Approved Drug Label (PDF)
4
Contraindications
Additions and/or revisions underlined:
SAMSCA is contraindicated in the following conditions:
Patients
with autosomal dominant polycystic kidney disease (ADPKD) outside of
FDA-approved REMS Warnings and Precautions (5.2)]
Unable to sense or respond to thirst
Hypovolemic
hyponatremia
Taking strong CYP3A inhibitors [see Warnings
and Precautions (5.5)]
Anuria
Hypersensitivity
(e.g., anaphylactic shock, rash generalized) to tolvaptan or any components of
the product
5
Warnings and Precautions
5.5 Drug
Interactions
Additions and/or revisions
underlined:
Tolvaptan is a
substrate of CYP3A. Moderate to strong CYP3A inhibitors can lead to a
marked increase in tolvaptan concentrations [see
Drug Interactions
(7.1)]. Do not use SAMSCA
with strong inhibitors of CYP3A [see Contraindications
(4)] and avoid
concomitant use with moderate CYP3A inhibitors.
Newly added
subsection:
5.7 Acute Urinary
Retention with Outflow Obstruction
Patients with
partial obstruction of urinary outflow, for example, patients with prostatic
hypertrophy or impairment of micturition, have an increased risk of developing
acute retention. Do not administer tolvaptan in patients with uncorrected
urinary outflow obstruction.
7
Drug Interactions
7.1 CYP3A
Inhibitors and Inducers
Strong CYP3A
Inhibitors
Tolvaptan's AUC
was 5.4 times as large and Cmax was 3.5 times as large after
co-administration of tolvaptan and 200 mg ketoconazole [see Warnings and Precautions
(5.5) and Clinical Pharmacology
(12.3)]. Larger doses of the strong CYP3A
inhibitor
would be expected to produce larger increases in tolvaptan exposure. Concomitant
use of tolvaptan with strong CYP3A inhibitors is contraindicated [see Contraindications (4)].
Moderate CYP3A Inhibitors
A substantial increase in the
exposure to tolvaptan would be expected when SAMSCA is co-administered with
moderate CYP3A inhibitors. Avoid co-administration of SAMSCA with
moderate CYP3A inhibitors [see Warnings and Precautions (5.5)].
Patients should avoid grapefruit juice beverages while
taking SAMSCA [see Clinical Pharmacology (12.3)].
Strong
CYP3A Inducers
Co-administration
of SAMSCA with strong CYP3A inducers reduces
exposure to SAMSCA [see Clinical Pharmacology (12.3)]. Avoid concomitant use of SAMSCA with strong CYP3A
inducers.
Additions and/or revisions
underlined:
7.2 Angiotensin Receptor
Blockers, Angiotensin Converting Enzyme Inhibitors and Potassium Sparing
Diuretics
Although specific interaction
studies were not performed, in clinical studies, tolvaptan was used
concomitantly …
7.3 V2-Receptor
Agonist
As a V2-receptor antagonist,
tolvaptan may interfere with the V2-agonist activity of desmopressin (dDAVP). Avoid
concomitant use of SAMSCA with a V2-agonist.
8
Use in Specific Populations
8.1 Pregnancy
PLLR conversion;
additions and/or revisions underlined:
Risk Summary
Available data
with SAMSCA use in pregnant women are insufficient to determine if there is a
drug-associated risk of adverse developmental outcomes. Tolvaptan did not cause
any developmental toxicity in rats or in rabbits at exposures approximately 2.8
and 0.8 times, respectively, the exposure in congestive heart failure (CHF)
patients at the
maximum recommended human dose (MRHD) of 60 mg once daily. However, effects
on embryo-fetal development occurred in both species at doses causing significant
maternally toxic doses. In rats, reduced fetal weights and delayed fetal
ossification occurred at 11 times the exposure in CHF patients, based on
AUC. In rabbits, increased abortions, embryo-fetal death, fetal
microphthalmia, open eyelids, cleft palate, brachymelia and skeletal
malformations occurred at approximately 1.6 times the exposure in CHF
patients (see Data).
The estimated
background risk of major birth defects and miscarriage for the indicated
population is unknown. All pregnancies have a background risk of birth defect,
loss, or other adverse outcomes. The estimated background risk of major birth
defects and miscarriage in the U.S. general population is 2 to 4% and 15 to 20%
of clinically recognized pregnancies, respectively.
Data
Animal
Data
Oral
administration of tolvaptan during the period of organogenesis in
Sprague-Dawley rats produced no evidence of teratogenesis at doses up to 100
mg/kg/day. Delayed ossification was seen at 1000 mg/kg, which is approximately
11 times the exposure in CHF patients at the MRHD of 60 mg (AUC24h 10271
ng*h/mL). The fetal effects are likely secondary to maternal toxicity
(decreased food intake and low body weights). In a prenatal and postnatal study
in rats, tolvaptan had no effect on physical development, reflex function,
learning ability or reproductive performance at doses up to 1000 mg/kg/day (11
times the exposure in CHF patients at the MRHD of 60 mg).
In rabbits,
teratogenicity (microphthalmia, embryo-fetal mortality, cleft palate,
brachymelia and skeletal malformations) was observed in rabbits at 1000 mg/kg
(approximately 1.6 times the exposure in CHF patients at the MRHD of 60 mg
dose). This dose also caused maternal toxicity (lower body weight gains and
food consumption).
8.2 Lactation
(PLLR conversion;
additions and/or revisions underlined):
Risk Summary
There are no data
on the presence of tolvaptan or its metabolites in human milk, the effects
on the breastfed infant, or the effects on milk production. Tolvaptan is present
in rat milk (see Data). When a drug
is present in animal milk, it is possible that the drug will be present in
human milk, but relative levels may vary (see Data). Because of the potential
for serious adverse reactions, including electrolyte abnormalities (e.g.,
hypernatremia), hypotension, and volume depletion in breastfed infants, advise
women not to breastfeed during treatment with SAMSCA.
Data
In lactating rats administered
radiolabeled tolvaptan, lacteal radioactivity concentrations reached the
highest level at 8 hours after administration and then decreased gradually with
time with a half-life of 27.3 hours. The level of activity in milk ranged from 1.5- to
15.8-fold those in maternal blood over a period of 72 hours post-dose.
Increased perinatal
death and decreased body weight of the offspring were observed during the
lactation period and after weaning at approximately 11 times the exposure in
CHF patients at the MRHD of 60 mg.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
Additions
and/or revisions underlined:
What should I tell my healthcare provider before
taking SAMSCA?
Tell your healthcare provider about all your medical conditions,
including if you:
PATIENT COUNSELING INFORMATION
Additions and/or
revisions underlined:
Pregnancy
Advise pregnant
women of the potential risk to a fetus. Advise females of reproductive
potential to inform their prescriber of a known or suspected
pregnancy [see Use in Specific
Populations (8.1)].
Lactation
Advise patients
not to breastfeed an infant if they are taking SAMSCA [see Use
in Specific Populations (8.2)].
Approved Drug Label (PDF)
Boxed Warning
Addition of the following:
WARNING: NOT FOR USE
FOR AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD)
Because of the risk
of hepatoxicity, tolvaptan should not be used for ADPKD outside of the FDA-approved
REMS
4
Contraindications
Addition of the following subsection:
4.1 Use
in patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD) outside of
FDA approved REMS
Tolvaptan can cause serious and potentially
fatal liver injury. Tolvaptan should not be prescribed or used outside of the FDA-approved
Risk Evaluation and Mitigation Strategy (REMS) for ADPKD patients.
5
Warnings and Precautions
5.2 Liver Injury
Additions
and/or revisions underlined:
Tolvaptan can cause serious
and potentially fatal liver injury. In placebo-controlled studies and an
open label extension study of chronically administered tolvaptan in patients with
ADPKD, cases of serious liver injury attributed to tolvaptan, generally
occuring during the first 18 months of therapy, were observed. In postmarketing
experience with tolvaptan in ADPKD, acute injury resulting in liver
failure requiring liver transplantation has been reported. Tolvaptan should not
be used to treat ADPKD outside of the FDA-approved risk evaluation and mitigation
strategy (REMS) for ADPKD patients … Patients with symptoms that may indicate
liver injury …
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
What is the most important
information I should know about SAMSCA?
Addition of the following:
3) If
you have autosomal dominant polycystic kidney disease (ADPKD), do not use
SAMSCA because you should receive the medicine (tolvaptan) through a program
that ensures laboratory monitoring of your liver.
Approved Drug Label (PDF)
5
Warnings and Precautions
5.1 Too Rapid Correction of Serum Sodium Can Cause Serious Neurologic Sequelae
(additions underlined)
Osmotic
demyelination syndrome is a risk associated with too rapid correction of
hyponatremia (e.g., >12 mEq/L/24 hours). Osmotic demyelination results in
dysarthria, mutism, dysphagia, lethargy, affective changes, spastic
quadriparesis, seizures, coma or death. In susceptible patients, including
those with severe malnutrition, alcoholism or advanced liver disease, slower
rates of correction may be advisable. In controlled clinical trials in which
tolvaptan was administered in titrated doses starting at 15 mg once daily, 7%
of tolvaptan-treated subjects with a serum sodium <130 mEq/L had an increase
in serum sodium greater than 8 mEq/L at approximately 8 hours and 2% had an
increase greater than 12 mEq/L at 24 hours. Approximately 1% of placebo-treated
subjects with a serum sodium <130 mEq/L had a rise greater than 8 mEq/L at 8
hours and no patient had a rise greater than 12 mEq/L/24 hours. Osmotic
demyelination syndrome has been reported in association with SAMSCA therapy
[see Adverse Reaction. Patients treated with SAMSCA should be monitored to
assess serum sodium concentrations and neurologic status, especially during
initiation and after titration. Subjects with SIADH or very low baseline serum
sodium concentrations may be at greater risk for too-rapid correction of serum
sodium. In patients receiving SAMSCA who develop too rapid a rise in serum
sodium, discontinue or interrupt treatment with SAMSCA and consider
administration of hypotonic fluid. Fluid restriction during the first 24 hours
of therapy with SAMSCA may increase the likelihood of overly-rapid correction
of serum sodium, and should generally be avoided. Co-administration of
diuretics also increases the risk of too rapid correction of serum sodium and
such patients should undergo close monitoring of serum sodium.
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