Approved Drug Label (PDF)
4
Contraindications
Additions and/or
revisions underlined:
5
Warnings and Precautions
Additions
and/or revisions underlined:
5.1
Angioedema and Anaphylactic Reactions
Angioedema of the face, lips, tongue,
and/or larynx have been reported with solifenacin succinate. In some
cases, angioedema occurred after the first dose, however, cases have
been reported to occur hours after the first dose or after multiple doses. Anaphylactic
reactions have also been reported in patients treated with solifenacin
succinate. Angioedema associated with upper airway swelling and
anaphylactic reactions may be life-threatening.
VESIcare is contraindicated in patients
with a known or suspected hypersensitivity to solifenacin succinate [see Contraindications (4)]. If involvement of
the tongue, hypopharynx, or larynx occurs, promptly discontinue VESIcare
and provide appropriate therapy and/or measures necessary to ensure a
patent airway.
5.2
Urinary Retention
The use of VESIcare, like
other antimuscarinic drugs, in patients with clinically significant
bladder outlet obstruction including patients with urinary retention,
may result in further urinary retention and kidney injury. The use of VESIcare
is not recommended in patients with clinically significant bladder outlet
obstruction and is contraindicated in patients with urinary retention [see Contraindications (4)].
5.3
Gastrointestinal Disorders
The use of VESIcare, like
other antimuscarinic drugs, in patients with conditions associated
with decreased gastrointestinal motility may
result in further decreased gastrointestinal motility. VESIcare is
contraindicated in patients with gastric retention [see Contraindications
(4)]. The use of VESIcare is not
recommended in patients with conditions associated with decreased
gastrointestinal motility.
5.4
Central Nervous System Disorders
VESIcare is associated with antimuscarinic
central nervous system (CNS) adverse reactions [see Adverse
Reactions (6.2)]. A variety of CNS antimuscarinic adverse reactions
have been reported, including headache, confusion, hallucinations, and somnolence.
Monitor patients for signs of antimuscarinic CNS adverse
reactions, particularly after beginning treatment or increasing the dose.
Advise patients not to drive or operate heavy machinery until they know how
VESIcare affects them. If a patient experiences antimuscarinic CNS adverse
reactions, consider dose reduction or drug discontinuation.
5.6 QT
Prolongation in Patients at High Risk of QT Prolongation
In a study of the effect of solifenacin succinate
on the QT interval conducted in 76 healthy women [see Clinical Pharmacology
(12.2)], solifenacin
succinate 30 mg (three times the largest maximum recommended dose in adult
patients) was associated with a mean increase in the Fridericia-corrected QT
interval of 8 msec (90% CI, 4, 13). The QT prolonging effect appeared less
with solifenacin succinate 10 mg than with solifenacin succinate 30
mg, and the effect of solifenacin succinate 30 mg did not appear as
large as that of the positive control moxifloxacin at its therapeutic dose.
The use of VESIcare is not recommended in
patients at high risk of QT prolongation, including patients with a
known history of QT prolongation and patients who are taking medications
known to prolong the QT interval.
6
Adverse Reactions
Additions
and/or revisions underlined:
6.1
Clinical Trials Experience
… VESIcare has been evaluated for safety
in 1811 adult patients in four randomized, placebo-controlled
trials (Studies 1-4) [see Clinical Studies
(14)]. Expected adverse
reactions of antimuscarinic agents are dry mouth, constipation, blurred vision
(accommodation abnormalities), urinary retention, and dry eyes. The incidence
of dry mouth and constipation in patients treated with VESIcare was higher in
the 10 mg dose group compared to the 5 mg dose group.
In the four 12-week double-blind clinical
trials, severe fecal impaction, colonic obstruction, and intestinal obstruction
were reported in one patient each, all in the VESIcare 10 mg group.
Angioneurotic edema was reported in one patient
taking VESIcare 5 mg. Compared to 12 weeks
of treatment with VESIcare, the incidence and severity of adverse reactions
were similar in patients who remained on drug for up to 12 months in Study 5
[see Clinical Studies (14)].
The most frequent adverse reaction leading
to study discontinuation was dry mouth (1.5%). Table 1 lists the rates of
identified adverse reactions, in the four randomized, placebo-controlled
trials at an incidence greater than placebo and in 1% or more of patients
treated with VESIcare 5 or 10 mg once daily for up to 12 weeks.
Table 1: Adverse Reactions Reported by greater
than or equal to 1% of Patients and Exceeding Placebo in Studies 1,
2, 3 and 4
6.2
Postmarketing Experience
The following adverse reactions have been
identified during post-approval use of solifenacin succinate in the U.S. and/or
outside of the U.S. Because these reactions are reported voluntarily from a
population of uncertain size, it is not always possible to reliably estimate
their frequency or establish a causal relationship to drug exposure.
General disorders
and administration site conditions: peripheral edema, hypersensitivity reactions (including angioedema with airway
obstruction, rash, pruritus, urticaria, anaphylactic reaction);
Nervous system disorders: dizziness, headache, confusion, hallucinations, delirium, somnolence;
Cardiac disorders: QT prolongation, Torsade de Pointes, atrial
fibrillation, tachycardia, palpitations;
Hepatobiliary disorders: liver disorders mostly characterized by abnormal liver function tests,
AST (aspartate aminotransferase), ALT (alanine aminotransferase), GGT (gamma-glutamyl transferase);
Renal and urinary disorders: renal impairment, urinary retention;
Metabolism and nutrition disorders: decreased appetite, hyperkalemia;
Skin and subcutaneous tissue disorders: exfoliative dermatitis, erythema multiforme, dry skin;
Eye disorders:
glaucoma;
Gastrointestinal disorders:
gastroesophageal reflux disease, ileus, vomiting, abdominal
pain, dysgeusia, sialadenitis;
Respiratory, thoracic and mediastinal disorders:
dysphonia, nasal dryness;
Musculoskeletal and connective tissue disorders: muscular weakness.
7
Drug Interactions
Additions
and/or revisions underlined:
7.1 Strong
CYP3A4 Inhibitors
Solifenacin is a substrate of CYP3A4.
Concomitant use
of ketoconazole, a strong CYP3A4 inhibitor, significantly increased
the exposure of solifenacin [see Clinical
Pharmacology (12.3)]. The dosage of
VESIcare greater than 5 mg once daily is not recommended when concomitantly
used with strong CYP3A4 inhibitors [see Dosage
and Administration (2.4)].
8
Use in Specific Populations
8.1
Pregnancy
PLLR
conversion; additions and/or revisions underlined:
Risk Summary
There are no studies with the use of
solifenacin succinate in pregnant women to inform a drug-associated risk
of major birth defects, miscarriages, or adverse maternal or fetal outcomes. No
adverse developmental outcomes were observed in animal reproduction studies
with oral administration of solifenacin succinate to pregnant mice during
the period of organogenesis at a dose resulting in 1.2 times the systemic
exposure at the maximum recommended human dose (MRHD) of 10 mg/day. However,
administration of doses 3.6 times and greater than the MRHD
during organogenesis produced maternal toxicity in the pregnant mice and
resulted in developmental toxicity and reduced fetal body weights in
offspring [see Data].
In the U.S. general population, the
estimated background risk of major birth defects or miscarriage in clinically
recognized pregnancies is 2-4% and 15-20%, respectively.
Data
Animal
Data
Oral administration of 14C-solifenacin
succinate to pregnant mice resulted in the recovery of radiolabel in the fetus
indicating that solifenacin-related product can cross the placental barrier. In
pregnant mice, administration of solifenacin succinate at a dose of 250
mg/kg/day (7.9 times the systemic exposure at the MRHD of 10 mg), resulted in
an increased incidence of cleft palate and increased maternal lethality.
Administration of solifenacin succinate to pregnant mice during organogenesis
at greater than or equal to 3.6 times (100 mg/kg/day and greater) the systemic
exposure at the MRHD, resulted in reduced fetal body weights and reduced
maternal body weight gain. No embryo-fetal toxicity or teratogenicity was
observed in fetuses from pregnant mice treated with solifenacin succinate at a
dose of 30 mg/kg/day (1.2 times the systemic exposure at the MRHD).
Administration of solifenacin succinate to pregnant rats and rabbits at a dose
of
50 mg/kg/day (< 1 times and 1.8 times
the systemic exposure at the MRHD, respectively), resulted in no findings of
embryo-fetal toxicity. Oral pre- and post-natal administration of solifenacin
succinate at 100 mg/kg/day (3.6 times the systemic exposure at the MRHD) during
the period of organogenesis through weaning, resulted in reduced peripartum and
postnatal survival, reduced body weight gain by the pups, and delayed
physical development (eye opening and vaginal patency). An increase in the
percentage of male offspring was also observed in litters from offspring (F2
generation) exposed to maternal doses of 250 mg/kg/day. There were no
effects on natural delivery in mice treated with 1.2 times
8.2
Lactation
PLLR
conversion; additions and/or revisions underlined:
Risk Summary
There is no information on the presence of solifenacin in
human milk, the effects on the breastfed child, or the effects on milk
production. Solifenacin is present in mouse milk [see Data]. When a drug is present in animal milk, it is likely
that the drug will be present in human milk. The developmental and health
benefits of breastfeeding should be considered along with the mother’s clinical
need for VESIcare and any potential adverse effects on the breastfed child from
VESIcare or from the underlying maternal condition.
Data
Animal
Data
Oral administration of 14C-solifenacin
succinate to lactating mice resulted in the recovery of radioactivity in
maternal milk. Lactating female mice orally administered solifenacin
succinate at a maternally toxic dose of 100 mg/kg/day (3.6 times the
systemic exposure at the MRHD) had increased postpartum pup
mortality, pups with reduced body weights, or delays in the onset of
reflex and physical development. Pups from lactating dams orally
administered solifenacin succinate at a dose of 30 mg/kg/day (1.2 times the
systemic exposure at the MRHD) had no discernible adverse findings. The
concentrations of solifenacin in animal milk does not necessarily predict the
concentration of drug in human milk.
Additions
and/or revisions underlined:
8.6
Renal Impairment
Solifenacin plasma concentrations are
greater in patients with severe renal impairment compared to subjects with
normal renal function [see Clinical
Pharmacology (12.3)]. Because
increased solifenacin plasma concentrations increase the risk of antimuscarinic
adverse reactions, the maximum recommended dose of VESIcare in patients with
severe renal impairment (CLcr < 30 mL/min/1.73 m2) is 5 mg once daily [see Dosage and Administration (2.2)]. The recommended dose in patients with
mild or moderate renal impairment is the same as in patients with normal renal
function.
5.7
Hepatic Impairment
Solifenacin plasma concentrations are
greater
in patients with moderate hepatic impairment compared to subjects with
normal hepatic function [see Clinical
Pharmacology (12.3)]. Because
increased solifenacin
plasma concentrations increase the risk of antimuscarinic adverse reactions,
the maximum recommended dose of VESIcare in patients with moderate hepatic
impairment (Child-Pugh B) is 5 mg once daily [see Dosage
and Administration (2.3)] and VESIcare is not
recommended for use in patients with severe hepatic impairment
(Child-Pugh C).
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
Additions
and/or revisions underlined:
Angioedema and Anaphylactic Reactions
Inform patients that angioedema and
anaphylactic reactions have been reported in patients treated with VESIcare.
Angioedema and anaphylactic reactions may be life-threatening. Advise
patients to promptly discontinue VESIcare therapy and seek immediate
attention if they experience edema of the tongue or laryngopharynx, or
difficulty breathing [see Contraindications
(4) and Warnings and
Precautions (5.1)].
Newly
added information:
Urinary Retention
Inform patients that VESIcare may cause
urinary retention in patients with conditions associated with bladder outlet
obstruction [see Warnings and
Precautions (5.2)].
Gastrointestinal Disorders
Inform patients that VESIcare may cause
further decrease in gastrointestinal motility in patients with conditions
associated with decreased gastrointestinal motility. VESIcare has been
associated with constipation and dry mouth. Advise patients to contact their
health care providers if they experience severe abdominal pain or become
constipated for 3 or more days [see Warnings and
Precautions (5.3)].
Central Nervous System Effects
Because VESIcare, like other
antimuscarinic agents, may cause central nervous system effects or blurred
vision, advise patients to exercise caution in decisions to engage in
potentially dangerous activities until the drug’s effect on the patient has been
determined [see Warnings and
Precautions (5.4)].
Narrow-Angle Glaucoma
Inform patients that VESIcare, like other
antimuscarinics, may cause worsening of the glaucoma condition in patients with
narrow-angle glaucoma [see Warnings and
Precautions (5.5)].
Dry Skin
Inform patients that VESIcare, like other
antimuscarinics, may cause dry skin due to decreased sweating. Heat prostration
due to decreased sweating can occur when VESIcare is used in a hot environment [see Adverse Reactions (6.2)].
PATIENT INFORMATION
Additions and/or
revisions underlined:
What
is VESIcare?
VESIcare 5 mg and 10 mg tablets are not approved
for use in children.
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