Approved Drug Label (PDF)
5
Warnings and Precautions
5.7 Steatorrhea and Malabsorption of Dietary Fats
New
subsection added:
New
onset steatorrhea, stool discoloration and loose stools have been reported in
patients receiving somatostatin analogs, including pasireotide products.
Somatostatin analogs reversibly inhibit secretion of pancreatic enzymes and
bile acids, which may result in malabsorption of dietary fats and subsequent
symptoms of steatorrhea, loose stools, abdominal bloating, and weight loss. If
new occurrence or worsening of these symptoms are reported in patients
receiving SIGNIFOR,
evaluate patients for potential pancreatic exocrine insufficiency and manage
accordingly.
6
Adverse Reactions
Addition of the
following to the bulleted line listing:
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING
INFORMATION
Additions
and/or revisions underlined:
…
Steatorrhea and Malabsorption of Dietary Fats: Advise
patients to contact their healthcare provider if they experience new or
worsening symptoms of steatorrhea, stool discoloration, loose stools, abdominal
bloating, and weight loss [see Warnings
and Precautions (5.7)]
…
MEDICATION GUIDE
Additions
and/or revisions underlined:
…
What
are the possible side effects of SIGNIFOR?
SIGNIFOR may cause
serious side effects, including:
…
fatty stool. SIGNIFOR may cause
your body to have issues absorbing dietary fats. Tell your doctor if you have
any new or worsening symptoms including fatty stools, changes in the color of
your stools, loose stools, stomach (abdominal) bloating or weight loss.
…
Approved Drug Label (PDF)
5
Warnings and Precautions
5.2 Hyperglycemia and Diabetes
(additions
underlined)
Blood
glucose elevations have been seen in healthy volunteers and patients
treated with SIGNIFOR. In the clinical study, patients developed pre-diabetes and
diabetes. Nearly all patients in the study, including those with normal glucose
status at baseline, pre-diabetes, and diabetes, developed worsening glycemia in
the first two weeks of treatment. Cushing’s disease patients with poor glycemic
control (HbA1c > 8%) may be at a higher risk of developing severe
hyperglycemia and associated complications, e.g., ketoacidosis.
Assess the patient’s
glycemic status prior to starting treatment with SIGNIFOR. In patients with
uncontrolled diabetes mellitus, optimize anti-diabetic therapy prior to
SIGNIFOR initiation. Glycemic monitoring should be done every week for
the first two to three months and periodically thereafter, as well as over the
first two to four weeks after any dose increase. If hyperglycemia develops,
initiate or adjust anti-diabetic treatment per standard of care. If
uncontrolled hyperglycemia persists despite appropriate treatment, reduce
the dose or discontinue SIGNIFOR and perform glycemic monitoring according
to clinical practice. Patients who were initiated on anti-diabetic treatment as
a result of SIGNIFOR require closer monitoring after discontinuation of
SIGNIFOR, especially if the anti-diabetic therapy has a risk of causing
hypoglycemia.
Approved Drug Label (PDF)
5
Warnings and Precautions
5.5 Cholelithiasis and Complications of Cholelithiasis
(additions
underlined)
Cholelithiasis
has been frequently reported in clinical studies with SIGNIFOR.There have been postmarketing
reports of cholelithiasis (gallstones) resulting in complications, including
cholecystitis or cholangitis and requiring cholecystectomy in patients taking
SIGNIFOR. Ultrasonic examination of the gallbladder before, and periodically
during SIGNIFOR therapy is recommended. If complications of cholelithiasis
are suspected, discontinue SIGNIFOR and treat appropriately.
6
Adverse Reactions
(addition underlined)
6.2 Postmarketing Experience
(new
subsection added)
Additional
adverse reactions have been identified during postapproval use of SIGNIFOR.
Because these reactions are reported voluntarily from a population of uncertain
size, it is generally not possible to reliably estimate their frequency or
establish a causal relationship to drug exposure.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
(additions
underlined)
…
What
are the possible side effects of SIGNIFOR?
SIGNIFOR
may cause serious side effects, including:
…
gallstones (cholelithiasis) and complications
that can happen if you have gallstones.
Gallstones
are a serious but common side effect of SIGNIFOR. Possible complications of
gallstones include inflammation and infection of the gallbladder. Your doctor should do atest
(ultrasound) to check for gallstones before you start using SIGNIFOR and while
you use it. Tell your healthcare provider if you get any of these symptoms.
sudden pain in your upper right stomach area
(abdomen)
yellowing of your skin and whites of your eyes
nausea
sudden pain in your right shoulder or between your
shoulder blades
fever with chills
…
PATIENT COUNSELING INFORMATION
(additions
underlined)
…
…
Approved Drug Label (PDF)
8
Use in Specific Populations
8.1 Pregnancy
PLLR conversion;
additions and/or revisions underlined:
Risk
Summary
The
limited data with SIGNIFOR in pregnant women are insufficient to inform a
drug-associated risk for major birth defects and miscarriage. In embryofetal
development studies in rabbits, findings indicating developmental delay
were observed with subcutaneous administration of pasireotide during organogenesis
at doses less than the exposure
in humans at the highest recommended dose; maternal toxicity was not observed
at this dose.
The
estimated background risk of major birth defects and miscarriage for the indicated
population is unknown. In the U.S. general population, the estimated background
risk of major birth defects and miscarriage in clinically recognized pregnancies
is 2-4% and 15-20%, respectively.
Data
Animal Data
In
embryofetal development studies … at the maximum therapeutic dose based on AUC comparisons
across species. An increased incidence of early/total resorptions and malrotated
limbs was observed in rats at 10 mg/kg/day. At 10 mg/kg/day in rats, the maternal
systemic exposure (AUC) was 42179 ng*hr/mL, approximately 144 times the exposure
in humans at the highest recommended dose of 900 µg SIGNIFOR administered
as a subcutaneous injection twice a day.
…
subcutaneously through organogenesis, maternal toxicity was observed at 1 mg/kg/day,
at a maternal systemic exposure (AUC) of 1906 ng*hr/mL, approximately
7 times higher than the maximum human therapeutic exposure. An increased
incidence of unossified forepaw phalanx, indicative of a developmental retardation,
was observed in rabbits at 0.05 mg/kg/day, with maternal systemic
exposures less than the systemic exposure in humans at the highest recommended
dose.
In
pre- and post-natal developmental studies in rats …
8.2 Lactation
PLLR conversion;
newly added information:
Risk
Summary
There
is no information available on the presence of SIGNIFOR in human milk, the effects
of the drug on the breastfed infant, or the effects of the drug on milk production.
Studies show that pasireotide administered subcutaneously passes into the milk of
lactating rats; however, due to species-specific differences in lactation physiology,
animal data may not reliably predict drug levels in human milk. The developmental and health benefits of
breastfeeding should be considered along with the mother’s clinical need for SIGNIFOR
and any potential adverse effects on the breast-fed child from SIGNIFOR or from
the underlying maternal condition.
Data
Available
data in animals have shown excretion of pasireotide in milk. After a single 1 mg/kg
[14C]-pasireotide subcutaneous dose to lactating rats, the transfer of radioactivity
into milk was observed. The overall milk:plasma (M/P) exposure ratio of total radioactivity
was 0.28, based on AUC0-infinity values.
8.3 Females and Males of Reproductive Potential
PLLR conversion;
newly added information:
Discuss
the potential for unintended pregnancy with premenopausal women as the therapeutic
benefits of a reduction or normalization of serum cortisol levels in female patients
with Cushing’s disease treated with pasireotide may lead to improved fertility.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
Additions and/or
revisions underlined:
The
most common side effects of SIGNIFOR include:
PATIENT COUNSELING INFORMATION
Additions and/or
revisions underlined:
Counsel
patients on the following possible significant adverse reactions:
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