (NA ION), a cause of decreased vision or loss of vision, has been
reported rarely post-marketing with the use of all FOES inhibitors, including sildenafil. Most of these patients had risk
factors such as low cup to disc ratio ("crowded disk"), age over 50, diabetes, hypertension, coronary artery disease,
hyperlipidemia and smoking. No causal relationship has been made between use of PDE5 inhibitors and NAION.
Physicians should discuss with patients the increased risk of NAION in individuals who have already experienced
NAION. The patients should be advised that in case of sudden visual loss, to stop taking sildenafil and consult a
physician immediately.
Caution is advised when sildenafil is administered to patients taking an alpha-blocker, as the coadministration may
lead to symptomatic hypotension in a few susceptible individuals (see section 4.5 Interaction with other medicinal
products and other forms of interaction). In order to minimize the potential for developing postural hypotension,
patients should be hemodynamically stable on alpha-blocker therapy prior to initiating sildenafil treatment. Initiation of
sildenafil at lower doses should be considered (see section 4.2 Posology and method of administration). In addition,
physicians should advise patients what to do in the event of postural hypotensive symptoms.
A minority of patients with the inherited condition retinitis pigmentosa have genetic disorders of retinal
phosphodiesterases. There is no safety information on the administration of sildenafil to patients with retinitis
pigmentosa, therefore, sildenafil should be administered with caution to these patients.
In vitro studies with human platelets indicate that sildenafil potentiates the antiaggregatory effect of sodium
nitroprusside (a nitric oxide donor). There is no safety information on the administration of sildenafil to patients
with bleeding disorders or active peptic ulceration, therefore sildenafil should be administered with caution to these
patients.
Agents for the treatment of erectile dysfunction should be used with caution in patients with anatomical deformation of
the penis (such as angulation, cavernosal fibrosis or Peyronie's disease), or in patients who have conditions which may
predispose them to priapism (such as sickle cell anemia, multiple myeloma or leukemia).
The safety and efficacy of combinations of sildenafil with other treatments for erectile dysfunction have not been
studied, and the use of such combinations is not recommended.
Sudden decrease or loss of hearing has been reported in a small number of postmarketing and clinical teals cases
with the use of all PDE5 inhibitors, including sildenafil. Most of these patients had risk factors for sudden decrease or
loss of hearing. No causal relationship has been made between the use of PDE5 inhibitors and sudden decrease or
loss of hearing. In case of sudden decrease or loss of hearing patients should be advised to stop taking sildenafil and
consult a physician promptly.
4.5 Interaction with other medicinal products and other forms of interaction
Effects of other medicinal products on sildenafil
In vitro studies:
Sildenafil metabolism is principally mediated by the cytochrome P450 (CYP) isoforms 3A4 (major route) and 2C9 (minor
route). Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance and inducers of these isoenzymes
may increase sildenafil clearance.
In vivo studies:
Population pharmacokinetic analysis of clinical trial data indicated a reduction in sildenafil clearance when co-
administered with CYP3A4 inhibitors (such as ketoconazole, erythromycin, cimetidine).
Cimetidine (800 mg), a cytochrome P450 inhibitor and a nonspecific CYP3A4 inhibitor, caused a 56% increase in
plasma sildenafil concentrations when co-administered with sildenafil (50 mg) to healthy volunteers.
When a single 100 mg dose of sildenafil was administered with erythromycin, a specific CYP3A4 inhibitor, at steady
state (500 mg twice daily for 5 days), there was a 182% increase in sildenafil systemic exposure (AUC). In addition,
coadministration of the HIV protease inhibitor saquinavir, a CYP3A4 inhibitor, at steady state (1200 mg three times
daily) with sildenafil (100 mg single dose) resulted in a 140% increase in sildenafil Cmax
and a 210% increase in
sildenafil AUC. Sildenafil had no effect on saquinavir pharmacokinetics. See section 4.2 Posology and method of
administration. Stronger CYP3A4 inhibitors such as ketoconazole and itraconazole would be expected to have greater
effects.
Coadministration with the HIV protease inhibitor ritonavir, which is a highly potent P450 inhibitor, at steady state (500
mg twice daily) with sildenafil (100 mg single dose) resulted in a 300% (4-fold) increase in sildenafil Cmax and a 1000%
(11-fold) increase in sildenafil plasma AUC. At 24 hours, the plasma levels of sildenafil were still approximately 200ng/
mL, compared to approximately 5ng/mL when sildenafil was dosed alone. This is consistent with ritonavir's marked
effects on a broad range of P450 substrates. Sildenafil had no effect on ritonavir pharmacokinetics. See section 4.2
Posology and method of administration.
When the dose of sildenafil for subjects receiving potent CYP3A4 inhibitors was administered as recommended, the
maximum free plasma sildenafil concentration did not exceed 200 nM for any individual and was consistently well
tolerated.
Single doses of antacid (magnesium hydroxide/aluminium hydroxide) did not affect the bioavailability of sildenafil.
Pharmacokinetic data from patients in clinical trials showed no effect on sildenafil pharmacokinetics of CYP2C9
inhibitors (such as tolbutamide, warfarin), CYP2D6 inhibitors (such as selective serotonin reuptake inhibitors, tricyclic
antidepressants), thiazide and related diuretics, angiotensin converting enzyme (ACE) inhibitors, and calcium channel
blockers.
In normal healthy male volunteers, there was no evidence of an effect of azithromycin (500 mg daily for 3 days) on the
AUC, Cmax, Tmax, elimination rate constant, or subsequent half-life of sildenafil or its major circulating metabolite.
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