Diabetes Pro Quarterly - Summer 2019 - 13

hypoglycemia by various definitions in the placebo-controlled trials.
Table 2. Hypoglycemia Adverse Reactions in Placebo-Controlled Trials
In Patients with Type 2 Diabetes Mellitus
OZEMPIC® OZEMPIC®
Placebo
0.5 mg
1 mg
Monotherapy
(30 weeks)
N=129
N=127
N=130
0%
0%
0%
Severe†
Documented symptomatic (≤70 mg/dL glucose
0%
1.6%
3.8%
threshold)
Severe† or Blood Glucose Confirmed Symptomatic
1.6%
0%
0%
(≤56 mg/dL glucose threshold)
Add-on to Basal Insulin with or without
Metformin
(30 weeks)
N=132
N=132
N=131
0%
0%
1.5%
Severe†
Documented symptomatic (≤70 mg/dL glucose
15.2%
16.7%
29.8%
threshold)
Severe† or Blood Glucose Confirmed Symptomatic
5.3%
8.3%
10.7%
(≤56 mg/dL glucose threshold)
†

"Severe" hypoglycemia adverse reactions are episodes requiring the assistance of another person.

Hypoglycemia was more frequent when OZEMPIC® was used in combination with
a sulfonylurea [see Warnings and Precautions]. Severe hypoglycemia occurred in
0.8% and 1.2% of patients when OZEMPIC® 0.5 mg and 1 mg, respectively, was
co-administered with a sulfonylurea. Documented symptomatic hypoglycemia
occurred in 17.3% and 24.4% of patients when OZEMPIC® 0.5 mg and 1 mg,
respectively, was co-administered with a sulfonylurea. Severe or blood glucose
confirmed symptomatic hypoglycemia occurred in 6.5% and 10.4% of patients when
OZEMPIC® 0.5 mg and 1 mg, respectively, was co-administered with a sulfonylurea.
Injection Site Reactions: In placebo-controlled trials, injection site reactions (e.g.,
injection-site discomfort, erythema) were reported in 0.2% of OZEMPIC®-treated
patients. Increases in Amylase and Lipase: In placebo-controlled trials, patients
exposed to OZEMPIC® had a mean increase from baseline in amylase of 13% and
lipase of 22%. These changes were not observed in placebo-treated patients.
Cholelithiasis: In placebo-controlled trials, cholelithiasis was reported in 1.5%
and 0.4% of patients-treated with OZEMPIC® 0.5 mg and 1 mg, respectively.
Cholelithiasis was not reported in placebo-treated patients. Increases in Heart Rate:
In placebo-controlled trials, OZEMPIC® 0.5 mg and 1 mg resulted in a mean increase
in heart rate of 2 to 3 beats per minute. There was a mean decrease in heart rate of
0.3 beats per minute in placebo-treated patients. Fatigue, Dysgeusia and Dizziness:
Other adverse reactions with a frequency of >0.4% were associated with OZEMPIC®
include fatigue, dysgeusia and dizziness. Immunogenicity: Consistent with the
potentially immunogenic properties of protein and peptide pharmaceuticals, patients
treated with OZEMPIC® may develop anti-semaglutide antibodies. The detection
of antibody formation is highly dependent on the sensitivity and specificity of the
assay. Additionally, the observed incidence of antibody (including neutralizing
antibody) positivity in an assay may be influenced by several factors including assay
methodology, sample handling, timing of sample collection, concomitant medications,
and underlying disease. For these reasons, the incidence of antibodies to semaglutide
in the studies described below cannot be directly compared with the incidence of
antibodies in other studies or to other products. Across the placebo- and activecontrolled glycemic control trials, 32 (1.0%) OZEMPIC®-treated patients developed
anti-drug antibodies (ADAs) to the active ingredient in OZEMPIC® (i.e., semaglutide).
Of the 32 semaglutide-treated patients that developed semaglutide ADAs, 19 patients
(0.6% of the overall population) developed antibodies cross-reacting with native
GLP-1. The in vitro neutralizing activity of the antibodies is uncertain at this time.
DRUG INTERACTIONS: Concomitant Use with an Insulin Secretagogue
(e.g., Sulfonylurea) or with Insulin: The risk of hypoglycemia is increased when
OZEMPIC® is used in combination with insulin secretagogues (e.g., sulfonylureas)
or insulin. The risk of hypoglycemia may be lowered by a reduction in the dose
of sulfonylurea (or other concomitantly administered insulin secretagogues) or
insulin [see Warnings and Precautions]. Oral Medications: OZEMPIC® causes
a delay of gastric emptying, and thereby has the potential to impact the absorption
of concomitantly administered oral medications. In clinical pharmacology trials,
semaglutide did not affect the absorption of orally administered medications to
any clinically relevant degree. Nonetheless, caution should be exercised when oral
medications are concomitantly administered with OZEMPIC®.
USE IN SPECIFIC POPULATIONS: Pregnancy: Risk Summary: There are limited
data with semaglutide use in pregnant women to inform a drug-associated risk for
adverse developmental outcomes. There are clinical considerations regarding
the risks of poorly controlled diabetes in pregnancy (see Clinical Considerations).
Based on animal reproduction studies, there may be potential risks to the fetus
from exposure to semaglutide during pregnancy. OZEMPIC® should be used during
pregnancy only if the potential benefit justifies the potential risk to the fetus. In
pregnant rats administered semaglutide during organogenesis, embryofetal mortality,
structural abnormalities and alterations to growth occurred at maternal exposures
below the maximum recommended human dose (MRHD) based on AUC. In rabbits
and cynomolgus monkeys administered semaglutide during organogenesis,
early pregnancy losses and structural abnormalities were observed at below the
MRHD (rabbit) and ≥5-fold the MRHD (monkey). These findings coincided with a

marked maternal body weight loss in both animal species (see Data). The estimated
background risk of major birth defects is 6-10% in women with pre-gestational
diabetes with an HbA1c >7 and has been reported to be as high as 20-25% in women
with a HbA1c >10. 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. Clinical Considerations: Disease associated maternal and
fetal risk: Poorly controlled diabetes during pregnancy increases the maternal risk
for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery,
stillbirth and delivery complications. Poorly controlled diabetes increases the fetal
risk for major birth defects, stillbirth, and macrosomia related morbidity. Data: Animal
Data: In a combined fertility and embryofetal development study in rats, subcutaneous
doses of 0.01, 0.03 and 0.09 mg/kg/day (0.1-, 0.4-, and 1.1-fold the MRHD) were
administered to males for 4 weeks prior to and throughout mating and to females for 2
weeks prior to mating, and throughout organogenesis to Gestation Day 17. In parental
animals, pharmacologically mediated reductions in body weight gain and food
consumption were observed at all dose levels. In the offspring, reduced growth and
fetuses with visceral (heart blood vessels) and skeletal (cranial bones, vertebra, ribs)
abnormalities were observed at the human exposure. In an embryofetal development
study in pregnant rabbits, subcutaneous doses of 0.0010, 0.0025 or 0.0075 mg/kg/
day (0.03-, 0.3-, and 2.3-fold the MRHD) were administered throughout organogenesis
from Gestation Day 6 to 19. Pharmacologically mediated reductions in maternal body
weight gain and food consumption were observed at all dose levels. Early pregnancy
losses and increased incidences of minor visceral (kidney, liver) and skeletal
(sternebra) fetal abnormalities were observed at ≥0.0025 mg/kg/day, at clinically
relevant exposures. In an embryofetal development study in pregnant cynomolgus
monkeys, subcutaneous doses of 0.015, 0.075, and 0.15 mg/kg twice weekly (1.0-,
5.2-, and 14.9-fold the MRHD) were administered throughout organogenesis, from
Gestation Day 16 to 50. Pharmacologically mediated, marked initial maternal body
weight loss and reductions in body weight gain and food consumption coincided with
the occurrence of sporadic abnormalities (vertebra, sternebra, ribs) at ≥0.075 mg/kg
twice weekly (≥5X human exposure). In a pre- and postnatal development study in
pregnant cynomolgus monkeys, subcutaneous doses of 0.015, 0.075, and 0.15 mg/
kg twice weekly (0.7-, 3.3-, and 7.2-fold the MRHD) were administered from Gestation
Day 16 to 140. Pharmacologically mediated marked initial maternal body weight loss
and reductions in body weight gain and food consumption coincided with an increase
in early pregnancy losses and led to delivery of slightly smaller offspring at ≥0.075
mg/kg twice weekly (≥3X human exposure). Lactation: Risk Summary: There are
no data on the presence of semaglutide in human milk, the effects on the breastfed
infant, or the effects on milk production. Semaglutide was present in the milk of
lactating rats, however, due to species-specific differences in lactation physiology,
the clinical relevance of these data are not clear (see Data). The developmental
and health benefits of breastfeeding should be considered along with the mother's
clinical need for OZEMPIC® and any potential adverse effects on the breastfed infant
from OZEMPIC® or from the underlying maternal condition. Data: In lactating rats,
semaglutide was detected in milk at levels 3-12 fold lower than in maternal plasma.
Females and Males of Reproductive Potential: Discontinue OZEMPIC®
in women at least 2 months before a planned pregnancy due to the long washout
period for semaglutide [see Use in Specific Populations]. Pediatric Use: Safety and
efficacy of OZEMPIC® have not been established in pediatric patients (younger than
18 years). Geriatric Use: In the pool of placebo- and active-controlled glycemic
control trials, 744 (23.6%) OZEMPIC®-treated patients were 65 years of age and over
and 102 OZEMPIC®-treated patients (3.2%) patients were 75 years of age and over.
In SUSTAIN 6, the cardiovascular outcome trial, 788 (48.0%) OZEMPIC®-treated
patients were 65 years of age and over and 157 OZEMPIC®-treated patients (9.6%)
patients were 75 years of age and over. No overall differences in safety or efficacy were
detected between these patients and younger patients, but greater sensitivity of some
older individuals cannot be ruled out. Renal Impairment: No dose adjustment of
OZEMPIC® is recommended for patients with renal impairment. In subjects with renal
impairment including end-stage renal disease (ESRD), no clinically relevant change
in semaglutide pharmacokinetics (PK) was observed. Hepatic Impairment: No
dose adjustment of OZEMPIC® is recommended for patients with hepatic impairment.
In a study in subjects with different degrees of hepatic impairment, no clinically
relevant change in semaglutide pharmacokinetics (PK) was observed.
OVERDOSAGE: In the event of overdose, appropriate supportive treatment should be
initiated according to the patient's clinical signs and symptoms. A prolonged period of
observation and treatment for these symptoms may be necessary, taking into account
the long half-life of OZEMPIC® of approximately 1 week.
More detailed information is available upon request.
For information about OZEMPIC® contact: Novo Nordisk Inc., 800 Scudders Mill
Road, Plainsboro, NJ 08536, 1-888-693-6742
Date of Issue: December 2017
Version: 1
Manufactured by: Novo Nordisk A/S, DK-2880 Bagsvaerd, Denmark
OZEMPIC® and NovoFine® are registered trademarks of Novo Nordisk A/S.
PATENT INFORMATION:
http://novonordisk-us.com/patients/products/product-patents.html
© 2017 Novo Nordisk USA17SEM04247 12/2017

http://www.novonordisk-us.com/patients/products/product-patents.html

Diabetes Pro Quarterly - Summer 2019

Table of Contents for the Digital Edition of Diabetes Pro Quarterly - Summer 2019