Victoza 6mg / 1ml Injection

Glycaemic control:

Victoza u00ae is indicated as an adjunct to diet and exercise to achieve glycaemic control in patients with type 2 diabetes mellitus. Victoza u00ae is indicated for once-daily administration as:

• monotherapy
• combination therapy with one or more oral antidiabetic medicines (metformin, sulphonylureas, sodium-glucose cotransporter 2 inhibitor (SGLT2i) or a thiazolidinedione) when previous therapy does not provide adequate glycaemic control.
• combination therapy with insulin in patients not achieving adequate glycaemic control with Victoza u00ae and metformin.

Prevention of cardiovascular events:

Victoza u00ae is indicated to prevent Major Adverse Cardiovascular Events (MACE: cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) in adults with type 2 diabetes mellitus at high cardiovascular risk, as an adjunct to standard of care therapy (see section 5 Pharmacological Properties).

Monotherapy

To reduce gastro-intestinal adverse effects for all patients, Victoza u00ae should be initiated with a dose of 0,6 mg for at least one week, after which the dose may be increased to 1,2 mg. Based on clinical response and after at least one week the dose can be increased to 1,8 mg to achieve maximum efficacy. Daily doses higher than 1,8 mg are not recommended.

Combination therapy

Victoza u00ae can be used in combination with other glucose lowering agents and no dose adjustments are required for metformin, thiazolidinedione and SGLT2i therapy.

When Victoza u00ae is added to a sulphonylurea therapy or insulin, a reduction in the dose of sulphonylurea or insulin should be considered to reduce the risk of hypoglycaemia (see section 4.4 Special warnings and precautions for use).

Self-monitoring of blood glucose is not needed in order to adjust the dose of Victoza u00ae. However, when initiating treatment with Victoza u00ae in combination with a sulphonylurea or insulin, blood glucose self-monitoring may become necessary to adjust the dose of the sulphonylurea or insulin.

Incompatibilities

Substances added to Victoza u00ae may cause degradation of liraglutide. Victoza u00ae must not be mixed with other medicinal products, e.g. infusion fluids.

Special populations

Elderly and Gender

No dosage adjustment is required based on age and gender.

Obesity

Population pharmacokinetic analysis suggests that body mass index (BMI) has no significant effect on the pharmacokinetics of liraglutide.

Hepatic impairment

No dose adjustment is required for patients with hepatic impairment (see 4.4 Special warnings and precautions for use).

Renal impairment

No dose adjustment is required for patients with mild, moderate or severe renal impairment. There is no therapeutic experience in patients with end-stage renal disease and Victoza u00ae is therefore not recommended for use in these patients (see 4.4 Special warnings and precautions for use).

Paediatric population

Victoza u00ae has not been studied in paediatric patients below 18 years of age (see 4.4 Special warnings and precautions for use).

Method of administration

Victoza u00ae must not be administered intravenously or intramuscularly. Victoza u00ae is administered once daily at any time, independent of meals, and can be injected subcutaneously in the abdomen, in the thigh or in the upper arm. Injection sites should always be rotated within the same region in order to reduce the risk of cutaneous amyloidosis (see section 4.8 Undesirable effects). The injection site and timing can be changed without dose adjustment.

• Hypersensitivity to liraglutide or any of its excipients
• A history of previous pancreatitis
• Type 1 diabetes mellitus
• Pregnancy and lactation (see section 4.6 Pregnancy)

Victoza u00ae should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis. Victoza u00ae should not be administered intravenously or intramuscularly. Victoza u00ae is not a substitute for insulin. Safety and efficacy of Victoza u00ae in patients below 18 years of age has not been established.

Patients above 70 years may experience more gastrointestinal effects when treated with Victoza u00ae. Patients with mild and moderate renal impairment (creatinine clearance 60 u2212 90 ml/min and 30 u2212 59 ml/min, respectively) may experience more gastrointestinal effects when treated with Victoza u00ae.

There is no therapeutic experience in patients with end-stage renal disease and Victoza u00ae is therefore not recommended for use in these patients.

There is no therapeutic experience in patients with congestive heart failure New York Heart Association (NYHA) class IV and Victoza u00ae is therefore not recommended for use in these patients.

There is limited experience in patients with inflammatory bowel disease and diabetic gastroparesis and Victoza u00ae is therefore not recommended for use in these patients. The use of Victoza u00ae is associated with gastrointestinal adverse reactions, including nausea, vomiting and diarrhoea.

Hypoglycaemia

Patients receiving Victoza u00ae in combination with a sulphonylurea or insulin may have an increased risk of hypoglycaemia. The risk of hypoglycaemia can be lowered by a reduction in the dose of sulphonylurea or insulin.

Immunogenicity

Consistent with the potentially immunogenic properties of protein and peptide pharmaceuticals, patients may develop anti-liraglutide antibodies following treatment with Victoza u00ae. On average, 8,6 % of patients developed antibodies. Antibody formation has not been associated with reduced efficacy of Victoza u00ae.

Injection site reactions

Injection site reaction has been reported in approximately 2 % of subjects receiving Victoza u00ae in long-term (26 weeks or longer) controlled trials. These reactions have usually been mild and did not lead to discontinuation of Victoza u00ae.

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, liraglutide should be discontinued. Once acute pancreatitis is confirmed, liraglutide or any other GLP-1 receptor agonist should never again be restarted. Caution should be exercised in patients with a history of pancreatitis.

Thyroid disease

Thyroid adverse events, such as goitre, have been reported in clinical trials, in particular in patients with pre-existing thyroid disease. Victoza u00ae should therefore be used with caution in these patients.

Allergic reactions

Allergic reactions including urticaria, rash and pruritus have been reported from marketed use of Victoza u00ae. Cases of anaphylactic reactions with additional symptoms such as hypotension, palpitations, dyspnoea and oedema have been reported with marketed use of Victoza u00ae (see 4.3 Contraindications).

Dehydration

Signs and symptoms of dehydration, including renal impairment and acute renal failure have been reported in patients treated with Victoza u00ae. Patients treated with Victoza u00ae should be advised of potential risk of dehydration in relation to gastrointestinal side effects and take precaution to avoid fluid depletion.

In vitro assessment of interaction studies

Victoza u00ae has shown a low potential involvement in pharmacokinetic interactions with other active substances related to cytochrome P450 (CYP) and plasma protein binding.

In vivo assessment of interaction studies

Interaction has been investigated using paracetamol, digoxin, lisinopril, griseofulvin and atorvastatin representing various degrees of solubility and permeability properties. In addition, the effect of liraglutide on the absorption of ethinyloestradiol and levonorgestrel administered in an oral combination contraceptive medicine has been investigated (see table 1 below).

The minor delay of gastric emptying caused by liraglutide did not affect the absorption of orally administered medicines to any clinically relevant degree and therefore no dose adjustment is required. Few patients treated with Victoza u00ae reported at least one episode of severe diarrhoea. Diarrhoea may affect the absorption of concomitant oral medicines.

Warfarin and other coumarin derivatives

No interaction study has been performed. A clinically relevant interaction with active substances with poor solubility or with narrow therapeutic index such as warfarin cannot be excluded. Upon initiation of Victoza u00ae treatment in patients on warfarin or other coumarin derivatives, more frequent monitoring of INR (International Normalised Ratio) is recommended.

Insulin

No pharmacokinetic or pharmacodynamic interactions were observed between Victoza u00ae and insulin detemir when administering a single dose of insulin detemir 0,5 U/kg with Victoza u00ae 1,8 mg at steady state in patients with type 2 diabetes.

Women of childbearing potential / Contraception in males and females

Apart from a slight decrease in the number of live implants, animal studies did not indicate harmful effects with respect to fertility.

Pregnancy

Victoza u00ae is contraindicated during pregnancy and lactation. There is no adequate data for use of Victoza u00ae in pregnant women. Victoza u00ae crossed the placental barrier in rabbits. Studies in animals have shown reproductive toxicity and Victoza u00ae should therefore not be used during pregnancy. The use of insulin is recommended. If a patient wishes to become pregnant, or pregnancy occurs, treatment with Victoza u00ae should be discontinued.

Breastfeeding

It is not known whether Victoza u00ae is excreted in human milk. In lactating rats, up to 3 % of the maternal dose was present in breast milk. Women on treatment with Victoza u00ae should not breastfeed.

No studies on the effects on the ability to drive and use machines have been performed. Victoza u00ae may affect the ability to drive or use machines. Patients should be advised to ensure that they are aware of the effect of Victoza u00ae on their abilities beforehand and to take precautions to avoid hypoglycaemia while driving and using machines, in particular when Victoza u00ae is used in combination with a sulphonylurea or insulin (see 4.8 Undesirable effects).

The most frequently reported adverse events during clinical trials were gastrointestinal adverse events: nausea and diarrhoea (reported by > 10 % of patients) and vomiting, dyspepsia, upper abdominal pain, constipation, gastritis, flatulence, abdominal distension, gastro-oesophageal reflux disease and eructation (reported by u2265 1 % and u2264 10 % of patients). Headache and upper respiratory tract infections were common. Furthermore, hypoglycaemia was common and very common especially when Victoza u00ae is used in combination with sulphonylurea.

Severe hypoglycaemia may occur uncommonly and has only been observed when combined with a sulphonylurea.

Table 2: Tabulated summary of side effects occurring during clinical trials and spontaneous (post-marketing) reports

Body system/ adverse reaction terms Frequency of occurrence Reactions Very Common (u2265 1/10) Common (u2265 1/100, < 1/10) Uncommon (u2265 1/1 000, < 1/100) Rare (u2265 1/10 000, < 1/1 000) Very Rare (u22641/10 000) Not known

Hypoglycaemia

Most episodes of confirmed hypoglycaemia in clinical studies were minor. No episodes of severe hypoglycaemia were observed in the study with Victoza u00ae used as monotherapy. Severe hypoglycaemia may occur uncommonly and has primarily been observed when Victoza u00ae is combined with a sulphonylurea (0, 02 events/subject year). Very few episodes (0, 001 events/subject year) were observed with administration of Victoza u00ae in combination with a non-sulphonylurea. In the LEADER u00ae trial, severe hypoglycaemic episodes were reported at a lower rate with liraglutide vs placebo (1,0 vs 1,5 events per 100 patient years of exposure; estimated rate ratio 0, 69 [0 ,51 to 0, 93]). For patients treated with premix insulin at baseline and at least for the following 26 weeks, the rate of severe hypoglycaemia for both liraglutide and placebo was 2,2 events per 100 patient years of exposure.

Cholelithiasis and cholecystitis

Few cases of cholelithiasis (0,4 %) and cholecystitis (0,1 %) have been reported during long-term, controlled phase 3a clinical trials with Victoza u00ae. In the LEADER u00ae trial, the frequency of cholelithiasis and cholecystitis was 1,5 % and 1,1 % for liraglutide and 1,1 % and 0,7 % for placebo, respectively.

Pancreatitis

Few cases of acute pancreatitis (< 0,2 %) of acute pancreatitis have been reported during long-term, controlled phase 3 during long-term clinical trials with Victoza u00ae. Pancreatitis was also reported from marketed use. In the LEADER u00ae trial, the frequency of acute pancreatitis confirmed by adjudication was 0,4 % for liraglutide and 0,5 % for placebo, respectively.

With overdose, the patients reported severe nausea, vomiting and diarrhoea, but recovered without complications. Severe hypoglycaemia has been observed. In the event of overdosage, appropriate supportive treatment should be initiated according to the patientu2019s clinical signs and symptoms. The patient should be observed for clinical signs of dehydration and blood glucose should be monitored.