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Effects of sildenafil on other medicinal products
In vitro studies:
Sildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC50>150
µM).
Given sildenafil peak plasma concentrations of approximately 1 uM after recommended doses, it is unlikely that
sildenafil will alter the clearance of substrates of these isoenzymes.
In vivo studies: Sildenafil was shown to potentiate the hypotensive effects of acute and chronic nitrates. Therefore, use of nitric oxide
donors, organic nitrates, or organic nitrites in any form either regularly or intermittently with sildenafil is contraindicated
(see Section 4.3 Contraindications).
In three specific drug-drug interaction studies, the alpha-blocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50
mg, or 100 mg) were administered simultaneously to patients with benign prostatic hyperplasia (BPH) stabilized on
doxazosin therapy. In these study populations, mean additional reductions of supine blood pressure of 7/7 mmHg, 9/5
mmHg, and 8/4 mmHg, and mean additional reductions of standing blood pressure of 6/6 mmHg, 11/4 mmHg, and
4/5 mmHg, respectively, were observed. When sildenafil and doxazosin were administered simultaneously to patients
stabilized on doxazosin therapy, there were infrequent reports of patients who experienced symptomatic postural
hypotension. These reports included dizziness and lightheadedness, but not syncope. Concomitant administration
of sildenafil to patients taking alpha-blocker therapy may lead to symptomatic hypotension in a few susceptible
individuals. (See section 4.2 Posology and method of administration and section 4.4 Special warnings and
precautions for use).
No significant interactions were shown when sildenafil (50mg) was co-administered with tolbutamide (250 mg) or
warfarin (40 mg), both of which are metabolized by CYP2C9.
Sildenafil (100mg) did not affect the steady state pharmacokinetics of the HIV protease inhibitors, saquinavir and
ritonavir, both of which are CYP3A4 substrates (see above, Effects of other medicinal products on sildenafil).
Sildenafil (50 mg) did not potentiate the increase in bleeding time caused by aspirin (150 mg).
Sildenafil (50 mg) did not potentiate the hypotensive effects of alcohol in healthy volunteers with mean maximum blood
alcohol levels of 0.08% (80 mg/dL).
No interaction was seen when sildenafil (100 mg) was coadministered with amlodipine in hypertensive patients. The
mean additional reduction on supine systolic blood pressure was 8 mmHg systolic and 7 mmHg diastolic.
Analysis of the safety database showed no difference in the side effect profile in patients taking sildenafil with and
without antihypertensive medication.
4.6 Pregnancy and lactation
Sildenafil is not indicated for use in women.
No teratogenic effects, impairment of fertility or adverse effects on peri/postnatal development were found in
reproduction studies in rats and rabbits following oral administration of sildenafil.
There are no adequate and well-controlled studies in pregnant or lactating women.
4.7 Effects on ability to drive and use machines
The effect of sildenafil on the ability to drive and use machinery has not been studied.
4.8 Undesirable effects
The adverse events were generally transient and mild to moderate in nature.
In fixed-dose studies, the incidence of some adverse events increased with dose.
The nature of the adverse events in flexible-dose studies, which more closely reflect the recommended dosage
regimen, was similar to that for fixed-dose studies.
The most commonly reported adverse reactions were headache and flushing, see tables 1 and 2 below:
| Table 1 Very common adverse reactions
( ≥
1/10 ) |
| MedDRA System Organ Class |
Adverse Reaction |
Sildenafil (%) N=3350 |
Placebo (%) N=2995 |
| Nervous system disorders |
headache |
10.8 |
2.8 |
| Vascular disordes |
Vasodilatation ( flushing ) |
10.9 |
1.4 |
| Table 2 Common adverse reactions
( ≥
1/100 and < 1/10 ) |
| MedDRA System Organ Class |
Adverse Reaction |
Sildenafil (%) N=3350 |
Placebo (%) N=2995 |
| Nervous system disorders |
Dizziness |
2.9 |
1.0 |
| Eye disorders |
Abnormal vision ( blurred vision, increased sensitivity to light
) |
2.5 |
0.4 |
| |
Chromatopsia ( mild and transient, predominantly color tinge to
vision ) |
1.1 |
0.03 |
| Cardiac disorders |
Palpitation |
1.0 |
0.2 |
| Respiratory, thoracic and mediastinal disorders |
Rhinitis ( nasal congestion ) |
2.1 |
0.3 |
| Gastrointestinal disorders |
Dyspepsia |
3.0 |
0.4 |
At doses above the recommended dose range, adverse events were similar to those detailed above but generally
were reported more frequently.
In an analysis of double-blind placebo-controlled clinical trials encompassing over 700 person-years of observation
on placebo and over 1300 person-years on sildenafil, there were no differences in the incidence rate of myocardial
infarction (MI) or in the rate of cardiovascular mortality for patients receiving sildenafil compared to those receiving
placebo. The rates of MI were 1.1 per 100 person-years for men receiving sildenafil and for those receiving placebo.
The rates of cardiovascular mortality were 0.3 per 100 person-years for men receiving sildenafil and those receiving
placebo.
The following adverse reactions were reported during post-marketing surveillance:
Immune system disorders: hypersensitivity reaction (including skin rash)
Nervous system disorders: seizure, seizure recurrence
Cardiac disorders: tachycardia
Vascular disorders: hypotension, syncope, epistaxis
Gastrointestinal disorders: vomiting
Eye disorders: eye pain, red eyes/bloodshot eyes
Reproductive system and breast disorders: prolonged erection and/or priapism
4.9 Overdose
In studies with healthy volunteers of single doses up to 800 mg, adverse events were similar to those seen at lower
doses but incidence rates and seventies were increased.
In cases of overdose, standard supportive measures should be adopted as required.
Renal dialysis is not expected to accelerate clearance as sildenafil is highly bound to plasma proteins and it is not
eliminated in the urine.
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