throbber
This medicinal product is subject to additional monitoring in Australia. This will allow
`quick identification of new safety information. Healthcare professionals are asked to
`report any suspected adverse events at www.tga.gov.au/reporting-problems.
`
`AUSTRALIAN PRODUCT INFORMATION
`
`OZEMPIC®
`
`(semaglutide) solution for injection
`
`1. NAME OF THE MEDICINE
`semaglutide (rys)
`
`2. QUALITATIVE AND QUANTITATIVE COMPOSITION
`Ozempic 0.25 mg, 0.5 mg/dose
`One mL of solution contains 1.34 mg of semaglutide. One pre-filled pen
`contains 2 mg semaglutide in 1.5 mL solution.
`
`Ozempic 1 mg/dose
`One mL of solution contains 1.34 mg semaglutide. One pre-filled pen
`contains 4 mg semaglutide in 3 mL solution.
`Semaglutide is a human glucagon-like-peptide-1 (GLP-1) receptor agonist
`produced in Saccharomyces cerevisiae by recombinant DNA technology
`followed by protein purification.
`For the full list of excipients, see Section 6.1 List of Excipients.
`
`3. PHARMACEUTICAL FORM
`Ozempic solution for injection is provided in a pre-filled multidose
`disposable pen, which contains semaglutide in a 1.5 mL or 3 mL cartridge.
`It is a clear and colourless, or almost colourless, isotonic solution with
`pH = 7.4.
`
`4. CLINICAL PARTICULARS
`
`4.1 Therapeutic Indications
`Ozempic is indicated for the treatment of adults with insufficiently
`controlled type 2 diabetes mellitus as an adjunct to diet and exercise:
`• as monotherapy when metformin is not tolerated or contraindicated.
`• in addition to other medicinal products for the treatment of type 2
`diabetes.
`
` 4.2 Dose and Method of Administration
`Dosage
`Ozempic starting dose is 0.25 mg once weekly. After 4 weeks, the dose
`should be increased to 0.5 mg once weekly. After at least 4 weeks with
`a dose of 0.5 mg once weekly, the dose can be increased to 1 mg once
`weekly to further improve glycaemic control.
`Ozempic 0.25 mg is not a maintenance dose.
`When Ozempic is added to existing metformin and/or thiazolidinedione
`therapy, the current dose of metformin and/or thiazolidinedione can be
`continued unchanged.
`When Ozempic is added to existing therapy of a sulfonylurea or insulin,
`a reduction in the dose of sulfonylurea or insulin should be considered to
`reduce the risk of hypoglycaemia (see section 4.4 Special Warnings and
`Precautions for Use).
`The use of Ozempic does not require blood glucose self-monitoring.
`Self-monitoring may be performed when Ozempic is used together with
`sulfonylurea or insulin in order to allow adjustment of the dose of these
`medications.
`
`Method of Administration
`Ozempic is to be administered once weekly, on the same day each week,
`at any time of the day, with or without meals.
`Ozempic is to be injected subcutaneously in the abdomen, in the thigh
`or in the upper arm. The injection site can be changed without dose
`adjustment. Ozempic should not be administered intravenously or
`intramuscularly. For further information on administration, see section 6
`Pharmaceutical Particulars.
`
`The day of weekly administration can be changed if necessary as long as
`the time between two doses is at least 3 days (>72 hours). After selecting
`a new dosing day, once-weekly dosing should be continued.
`If a dose is missed, it should be administered as soon as possible and within
`5 days after the missed dose. If more than 5 days have passed, the missed
`dose should be skipped, and the next dose should be administered on
`the regularly scheduled day. In each case, patients can then resume their
`regular once weekly dosing schedule.
`
`Dosage Adjustment
`Elderly (≥ 65 years old)
`No dose adjustment is required based on age. Therapeutic experience
`in patients ≥ 75 years of age is limited (see section 5.2 Pharmacokinetic
`Properties).
`
`Gender
`No dose adjustment is required based on gender.
`
`Race and Ethnicity
`No dose adjustment is required based on race and ethnicity.
`
`Patients with hepatic impairment
`No dose adjustment is required for patients with hepatic impairment
`(see section 5.2 Pharmacokinetic Properties). Experience with the use of
`semaglutide in patients with severe hepatic impairment is limited. Caution
`should be exercised when treating these patients with semaglutide.
`
`Patients with renal impairment
`No dose adjustment is required for patients with renal impairment.
`Experience with the use of semaglutide in patients with severe
`(CrCL < 30 mL/min) renal impairment is limited. Semaglutide is not
`recommended for use in patients with end-stage renal disease (see
`section 5.2 Pharmacokinetic Properties).
`
`Children and adolescents
`Safety and efficacy of Ozempic in children and adolescents below 18 years
`have not been studied.
`
`4.3 Contraindications
`Hypersensitivity to the active substance or to any of the excipients listed in
`section 6.1 List of Excipients.
`
`4.4 Special Warnings and Precautions for Use
`Ozempic should not be used in patients with type 1 diabetes mellitus or for
`the treatment of diabetic ketoacidosis.
`Ozempic is not a substitute for insulin.
`
`Gastrointestinal Effects
`Use of GLP-1 receptor agonists may be associated with gastrointestinal
`adverse reactions. This should be considered when treating patients with
`impaired renal function as nausea, vomiting, and diarrhoea, may cause
`dehydration which could cause a deterioration of renal function.
`
`Acute Pancreatitis
`Acute pancreatitis has been observed with the use of GLP-1 receptor
`agonists. Patients should be informed of the characteristic symptoms
`of acute pancreatitis. If pancreatitis is suspected, Ozempic should be
`discontinued; if confirmed, Ozempic should not be restarted. Caution
`should be exercised in patients with a history of pancreatitis.
`
`Hypoglycaemia
`Patients treated with Ozempic in combination with a sulfonylurea or insulin
`may have an increased risk of hypoglycaemia. The risk of hypoglycaemia
`can be lowered by reducing the dose of sulfonylurea or insulin when
`initiating treatment with Ozempic.
`
`Diabetic Retinopathy
`In patients with diabetic retinopathy treated with insulin and semaglutide,
`an increased risk of developing diabetic retinopathy complications has been
`observed (see section 4.8 Adverse Effects (Undesirable Effects)). Caution
`should be exercised when using semaglutide in patients with diabetic
`retinopathy treated with insulin. Rapid improvement in glucose control
`has been associated with a temporary worsening of diabetic retinopathy.
`
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`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00001
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`PRODUCT INFORMATION | OZEMPIC® (semaglutide) solution for injection
`
`Page 2 of 12
`
`Long-term glycaemic control decreases the risk of diabetic retinopathy.
`Patients with a history of diabetic retinopathy should be monitored for
`worsening and treated according to clinical guidelines.
`
`Heart Failure
`There is no therapeutic experience in patients with congestive heart
`failure New York Heart Association (NYHA) class IV and therefore use of
`semaglutide is not recommended in these patients.
`
`Use in hepatic impairment
`Experience with the use of semaglutide in patients with severe hepatic
`impairment is limited. Caution should be exercised when treating these
`patients with semaglutide.
`
`Use in renal impairment
`Experience with the use of semaglutide in patients with severe (CrCL
`< 30 mL/min) renal impairment is limited. Semaglutide is not recommended
`for use in patients with end-stage renal disease (see sections 5.1
`Pharmacodynamic Properties and 5.2 Pharmacokinetic Properties).
`
`Use in elderly
`See section 5.2 Pharmacokinetic Properties.
`
`Paediatric Use
`The safety and efficacy of semaglutide in children and adolescents aged
`below 18 years has not been studied.
`
`Effects on laboratory tests
`No data available.
`
`4.5 Interactions with Other Medicines and Other Forms of
`Interactions
`In vitro studies have shown very low potential for semaglutide to inhibit or
`induce CYP enzymes, and to inhibit drug transporters.
`The delay of gastric emptying with semaglutide may influence the
`absorption of concomitantly administered oral medicinal products,
`therefore semaglutide should be used with caution in patients receiving
`oral medicinal products that require rapid gastrointestinal absorption.
`The potential effect of semaglutide on the absorption of co-administered
`oral medications was studied in trials at semaglutide 1 mg steady state
`exposure.
`No clinically relevant drug–drug interaction with semaglutide (Figure 1)
`was observed based on the evaluated medications. Therefore, no dose
`adjustment is required when co-administered with semaglutide.
`
`Oral Contraceptives
`Semaglutide is not anticipated to decrease the effectiveness of oral
`contraceptives as semaglutide did not change the overall exposure
`of ethinylestradiol and levonorgestrel to a clinically relevant degree
`when an oral contraceptive combination medicinal product (0.03 mg
`ethinylestradiol/0.15 mg
`levonorgestrel) was co-administered with
`semaglutide. Exposure of ethinylestradiol was not affected; an increase of
`20% was observed for levonorgestrel exposure at steady state. Cmax was
`not affected for any of the compounds.
`
`Atorvastatin
`Semaglutide did not change the overall exposure of atorvastatin following
`a single dose administration of atorvastatin (40 mg). Atorvastatin Cmax was
`decreased by 38%. This was assessed not to be clinically relevant.
`
`Digoxin
`Semaglutide did not change the overall exposure or Cmax of digoxin
`following a single dose of digoxin (0.5 mg).
`
`Metformin
`Semaglutide did not change the overall exposure or Cmax of metformin
`following dosing of 500 mg twice daily over 3.5 days.
`
`Warfarin
`Semaglutide did not change overall exposure or Cmax of R- and S-warfarin
`following a single dose of warfarin (25 mg), and the pharmacodynamic
`effects of warfarin as measured by the international normalised ratio were
`not affected in a clinically relevant manner.
`
`4.6 Fertility, Pregnancy and Lactation
`Effects on fertility
`The effect of semaglutide on fertility in humans is unknown. Semaglutide
`did not affect male fertility in rats at daily SC doses of 828 μg/kg, resulting
`in exposures approximately 13 times the clinical AUC. In female rats, an
`increase in oestrous length and a small reduction in number of ovulations
`were observed at doses associated with maternal body weight loss (≥ 30 μg/
`kg/day SC, resulting in subclinical exposures).
`
`Use in pregnancy
`Pregnancy Category: D
`Semaglutide should not be used during pregnancy. Women of childbearing
`potential are recommended to use contraception when treated with
`semaglutide. If a patient wishes to become pregnant, or pregnancy occurs,
`semaglutide should be discontinued. Semaglutide should be discontinued
`at least 2 months before a planned pregnancy due to the long half-life (see
`section 5.1 Pharmacodynamic Properties).
`Studies in animals have shown reproductive toxicity when semaglutide
`was administered during organogenesis. In pregnant rats, embryofetal
`toxicity (lethality, impaired growth and an increased incidence of fetal
`abnormalities) was observed at subclinical plasma exposures. Mechanistic
`
`Co-administered
`medication
`
`Relative exposure
`Ratio and 90% CI
`
`Metformin
`
`S-warfarin
`
`R-warfarin
`
`Digoxin
`
`Atorvastatin
`
`Ethinylestradiol
`
`Levonorgestrel
`
`AUC0-12h
`Cmax
`AUC0-168h
`Cmax
`AUC0-168h
`Cmax
`AUC0-120h
`Cmax
`AUC0-72h
`Cmax
`AUC0-24h
`Cmax
`AUC0-24h
`Cmax
`
`Recommendation
`
`No dose adjustment
`
`No dose adjustment
`
`No dose adjustment
`
`No dose adjustment
`
`No dose adjustment
`
`No dose adjustment
`
`No dose adjustment
`
`0.5
`
`1
`
`2
`
`Relative exposure in terms of AUC and Cmax for each medication when given with semaglutide compared to without semaglutide. Metformin and oral contraceptive drug
`(ethinylestradiol/levonorgestrel) were assessed at steady state. Warfarin (S-warfarin/R-warfarin), digoxin and atorvastatin were assessed after a single dose.
`Abbreviations: AUC: area under the curve. Cmax: maximum concentration. CI: confidence interval.
`Figure 1: Impact of semaglutide on the exposure of co-administered oral medications
`
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`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00002
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`PRODUCT INFORMATION | OZEMPIC® (semaglutide) solution for injection
`
`Page 3 of 12
`
`studies suggest a direct GLP-1 receptor mediated role of semaglutide
`on some of the effects in rats (species specific). In pregnant rabbits,
`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 pregnant cynomolgus monkeys,
`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) and
`with an increase in early pregnancy losses at ≥ 0.075 mg/kg twice weekly
`(> 2.7 fold clinical exposure at 1 mg/week). Exposures at the NOAEL in all
`species were subclinical and a direct effect of semaglutide on the fetus
`cannot be excluded.
`
`Use in lactation
`In lactating rats, semaglutide was excreted in milk. A risk to a breast-fed
`child cannot be excluded. Semaglutide should not be used during breast-
`feeding.
`
`4.7 Effects on Ability to Drive and Use Machines
`Ozempic has no or negligible influence on the ability to drive or use
`machines. When it is used in combination with a sulfonylurea or insulin,
`patients should be advised to take precautions to avoid hypoglycaemia
`while driving and using machines.
`Adverse effects of Ozempic include dizziness which could affect the ability
`to drive or use machines (see Section 4.8 Adverse Effects (Undesirable
`Effects)).
`
`4.8 Adverse Effects (Undesirable Effects)
`Summary of the Safety Profile
`In 8 phase 3a trials, 4,792 patients were exposed to Ozempic alone or in
`combination with other glucose lowering medicinal products. The duration
`of the treatment ranged from 30 weeks to 2 years.
`The most frequently reported adverse reactions in clinical trials were
`gastrointestinal disorders, including nausea, diarrhoea and vomiting. In
`general, these reactions were mild or moderate in severity and of short
`duration.
`
`Reporting suspected adverse effects
`Reporting suspected adverse reactions after registration of the medicinal
`product is important. It allows continued monitoring of the benefit–risk
`balance of the medicinal product. Healthcare professionals are asked to
`report any suspected adverse reactions at www.tga.gov.au/reporting-
`problems.
`
`Tabulated List of Adverse Events
`Table 1: Treatment-emergent adverse events with frequency
`≥ 5% comparing Ozempic 0.5 mg dose, Ozempic 1.0 mg dose with
`comparators
`
`Adverse Event
`Term
`
`Nausea
`Vomiting
`Dyspepsia
`Diarrhoea
`Constipation
`Nasopharyngitis
`Lipase increased
`Headache
`Decreased appetite
`
`Ozempic
`0.5 mg dose %
`(n=1373)
`17.0
`6.4
`4.1
`12.2
`6.9
`14.5
`8.7
`5.3
`6.3
`
`
`
`
`
`
`
`
`
`
`
`Ozempic
`1.0 mg dose %
`(n=1777)
`19.9
`8.4
`5.2
`13.3
`6.2
`10.7
`8.5
`6.4
`7.2
`
`
`
`
`
`
`
`
`
`
`
`Comparator
`%
`(n=1657)
`6.3
`3.3
`2.1
`5.7
`2.7
`13.8
`6.3
`5.5
`2.0
`
`
`
`
`
`
`
`
`
`
`
`Adverse Reactions
`Table 2 lists adverse reactions identified in phase 3a trials in patients
`with type 2 diabetes (further described in section 5.1 Pharmacodynamic
`Properties). The frequencies of the adverse reactions are based on a pool of
`the phase 3a trials excluding the cardiovascular outcomes trial.
`The reactions are listed below by system organ class and absolute
`frequency. Frequencies are defined as: very common: (≥ 1/10); common:
`(≥ 1/100 to <1/10); uncommon (≥ 1/1,000 to <1/100); rare: (≥ 1/10,000 to
`<1/1,000); and very rare: (<1/10,000). Within each frequency grouping,
`adverse reactions are presented in order of decreasing seriousness.
`
`Table 2: Adverse reactions from controlled phase 3a trials
`
`Very common Common
`
`Uncommon
`
`Rare
`
`Hypersensitivityc Anaphylactic
`reaction
`
`MedDRA system
`organ class
`Immune-system
`disorders
`Metabolism
`and nutrition
`disorders
`
`Nervous system
`disorders
`Eye disorders
`
`Hypoglycaemiaa
`when used
`with insulin or
`sulfonylurea
`
`Cardiac
`disorders
`Gastrointestinal
`disorders
`
`Nausea
`Diarrhoea
`
`Hypoglycaemiaa
`when used with
`other OADs
`Decreased
`appetite
`Dizziness
`
`Diabetic
`retinopathy
`complicationsb
`
`Vomiting
`Abdominal pain
`Abdominal
`distension
`Constipation
`Dyspepsia
`Gastritis
`Gastro-
`oesophageal
`reflux disease
`Eructation
`Flatulence
`Cholelithiasis
`
`Fatigue
`
`Dysgeusia
`
`Increased heart
`rate
`Acute
`pancreatitis
`
`Injection site
`reactions
`
`Hepatobiliary
`disorders
`General
`disorders and
`administration
`site conditions
`Investigations
`
`Increased lipase
`Increased amylase
`Weight decreased
`a Hypoglycaemia defined as severe (requiring the assistance of another person)
`or symptomatic in combination with a blood glucose <3.1 mmol/L.
`b Diabetic retinopathy complications is a composite of: need for retinal
`photocoagulation, need for treatment with intravitreal agents, vitreous
`haemorrhage, onset of diabetes-related blindness. Frequency based on
`cardiovascular outcomes trial.
`c Grouped term covering also adverse events related to hypersensitivity such as
`rash and urticaria.
`
`2-year cardiovascular outcomes and safety trial
`In a high cardiovascular risk population, the adverse reaction profile was
`similar to that seen in the other phase 3a trials (described in section 5.1
`Pharmacokinetic Properties).
`
`Description of Selected Adverse Reactions
`Hypoglycaemia
`No episodes of severe hypoglycaemia were observed when Ozempic was
`used as monotherapy. Severe hypoglycaemia was primarily observed when
`Ozempic was used with a sulfonylurea (1.2% of subjects, 0.03 events/
`patient year) or insulin (1.5% of subjects, 0.02 events/patient year).
`Few severe episodes (0.1% of subjects, 0.001 events/patient year) were
`observed with Ozempic in combination with oral antidiabetics other than
`sulfonylureas.
`
`Gastrointestinal Adverse Reactions
`Nausea occurred in 17.0% and 19.9% patients when treated with Ozempic
`0.5 mg and 1 mg respectively, diarrhoea in 12.2% and 13.3% and vomiting
`in 6.4% and 8.4%. Most events were mild to moderate in severity and of
`short duration. The events led to treatment discontinuation in 3.9% and
`5.9% of subjects. The events were most frequently reported during the
`first months on treatment. Patients with low body weight may experience
`more gastrointestinal side effects when treated with semaglutide.
`
`Diabetic Retinopathy Complications
`In a 2-year clinical trial involving 3,297 patients with type 2 diabetes and
`high cardiovascular risk, long duration of diabetes and poorly controlled
`
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`IPR2023-00724
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`PRODUCT INFORMATION | OZEMPIC® (semaglutide) solution for injection
`
`Page 4 of 12
`
`Mechanism of action
`Semaglutide is a GLP-1 analogue with 94% sequence homology to human
`GLP-1. Semaglutide acts as a GLP-1 receptor agonist that binds to and
`activates the GLP-1 receptor, the target for native GLP-1.
`GLP-1 is a physiological hormone that has multiple actions in glucose
`and appetite regulation, and in the cardiovascular system. The glucose
`and appetite effects are specifically mediated via GLP-1 receptors in the
`pancreas and the brain. GLP-1 receptors are also expressed in the heart,
`vasculature and immune system and kidney from where it may mediate
`cardiovascular and microvascular effects.
`Compared to native GLP-1, semaglutide has a prolonged half-life of
`around 1 week making it suitable for once weekly s.c. administration. The
`principal mechanism of protraction is albumin binding, which results in
`decreased renal clearance and protection from metabolic degradation.
`Furthermore, semaglutide is stabilised against degradation by the DPP-4
`enzyme.
`Semaglutide reduces blood glucose through a mechanism where it
`stimulates insulin secretion and lowers glucagon secretion, both in a
`glucose-dependent manner. Thus, when blood glucose is high, insulin
`secretion is stimulated and glucagon secretion is inhibited. The mechanism
`of blood glucose lowering also involves a minor delay in gastric emptying
`in the early postprandial phase. During hypoglycaemia semaglutide
`diminishes insulin secretion and does not impair glucagon secretion.
`Semaglutide reduces body weight and body fat mass through lowered
`energy intake, involving an overall reduced appetite, which includes
`increased satiety and reduced hunger, as well as improved control of eating
`and decreased food cravings. Insulin resistance is also reduced, probably
`through reduction in body weight. In addition, semaglutide reduces the
`preference for high fat foods. Semaglutide had a beneficial effect on
`plasma lipids, lowered systolic blood pressure and reduced inflammation
`in clinical studies.
`the development of
`In animal studies, semaglutide attenuates
`atherosclerosis by preventing aortic plaque progression and reducing
`inflammation in the plaque.
`
`Pharmacodynamic Effects
`All pharmacodynamic evaluations were performed after 12 weeks of
`treatment (including dose escalation) at steady state with semaglutide
`1 mg once weekly.
`
`Fasting and Postprandial Glucose
`Semaglutide reduces fasting and postprandial glucose concentrations. In
`patients with type 2 diabetes, treatment with semaglutide 1 mg resulted
`in reductions in glucose in terms of absolute change from baseline
`(mmol/L / mg/dL) and relative reduction compared to placebo (%) for
`fasting glucose (1.6 mmol/L / 29 mg/dL; 22%), 2 hour postprandial glucose
`(4.1mmol/L / 74 mg/dL; 37%), mean 24 hour glucose concentration
`(1.7 mmol/L / 30 mg/dL; 22% reduction) and postprandial glucose
`excursions over 3 meals (0.6–1.1mmol/L / 11–20 mg/dL) compared to
`placebo (see Figure 2).
`Semaglutide lowered fasting glucose after the first dose.
`
`Plasma glucose (mg/dL)
`
`Plasma glucose (mmol/L)
`
`Time since start of breakfast meal (hours)
`Semaglutide 1 mg – end of treatment (n=36)
`Semaglutide – baseline (n=37)
`Placebo – baseline (n=38)
`Placebo – end of treatment (n=37)
`
`Figure 2: Mean 24 hour plasma glucose profiles (standardised meals) in
`patients with type 2 diabetes before (baseline) and after 12 weeks of
`treatment with semaglutide or placebo
`
`blood glucose, adjudicated events of diabetic retinopathy complications
`occurred in more patients treated with Ozempic (3.0%) compared to
`placebo (1.8%). The treatment difference appeared early and persisted
`throughout the trial. The absolute risk increase for diabetic retinopathy
`complications was larger among patients with a history of diabetic
`retinopathy treated with insulin at baseline. In the patients that did not
`have a documented history of diabetic retinopathy the number of events
`were similar for Ozempic and placebo.
`In other clinical trials up to 1 year involving 4,807 patients with type 2
`diabetes patients, adverse events related to diabetic retinopathy were
`reported in similar proportions of subjects treated with Ozempic (1.7%)
`and comparators (2.0%).
`
`Discontinuation Due to an Adverse Event
`The incidence of discontinuation of treatment due to adverse events was
`6.1% and 8.7% for patients treated with semaglutide 0.5 mg and 1 mg
`respectively, versus 1.5% for placebo. The most frequent adverse events
`leading to discontinuation were gastrointestinal.
`
`Injection Site Reactions
`Injection site reactions (e.g. injection site rash, erythema) have been
`reported by 0.6% and 0.5% of patients receiving semaglutide 0.5 mg and
`1 mg respectively. A similar rate of injection site reactions was experienced
`by patients receiving placebo. These reactions have usually been mild.
`
`Immunogenicity
`Consistent with the potentially immunogenic properties of medicinal
`products containing proteins or peptides, patients may develop antibodies
`following treatment with semaglutide. The proportion of patients tested
`positive for anti-semaglutide antibodies at any time point post-baseline was
`low (1–2%) and no patients had anti-semaglutide neutralising antibodies
`or anti-semaglutide antibodies with endogenous GLP-1 neutralising effect
`at end-of-trial.
`
`Heart Rate Increase
`Increased heart rate has been observed with GLP-1 receptor agonists.
`In the phase 3a trials, mean increases of 1 to 6 beats per minute (bpm)
`from a baseline of 72 to 76 bpm were observed in subjects treated with
`semaglutide. In a long-term trial in subjects with cardiovascular risk
`factors, 16% of semaglutide-treated subjects had an increase in heart rate
`of >10 bpm compared to 11% of subjects on placebo after 2 years of
`treatment.
`
`Increases in Amylase and Lipase
`In placebo-controlled trials, patients exposed to semaglutide had a mean
`increase from baseline in amylase of 13% and lipase of 22%. These
`changes were not observed in placebo-treated patients. In the absence of
`other signs and symptoms of acute pancreatitis, elevations in pancreatic
`enzymes alone are not predictive of acute pancreatitis.
`
`Cholelithiasis
`In placebo-controlled trials, cholelithiasis was reported in 1.5% and
`0.4% of patients-treated with semaglutide 0.5 mg and 1 mg respectively.
`Cholelithiasis was not reported in placebo-treated patients.
`
`Fatigue, Dysgeusia and Dizziness
`Other adverse reactions with a frequency of > 0.4% associated with
`semaglutide include fatigue, dysgeusia and dizziness.
`
`4.9 Overdose
`Overdoses of up to 4 mg in a single dose, and up to 4 mg in a week have
`been reported in clinical trials. The most commonly reported adverse event
`was nausea. All patients recovered without complications.
`There is no specific antidote for overdose with Ozempic. 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 (see
`section 5.2 Pharmacokinetic Properties).
`For information on the management of overdose, contact the Poisons
`Information Centre on 13 11 26 (Australia).
`
`5. PHARMACOLOGICAL PROPERTIES
`
`5.1 Pharmacodynamic Properties
`Pharmacotherapeutic group: Drugs used in diabetes, Glucagon-like
`peptide-1 (GLP-1) analogues, ATC code: A10BJ06.
`
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`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00004
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`

`

`PRODUCT INFORMATION | OZEMPIC® (semaglutide) solution for injection
`
`Page 5 of 12
`
`Clinical trials
`Both improvement of glycaemic control and reduction of cardiovascular
`morbidity and mortality are an integral part of the treatment of type 2
`diabetes.
`The efficacy and safety of Ozempic 0.5 mg and 1 mg once weekly were
`evaluated in six randomised controlled phase 3a trials. Of these, five trials
`(SUSTAIN 1–5) had glycaemic efficacy assessment as the primary objective,
`while one trial (SUSTAIN 6) had cardiovascular outcome as the primary
`objective. Additionally, two phase 3 trials were conducted with Ozempic
`in Japanese patients with safety as the primary objective and efficacy the
`secondary objective.
`The trials included in total 8,124 randomised patients with type 2 diabetes
`(4,792 treated with semaglutide).
`An additional trial including 1,201 patients was conducted to compare
`the efficacy and safety of Ozempic 0.5 mg and 1 mg once weekly versus
`dulaglutide 0.75 mg and 1.5 mg once weekly, respectively.
`Treatment with Ozempic demonstrated statistically significant and clinically
`meaningful reductions in HbA1c (see Figure 4) and body weight maintained
`for up to 2 years compared to placebo and active control treatment
`(sitagliptin, insulin glargine, exenatide ER and dulaglutide).
`The efficacy of Ozempic was not impacted by age, gender, race, ethnicity,
`BMI at baseline, body weight (kg) at baseline, diabetes duration and level
`of renal function impairment.
`
`SUSTAIN 1 – Monotherapy
`In a 30-week double-blind trial, 388 patients inadequately controlled with
`diet and exercise were randomised to Ozempic 0.5 mg or Ozempic 1 mg
`once weekly or placebo.
`Patients had a mean age of 54 years and a mean duration of type 2
`diabetes of 4.2 years. There were 64% White patients, 8% were Black or
`African Americans and 21% were Asian. For ethnicity, 30% of patients
`(n=115) were Hispanic or Latino. The mean BMI was 33 kg/m2.
`
`Table 3: Results at 30 weeks, monotherapy trial (SUSTAIN 1)
`
`Beta-cell function and insulin secretion
`Semaglutide improves beta-cell function. Semaglutide, compared to
`placebo, improved first- and second-phase insulin response, with a 3- and
`2-fold increase, respectively, following an intravenous bolus of glucose,
`and increased maximal beta-cell secretory capacity after an arginine
`stimulation test in patients with type 2 diabetes. In addition, semaglutide
`treatment increased fasting insulin concentrations compared to placebo.
`
`Glucagon Secretion
`Semaglutide lowers the fasting and postprandial glucagon concentrations.
`In patients with type 2 diabetes, semaglutide resulted in the following
`relative reductions in glucagon compared to placebo: fasting glucagon
`(8–21%), postprandial glucagon response (14–15%) and mean 24 hour
`glucagon concentration (12%).
`
`Glucose Dependent Insulin and Glucagon Secretion
`Semaglutide lowered high blood glucose concentrations by stimulating
`insulin secretion and lowering glucagon secretion in a glucose dependent
`manner. With semaglutide, the insulin secretion rate in patients with
`type 2 diabetes was comparable to that of healthy subjects (see Figure 3).
`
`Plasma glucose (mg/dL)
`
`Insulin secretion rate (pmol/kg/min)
`
`5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0 10.5 11.0 11.5 12.0
`Plasma glucose (mmol/L)
`
`Insulin secretion rate (pmol/kg/min)
`
`Semaglutide – baseline (n=37)
`Placebo – baseline (n=38)
`Healthy subjects (n=12)
`
`Semaglutide 1 mg – end of treatment (n=36)
`Placebo – end of treatment (n=37)
`
`Figure 3: Mean insulin secretion rate versus glucose concentration in
`patients with type 2 diabetes during graded glucose infusion before
`(baseline) and after 12 weeks of treatment with semaglutide or placebo
`and in untreated healthy subjects
`
`During induced hypoglycaemia, semaglutide compared to placebo did not
`alter the counter regulatory responses of increased glucagon, and did not
`impair the decrease of C-peptide in patients with type 2 diabetes.
`
`Gastric Emptying
`Semaglutide caused a minor delay of early postprandial gastric emptying,
`thereby reducing the rate at which glucose appears in the circulation
`postprandially.
`
`Body Weight and Body Composition
`A greater reduction in body weight was observed with semaglutide
`compared to studied comparators (placebo, sitagliptin, exenatide ER
`and insulin glargine) (section 5.1 Pharmacodynamic Properties). The body
`weight loss with semaglutide was predominantly from fat tissue with loss
`of fat mass being 3-fold larger than loss of lean mass.
`
`Appetite, Energy Intake and Food Choice
`Semaglutide compared to placebo lowered the energy intake of
`3 consecutive ad libitum meals by 18–35%. This was supported by a
`semaglutide-induced suppression of appetite in the fasting state as well as
`postprandially, improved control of eating, less food cravings and a relative
`lower preference for high fat food.
`
`Fasting and Postprandial Lipids
`Semaglutide compared to placebo lowered fasting triglyceride and VLDL
`cholesterol concentrations by 12% and 21%, respectively. The postprandial
`triglyceride and VLDL cholesterol response to a high fat meal was reduced
`by > 40%.
`
`Cardiac Electrophysiology (QTc)
`The effect of semaglutide on cardiac repolarization was tested in a
`thorough QTc trial. Semaglutide did not prolong QTc intervals at supra-
`therapeutic dose levels (up to 1.5 mg at steady state).
`
`Intent-to-Treat (ITT) Population (N)
`HbA1c (%)
`Baseline (mean)
`Change from baseline at week 30
`Difference from placebo
`[95% CI]
`Patients (%) achieving HbA1c < 7%
`Patients (%) achieving HbA1c ≤ 6.5%
`FPG (mmol/L)
`Baseline (mean)
`Change from baseline at week 30
`Difference from placebo
`[95% CI]
`Body weight (kg)
`89.8
`Baseline (mean)
`-3.7
`Change from baseline at week 30
`-2.7
`Difference from placebo
`[-3.9; -1.6]a
`[95% CI]
`Patients (%) achieving weight loss ≥ 5% 37b
`Patients (%) achieving weight loss ≥ 10% 8c
`a p < 0.0001 (2-sided) for superiority, adjusted for multiplicity based on hierarchical
`testing of HbA1c and body weight
`b p < 0.0001 for treatment difference, unadjusted for multiplicity
`c p < 0.05 for treatment difference, unadjusted for multiplicity
`
`Placebo
`
`129
`
`8.0
`0
`–
`
`25
`13
`
`9.7
`-0.6
`–
`
`89.1
`-1.0
`–
`
`7
`2
`
`Ozempic
`0.5 mg
`128
`
`Ozempic
`1 mg
`130
`
`8.1
`-1.5
`-1

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