1. Name Of The Medicinal Product
Victoza
2. Qualitative And Quantitative Composition
One ml of solution contains 6 mg of liraglutide*. One pre-filled pen contains 18 mg liraglutide in 3 ml.
* human glucagon-like peptide-1 (GLP-1) analogue produced by recombinant DNA technology in Saccharomyces cerevisiae.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Solution for injection in pre-filled pen (injection).
Clear, colourless, isotonic solution; pH=8.15.
4. Clinical Particulars
4.1 Therapeutic Indications
Victoza is indicated for treatment of adults with type 2 diabetes mellitus to achieve glycaemic control:
In combination with:
– Metformin or a sulphonylurea, in patients with insufficient glycaemic control despite maximal tolerated dose of monotherapy with metformin or sulphonylurea.
In combination with:
– Metformin and a sulphonylurea or metformin and a thiazolidinedione in patients with insufficient glycaemic control despite dual therapy.
4.2 Posology And Method Of Administration
Posology
To improve gastro-intestinal tolerability, the starting dose is 0.6 mg liraglutide daily. After at least one week, the dose should be increased to 1.2 mg. Some patients are expected to benefit from an increase in dose from 1.2 mg to 1.8 mg and based on clinical response, after at least one week the dose can be increased to 1.8 mg to further improve glycaemic control. Daily doses higher than 1.8 mg are not recommended.
Victoza can be added to existing metformin or to a combination of metformin and thiazolidinedione therapy. The current dose of metformin and thiazolidinedione can be continued unchanged.
Victoza can be added to existing sulphonylurea or to a combination of metformin and sulphonylurea therapy. When Victoza is added to sulphonylurea therapy, a reduction in the dose of sulphonylurea should be considered to reduce the risk of hypoglycaemia (see section 4.4).
Self-monitoring of blood glucose is not needed in order to adjust the dose of Victoza. However, when initiating treatment with Victoza in combination with a sulphonylurea, blood glucose self-monitoring may become necessary to adjust the dose of the sulphonylurea.
Special populations
Elderly (>65 years old): No dose adjustment is required based on age. Therapeutic experience in patients
Renal impairment: No dose adjustment is required for patients with mild renal impairment (creatinine clearance 60-90 ml/min). There is very limited therapeutic experience in patients with moderate renal impairment (creatinine clearance of 30-59 ml/min) and no therapeutic experience in patients with severe renal impairment (creatinine clearance below 30 ml/min). Victoza can currently not be recommended for use in patients with moderate and severe renal impairment including patients with end-stage renal disease (see section 5.2).
Hepatic impairment: The therapeutic experience in patients with all degrees of hepatic impairment is currently too limited to recommend the use in patients with mild, moderate or severe hepatic impairment (see section 5.2).
Paediatric population: Victoza is not recommended for use in children below 18 years of age due to lack of data on its safety and efficacy.
Method of administration
Victoza should not be administered intravenously or intramuscularly.
Victoza 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. The injection site and timing can be changed without dose adjustment. However, it is preferable that Victoza is injected around the same time of the day, when the most convenient time of the day has been chosen. For further instructions on administration, see section 6.6.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients.
4.4 Special Warnings And Precautions For Use
Victoza should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.
Victoza is not a substitute for insulin.
The addition of liraglutide in patients already treated with insulin has not been evaluated and is therefore not recommended.
There is limited experience in patients with congestive heart failure New York Heart Association (NYHA) class I-II. There is no experience in patients with congestive heart failure NYHA class III-IV.
There is limited experience in patients with inflammatory bowel disease and diabetic gastroparesis and Victoza is therefore not recommended in these patients. The use of Victoza is associated with transient gastrointestinal adverse reactions, including nausea, vomiting and diarrhoea.
Use of GLP-1 analogues has been associated with the risk of pancreatitis. There have been few reported events of acute pancreatitis. Patients should be informed of the characteristic symptom of acute pancreatitis: persistent, severe abdominal pain. If pancreatitis is suspected, Victoza and other potentially suspect medicinal products should be discontinued.
Thyroid adverse events, including increased blood calcitonin, goitre and thyroid neoplasm have been reported in clinical trials in particular in patients with pre-existing thyroid disease (see section 4.8).
Patients receiving Victoza in combination with a sulphonylurea may have an increased risk of hypoglycaemia (see section 4.8). The risk of hypoglycaemia can be lowered by a reduction in the dose of sulphonylurea.
Signs and symptoms of dehydration, including altered renal function have been reported in patients treated with Victoza. Patients treated with Victoza should be advised of the potential risk of dehydration in relation to gastrointestinal side effects and take precautions to avoid fluid depletion.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
In vitro, liraglutide has shown very low potential to be involved in pharmacokinetic interactions with other active substances related to cytochrome P450 and plasma protein binding.
The small delay of gastric emptying with liraglutide may influence absorption of concomitantly administered oral medicinal products. Interaction studies did not show any clinically relevant delay of absorption. Few patients treated with liraglutide reported at least one episode of severe diarrhoea. Diarrhoea may affect the absorption of concomitant oral medicinal products.
Paracetamol
Liraglutide did not change the overall exposure of paracetamol following a single dose of 1000 mg. Paracetamol Cmax was decreased by 31% and median tmax was delayed up to 15 min. No dose adjustment for concomitant use of paracetamol is required.
Atorvastatin
Liraglutide did not change the overall exposure of atorvastatin to a clinical relevant degree following single dose administration of atorvastatin 40 mg. Therefore, no dose adjustment of atorvastatin is required when given with liraglutide. Atorvastatin Cmax was decreased by 38% and median tmax was delayed from 1 h to 3 h with liraglutide.
Griseofulvin
Liraglutide did not change the overall exposure of griseofulvin following administration of a single dose of griseofulvin 500 mg. Griseofulvin Cmax increased by 37% while median tmax did not change. Dose adjustments of griseofulvin and other compounds with low solubility and high permeability are not required.
Digoxin
A Single dose administration of digoxin 1 mg with liraglutide resultated in a reduction of digoxin AUC by 16%; Cmax decreased by 31%. Digoxin median tmax was delayed from 1 h to 1.5 h. No adjustment of digoxin dose is required based on these results.
Lisinopril
A single dose administration of lisinopril 20 mg with liraglutide resultated in a reduction of lisinopril AUC by 15% ; Cmax decreased by 27%. Lisinopril median tmax was delayed from 6 h to 8 h with liraglutide. No dose adjustment of lisinopril is required based on these results.
Oral contraceptives
Liraglutide lowered ethinyloestradiol and levonorgestrel Cmax by 12 and 13%, respectively, following administration of a single dose of an oral contraceptive product. Tmax was delayed by 1.5 h with liraglutide for both compounds. There was no clinically relevant effect on the overall exposure of either ethinyloestradiol or levonorgestrel. The contraceptive effect is therefore anticipated to be unaffected when co-administered with liraglutide.
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 liraglutide 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 liraglutide and insulin detemir when administering a single dose of insulin detemir 0.5 U/kg with liraglutide 1.8 mg at steady state in patients with type 2 diabetes.
4.6 Pregnancy And Lactation
Pregnancy
There are no adequate data from the use of Victoza in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.
Victoza should not be used during pregnancy, and the use of insulin is recommended instead. If a patient wishes to become pregnant, or pregnancy occurs, treatment with Victoza should be discontinued.
Lactation
It is not known whether liraglutide is excreted in human milk. Animal studies have shown that the transfer of liraglutide and metabolites of close structural relationship into milk is low. Non-clinical studies have shown a treatment-related reduction of neonatal growth in suckling rat pups (see section 5.3). Because of lack of experience, Victoza should not be used during breast-feeding.
Fertility
Apart from a slight decrease in the number of live implants, animal studies did not indicate harmful effects with respect to fertility.
4.7 Effects On Ability To Drive And Use Machines
No studies on the effects on the ability to drive and use machines have been performed. Patients should be advised to take precautions to avoid hypoglycaemia while driving and using machines, in particular when Victoza is used in combination with a sulphonylurea.
4.8 Undesirable Effects
In five large long-term clinical trials over 2500 patients have received treatment with Victoza alone or in combination with metformin, a sulphonylurea (with or without metformin) or metformin plus rosiglitazone.
Frequencies are defined as: Very common (
The most frequently reported adverse reactions during clinical trials were gastrointestinal disorders: nausea and diarrhoea were very common, whereas vomiting, constipation, abdominal pain, and dyspepsia were common. At the beginning of Victoza therapy, these gastrointestinal adverse reactions may occur more frequently. These reactions usually diminish within a few days or weeks on continued treatment. Headache and nasopharyngitis were also common. Furthermore, hypoglycaemia was common, and very common when Victoza is used in combination with a sulphonylurea. Major hypoglycaemia has primarily been observed when combined with a sulphonylurea.
Table 1 lists related adverse reactions identified from Phase III combination-studies with Victoza. The table presents adverse reactions that occurred with a frequency >5% if the frequency was higher among Victoza-treated patients than patients treated with comparator. The table also includes adverse reactions with a frequency
Table 1 Adverse reactions identified from long-term controlled phase III studies
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In a clinical trial with Victoza as monotherapy rates of hypoglycaemia reported with Victoza were lower than rates reported for patients treated with active comparator (glimepiride). The most frequently reported adverse events were gastrointestinal and infections and infestations.
Hypoglycaemia
Most episodes of confirmed hypoglycaemia in clinical studies were minor. No episodes of major hypoglycaemia were observed in the study with Victoza used as monotherapy. Major hypoglycaemia may occur uncommonly and has primarily been observed when Victoza is combined with a sulphonylurea (0.02 events/subject year). Very few episodes (0.001 events/subject year) were observed with administration of Victoza in combination with oral antidiabetics other than sulphonylureas.
Gastrointestinal adverse reactions
When combining Victoza with metformin, 20.7% of patients reported at least one episode of nausea, and 12.6% of patients reported at least one episode of diarrhoea. When combining Victoza with a sulphonylurea, 9.1% of patients reported at least one episode of nausea and 7.9% of patients reported at least one episode of diarrhoea. Most episodes were mild to moderate and occurred in a dose-dependent fashion. With continued therapy, the frequency and severity decreased in most patients who initially experienced nausea.
Patients >70 years may experience more gastrointestinal effects when treated with liraglutide.
Patients with mild renal impairment (creatinine clearance 60-90 ml/min) may experience more gastrointestinal effects when treated with liraglutide.
Withdrawal
The incidence of withdrawal due to adverse reactions was 7.8% for Victoza-treated patients and 3.4% for comparator-treated patients in the long-term controlled trials (26 weeks or longer). The most frequent adverse reactions leading to withdrawal for Victoza-treated patients were nausea (2.8% of patients) and vomiting (1.5%).
Immunogenicity
Consistent with the potentially immunogenic properties of medicinal products containing proteins or peptides, patients may develop anti-liraglutide antibodies following treatment with Victoza. On average, 8.6% of patients developed antibodies. Antibody formation has not been associated with reduced efficacy of Victoza.
Few cases (0.05%) of angioedema have been reported during all long-term clinical trials with Victoza.
Injection site reactions
Injection site reaction has been reported in approximately 2% of subjects receiving Victoza in long-term (26 weeks or longer) controlled trials. These reactions have usually been mild and did not lead to discontinuation of Victoza.
Pancreatitis
Few cases (<0.2%) of acute pancreatitis have been reported during long-term clinical trials with Victoza.
Thyroid events
The overall rates of thyroid adverse events in all intermediate and long-term trials are 33.5, 30.0 and 21.7 events per 1000 subject years of exposure for total liraglutide, placebo and total comparators; 5.4, 2.1 and 1.2 events, respectively concern serious thyroid adverse events.
Thyroid neoplasms, increased blood calcitonin and goiters were the most frequently thyroid adverse events. The rates per 1,000 subject years of exposure were 6.8, 10.9 and 5.4 of liraglutide treated patients in comparison with 6.4, 10.7 and 2.1 of placebo treated and 2.4, 6.0 and 1.8 of total comparator treated patients respectively.
4.9 Overdose
In a clinical study of Victoza, one patient with type 2 diabetes experienced a single overdose of 17.4 mg subcutaneous (10 times the maximal recommended maintenance dose of 1.8 mg). Effects of the overdose included severe nausea and vomiting, but not hypoglycaemia. The patient recovered without complications.
In the event of overdose, appropriate supportive treatment should be initiated according to the patient's clinical signs and symptoms.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Other blood glucose lowering drugs, excl. insulins. ATC code: A10BX07
Mechanism of action
Liraglutide is a GLP-1 analogue with 97% sequence homology to human GLP-1 that binds to and activates the GLP-1 receptor. The GLP-1 receptor is the target for native GLP-1, an endogenous incretin hormone that potentiates glucose-dependent insulin secretion from the pancreatic beta cells. Unlike native GLP-1, liraglutide has a pharmacokinetic and pharmacodynamic profile in humans suitable for once daily administration. Following subcutaneous administration, the protracted action profile is based on three mechanisms: self-association, which results in slow absorption; binding to albumin; and higher enzymatic stability towards the dipeptidyl peptidase IV (DPP-IV) and neutral endopeptidase (NEP) enzymes, resulting in a long plasma half-life.
Liraglutide action is mediated via a specific interaction with GLP-1 receptors, leading to an increase in cyclic adenosine monophosphate (cAMP). Liraglutide stimulates insulin secretion in a glucose-dependent manner. Simultaneously, liraglutide lowers inappropriately high glucagon secretion, also in a glucose-dependent manner. Thus, when blood glucose is high, insulin secretion is stimulated and glucagon secretion is inhibited. Conversely, during hypoglycaemia liraglutide diminishes insulin secretion and does not impair glucagon secretion. The mechanism of blood glucose lowering also involves a minor delay in gastric emptying. Liraglutide reduces body weight and body fat mass through mechanisms involving reduced hunger and lowered energy intake.
Pharmacodynamic effects
Liraglutide has 24-hour duration of action and improves glycaemic control by lowering fasting and postprandial blood glucose in patients with type 2 diabetes mellitus.
Clinical efficacy
Five double-blind, randomised, controlled clinical trials were conducted to evaluate the effects of Victoza on glycaemic control. Treatment with Victoza produced clinically and statistically significant improvements in glycosylated haemoglobin A1c (HbA1c), fasting plasma glucose and post-prandial glucose compared with placebo.
These studies included 3,978 exposed patients with type 2 diabetes (2,501 subjects treated with Victoza), 53.7% men and 46.3% women, 797 subjects (508 treated with Victoza) were
There was an additional open-label randomised controlled study comparing liraglutide with exenatide.
In a 52 week clinical trial, the addition of insulin detemir to Victoza 1.8 mg and metformin in patients not achieving glycemic targets on Victoza and metformin alone, resulted in a HbA1c decrease from baseline of 0.54%, compared to 0.20% in the Victoza 1.8 mg and metformin control group. Weight loss was sustained. There was a small increase in the rate of minor hypoglycaemic episodes (0.23 versus 0.03 events per subject years). The addition of liraglutide in patients already treated with insulin has not been evaluated (see section 4.4).
Glycaemic control
Victoza in combination therapy, for 26 weeks, with metformin, glimepiride or metformin and rosiglitazone resulted in statistically significant (p<0.0001) and sustained reductions in HbA1c compared with patients receiving placebo (Tables 2 and 3).
Table 2 Results of two 26 week trials. Victoza in combination with metformin and Victoza in combination with glimepiride.
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1 Rosiglitazone 4 mg/day; 2 glimepiride 4 mg/day; 3 metformin 2000 mg/day
Table 3 Results of two 26 week trials. Victoza in combination with metformin + rosiglitazone and Victoza in combination with glimepiride + metformin.
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1 The dosing of insulin glargine was open-labelled and was applied according to the following titration guideline. Titration of the insulin glargine dose was managed by the patient after instruction by the investigator.
Guideline for titration of insulin glargine
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