Victoza - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Undesirable Effects Shelf life and Storage Composition and pharmaceutical form

Active ingredients: Liraglutide

Victoza 6 mg / ml solution for injection in pre-filled pen

Why is Victoza used? What is it for?

Victoza contains the active substance liraglutide which helps the body to lower its blood sugar level only when it is too high. It also slows the passage of food into the stomach.

Victoza is used with other diabetes medicines when they are not enough to control your blood sugar level. They are included:

  • Oral antidiabetic medicines (such as metformin, pioglitazone, sulfonylurea) and / or basal insulin, a long-acting type of insulin.

Contraindications When Victoza should not be used

Do not use Victoza

  • if you are allergic to liraglutide or any of the other ingredients of this medicine (listed in section 6).

Precautions for use What you need to know before taking Victoza

Talk to your doctor, pharmacist or nurse:

  • before using Victoza
  • if you have or have ever had pancreatic disease.

This medicine should not be used if you have type 1 diabetes (your body does not produce insulin) or diabetic ketoacidosis (a complication of diabetes which leads to high blood sugar and increased difficulty in breathing). It is not an insulin and therefore should not be used as a substitute for insulin.

The use of Victoza is not recommended if you have severe kidney disease or are on dialysis.

There is limited experience with the use of this medicine in patients with liver problems. Use of the medicine is not recommended if you have liver disease.

There is little to no experience of using this medicine in patients with heart failure. It is not recommended if you have severe heart failure.

The use of this medicine is not recommended if you have severe gastrointestinal disease, manifested by slowed gastric emptying (called gastroparesis) or inflammatory bowel disease.

If you experience symptoms of acute pancreatitis, such as severe and persistent stomach pain, you should see your doctor immediately (see section 4).

If you have thyroid disease, including nodules and an enlarged thyroid gland, please consult your doctor.

When starting Victoza treatment, you may experience fluid loss / dehydration in some cases such as vomiting, nausea and diarrhea. It is important to avoid dehydration by drinking fluids. Contact your doctor if you have any concerns or questions.

Children and adolescents

Victoza is not recommended in children and adolescents below 18 years of age as efficacy and safety has not been established in this age group.

Interactions Which drugs or foods may change the effect of Victoza

Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other medicines.

In particular, tell your doctor, pharmacist or nurse if you are using medicines that contain any of the following active ingredients:

  • Sulfonylurea (e.g. glimepiride or glibenclamide). You may have hypoglycaemia (low blood sugar) if you use Victoza together with a sulphonylurea, because sulphonylurea increases the risk of hypoglycaemia. When you start using these medicines together, your doctor may ask you to reduce the dose of the sulfonylurea. See section 4 for the warning signs of low blood sugar. If you are also taking a sulphonylurea (such as glimepiride or glibenclamide), your doctor should check your blood sugar level. This will help the doctor decide if the dose of sulphonylurea you need needs to be changed.
  • Warfarin or other oral anti-coagulant medicines. Frequent blood tests are needed to determine the blood's ability to clot.

Warnings It is important to know that:

Pregnancy and breastfeeding

Tell your doctor if you are, or think you are, pregnant or planning to become pregnant. Victoza should not be used during pregnancy because it is not known whether it could harm the baby before birth.

It is not known if Victoza passes into breast milk so do not use this medicine if you are breastfeeding.

Driving and using machines

Low blood sugar (hypoglycemia) can reduce your ability to focus. Avoid driving or operating machinery if you experience signs of hypoglycaemia. See section 4 for the warning signs of low blood sugar. Consult your doctor for more information on this topic.

Dose, Method and Time of Administration How to use Victoza: Posology

Always use the medicine exactly as your doctor has told you. If in doubt, consult your doctor, pharmacist or nurse.

  • The starting dose is 0.6 mg once a day, for at least one week.
  • Your doctor will tell you when to increase it to 1.2 mg once a day.
  • Your doctor may tell you to further increase the dose to 1.8 mg once a day if your blood sugar level is not adequately controlled with a 1.2 mg dose.

Do not change your dose unless your doctor tells you to.

Victoza is given as an injection under the skin (subcutaneous). Do not inject into a vein or muscle. The best places to inject are the front of the thighs, the abdomen (belly) or the upper part of the body. arm.

You can inject yourself at any time of the day, regardless of meals. Once you have chosen the most convenient time, it is preferable that you inject Victoza at approximately the same time.

Before using the pen for the first time, your doctor or nurse will show you how to do it. Detailed instructions for use are provided on the back of this leaflet.

INSTRUCTIONS FOR USING THE VICTOZA PEN.

Please read these instructions carefully before using your pen.

The pen contains 18 mg of liraglutide. It can select doses of 0.6 mg, 1.2 mg and 1.8 mg. The pen is designed to be used with NovoFine and NovoTwist disposable needles up to 8 mm long and up to 32 G (0.25 / 0.23 mm) thin.

Preparing the pen

Check the name and color label on the pen to make sure it contains liraglutide. Using an incorrect medicine can seriously harm you. Remove the cap from the pen.

Remove the protective seal from a new disposable needle. Screw the needle firmly straight onto your pen. Pull off the outer needle cap and keep it for later. Pull off the inner needle cap and throw it away.

  • Always use a new needle for each injection. This reduces the risk of contamination, infection, liraglutide spills, clogged needles and inaccurate doses.
  • Be careful not to bend or damage the needle.
  • Never try to put the inner needle cap back on after removing it. You could get hurt with the needle.

Pen maintenance

  • Do not try to repair or disassemble the pen.
  • Keep the pen away from dust, dirt and any type of liquid.
  • Clean the pen with a cloth moistened with a mild detergent.
  • Do not try to wash it, soak it in liquid or lubricate it - this can damage the pen.

Important information

  • Do not share your pen or needles with anyone else.
  • Keep the pen out of the reach of others, especially children

Check the flow with a new pen

Check the flow before an injection with a new pen. If you have already used the pen, go directly to the "Dose selection" step H. Turn the dose selector until the flow control symbol lines up with the pointer. .

Hold the pen with the needle pointing up. Gently tap the cartridge a few times with your finger so that the air bubbles collect on the top of the cartridge. Hold the needle pointing up and press the injection button until the indicator lines up. 0 mg.

A drop of liraglutide should come out of the tip of the needle. If no drops are coming out, repeat steps E to G up to four times. If still no drop of liraglutide appears, change the needle and repeat steps E to G Once again. If there are still no drops of liraglutide, do not use the pen. This indicates that the pen is defective and a new one must be used. If the pen has bumped into a hard surface or if you suspect it is defective, always insert a new disposable needle and check the flow before giving yourself the injection.

Dose selection

Always check that the indicator lines up with 0 mg.

Turn the dose selector until your needed dose lines up with the indicator (0.6 mg, 1.2 mg or 1.8 mg).

If you have mistakenly selected an incorrect dose, simply correct it by turning the dose selector forward or back until the indicator lines up with the correct dose.

Be careful not to press the injection button while turning the dose selector back as this may cause a leak of liraglutide.

If the dose selector locks up before the required dose lines up with the marker, there is not enough liraglutide left in the cartridge for a full dose. In this case, you can:

Divide your dose into two injections: Turn the dose selector forward or backward until the indicator lines up with 0.6 mg or 1.2 mg. Inject your dose. Then, prepare a new pen for injection and inject the remaining number of mg to complete the dose.

You can divide the dose between your current pen and your new pen only if instructed by your healthcare professional. You use a calculator to plan the doses. If you split the doses incorrectly, you may inject too much or too little liraglutide.

Inject the full dose with a new pen: If the dose selector locks before the indicator lines up with 0.6 mg, prepare a new pen and inject the full dose with the new pen.

Do not try to select doses other than 0.6 mg, 1.2 mg or 1.8 mg. The numbers on the display must align precisely with the indicator to ensure that the correct dose is being delivered. When you turn the dose selector, you will hear "clicks". Do not use these clicks as indicators to select the amount of liraglutide Do not use the scale on the cartridge to measure the amount of liraglutide to inject because it is not accurate enough.

Inject the dose

Insert the needle into the skin using the injection technique shown by your doctor or nurse. Then follow the instructions below:

Press the injection button until the indicator lines up with 0 mg. Be careful not to touch the display with your other fingers and not to push the dose selector to the side when injecting. This could block the injection. Press and hold the injection button and leave the needle under the skin for at least 6 seconds. This will ensure that the full dose is delivered.

Pull the needle out of your skin. You may then see a drop of liraglutide at the tip of the needle. This phenomenon is normal and does not affect the dose just given.

Insert the tip of the needle into the outer needle cap without touching the needle or the cap itself.

When the needle is covered, carefully push the outer cap all the way down and then unscrew the needle. Throw away the needle carefully and put the cap back on the pen.

When the pen is empty, discard it carefully without the needle inserted. Throw away the pen and needle according to local regulations.

  • Always remove the needle after each injection and store the pen without the needle attached.
  • This reduces the risk of contamination, infections, liraglutide spills, clogged needles and inaccurate doses.
  • Anyone caring for the patient must be very careful when handling used needles to prevent cross-infection and needle wounds.

Overdose What to do if you have taken too much Victoza

If you use more Victoza than you should

If you use more Victoza than you should, tell your doctor immediately as you may need medical treatment. You may have nausea, vomiting or diarrhea.

If you forget to use Victoza

If you forget a dose, take Victoza as soon as you remember.

However, if it has been more than 12 hours since you should have used Victoza, skip the missed dose and take the next one as usual the next day.

Do not use a double dose or increase the dose the next day to make up for a forgotten previous dose.

If you stop taking Victoza

Do not stop taking Victoza without talking to your doctor. If you stop treatment, your blood sugar levels may rise.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

Side Effects What are the side effects of Victoza

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Serious side effects

Common: affects up to 1 in 10 people

  • Hypoglycemia (low blood sugar). The warning signs of low blood sugar can come on suddenly and can include: cold sweat, cold pale skin, headache, rapid heartbeat, feeling sick (nausea), feeling very hungry, changes in vision , sleepiness, feeling of weakness, nervousness, anxiety, confusion, difficulty concentrating, tremor. Your doctor will tell you how to treat low blood sugar and what to do if you notice these warning signs. This is what can happen if you take a sulfonylurea or basal insulin. Before you start using Victoza, your doctor may reduce the dose of these medicines.

Rare: affects up to 1 in 1,000 people

  • A severe form of allergic reaction (anaphylactic reaction) with additional symptoms such as breathing problems, swelling of the throat and face, rapid heartbeat, etc. If these symptoms occur, you should seek medical attention immediately and notify your doctor as soon as possible.
  • Intestinal obstruction. A severe form of constipation with additional symptoms such as stomach pain, bloating, vomiting etc.

Very rare: affects up to 1 in 10,000 people

  • Cases of inflammation of the pancreas (pancreatitis). Pancreatitis can be a serious, potentially life-threatening medical condition. If you notice any of the following serious side effects, stop Victoza and contact your doctor immediately: Severe and persistent pain in the abdomen (stomach region) which may reach your back, as well as nausea and vomiting, may be a sign of inflammation. of the pancreas (pancreatitis).

Other side effects

Very common: affects more than 1 in 10 people

  • Nausea (feeling sick). It generally disappears over time.
  • Diarrhea. It generally disappears over time.

common

  • He retched.

When starting Victoza treatment, you may experience fluid loss / dehydration in some cases, such as vomiting, nausea and diarrhea. It is important to avoid dehydration by drinking plenty of fluids

  • Headache
  • Difficulty digesting
  • Inflammation of the stomach (gastritis). The signs include stomach pain, nausea, and vomiting.
  • Gastroesophageal reflux disease (GORD). The signs include heartburn.
  • Pain or swelling in the belly (abdomen)
  • Abdominal discomfort
  • Constipation
  • Intestinal gas (flatulence)
  • Decreased appetite
  • Bronchitis
  • Common cold
  • Dizziness
  • Increased heart rate
  • Fatigue
  • Toothache
  • Reactions at the injection site (such as bruising, pain, irritation, itching and rash).

Uncommon: affects up to 1 in 100 people

  • Allergic reaction such as itching and hives (a type of skin rash).
  • Dehydration, sometimes with decreased kidney function
  • Malaise.

Reporting of side effects

If you get any side effects, please tell your doctor, pharmacist or nurse. This also includes any side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.

Expiry and Retention

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the pen label and carton after "EXP". The expiry date refers to the last day of the month.

Before opening:

Store in a refrigerator (2 ° C - 8 ° C). Do not freeze. Keep away from the freezer compartment.

During use:

You can store the pen for 1 month below 30? C or in the refrigerator (2? C - 8? C), away from the freezer compartment. Do not freeze.

When you are not using the pen, keep it with the cap on to protect the product from light.

Do not use the medicine if the solution is not clear and colorless or almost colorless.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of unused medicines. This will help protect the environment.

Composition and pharmaceutical form

What Victoza contains

  • The active ingredient is liraglutide. One ml of solution for injection contains 6 mg of liraglutide. One pre-filled pen contains 18 mg of liraglutide.
  • The other ingredients are disodium phosphate dihydrate, propylene glycol, phenol, water for injections.

Description of what Victoza looks like and contents of the pack

Victoza is supplied as a clear and colorless or nearly colorless solution for injection in a pre-filled pen. Each pen contains 3 ml of solution, which correspond to 30 doses of 0.6 mg, 15 doses of 1.2 mg or 10 doses of 1.8 mg.

Victoza is available in packs containing 1, 2, 3, 5 or 10 pens. Not all pack sizes may be marketed. Needles are not included.

Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.

More information about Victoza can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION 03.0 PHARMACEUTICAL FORM 04.0 CLINICAL PARTICULARS 04.1 Therapeutic indications 04.2 Posology and method of administration 04.3 Contraindications 04.4 Special warnings and appropriate precautions for use 04.5 Interactions with other medicinal products and other forms of interaction 04.6 Pregnancy and lactation 04.7 Effects on ability to drive and use machines 04.8 Undesirable effects 04.9 Overdose 05.0 PHARMACOLOGICAL PROPERTIES 05.1 Pharmacodynamic properties 05.2 Pharmacokinetic properties 05.3 Preclinical safety data 06.0 PHARMACEUTICAL PARTICULARS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the immediate packaging and contents of the package 06.6 Instructions for use and handling 07.0 MARKETING AUTHORIZATION HOLDER 08.0 MARKETING AUTHORIZATION NUMBER 09 .0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIO DRUGS, COMPLETE DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS AND QUALITY CONTROLS

01.0 NAME OF THE MEDICINAL PRODUCT

VICTOZA 6 MG / ML SOLUTION FOR INJECTION IN PRE-FILLED PEN

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

One ml of solution contains 6 mg of liraglutide *. One pre-filled pen contains 18 mg of liraglutide in 3 ml.

* human glucagon-like peptide-1 (GLP-1) analog produced by recombinant DNA technology by Saccharomyces cerevisiae.

Excipients with known effects:

for the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM

Solution for injection in pre-filled pen (injection).

Clear, colorless isotonic solution; pH = 8.15.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

Victoza is indicated for the treatment of adults with type 2 diabetes mellitus to achieve glycemic control:

In combination with:

- Metformin or a sulphonylurea, in patients with insufficient glycemic control despite the maximum tolerated dose of metformin or sulfonylurea alone.

In combination with:

- Metformin and a sulphonylurea or metformin and a thiazolidinedione in patients with insufficient glycemic control despite combination therapy with two drugs.


04.2 Posology and method of administration

Dosage

To improve gastrointestinal tolerability, the starting dose is 0.6 mg of liraglutide per day. After at least one week, the dose should be increased to 1.2 mg. Some patients are expected to benefit from increasing the dose from 1.2 mg to 1.8 mg and, based on clinical response, after at least one additional week, the dose may be increased to 1.8 mg to further improve control. glycemic. Doses higher than 1.8 mg per day are not recommended.

Victoza can be added to existing metformin or metformin and thiazolidinedione therapy in combination. The dose of metformin and thiazolidinedione can be maintained unchanged.

Victoza can be added to existing sulfonylurea or metformin and sulphonylurea in combination therapy. When Victoza is added to sulfonylurea therapy, a reduction in the dose of the sulfonylurea should be considered to reduce the risk of hypoglycaemia (see section 4.4).

It is not necessary to self-monitor your blood glucose to adjust the dose of Victoza.However, when initiating treatment with Victoza in combination with a sulfonylurea, self-monitoring of blood glucose may become necessary to adjust the dose of the sulfonylurea.

Special populations

Elderly patients (> 65 years): No dose adjustment is required based on age. Therapeutic experience in patients ≥ 75 years of age is limited (see section 5.2).

Patients with renal insufficiency: 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 insufficiency (creatinine clearance of 30-59 ml / min) and there is no therapeutic experience in patients with severe renal insufficiency (creatinine clearance less than 30 ml / min). Victoza cannot currently be recommended for use in patients with moderate or severe renal impairment, including patients with end-stage renal disease (see section 5.2).

Patients with hepatic insufficiency: The therapeutic experience in patients with any degree of hepatic impairment is currently too limited to recommend use in patients with mild, moderate or severe hepatic impairment (see section 5.2).

Pediatric population: safety and efficacy of Victoza have not been established in children and adolescents below 18 years of age (see section 5.1). No data are available.

Method of administration

Victoza must not be administered intravenously or intramuscularly.

Victoza is given once daily at any time, regardless of meals, and can be injected subcutaneously in the abdomen, thigh or upper arm. The times and site of the injection can be changed without the need for correction. of the dose. However, once you have chosen the most convenient time of day, it is preferable to inject Victoza around the same time. For further instructions on administration, see section 6.6.


04.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.


04.4 Special warnings and appropriate 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.

Clinical experience in patients with NYHA class I-II congestive heart failure (New York Heart Association) is limited. There is no clinical experience in patients with NYHA class III-IV congestive heart failure.

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

Pancreatitis

The use of GLP-1 analogues has been associated with the risk of pancreatitis. Few cases of acute pancreatitis have been reported. Patients should be informed of the characteristic symptom of acute pancreatitis: severe and persistent abdominal pain. If pancreatitis is suspected. , administration of Victoza and other potentially suspect drugs should be discontinued.

Thyroid pathology

Thyroid adverse events, including increased plasma calcitonin, goiter and thyroid neoplasia, have been reported in clinical trials, particularly in patients with pre-existing thyroid disease (see section 4.8).

Hypoglycemia

Patients treated with Victoza in combination with a sulfonylurea may be at an increased risk of hypoglycaemia (see section 4.8). The risk of hypoglycaemia can be reduced by decreasing the dose of sulfonylurea.

Dehydration

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


04.5 Interactions with other medicinal products and other forms of interaction

In vitro, liraglutide showed a very low potential for involvement in pharmacokinetic interactions with other active substances related to cytochrome P450 and plasma protein binding.

The slight delay in gastric emptying induced by liraglutide may affect the absorption of concomitant oral medicinal products. Interaction studies have shown no clinically relevant delay in absorption. Few patients treated with liraglutide reported at least one episode of severe diarrhea. Diarrhea may affect the absorption of concomitant oral medicinal products.

Paracetamol

Liraglutide did not change the total exposure of paracetamol after a single dose of 1000 mg. The Cmax of paracetamol was decreased by 31% and the median tmax was delayed up to 15 min. No dose adjustment is required for use. concomitant with paracetamol.

Atorvastatin

Liraglutide did not change the total exposure of atorvastatin to a clinically relevant extent following administration of a single 40 mg dose of atorvastatin. Therefore, no dose adjustment of atorvastatin is required when given with liraglutide. Cmax of atorvastatin is decreased. 38% and median tmax was delayed from 1 hour to 3 hours with liraglutide.

Griseofulvin

Liraglutide did not change the total exposure of griseofulvin after administration of a single 500 mg dose of griseofulvin. Griseofulvin Cmax increased by 37%, while median tmax did not change. No dose adjustment of griseofulvin is required. and other compounds with low solubility and high permeability.

Digoxin

Administration of a single 1 mg dose of digoxin together with liraglutide resulted in a reduction in digoxin AUC by 16%; C decreased by 31%. Median digoxin tmax was delayed from 1 hour to 1, 5 hours Based on these results, no dose adjustment of digoxin is required.

Lisinopril

Single dose administration of 20 mg lisinopril together with liraglutide resulted in a reduction in lisinopril AUC by 15%; C decreased by 27%. Median tmax of lisinopril was delayed from 6 to 8 hours with liraglutide Based on these results, no dose adjustment of lisinopril is required.

Oral contraceptives

Liraglutide reduced the Cmax of ethinylestradiol and levonorgestrel by 12% and 13%, respectively, following administration of a single dose of an oral contraceptive. Tmax was delayed by 1.5 hours with liraglutide for both compounds. No clinically relevant effects were observed on general exposure of ethinylestradiol or levonorgestrel. Therefore, the contraceptive effect is not expected to be altered when administered concomitantly with liraglutide.

Warfarin and other coumarin derivatives

No interaction studies have been performed. A clinically relevant interaction with active substances with low solubility or narrow therapeutic index, such as warfarin, cannot be excluded. More frequent monitoring of INR is recommended at the initiation of liraglutide therapy in patients treated with warfarin or other coumarin derivatives ( International Normalized Ratio).

Insulin

No pharmacokinetic or pharmacodynamic interaction was observed between liraglutide and insulin detemir (Levemir) when a single 0.5 U / kg dose of insulin detemir and 1.8 mg liraglutide at steady state was administered in patients with type 2 diabetes.


04.6 Pregnancy and breastfeeding

Pregnancy

There are no adequate data from the use of Victoza in pregnant women. Animal studies have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.

Victoza should not be used during pregnancy; the use of insulin is recommended instead. If a patient wishes to become pregnant or if she becomes pregnant, treatment with Victoza should be stopped.

Feeding time

It is not known whether liraglutide is excreted in human milk. Animal studies have shown that the transfer of liraglutide and metabolites with similar structural relationship into milk is low. Non-clinical studies have shown a treatment-related reduction in neonatal growth in lactating rats (see section 5.3). As there is no experience, Victoza should not be used during breastfeeding.

Fertility

Except for a slight decrease in the number of engraftings, animal studies did not indicate direct adverse effects on fertility.


04.7 Effects on ability to drive and use machines

Victoza has no or negligible influence on the ability to drive and use machines. Patients should be advised to take necessary precautions to avoid hypoglycaemia while driving or using machines, particularly when Victoza is used in combination with a sulfonylurea.


04.8 Undesirable effects

Summary of the safety profile

In five large-scale, long-term clinical trials, over 2,500 patients were treated with Victoza alone or in combination with metformin, a sulphonylurea (with or without metformin) or metformin plus rosiglitazone.

The most frequently reported adverse reactions during clinical trials related to gastrointestinal disorders: nausea and diarrhea were very common, while vomiting, constipation, abdominal pain and dyspepsia were common. Upon initiation of Victoza therapy, these gastrointestinal adverse reactions may occur more frequently and generally subside over a few days or weeks of continued treatment. Headache and nasopharyngitis were also common. Furthermore, hypoglycaemia was common, and very common when Victoza was used in combination with a sulphonylurea. Severe hypoglycaemia was observed mainly in combination with a sulphonylurea.

Tabulated list of adverse reactions

Table 1 lists the adverse reactions identified in the Phase III combination studies with Victoza. The table shows adverse reactions that occurred with a frequency> 5% if the frequency was higher among patients treated with Victoza than in those treated with the comparator compound. The table also reports adverse reactions with a frequency ≥2% if the frequency was> 2 times the frequency for subjects treated with the comparator compound. Frequencies are defined as: very common (≥1 / 10); common (≥1 / 100,

Table 1 Adverse reactions identified in long-term phase III controlled studies and spontaneous reports

Adverse reaction Frequency of adverse reaction by treatment group Liraglutide with metformin Liraglutide with glimepiride Liraglutide with metformin and glimepiride Liraglutide with metformin and rosiglitazone Spontaneous reports Infections and infestations Nasopharyngitis common common Bronchitis common Metabolism and nutrition disorders Hypoglycemia common Very common common Anorexia common common common common Decreased appetite common common Nervous system disorders Headache Very common common common Dizziness common Gastrointestinal disorders Nausea Very common common Very common Very common Diarrhea Very common common Very common Very common He retched common common common Very common Dyspepsia common common common common Upper abdominal pain common Constipation common common common Gastritis common Flatulence common Abdominal dilation common Gastroesophageal reflux disease common Abdominal discomfort common Odontalgia common Viral gastroenteritis common General disorders and administration site conditions Fatigue common Malaise * Uncommon Pyrexia common Injection site reactions * common common Uncommon common Renal and urinary disorders Acute renal failure * # Uncommon Renal impairment * # Uncommon Metabolism and nutrition disorders Dehydration*# Uncommon Skin and subcutaneous tissue disorders Urticaria* Uncommon

* Not in accordance with the criteria mentioned above, but still considered an expected adverse reaction.

# See section 4.4 (Special warnings and precautions for use)

Description of selected adverse reactions

In a clinical study with Victoza monotherapy the rates of hypoglycaemia reported with Victoza were lower than those reported for patients treated with the active comparator (glimepiride). The most frequently reported adverse events were gastrointestinal and infections and infestations.

Hypoglycemia

Most of the hypoglycaemic episodes confirmed in clinical studies were mild in severity. No episodes of severe hypoglycaemia were observed in the Victoza monotherapy study. Severe hypoglycaemia may occur uncommonly and has mainly been observed with Victoza in combination with sulfonylurea (0.02 events / subject year). Very few episodes have been observed with administration of Victoza in combination with oral antidiabetic agents other than sulfonylureas ( 0.001 events / subject year).

Gastrointestinal adverse reactions

With Victoza in combination with metformin, 20.7% of patients reported at least one episode of nausea and 12.6% reported at least one episode of diarrhea. With Victoza in combination with a sulphonylurea, 9.1% of patients reported at least one episode of nausea and 7.9% reported at least one episode of diarrhea. Most episodes were mild to moderate in severity and occurred in a dose-dependent manner. With continued therapy, frequency and severity decreased in most patients who initially experienced nausea.

Patients> 70 years of age may experience more gastrointestinal effects when treated with liraglutide.

Patients with mild renal insufficiency (creatinine clearance 60-90 ml / min) may experience gastrointestinal effects during treatment with liraglutide.

Withdrawal from the study

In long-term controlled studies (26 weeks or longer), the incidence of study withdrawals due to adverse reactions was 7.8% for patients treated with Victoza and 3.4% for patients treated with the compound. The most frequent adverse reactions leading to study withdrawal for Victoza-treated patients were nausea (2.8% of patients) and vomiting (1.5%).

Immunogenicity

In line with the potential immunogenic properties of medicinal products containing proteins or peptides, patients may develop antibodies to liraglutide following treatment with Victoza. On average, 8.6% of patients developed antibodies. Antibody formation was not associated with a reduction in Victoza's efficacy.

Few cases (0.05%) of angioedema were reported during all long-term clinical trials with Victoza.

Injection site reactions

In long-term controlled studies (26 weeks or longer), injection site reactions were reported in approximately 2% of subjects treated with Victoza. These reactions were generally mild.

Pancreatitis

Few cases (including post-marketing pancreatitis) have been reported during the long-term clinical trials of Victoza.

Thyroid events

The overall incidence rate of thyroid adverse events across all mid- and long-term clinical trials is 33.5, 30.0, and 21.7 events per 1,000 subject-years exposed to (total) liraglutide, placebo, and liraglutide, respectively. to the comparator drugs (total); 5.4, ​​2.1 and 1.2 events, respectively, are serious thyroid adverse events.

In patients treated with liraglutide, the most frequent thyroid adverse events were thyroid malignancy, increased blood levels of calcitonin and goiter.

The incidence rates per 1,000 exposed subject-years were 6.8, 10.9 and 5.4 for patients treated with liraglutide compared with 6.4, 10.7 and 2.1 for patients treated with placebo and 2, respectively. , 4, 6.0 and 1.8 for patients treated with comparator drugs (total).


04.9 Overdose

In a clinical study of Victoza, a single episode of overdose was reported with a 17.4 mg subcutaneous dose (10 times the maximum recommended maintenance dose of 1.8 mg) in a patient with type 2 diabetes. Effects of overdose included severe nausea and vomiting, but not hypoglycemia. The patient recovered without complications.

In the event of an overdose, appropriate supportive treatment should be initiated depending on the patient's symptoms and clinical signs.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: drugs used in diabetes, other hypoglycemic agents, excluding insulins. ATC code: A10BX07

Mechanism of action

Liraglutide is a GLP-1 analog, with 97% sequence homology to human GLP-1, which binds to the GLP-1 receptor and activates it. The GLP-1 receptor is the target of native GLP-1 , an endogenous incretin hormone that potentiates glucose-dependent insulin secretion from 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 prolonged action profile is based on three mechanisms: self-association, which induces slow absorption; binding with albumin; and greater enzymatic stability towards dipeptidyl-peptidase IV (DPP-IV) and neutral endopeptidase (NEP) enzymes, resulting in a long plasma half-life.

The action of liraglutide is mediated by a specific interaction with GLP-1 receptors, which leads to an increase in cyclic adenosine monophosphate (cAMP). Liraglutide stimulates insulin secretion in a glucose-dependent manner. Simultaneously, liraglutide reduces the inappropriately elevated secretion of glucagon, again in a glucose-dependent manner. Thus, when blood glucose is elevated, insulin secretion is stimulated while that of glucagon is inhibited. Conversely, during hypoglycemia, liraglutide reduces secretion of insulin and does not hinder that of glucagon. The hypoglycemic mechanism also involves a slight delay in gastric emptying. Liraglutide reduces body weight and fat mass through mechanisms that involve decreased appetite and reduced calorie intake.

Pharmacodynamic effects

Liraglutide has a duration of action of 24 hours and improves glycemic control by reducing fasting and postprandial blood glucose in patients with type 2 diabetes mellitus.

Clinical efficacy

Five randomized, double-blind, controlled clinical trials were conducted to evaluate the effects of Victoza on glycemic control. Victoza treatment resulted in clinically and statistically significant improvements in glycosylated hemoglobin A1c (HbA1c), fasting plasma glucose and postprandial blood glucose compared to 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 ≥65 years of age and 113 subjects (66 treated with Victoza) were ≥75 years of age.

An open-label randomized controlled trial comparing liraglutide with exenatide was also conducted.

In a 52-week clinical study, adding insulin detemir to Victoza 1.8 mg and metformin in patients who did not achieve glycemic targets on Victoza and metformin alone resulted in a decrease in HbA1c from baseline by 0.54%. compared to 0.20% of the control group with 1.8 mg Victoza and metformin. Weight loss was confirmed. A slight increase in the rate of nocturnal hypoglycemic episodes was observed (0.23 versus 0.03 events per subject to year). The addition of liraglutide in patients already treated with insulin has not been evaluated (see section 4.4).

Glycemic control

Victoza administered for 26 weeks in combination with metformin, glimepiride or metformin and rosiglitazone resulted in statistically significant reductions (p

Table 2 Results from two studies lasting 26 weeks. Victoza in combination with metformin and Victoza in combination with glimepiride.

Therapy in addition to metformin Liraglutide 1.8 mg + metformin 3 Liraglutide 1.2 mg + metformin 3 Placebo + metformin 3 Glimepiride2 + metformin3 No. 242 240 121 242 Mean HbA1c value (%) Basal 8,4 8,3 8,4 8,4 Change from baseline -1,00 -0,97 0,09 -0,98 Patients (%) who achieved HbA1c All patients 42,4 35,3 10,8 36,3 In previous treatment with OAD alone 66,3 52,8 22,5 56,0 Average body weight (kg) Basal 88,0 88,5 91,0 89,0 Change from baseline -2,79 -2,58 -1,51 0,95 Therapy in addition to glimepiride Liraglutide 1.8 mg + glimepiride2 Liraglutide 1.2 mg + glimepiride2 Placebo + glimepiride2 Rosiglitazone1 + glimepiride2 No. 234 228 114 231 Mean HbA1c value (%) Basal 8,5 8,5 8,4 8,4 Change from baseline -1,13 -1,08 0,23 -0,44 Patients (%) who achieved HbA1c All patients 41,6 34,5 7,5 21,9 In previous treatment with OAD alone 55,9 57,4 11,8 36,1 Average body weight (kg) Basal 83,0 80,0 81,9 80,6 Change from baseline -0,23 0,32 -0,10 2,11

1 Rosiglitazone 4 mg / day; 2glimepiride 4 mg / day; 3metformin 2000 mg / day

Table 3 Results from two studies lasting 26 weeks. Victoza in combination with metformin + rosiglitazone and Victoza in combination with glimepiride + metformin.

Therapy in addition to metformin + Liraglutide 1.8 mg + metformin 2 Liraglutide 1.2 mg + metformin 2 Placebo + metformin 2 N / A rosiglitazone + rosiglitazone3 + rosiglitazone3 + rosiglitazone3 No. 178 177 175 Mean HbA1c value (%) Basal 8,56 8,48 8,42 Change from baseline -1,48 -1,48 -0,54 Patients (%) who achieved HbA1c All patients 53,7 57,5 28,1 Average body weight (kg) Basal 94,9 95,3 98,5 Change from baseline -2,02 -1,02 0,60 Therapy in addition to metformin + glimepiride Liraglutide 1.8 mg + metformin2 + glimepiride 4 N / A Placebo + metformin2 + glimepiride 4 Insulin glargine1 + metformin2 + glimepiride 4 No. 230 114 232 Mean HbA1c value (%) Basal 8,3 8,3 8,1 Change from baseline -1,33 -0,24 -1,09 Patients (%) who achieved HbA1c All patients 53,1 15,3 45,8 Average body weight (kg) Basal 85,8 85,4 85,2 Change from baseline -1,81 -0,42 1,62

1 The insulin glargine assay was open label and was applied according to the following titration guideline. The dose titration of insulin glargine was managed by the patient according to the investigator's instructions.

Guideline for titration of insulin glargine

Fasting blood glucose (FPG) self-check Increased dose of insulin glargine (IU) ≤5.5 mmol / L (≤100 mg / dL) Target No adjustment > 5.5 and 100 e 0 - 2 IUa ≥6.7 mmol / L (≥120 mg / dL) 2 IU

a Based on the investigator's individual recommendations at the previous visit, such as whether the subject has had hypoglycemic episodes.

2Metformin 2000 mg / day; 3rosiglitazone 4 mg twice daily; 4glimepiride 4 mg / day.

Percentage of patients who achieved reductions in HbA1c

Victoza in combination with metformin, glimepiride or metformin and rosiglitazone achieved HbA1c values ​​of ≤6.5% at 26 weeks in a statistically significant (p≤0.0001) higher percentage of patients than in patients treated with aforementioned drugs without Victoza.

Fasting plasma glucose

Treatment with Victoza alone or in combination with one or two oral antidiabetics resulted in a reduction in fasting plasma glucose of 13-43.5 mg / dL (0.72-2.42 mmol / L). This reduction was observed within the first two weeks of treatment.

Postprandial blood sugar

Victoza reduces postprandial blood glucose by 31-49 mg / dL (1.68-2.71 mmol / L) after all three daily meals.

Functionality of beta cells

Clinical studies conducted on Victoza show improvement in beta cell function as measured by the Homeostasis Evaluation Model for Beta Cell Function (HOMA-B) and by the ratio of proinsulin to insulin. In a subgroup of patients with type diabetes 2 (N = 29) an improvement in the first and second phase of insulin secretion was demonstrated after 52 weeks of treatment with Victoza.

Body weight

Victoza in combination with metformin, metformin and glimepiride or metformin and rosiglitazone was associated with weight loss ranging from 1.0 kg to 2.8 kg, which was maintained throughout the studies.

Greater weight losses were observed in patients who had a body mass index at baseline (Body Mass Index, BMI) higher.

Blood pressure

Victoza, over the entire duration of the studies, reduced systolic blood pressure by an average of 2.3-6.7 mmHg from baseline and, compared to the active comparison, the reduction was 1.9-4.5. mmHg.

Pediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with Victoza in one or more subsets of the pediatric population with type 2 diabetes mellitus (see section 4.2 for information on pediatric use).

Other clinical data

In an open-label comparative study of the efficacy and safety of Victoza (1.2 mg and 1.8 mg) and sitagliptin (a DPP-4 inhibitor, 100 mg) in patients inadequately controlled on metformin therapy (mean HbA1c 8.5 %), Victoza in the two doses was statistically superior to treatment with sitagliptin in the reduction of HbA1c after 26 weeks (-1.24%, -1.50% vs -0.90%, body weight loss compared to patients treated with sitagliptin (-2.9 kg and -3.4 kg vs -1.0 kg ,, p

In an open-label comparative study of the efficacy and safety of Victoza 1.8 mg administered once daily and exenatide 10 micrograms administered twice daily in patients inadequately controlled on metformin and / or sulfonylurea therapy (mean HbA1c 8.3%) , Victoza was statistically superior to exenatide treatment in HbA1c reduction after 26 weeks

(-1.12% vs -0.79%; estimated treatment difference: -0.33; 95% CI -0.47 - -0.18).

Significantly more patients achieved HbA1c below 7% with Victoza than with exenatide (54.2% vs 43.4%, p = 0.0015). Both treatments resulted in an average weight loss of around 3 kg. Switching patients from exenatide to Victoza after 26 weeks of treatment led to a "further and statistically significant reduction in HbA1c (-0.32%, 95% CI: -0.41 -

-0.24) at week 40, but no formal control group is available. During the 26 weeks, 12 serious adverse events occurred in 235 patients (5.1%) treated with liraglutide, while 6 serious adverse events occurred in 232 patients (2.6%) treated with exenatide. There was no consistent sample of events with respect to the frequency class.


05.2 "Pharmacokinetic properties

Absorption

The absorption of liraglutide after subcutaneous injection is slow and the maximum concentration is reached 8-12 hours after administration. The maximum estimated concentration of liraglutide is 9.4 nmol / l for a single subcutaneous dose of 0.6 mg liraglutide. At the 1.8 mg dose, the mean steady state concentration of liraglutide (AUC? / 24) was approximately 34 nmol / L. Liraglutide exposure increased in proportion to dose. The intra-individual coefficient of variation for liraglutide AUC was 11% after single dose administration.

The absolute bioavailability of liraglutide after subcutaneous administration is approximately 55%.

Distribution

The apparent volume of distribution after subcutaneous administration is 11-17 l. The mean volume of distribution following intravenous administration of liraglutide is 0.07 L / kg. Liraglutide is extensively bound to plasma proteins (> 98%).

Biotransformation

During the 24 hours following the administration of a single dose of radiolabelled [3H] liraglutide to healthy subjects, the main component in plasma was intact liraglutide. Two minor plasma metabolites (≤9% and ≤5% of total plasma radioactivity exposure) have been identified. Liraglutide is metabolised similarly to large proteins without a specific organ being identified as the major route of elimination.

Elimination

After one dose of liraglutide [3H], no intact liraglutide was detected in urine or faeces. Only a minor part of the administered radioactivity was excreted as liraglutide-related metabolites in the urine or faeces (6% and 5%, respectively). The radioactivity was excreted in the urine and faeces mainly in the first 6-8 days and corresponded to three minor metabolites, respectively.

The mean clearance following subcutaneous administration of a single dose of liraglutide is approximately 1.2 L / hour with an elimination half-life of approximately 13 hours.

Special populations

Senior citizensAge has not been shown to have clinically relevant effects on the pharmacokinetics of liraglutide based on the results of a pharmacokinetic study in healthy subjects and analysis of population pharmacokinetic data in patients aged 18 to 80 years.

Sex: Gender was not shown to have clinically significant effects on the pharmacokinetics of liraglutide based on the results of population pharmacokinetic data analysis in male and female patients and a pharmacokinetic study in healthy subjects.

ethnic background: Ethnicity was not shown to have clinically relevant effects on the pharmacokinetics of liraglutide based on the results of population pharmacokinetic data analysis in patients that included Caucasian, Black, Asian and Hispanic subjects.

Obesity: Population pharmacokinetic analysis suggests that body mass index (Body Mass Index, BMI) has no significant effect on the pharmacokinetics of liraglutide.

Hepatic insufficiency: The pharmacokinetics of liraglutide were evaluated in subjects with varying degrees of hepatic impairment in a single dose study. Liraglutide exposure was reduced by 13-23% in subjects with mild to moderate hepatic impairment compared to healthy subjects.

Exposure was significantly lower (44%) in subjects with severe hepatic impairment (Child Pugh score> 9).

Kidney failure: Liraglutide exposure was reduced in subjects with renal insufficiency compared to those with normal renal function. Liraglutide exposure was reduced by 33%, 14%, 27% and 28% in subjects with mild impairment, respectively (creatinine clearance , CrCl 50-80 ml / min), moderate (CrCl 30-50 ml / min) and severe (CrCl dialysis.


05.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity or reproductive toxicity.

Benign thyroid C-cell tumors were observed in 2-year carcinogenicity studies in rats and mice. In rats there was no dose with no observable adverse event (No Observed Adverse Effect Level, NOAEL). These tumors were not observed in the monkeys treated for 20 months. These findings in rodents are caused by a non-genotoxic mechanism, mediated by the specific GLP-1 receptor, to which rodents are particularly sensitive. The relevance for humans is likely to be low but cannot be completely ruled out. No other treatment-related tumors were observed.

Animal studies did not indicate direct harmful effects with respect to fertility, but a small increase in early death of embryos was observed at higher doses. Administration of Victoza during mid-pregnancy caused reduced maternal weight and fetal growth with equivocal rib effects in rats and skeletal changes in rabbits. Neonatal growth which was reduced in rats during Victoza exposure persisted into the post-weaning period in the high dose group. It is not known whether the reduction in neonatal growth is caused by the reduction in milk consumption due to a direct effect. of GLP-1 or the reduction in breast milk production due to the decrease in caloric intake.

06.0 PHARMACEUTICAL INFORMATION

06.1 Excipients

Disodium phosphate dihydrate

Propylene glycol

Phenol

Water for injections


06.2 Incompatibility

Substances added to Victoza can cause degradation of liraglutide. In the absence of compatibility studies, this medicinal product must not be mixed with other products.


06.3 Period of validity

30 months.

After the first use: 1 month.


06.4 Special precautions for storage

Store in a refrigerator (2 ° C - 8 ° C). Do not freeze.

Keep away from the freezer compartment.

After the first use: Store below 30 ° C or refrigerate (2 ° C - 8 ° C). Do not freeze.

Keep the cap on the pen to protect the product from light.


06.5 Nature of the immediate packaging and contents of the package

3 ml solution in cartridge (type 1 glass), with plunger (bromobutyl) and stopper (bromobutyl / polyisoprene) in a single-use pre-filled multidose pen made of polyolefin and polyacetal.

Each pen contains 3 ml of solution, which correspond to 30 doses of 0.6 mg, 15 doses of 1.2 mg or 10 doses of 1.8 mg.

Packs of 1, 2, 3, 5 or 10 pre-filled pens.

Not all pack sizes may be marketed.


06.6 Instructions for use and handling

Do not use Victoza if the product does not appear clear and colorless.

Victoza must not be used if it has been frozen.

Victoza can be administered with needles up to 8mm long and up to 32G thin. The pen is designed to be used with NovoFine or NovoTwist disposable needles.

Injection needles are not included.

The patient should be advised to discard the needle after each injection according to local regulations and to store the Victoza pen without the needle inserted to avoid contamination, infection and leakage. Compliance with these instructions also ensures accuracy of the dose.

07.0 MARKETING AUTHORIZATION HOLDER

Novo Nordisk A / S

Novo Allé

DK-2880 Bagsvaerd

Denmark

08.0 MARKETING AUTHORIZATION NUMBER

EU / 1/09/529 / 001-005

039365010

039365022

09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION

30/06/2009

10.0 DATE OF REVISION OF THE TEXT

05/2012

11.0 FOR RADIO DRUGS, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY

12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON EXEMPORARY PREPARATION AND QUALITY CONTROL

none:  Power supply exercises-pilates sleep