General
Before prescribing REVATIO, it is important to note the following:
-
Caution is advised when phosphodiesterase type 5 (PDE5) inhibitors are co-administered
with alpha-blockers. PDE5 inhibitors, including sildenafil, and alpha-adrenergic
blocking agents are both vasodilators with blood pressure lowering effects. When
vasodilators are used in combination, an additive effect on blood pressure may be
anticipated. In some patients, concomitant use of these two drug classes can lower
blood pressure significantly, leading to symptomatic hypotension. In the sildenafil
interaction studies with alpha-blockers (see Drug Interactions), cases of
symptomatic hypotension consisting of dizziness and lightheadedness were reported.
No cases of syncope or fainting were reported during these interaction studies.
Consideration should be given to the fact that safety of combined use of PDE5 inhibitors
and alpha-blockers may be affected by other variables, including intravascular volume
depletion and concomitant use of anti-hypertensive drugs.
- REVATIO 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). In the event of an erection that persists
longer than 4 hours, the patient should seek immediate medical assistance. If priapism
(painful erections greater than 6 hours in duration) is not treated immediately,
penile tissue damage and permanent loss of potency could result.
- In humans, sildenafil has no effect on bleeding time when taken alone or with aspirin.
In vitro studies with human platelets indicate that sildenafil potentiates
the anti-aggregatory effect of sodium nitroprusside (a nitric oxide donor). The
combination of heparin and sildenafil had an additive effect on bleeding time in
the anesthetized rabbit, but this interaction has not been studied in humans.
- The incidence of epistaxis was higher in patients with PAH secondary to CTD (sildenafil
13%, placebo 0%) than in PPH patients (sildenafil 3%, placebo 2%). The incidence
of epistaxis was also higher in sildenafil-treated patients with concomitant oral
vitamin K antagonist (9% versus 2% in those not treated with concomitant vitamin
K antagonist).
- The safety of REVATIO is unknown in patients with bleeding disorders and patients
with active peptic ulceration.
Information for Patients
Physicians should discuss with patients the contraindication of REVATIO with regular
and/or intermittent use of organic nitrates.
Sildenafil is also marketed as VIAGRA® for male erectile
dysfunction.
Physicians should advise patients to seek immediate medical attention in the event
of a sudden loss of vision in one or both eyes while taking all PDE5 inhibitors,
including REVATIO. Such an event may be a sign of non-arteritic anterior ischemic
optic neuropathy (NAION), a cause of decreased vision including permanent loss of
vision, that has been reported rarely post-marketing in temporal association with
the use of all PDE5 inhibitors when used in the treatment of male-erectile dysfunction.
It is not possible to determine whether these events are related directly to the
use of PDE5 inhibitors or to other factors. Physicians should also discuss with
patients the increased risk of NAION in individuals who have already experienced
NAION in one eye, including whether such individuals could be adversely affected
by use of vasodilators, such as PDE5 inhibitors (see ADVERSE REACTIONS).
Physicians should advise patients to seek prompt medical attention in the event
of sudden decrease or loss of hearing while taking all PDE5 inhibitors, including
REVATIO. These events, which may be accompanied by tinnitus and dizziness, have
been reported in temporal association to the intake of PDE5 inhibitors, including
REVATIO. It is not possible to determine whether these events are related directly
to the use of PDE5 inhibitors or to other factors (see ADVERSE REACTIONS, Clinical
Trials and Post-Marketing Experience).
Drug Interactions
In PAH patients, the concomitant use of vitamin K antagonists and sildenafil resulted
in a greater incidence of reports of bleeding (primarily epistaxis) versus placebo.
Effects of Other Drugs on REVATIO
In vitro studies: Sildenafil metabolism is principally mediated by
the CYP3A4 (major route) and CYP2C9 (minor route) cytochrome P450 isoforms. 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 and/or an increase of oral bioavailability
when co-administered with CYP3A4 substrates and the combination of CYP3A4 substrates
and beta-blockers. These were the only factors with a statistically significant
impact on sildenafil pharmacokinetics.
Population data from patients in clinical trials indicated a reduction in sildenafil
clearance when it was co-administered with CYP3A4 inhibitors. Sildenafil exposure
without concomitant medication is shown to be 5-fold higher at a dose of 80 mg t.i.d.
compared to its exposure at a dose of 20 mg t.i.d. This concentration range covers
the same increased sildenafil exposure observed in specifically-designed drug interaction
studies with CYP3A4 inhibitors (except for potent inhibitors such as ketoconazole,
itraconazole, and ritonavir). Cimetidine (800 mg), a nonspecific CYP 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 co-administered with erythromycin, a CYP3A4 inhibitor, at steady state (500
mg twice daily [b.i.d.] for 5 days), there was a 182% increase in sildenafil systemic
exposure (AUC). In a study performed in healthy volunteers, co-administration of
the HIV protease inhibitor saquinavir, a CYP3A4 inhibitor, at steady state (1200
mg t.i.d.) with sildenafil (100 mg single dose) resulted in a 140% increase in sildenafil
Cmax and a 210% increase in sildenafil AUC.
Stronger CYP3A4 inhibitors will have still greater effects on plasma levels of sildenafil
(see DOSAGE AND ADMINISTRATION).
In another study in healthy volunteers, co-administration with the HIV protease
inhibitor ritonavir, a potent CYP3A4 inhibitor, at steady state (500 mg b.i.d.)
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 200 ng/mL,
compared to approximately
5 ng/mL when sildenafil was dosed alone. This is consistent with ritonavir's marked
effects on a broad range of P450 substrates (see WARNINGS and DOSAGE AND ADMINISTRATION).
Although the interaction between other protease inhibitors and REVATIO has not been
studied, their concomitant use is expected to increase sildenafil levels.
In a study of healthy male volunteers, co-administration of sildenafil at steady
state (80 mg t.i.d.) with the endothelin receptor antagonist bosentan (a moderate
inducer of CYP3A4, CYP2C9 and possibly of cytochrome P450 2C19) at steady state
(125 mg b.i.d.) resulted in a 63% decrease of sildenafil AUC and a 55% decrease
in sildenafil Cmax. The combination of both drugs did
not lead to clinically significant changes in blood pressure (supine or standing).
Concomitant administration of potent CYP3A4 inducers is expected to cause greater
decreases in plasma levels of sildenafil.
In drug-drug interaction studies, sildenafil (25 mg, 50 mg, or 100 mg) and the alpha-blocker
doxazosin (4 mg or 8 mg) were administered simultaneously to patients with benign
prostatic hyperplasia (BPH) stabilized on doxazosin therapy. In these study populations,
mean additional reductions of supine systolic and diastolic blood pressure of 7/7
mmHg, 9/5 mmHg, and 8/4 mmHg, respectively, were observed. Mean additional reductions
of standing blood pressure of 6/6 mmHg, 11/4 mmHg, and 4/5 mmHg, respectively, were
also observed. There were infrequent reports of patients who experienced symptomatic
postural hypotension. These reports included dizziness and light-headedness, but
not syncope (see PRECAUTIONS: General).
Concomitant administration of oral contraceptives (ethinyl estradiol 30 µg and levonorgestrel
150 µg) did not affect the pharmacokinetics of sildenafil.
Concomitant administration of a single 100 mg dose of sildenafil with 10 mg of atorvastatin
did not alter the pharmacokinetics of either sildenafil or atorvastatin.
Single doses of antacid (magnesium hydroxide/aluminum hydroxide) did not affect
the bioavailability of sildenafil.
Effects of REVATIO on Other Drugs
In vitro studies: Sildenafil is a weak inhibitor of the cytochrome
P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC50 >150 µM).
In vivo studies: When sildenafil 100 mg oral was co-administered with
amlodipine, 5 mg or 10 mg oral, to hypertensive patients, the mean additional reduction
on supine blood pressure was 8 mmHg systolic and 7 mmHg diastolic.
No significant interactions were shown with tolbutamide (250 mg) or warfarin
(40 mg), both of which are metabolized by CYP2C9.
Sildenafil (50 mg) did not potentiate the increase in bleeding time caused by aspirin
(150 mg).
Sildenafil (50 mg) did not potentiate the hypotensive effect of alcohol in healthy
volunteers with mean maximum blood alcohol levels of 0.08%.
In healthy subjects, co-administration of 125 mg b.i.d. bosentan and 80 mg t.i.d.
sildenafil resulted in a 63% decrease in AUC of sildenafil and a 50% increase in
AUC of bosentan.
In a study of healthy volunteers, sildenafil (100 mg) did not affect the steady-state
pharmacokinetics of the HIV protease inhibitors saquinavir and ritonavir, both of
which are CYP3A4 substrates.
Sildenafil had no impact on the plasma levels of oral contraceptives (ethinyl estradiol
30 µg and levonorgestrel 150 µg).
Carcinogenesis, Mutagenesis, Impairment of Fertility
Sildenafil was not carcinogenic when administered to rats for up to 24 months at
60 mg/kg/day, a dose resulting in total systemic exposure (AUC) to unbound sildenafil
and its major metabolite 33 and 37 times, for male and female rats respectively,
the human exposure at the Recommended Human Dose (RHD) of
20 mg t.i.d. Sildenafil was not carcinogenic when administered to male and female
mice for up to 21 and 18 months, respectively, at doses up to a maximally tolerated
level of 10 mg/kg/day, a dose equivalent to the RHD on a mg/m2
basis.
Sildenafil was negative in in vitro bacterial and Chinese hamster ovary cell
assays to detect mutagenicity, and in vitro human lymphocytes and in vivo
mouse micronucleus assays to detect clastogenicity.
There was no impairment of fertility in male or female rats given up to 60 mg sildenafil/kg/day,
a dose producing a total systemic exposure (AUC) to unbound sildenafil and its major
metabolite of 19 and 38 times for males and females, respectively, the human exposure
at the RHD of 20 mg t.i.d.
Pregnancy
Pregnancy Category B. No evidence of teratogenicity, embryotoxicity or fetotoxicity
was observed in pregnant rats or rabbits, dosed with 200 mg sildenafil/kg/day during
organogenesis, a level that is, on a mg/m2 basis, 32-
and 68-times, respectively, the RHD of 20 mg t.i.d. In a rat pre- and postnatal
development study, the no-observed-adverse-effect dose was 30 mg/kg/day (equivalent
to 5-times the RHD on a mg/m2 basis). There are no adequate
and well-controlled studies of sildenafil in pregnant women.
Nursing Mothers
It is not known if sildenafil citrate and/or metabolites are excreted in human breast
milk. Since many drugs are excreted in human milk, caution should be used when REVATIO
is administered to nursing women.
Pediatric Use
Safety and Effectiveness of sildenafil in pediatric pulmonary hypertension patients
has not been established.
Geriatric Use
Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil,
but studies did not include sufficient numbers of subjects to determine whether
they respond differently from younger subjects. Other reported clinical experience
has not identified differences in response between the elderly and younger pulmonary
arterial hypertension patients. In general, dose selection for an elderly patient
should be cautious, reflecting the greater frequency of decreased hepatic, renal,
or cardiac function, and of concomitant disease or other drug therapy.