TRAJENTA DUO 2.5 MG 1000 MG

Israel - English - Ministry of Health

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Active ingredient:
LINAGLIPTIN; METFORMIN HYDROCHLORIDE
Available from:
BOEHRINGER INGELHEIM ISRAEL LTD.
ATC code:
A10BA02
Pharmaceutical form:
FILM COATED TABLETS
Composition:
LINAGLIPTIN 2.5 MG; METFORMIN HYDROCHLORIDE 1000 MG
Administration route:
PER OS
Prescription type:
Required
Manufactured by:
BOEHRINGER INGELHEIM PHARMA GMBH & CO.KG, GERMANY
Therapeutic group:
METFORMIN
Therapeutic area:
METFORMIN
Therapeutic indications:
As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both linagliptin and metformin is appropriate. TRAJENTA-DUO should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings. TRAJENTA-DUO has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at an increased risk for the development of pancreatitis while using TRAJENTA-DUO.
Authorization number:
150 19 33741 00
Authorization date:
2018-06-30

Documents in other languages

Patient Information leaflet Patient Information leaflet - Hebrew

19-07-2020

Trajenta Duo 2.5/500 mg, 2.5/850 mg, 2.5/1000 mg

Proposed patient information

File coated tablets

May 2020

Patient leaflet in accordance with the Pharmacists' Regulations (Preparations) - 1986

This medicine is dispensed with a doctor’s prescription only

Trajenta Duo

®

2.5 mg/500 mg

Trajenta Duo

®

2.5 mg/850 mg

Trajenta Duo

®

2.5 mg/1000 mg

Film-coated tablets

Film-coated tablets Film-coated tablets

Each film-coated tablet of

Trajenta Duo

2.5 mg/500 mg contains:

Each film-coated tablet

of Trajenta Duo

2.5 mg/850 mg contains:

Each film-coated tablet of

Trajenta Duo 2.5 mg/1000 mg

contains:

2.5 mg linagliptin

500 mg metformin

hydrochloride

2.5 mg linagliptin

850 mg metformin

hydrochloride

2.5 mg linagliptin

1000 mg metformin hydrochloride

Inactive ingredients and allergens in this medicine: see section 6 ‘Additional information’.

Read the entire leaflet carefully before you start using this medicine. This leaflet

contains concise information about this medicine. If you have any further questions, consult

your doctor or pharmacist. This medicine has been prescribed to treat your illness. Do not

pass it on to others. It may harm them, even if it seems to you that their illness is similar to

yours.

1.

What is this medicine intended for?

Trajenta Duo is intended, in addition to diet and physical exercise, to control blood sugar

levels in adults with type 2 diabetes for whom combined treatment with two active

ingredients, linagliptin and metformin hydrochloride is appropriate.

Limitations of use: Do not use Trajenta Duo to treat type 1 diabetes or diabetic

ketoacidosis, because Trajenta Duo is not effective with these conditions.

Trajenta Duo has not been studied in patients who have previously had pancreatitis

(inflammation of the pancreas). It is not known whether patients who have previously had

pancreatitis are at an increased risk of developing pancreatitis during treatment with

Trajenta Duo.

Therapeutic groups:

Linagliptin: DPP-4 (dipeptidyl peptidase-4) inhibitor.

Metformin: biguanides.

2.

Before using this medicine

Trajenta Duo 2.5/500 mg, 2.5/850 mg, 2.5/1000 mg

Proposed patient information

File coated tablets

May 2020

Do not use this medicine if:

You are sensitive (allergic) to the active ingredients or to any of the other ingredients

in this medicine (for a list of inactive ingredients, please see section 6). Symptoms of

severe allergy to Trajenta Duo may include skin rash, itching, peeling of the skin,

hives (red raised patches on the skin), swelling of the face, lips, tongue, and throat,

which may cause difficulty breathing or swallowing. If you experience any of these

symptoms, stop taking this medicine and contact your doctor or go to the nearest

hospital emergency room as soon as possible.

You have either type 1 diabetes (your body does not produce insulin), or acute or

chronic metabolic ketoacidosis including diabetic ketoacidosis (increased ketone

levels in your blood and/or urine). Trajenta Duo is not suitable for treating these

conditions.

You have severely reduced kidney function (your doctor will tell you how badly your

kidney function is affected).

Special warnings about using this medicine:

1. Lactic acidosis:

Metformin hydrochloride, one of the ingredients of Trajenta Duo, can cause a rare but

serious side effect called lactic acidosis, which manifests in build-up of lactic acid in the

blood and may be fatal. Lactic acidosis is a medical emergency requiring treatment in

hospital. If you feel symptoms of lactic acidosis, stop taking Trajenta Duo and see your

doctor immediately (see more information in section 4: ‘Side effects’).

Stop taking Trajenta Duo and consult your doctor immediately or go to the

emergency room if you develop any of the following symptoms of lactic acidosis:

feeling of weakness or tiredness, unusual muscle pain, difficulty breathing, unusual

sleepiness or sleeping longer than usual, unexplained stomach or intestinal problems

accompanied by nausea and vomiting, or diarrhea, feeling cold, especially in the hands

and feet, dizziness, irregular or slow heartbeat.

Most of the people who developed lactic acidosis while taking metformin hydrochloride

had other problems which, combined with metformin hydrochloride, led to lactic acidosis.

You have a higher chance of developing lactic acidosis if you:

have severe kidney problems.

have liver problems.

drink a lot of alcohol very often or in short period of time (see the section ‘Using this

medicine and alcohol consumption’).

get dehydrated (lose a large amount of body fluids). This can happen if you do not

drink enough fluids or if you have fever, vomiting, or diarrhea. Dehydration can also

happen when you sweat a lot with normal activity or with exercise.

have certain x-ray tests with injectable dyes or contrast agents.

have surgery or other procedures for which you need to restrict the amount of food and

liquid you eat and drink.

have congestive heart failure.

have a heart attack, severe infection, or stroke.

are 65 years of age or older.

Tell your doctor if you have any of the problems listed above. Tell your doctor that you

are taking Trajenta Duo before you have surgery or x-ray tests

Your doctor may decide to stop your Trajenta Duo treatment for a while if you have

surgery or certain x-ray tests.

Trajenta Duo 2.5/500 mg, 2.5/850 mg, 2.5/1000 mg

Proposed patient information

File coated tablets

May 2020

2.

Pancreatitis (see more information in section 4 ‘Side effects’) may occur in patients

treated with Trajenta Duo; it may be severe and even life threatening. Certain medical

problems may increase the risk of pancreatitis.

Before you start taking Trajenta Duo, consult your doctor if you currently have or

have ever had any of the following conditions:

pancreatitis.

stones in your gall bladder.

a history of alcoholism.

high levels of triglycerides in your blood.

Stop taking Trajenta Duo and consult a doctor immediately if you have severe

abdominal pain that will not go away. You may feel pain going from your abdomen

through to your back and it may appear with or without vomiting. These may be

symptoms of pancreatitis.

If you have ever had pancreatitis, it is unknown whether your chance of having

pancreatitis is higher while you are taking Trajenta Duo.

3. Heart failure: Before you start taking Trajenta Duo, tell your doctor if you currently have

or have ever had heart failure or problems with your kidneys. Consult your doctor

immediately if you experience any of the following symptoms:

increasing shortness of breath or trouble breathing, especially when you lie

down.

swelling or fluid retention, especially in the feet, ankles or legs.

an unusually fast increase in weight.

unusual tiredness.

All these may be symptoms of heart failure. Heart failure means that your heart does not

pump blood well enough.

Before using Trajenta Duo, tell your doctor if:

You have, or have ever had pancreatitis.

You have kidney problems.

You have impaired liver or heart function (including heart failure) or any other medical

problem.

You are 65 years of age or older.

You drink alcohol very often, or drink a lot of alcohol in a short period of time (binge

drinking).

You are going to get an injection of dye or contrast agent for an x-ray procedure. You

may need to stop taking Trajenta Duo for a short time. Talk to your doctor about when

you should stop Trajenta Duo and when you should start taking it again.

You have type 1 diabetes. Trajenta Duo is not intended for use in patients with type 1

diabetes.

You have low levels of vitamin B

in your blood.

You are pregnant or plan to become pregnant, are breastfeeding or planning to

breastfeed (see the section ‘Pregnancy, breastfeeding, and fertility’).

You are breastfeeding or planning to breastfeed. Trajenta Duo may pass into your breast

milk and may cause harm to your baby. Consult your doctor about the best way to feed

your baby if you are taking Trajenta Duo.

You are a premenopausal woman who does not have periods regularly or at all. Trajenta

Duo may cause release of an egg from an ovary in a woman (ovulation). This may

increase your chance of getting pregnant. Tell your doctor immediately if you become

pregnant while taking Trajenta Duo.

Trajenta Duo 2.5/500 mg, 2.5/850 mg, 2.5/1000 mg

Proposed patient information

File coated tablets

May 2020

Children and adolescents

The safety and efficacy of this medicine have not been tested in children and adolescents under

18 years old.

Tests and follow-up

During the course of treatment, your blood sugar levels must be tested according to the

doctor’s instructions.

Taking metformin hydrochloride (one of the ingredients of Trajenta Duo) may cause a

decrease in vitamin B

levels in the blood, therefore your doctor may ask you to perform

blood tests to check your vitamin B

levels.

Other medicines and Trajenta Duo

If you are taking or have recently taken other medicines, including nonprescription

medications and dietary supplements, tell your doctor or pharmacist. Particularly if you

are taking:

Insulin or other blood sugar lowering medicines: especially sulfonylurea or insulin

medicines. Combining these medicines with Trajenta Duo increases the risk of a drop in

blood sugar level (hypoglycemia). Please see section 2, above, under ‘Do not use this

medicine if’, and section 4 ‘Side effects’.

Diuretics.

Rifampicin (an antibiotic for treating tuberculosis): This combination may reduce the

efficacy of Trajenta Duo.

Ranolazine, vandetanib, dolutegravir, and cimetidine: The combination may increase the

levels of metformin (one of the ingredients in Trajenta Duo) in your blood which

increases the risk of lactic acidosis. Topiramate (a medicine used to treat epileptic

seizures), zonisamide, acetazolamide, or dichlorphenamide: The combination may

increase the risk of lactic acidosis (see also section 2 under 'Special warnings about

using this medicine').

Using this medicine and food

Take this medicine with a meal. Taking this medicine with food can reduce digestive tract

problems.

Using this medicine and alcohol consumption

Do not consume alcohol often or in large amounts in a short time period. Consuming alcohol

increases your risk of experiencing side effects.

Pregnancy, breastfeeding, and fertility

If you are pregnant or planning to become pregnant, or if you are breastfeeding, consult your

doctor before taking this medicine.

There is no information about the effect of this medicine on your unborn baby. If you are

pregnant, talk to your doctor about the best way to control your sugar levels during

pregnancy.

There is no information about this medicine passing into breastmilk. Consult your doctor

about the best way to feed your baby while using this medicine.

3. How to use this medicine?

Trajenta Duo 2.5/500 mg, 2.5/850 mg, 2.5/1000 mg

Proposed patient information

File coated tablets

May 2020

Always use this medicine according to your doctor's instructions. Check with your doctor or

pharmacist if you are not sure about your dose or about how to take this medicine. Only your

doctor will determine your dose and how you should take this medicine.

The recommended dose is usually one tablet twice a day with meals. If your kidney function

is impaired, your doctor may prescribe you a lower dose.

Taking this medicine with a meal can help lower the risk of abdominal pain. Do not exceed

the recommended dose.

Swallow the medicine with water. There is no information about crushing/splitting/chewing

the tablets.

If you are taking Trajenta Duo with other medicines for lowering blood sugar, you are at a

higher risk of getting low blood sugar levels (hypoglycemia). Your doctor may decide to

change your dose of these medicines.

If you have accidentally taken a higher dose: If you have taken an overdose, or if a child

has accidentally swallowed some medicine, immediately see a doctor or go to a hospital

emergency room and bring the medicine package with you.

If you forget to take the medicine at the scheduled time, take it with food as soon as you

remember. If it is time to take the next dose, skip the forgotten dose and go back to your

regular schedule. Do not take two doses together. Adhere to the treatment as recommended

by your doctor.

Even if your health improves, do not stop taking this medicine without consulting your doctor

or pharmacist. If you stop taking this medicine, your blood sugar levels may go up.

Do not take medicines in the dark! Check the label and dose every time you take medicine.

Wear glasses if you need them. If you have any further questions about using this

medicine, consult your doctor or pharmacist.

4.

Side effects

Like with all medicines, using Trajenta Duo may cause side effects in some users. Do not be

alarmed by this list of side effects; you may not experience any of them. See further

important information in section 2 under 'Special warnings about using this medicine’.

Low blood sugar levels (hypoglycemia):

Signs and symptoms of low blood sugar level may include the following: headache, hunger, fast

heart beat, sweating, irritability, drowsiness, weakness, dizziness, confusion, tremor and

nervousness. If you take Trajenta Duo with other medicines that can cause low blood sugar levels,

such as sulfonylurea or insulin, your risk of getting low blood sugar levels is higher. If you notice

any of these signs, check your blood sugar levels, treat them if they are low, and contact your

doctor.

Allergic reactions (hypersensitivity):

Severe allergic reactions have occurred in people taking Trajenta Duo. The symptoms may

include:

swelling of the face, lips, throat and other areas on your skin.

difficulty breathing or swallowing.

hives (raised red patches on the skin).

rash, itch, peeling of the skin.

Trajenta Duo 2.5/500 mg, 2.5/850 mg, 2.5/1000 mg

Proposed patient information

File coated tablets

May 2020

If symptoms of a severe allergic reaction develop, stop taking the treatment and contact your

doctor or go to the nearest hospital emergency room right away.

Low vitamin B

12

(vitamin B

12

deficiency):

Using metformin for long periods of time may cause a decrease in vitamin B

levels in the

blood, especially if you have had low vitamin B

levels before. Your doctor may ask you to

perform blood tests to check your vitamin B

levels.

Joint pain:

Some people who take medicines called DPP-4 inhibitors, one of the ingredients in Trajenta

Duo, may develop joint pain that can be severe and disabling (arthralgia). Consult your

doctor if you have severe joint pain.

Skin reactions:

Some patients who take medicines called DPP-4 inhibitors, one of the ingredients in Trajenta

Duo, may develop a skin reaction called bullous pemphigoid which may require treatment in

hospital. Consult a doctor immediately if you develop blisters or sores on the upper layer of

your skin (erosions). Your doctor may advise you to stop taking Trajenta Duo.

Pancreatitis:

Pancreatitis can appear in patients who are taking Trajenta Duo and it may be severe and

even life-threatening (see also section 2 under 'Special warnings about using this

medicine').

Stop taking this medicine and consult a doctor immediately if you have severe

abdominal pain that will not go away. The pain may radiate to the back and may appear with

or without vomiting. These may be symptoms of pancreatitis.

Lactic acidosis:

Stop using this medicine and consult a doctor immediately if you develop any

symptoms of lactic acidosis (see also section 2 under 'Special warnings about using this

medicine'): feeling cold, especially in your hands and feet, dizziness, irregular or slow heart

beat, feeling weak or tired, unusual muscle pain, difficulty breathing, feeling unusually sleepy

or sleeping longer than usual, unexplained stomach or intestinal problems accompanied by

nausea and vomiting, or diarrhea.

Very common side effects (appear in 1-10 in 10 users):

low blood sugar level (hypoglycemia).

Common side effects (appear in 1-10 in 100 users):

stuffy or runny nose, sore throat and diarrhea.

Side effects that were observed when taking one of the ingredients of Trajenta Duo

(linagliptin/metformin): cough, constipation, increase in uric acid, increase in enzymes that

break down fat (lipase), increase in amylase and reduced levels of vitamin B

Uncommon side effects (appear in 1-10 in 1,000 users):

decreased appetite, hypersensitivity, nausea, vomiting, damage to the liver, rash.

Rare side effects (appear in 1-10 in 10,000 users):

blister and/or wound shaped skin reactions (bullous pemphigoid), mouth sores.

Side effects of unknown frequency (the frequency of these effects has not been

established yet):

itch, pancreatitis, muscle pain, swelling, weakness, digestion pain, abdominal discomfort,

and headache.

Trajenta Duo 2.5/500 mg, 2.5/850 mg, 2.5/1000 mg

Proposed patient information

File coated tablets

May 2020

Spontaneous post-marketing reports mention side effects that were observed when

taking either one of the ingredients of Trajenta Duo (linagliptin/metformin):

rash

acute pancreatitis that was even fatal

hypersensitivity

severe and disabling joint pain

mouth sores, inflammation of the mouth

blister and/or wound shaped skin reactions (bullous pemphigoid)

damage to the liver

breakdown of skeletal muscle (rhabdomyolysis)

If you experience any side effect, if any side effect gets worse, or if you experience a

side effect not mentioned in this leaflet, consult your doctor.

You can report side effects to the Ministry of Health by following the link ‘Reporting Side

Effects of Drug Treatment' on the Ministry of Health home page (www.health.gov.il) which

links to an online form for reporting side effects. You can also use this link:

https://sideeffects.health.gov.il

5.

How to store the medicine?

Prevent poisoning! To prevent poisoning, keep this, and all other medicines, in a closed

place, out of the reach and sight of children and/or infants. Do not induce vomiting

unless explicitly instructed to do so by a doctor.

Do not use the medicine after the expiry date (exp. date) which is stated on the package.

The expiry date refers to the last day of that month.

Storage conditions:

Store below 25˚C.

6.

Additional information

In addition to the active ingredients, this medicine also contains the following inactive

ingredients:

arginine, maize starch, copovidone, silica colloidal anhydrous, magnesium stearate,

hypromellose, propylene glycol, titanium dioxide, talc.

Trajenta Duo 2.5 mg/500 mg and Trajenta Duo 2.5 mg/850 mg also contain yellow iron

oxide.

Trajenta Duo 2.5 mg/850 mg and Trajenta Duo 2.5 mg/1000 mg also contain red iron

oxide.

What the medicine looks like and contents of the pack:

Trajenta Duo 2.5 mg/500 mg is a light yellow, convex, oval tablet imprinted with D2/500

on one side and the Boehringer Ingelheim logo on the other.

Trajenta Duo 2.5 mg/850 mg is a light orange, convex, oval tablet imprinted with D2/850

on one side and the Boehringer Ingelheim logo on the other.

Trajenta Duo 2.5 mg/1000 mg is a light pink, convex, oval tablet imprinted with D2/1000

on one side and the Boehringer Ingelheim logo on the other.

The packages contain blister trays of 7 or 10 tablets. Each package contains 14 or 60

film-coated tablets.

Not all pack sizes may be marketed.

Registration holder’s name and address:

Trajenta Duo 2.5/500 mg, 2.5/850 mg, 2.5/1000 mg

Proposed patient information

File coated tablets

May 2020

Boehringer Ingelheim Israel Ltd., 89 Medinat Heyehudim St., P.O.B. 4124, Herzeliya

Pituach 4676672.

Manufacturer’s name and address: Boehringer Ingelheim Pharma, Binger Strasse

173, Ingelheim am Rheine, Germany

or Boehringer Ingelheim Ellas A. E., Koropi, Greece

or Dragenopharm Apotheker Püschl GmbH, Tittmoning, Germany

This leaflet was revised in May 2020.

Registration number of the medicine in the Ministry of Health’s National Drug

Registry:

Trajenta Duo 2.5 mg/500 mg: 150-17-33739

Trajenta Duo 2.5 mg/850 mg: 150-18-33740

Trajenta Duo 2.5 mg/1000 mg: 150-19-33741

Trajenta duo

Prescribing Information

File coated tablets 2.5mg/500mg, 2.5mg/850mg,

2.5mg/1,000mg

May 2020

1 NAME OF THE MEDICINAL PRODUCT

TRAJENTA DUO 2.5 mg/500 mg

TRAJENTA DUO 2.5 mg/850 mg

TRAJENTA DUO 2.5 mg/1,000 mg

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains Linagliptin 2.5 mg and 500/850/1000 mg Metformin.

For the full list of excipients, see section “Description”.

3 PHARMACEUTICAL FORM

Film coated tablets.

WARNING: RISK OF LACTIC ACIDOSIS

Postmarketing cases of metformin-associated lactic acidosis have resulted in death,

hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-

associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as

malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-

associated lactic acidosis was characterized by elevated blood lactate levels (>5 mmol/Liter),

anion gap acidosis (without evidence of ketonuria or ketonemia), an increased

lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL

[see Warnings

and Precautions (8.1)].

Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant

use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years

old or greater, having a radiological study with contrast, surgery and other procedures,

hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic

impairment.

Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high

risk groups are provided in the full prescribing information

[see Dosage and Administration

(5.2), Contraindications (7), Warnings and Precautions (8.1), Drug Interactions (10.1), and

Use in Specific Populations (11.6, 11.7)].

If metformin-associated lactic acidosis is suspected, immediately discontinue Trajenta Duo

and institute general supportive measures in a hospital setting. Prompt hemodialysis is

recommended

[see Warnings and Precautions (8.1)].

4

INDICATIONS AND USAGE

4.1 Indication

Trajenta duo

Prescribing Information

File coated tablets 2.5mg/500mg, 2.5mg/850mg,

2.5mg/1,000mg

May 2020

Boehringer Ingelheim Israel

TRAJENTA DUO is indicated as an adjunct to diet and exercise to improve glycemic control in

adults with type 2 diabetes mellitus when treatment with both linagliptin and metformin is

appropriate [see Dosage and Administration (5.1) and Clinical Studies (16.1)].

4.2 Important Limitations of Use

TRAJENTA DUO should not be used in patients with type 1 diabetes or for the treatment of diabetic

ketoacidosis, as it would not be effective in these settings. TRAJENTA DUO has not been studied in

patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis

are at an increased risk for the development of pancreatitis while using TRAJENTA DUO [see

Warnings and Precautions (8.2)].

5

DOSAGE AND ADMINISTRATION

5.1 DosageAdults with normal renal function (glomerular filtration rate [GFR] ≥ 90 ml/min)

The dosage of TRAJENTA DUO should be individualized on the basis of both effectiveness and

tolerability, while not exceeding the maximum recommended dose of 2.5 mg linagliptin/1000 mg

metformin hydrochloride twice daily. TRAJENTA DUO should be given twice daily with meals.

Dose escalation should be gradual to reduce the gastrointestinal (GI) side effects associated with

metformin use. For available dosage forms and strengths [see Dosage Forms and Strengths (6)].

Recommended starting dose:

In patients currently not treated with metformin, initiate treatment with 2.5 mg linagliptin/500

mg metformin hydrochloride twice daily

In patients already treated with metformin, start with 2.5 mg linagliptin and the current dose of

metformin taken at each of the two daily meals (e.g., a patient on metformin 1000 mg twice daily

would be started on 2.5 mg linagliptin/1000 mg metformin hydrochloride twice daily with

meals).

Patients already treated with linagliptin and metformin individual components may be switched

to TRAJENTA DUO containing the same doses of each component.

No studies have been performed specifically examining the safety and efficacy of TRAJENTA DUO

in patients previously treated with other oral antihyperglycemic agents and switched to TRAJENTA

DUO. Any change in therapy of type 2 diabetes mellitus should be undertaken with care and

appropriate monitoring as changes in glycemic control can occur.

5.2

Recommended Dosing in Renal Impairment

A GFR should be assessed before initiation of treatment with metformin containing products and at

least annually thereafter. In patients at increased risk of further progression of renal impairment

and in the elderly, renal function should be assessed more frequently, e.g. every 3-6 months.

The maximum daily dose of metformin should preferably be divided into 2-3 daily doses. Factors

that may increase the risk of lactic acidosis [see Warnings and Precautions (8.1)] should be

reviewed before considering initiation of metformin in patients with GFR<60 ml/min.

If no adequate strength of Trajenta Duo is available, individual monocomponents should be used

instead of the fixed dose combination.

Trajenta duo

Prescribing Information

File coated tablets 2.5mg/500mg, 2.5mg/850mg,

2.5mg/1,000mg

May 2020

Boehringer Ingelheim Israel

linagliptin

metformin

GFR ml/min

No dose adjustment

Maximum daily dose is 2550 mg

Dose reduction may be considered in

relation to declining renal function.

60-89

No dose adjustment

Maximum daily dose is 2000 mg

The starting dose is at most half of the

maximum dose.

45-59

No dose adjustment

Maximum daily dose is 1000 mg.

The starting dose is at most half of the

maximum dose.

30-44

No dose adjustment

Metformin is contraindicated

<30

6

DOSAGE FORMS AND STRENGTHS

TRAJENTA DUO is a combination of linagliptin and metformin HCl. TRAJENTA DUO tablets are

available in the following dosage forms and strengths:

2.5 mg linagliptin/500 mg metformin HCl tablets are light yellow, oval, biconvex tablets

debossed with “D2/500” on one side and the Boehringer Ingelheim logo on the other side

2.5 mg linagliptin/850 mg metformin HCl tablets are light orange, oval, biconvex tablets

debossed with “D2/850” on one side and the Boehringer Ingelheim logo on the other side

2.5 mg linagliptin/1000 mg metformin HCl tablets are light pink, oval, biconvex tablets debossed

with “D2/1000” on one side and the Boehringer Ingelheim logo on the other side

7

CONTRAINDICATIONS

TRAJENTA DUO is contraindicated in patients with:

Severe renal impairment eGFR below 30 mL/min/1.73 m2) [see Warnings and Precautions (8.1)]

Acute or chronic metabolic acidosis, including diabetic ketoacidosis. [see Warnings and

Precautions (8.1)]

Hypersensitivity to linagliptin, metformin, or any excipients in Trajenta Duo, reactions such as

anaphylaxis, angioedema, exfoliative skin conditions, urticaria, or bronchial hyperreactivity

have occurred with linagliptin [see Warnings and Precautions (8.5), Adverse Reactions (9.1) and

Description (13)]

8

WARNINGS AND PRECAUTIONS

8.1 Lactic Acidosis

Metformin

Trajenta duo

Prescribing Information

File coated tablets 2.5mg/500mg, 2.5mg/850mg,

2.5mg/1,000mg

May 2020

Boehringer Ingelheim Israel

There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases.

These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise,

myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia,

hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-

associated lactic acidosis was characterized by elevated blood lactate concentrations (>5

mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased

lactate pyruvate ratio; metformin plasma levels generally >5 mcg/mL. Metformin decreases liver

uptake of lactate increasing lactate blood levels which may increase risk of lactic acidosis, especially

in patients at risk.

If metformin-associated lactic acidosis is suspected, general supportive measures should be

instituted promptly in a hospital setting, along with immediate discontinuation of TRAJENTA DUO.

In TRAJENTA DUO-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt

hemodialysis is recommended to correct the acidosis and remove accumulated metformin

(metformin hydrochloride is dialyzable, with clearance of up to 170 mL/min under good

hemodynamic conditions) Hemodialysis has often resulted in reversal of symptoms and recovery.

Educate patients and their families about the symptoms of lactic acidosis and if these symptoms

occur instruct them to discontinue TRAJENTA DUO and report these symptoms to their healthcare

provider.

For each of the known and possible risk factors for metformin-associated lactic acidosis,

recommendations to reduce the risk of and manage metformin-associated lactic acidosis are

provided below:

Renal Impairment: The postmarketing metformin-associated lactic acidosis cases primarily

occurred in patients with significant renal impairment. The risk of metformin accumulation and

metformin-associated lactic acidosis increases with the severity of renal impairment because

metformin is substantially excreted by the kidney. Clinical recommendations based upon the

patient’s renal function include [see Dosage and Administration (5.2) and Clinical Pharmacology

(14.3)]:

Before initiating TRAJENTA DUO, obtain an estimated glomerular filtration rate (eGFR).

TRAJENTA DUO is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m

[see Contraindications (7)].

Initiation of TRAJENTA DUO is not recommended in patients with eGFR between 30 – 45

mL/min/1.73 m

Obtain an eGFR at least annually in all patients taking TRAJENTA DUO. In patients at

increased risk for the development of renal impairment (e.g., the

elderly), renal function

should be assessed more frequently.

In patients taking TRAJENTA DUO whose eGFR later falls below 45 mL/min/1.73 m

assess the benefit and risk of continuing therapy

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Drug Interactions: The concomitant use of TRAJENTA DUO with specific drugs may increase the

risk of metformin-associated lactic acidosis: those that impair renal function, result in significant

hemodynamic change, interfere with acid-base balance or increase metformin accumulation [see

Drug Interactions (8.1)]. Therefore, consider more frequent monitoring of patients.

Age 65 or Greater: The risk of metformin-associated lactic acidosis increases with the patient’s age

because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment

than younger patients. Assess renal function more frequently in elderly patients [see Use in Specific

Populations (11.5)].

Radiological studies and surgical procedures:

Radiologic studies involving the use of intravascular iodinated contrast materials (e.g., intravenous

urogram, intravenous cholangiography, angiography, and computed tomography) can lead to acute

alteration of renal function and have been associated with lactic acidosis in patients receiving

metformin. Therefore, in patients in whom any such study is planned, TRAJENTA-DUO should be

temporarily discontinued at the time of or prior to the procedure, and withheld for 48 hours

subsequent to the procedure and reinstituted only after renal function has been confirmed to be

stable.

Surgery and Other Procedures: Withholding of food and fluids during surgical or other procedures

may increase the risk for volume depletion, hypotension and renal impairment. TRAJENTA DUO

should be temporarily discontinued while patients have restricted food and fluid intake.

Hypoxic States: Several of the postmarketing cases of metformin-associated lactic acidosis occurred

in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion

and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other

conditions associated with hypoxemia have been associated with lactic acidosis and may also cause

prerenal azotemia. When such events occur, discontinue TRAJENTA DUO.

Excessive Alcohol Intake: Alcohol potentiates the effect of metformin on lactate metabolism and

this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive

alcohol intake while receiving TRAJENTA DUO.

Hepatic Impairment: Patients with hepatic impairment have developed cases of metformin-

associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate

blood levels. Therefore, avoid use of TRAJENTA DUO in patients with clinical or laboratory

evidence of hepatic disease.

8.2 Pancreatitis

Acute pancreatitis, including fatal pancreatitis, has been reported in patients treated with

linagliptin. In the CARMELINA trial [see Clinical Studies (14.2)], acute pancreatitis was reported in

9 (0.3%) patients treated with linagliptin and in 5 (0.1%) patients treated with placebo. Two patients

treated with linagliptin in the CARMELINA trial had acute pancreatitis with a fatal outcome.

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There have been postmarketing reports of acute pancreatitis, including fatal pancreatitis, in patients

treated with linagliptin. Take careful notice of potential signs and symptoms of pancreatitis. If

pancreatitis is suspected, promptly discontinue TRAJENTA DUO and initiate appropriate

management. It is unknown whether patients with a history of pancreatitis are at increased risk for

the development of pancreatitis while using TRAJENTA DUO.

8.3 Heart Failure

An association between DPP-4 inhibitor treatment and heart failure has been observed in

cardiovascular outcomes trials for two other members of the DPP-4 inhibitor class. These trials

evaluated patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease.

Consider the risks and benefits of TRAJENTA DUO prior to initiating treatment in patients at risk

for heart failure, such as those with a prior history of heart failure and a history of renal

impairment, and observe these patients for signs and symptoms of heart failure during therapy.

Advise patients of the characteristic symptoms of heart failure and to immediately report such

symptoms. If heart failure develops, evaluate and manage according to current standards of care

and consider discontinuation of TRAJENTA DUO.

8.4 Use with Medications Known to Cause Hypoglycemia

Insulin secretagogues and insulin are known to cause hypoglycemia. The use of linagliptin in

combination with an insulin secretagogue (e.g., sulfonylurea) or insulin was associated with a

higher rate of hypoglycemia compared with placebo in clinical trials [see Adverse Reactions (9.1)].

Metformin may increase the risk of hypoglycemia when combined with insulin and/or an insulin

secretagogue.

Therefore, a lower dose of the insulin secretagogue or insulin may be required to

reduce the risk of hypoglycemia when used in combination with TRAJENTA DUO [see Drug

Interactions (10.3)].

8.5 Hypersensitivity Reactions

There have been postmarketing reports of serious hypersensitivity reactions in patients treated with

linagliptin (one of the components of TRAJENTA DUO). These reactions include anaphylaxis,

angioedema, and exfoliative skin conditions. Onset of these reactions occurred

predominantly

within the first 3 months after initiation of treatment with linagliptin, with some reports occurring

after the first dose. If a serious hypersensitivity reaction is suspected, discontinue TRAJENTA DUO,

assess for other potential causes for the event, and institute alternative treatment for diabetes.

Angioedema has also been reported with other dipeptidyl peptidase-4 (DPP-4) inhibitors. Use

caution in a patient with a history of angioedema to another DPP-4 inhibitor because it is unknown

whether such patients will be predisposed to angioedema with TRAJENTA DUO.

8.6 Vitamin B

12

Levels

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In controlled, 29-week clinical trials of metformin, a decrease to subnormal levels of previously

normal serum vitamin B

levels, without clinical manifestations, was observed in approximately

7% of metformin-treated patients. Such decrease, possibly due to interference with B

absorption

from the B

-intrinsic factor complex, may be associated with anemia or neurologic manifestations.

This risk may be more relevant to patients receiving long-term treatment with metformin, and

adverse hematologic and neurologic reactions have been reported postmarketing. The decrease in

vitamin B

levels appears to be rapidly reversible with discontinuation of metformin or vitamin B

supplementation. Measurement of hematologic parameters on an annual basis and routine serum

vitamin B12 measurement at 2- to 3-year intervals is advised in patients on TRAJENTA DUO and

any apparent abnormalities should be appropriately investigated and managed. Certain individuals

(those with inadequate vitamin B

or calcium intake or absorption) appear to be predisposed to

developing subnormal vitamin B

levels.

8.7 Severe and Disabling Arthralgia

There have been postmarketing reports of severe and disabling arthralgia in patients taking DPP-4

inhibitors. The time to onset of symptoms following initiation of drug therapy varied from one day

to years. Patients experienced relief of symptoms upon discontinuation of the medication. A subset

of patients experienced a recurrence of symptoms when restarting the same drug or a different

DPP-4 inhibitor. Consider DPP-4 inhibitors as a possible cause for severe joint pain and discontinue

drug if appropriate.

8.8 Bullous Pemphigoid

Bullous pemphigoid was reported in 7 (0.2%) patients treated with linagliptin compared to none in

patients treated with placebo in the CARMELINA trial [see Clinical Studies (16.2)], and 3 of these

patients were hospitalized due to bullous pemphigoid. Postmarketing cases of bullous pemphigoid

requiring hospitalization have been reported with DPP-4 inhibitor use. In reported cases, patients

typically recovered with topical or systemic immunosuppressive treatment and discontinuation of

the DPP-4 inhibitor. Tell patients to report development of blisters or erosions while receiving

TRAJENTA DUO. If bullous pemphigoid is suspected, TRAJENTA DUO should be discontinued and

referral to a dermatologist should be considered for diagnosis and appropriate treatment.

9

ADVERSE REACTIONS

The following serious adverse reactions are described below or elsewhere in the prescribing

information:

Lactic Acidosis [see Warnings and Precautions (8.1)]

Pancreatitis [see Warnings and Precautions (8.2)]

Heart Failure [see Warnings and Precautions (8.3)]

Use with Medications Known to Cause Hypoglycemia [see Warnings and Precautions (8.4)]

Hypersensitivity Reactions [see Warnings and Precautions (8.5)]

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Vitamin B12 Levels [see Warnings and Precautions (8.6)]

Severe and Disabling Arthralgia [see Warnings and Precautions (8.7)]

Bullous Pemphigoid [see Warnings and Precautions (8.8)]

9.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates

observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of

another drug and may not reflect the rates observed in practice.

Linagliptin/Metformin

The safety of concomitantly administered linagliptin (daily dose 5 mg) and metformin (mean daily

dose of approximately 1800 mg) has been evaluated in 2816 patients with type 2 diabetes mellitus

treated for

12 weeks in clinical trials.

Three placebo-controlled studies with linagliptin + metformin were conducted: 2 studies were 24

weeks in duration, 1 study was 12 weeks in duration. In the 3 placebo-controlled clinical studies,

adverse reactions which occurred in

5% of patients receiving linagliptin + metformin (n=875) and

were more common than in patients given placebo + metformin (n=539) included nasopharyngitis

(5.7% vs 4.3%).

In a 24-week factorial design study, adverse reactions reported in

5% of patients receiving

linagliptin + metformin and were more common than in patients given placebo are shown in Table

Table 1

Adverse Reactions Reported in

5% of Patients Treated with Linagliptin +

Metformin and

Greater than with Placebo in a 24-week Factorial-Design Study

Placebo

n=72

Linagliptin

Monotherapy

n=142

Metformin

Monotherapy

n=291

Combination of

Linagliptin with

Metformin

n=286

n (%)

n (%)

n (%)

n (%)

Nasopharyng

itis

1 (1.4)

8 (5.6)

8 (2.7)

18 (6.3)

Diarrhea

2 (2.8)

5 (3.5)

11 (3.8)

18 (6.3)

Other adverse reactions reported in clinical studies with treatment of linagliptin + metformin were

hypersensitivity (e.g., urticaria, angioedema, or bronchial hyperreactivity), cough, decreased

appetite, nausea, vomiting, pruritus, and pancreatitis.

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Linagliptin

Adverse reactions reported in

2% of patients treated with linagliptin 5mg and more commonly

than in patients treated with placebo included: nasopharyngitis

(7.0% vs 6.1%), diarrhea (3.3% vs

3.0%), and cough (2.1% vs 1.4%).

Rates for other adverse reactions for linagliptin 5 mg vs placebo when linagliptin was used in

combination with specific anti-diabetic agents were: urinary tract infection (3.1% vs 0%) and

hypertriglyceridemia (2.4% vs 0%) when linagliptin was used as add-on to sulfonylurea;

hyperlipidemia (2.7% vs 0.8%) and weight increased (2.3% vs 0.8%) when linagliptin was used as

add-on to pioglitazone; and constipation (2.1% vs 1%) when linagliptin was used as add-on to basal

insulin therapy.

Other adverse reactions reported in clinical studies with treatment of linagliptin monotherapy were

hypersensitivity (e.g., urticaria, angioedema, localized skin exfoliation, or bronchial hyperreactivity)

and myalgia. In the clinical trial program, pancreatitis was reported in 15.2 cases per 10,000 patient

year exposure while being treated with linagliptin compared with 3.7 cases per 10,000 patient year

exposure while being treated with comparator (placebo and active comparator, sulfonylurea). Three

additional cases of pancreatitis were reported following the last administered dose of linagliptin.

Metformin

The most common adverse reactions due to initiation of metformin are diarrhea, nausea/vomiting,

flatulence, asthenia, indigestion, abdominal discomfort, and headache.

Hypoglycemia

Linagliptin/Metformin

In a 24-week factorial design study, hypoglycemia was reported in 4 (1.4%) of 286 subjects treated

with linagliptin + metformin, 6 (2.1%) of 291 subjects treated with metformin, and 1 (1.4%) of 72

subjects treated with placebo. The incidence of hypoglycemia with plasma glucose <54 mg/dL was

8.1% in the linagliptin group (N=792) compared to 5.3% in the placebo group (N=263) when

administered in combination with metformin and sulfonylurea in a 24-week study.

Linagliptin

The incidence of severe hypoglycemia (requiring assistance) was 1.7% in the linagliptin group

(N=631) compared to 1.1% in the placebo group (N=630) when administered in combination with

basal insulin in a 52 week study.

Laboratory Tests

Linagliptin

Increase in Uric Acid: Changes in laboratory values that occurred more frequently in the linagliptin

group and

1% more than in the placebo group were increases in uric acid (1.3% in the placebo

group, 2.7% in the linagliptin group).

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Increase in Lipase: In a placebo-controlled clinical trial with linagliptin in type 2 diabetes mellitus

patients with micro- or macroalbuminuria, a mean increase of 30% in lipase concentrations from

baseline to 24 weeks was observed in the linagliptin arm compared to a mean decrease of 2% in the

placebo arm. Lipase levels above 3 times upper limit of normal were seen in 8.2% compared to 1.7%

patients in the linagliptin and placebo arms, respectively.

Increase in Amylase: In a cardiovascular safety study comparing linagliptin versus glimepiride in

patients with type 2 diabetes mellitus, amylase levels above 3 times upper limit of normal were seen

in 1.0% compared to 0.5% of patients in the linagliptin and glimepiride arms, respectively.

The clinical significance of elevations in lipase and amylase with linagliptin is unknown in the

absence of potential signs and symptoms of pancreatitis [see Warnings and Precautions (5.2)].

Metformin

Decrease in Vitamin B

12

Absorption: Treatment with metformin has been associated with a decrease

in vitamin B

absorption which may result in clinically significant vitamin B

deficiency (e.g.,

megaloblastic anemia) [see Warnings and Precautions (8.6)].

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It

allows continued monitoring of the benefit/risk balance of the medicinal product.

Any suspected adverse events should be reported to the Ministry of Health according to the National

Regulation by using an online form

https://sideeffects.health.gov.il/

9.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use. Because these

reactions are reported voluntarily from a population of uncertain size, it is generally not possible to

reliably estimate their frequency or establish a causal relationship to drug exposure.

Linagliptin

Acute pancreatitis, including fatal pancreatitis [see Indications and Usage (4)

Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin

conditions

Severe and disabling arthralgia

Rash

Bullous pemphigoid

Mouth ulceration, stomatitis

Rhabdomyolysis

Metformin

Cholestatic, hepatocellular, and mixed hepatocellular liver injury

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10

DRUG INTERACTIONS

10.1 Drug Interactions with Metformin

Carbonic Anhydrase Inhibitors

Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or

dichlorphenamide) frequently cause a decrease in serum bicarbonate and induce non-anion gap,

hyperchloremic metabolic acidosis. Concomitant use of these drugs with TRAJENTA DUO may

increase the risk of lactic acidosis Consider more frequent monitoring of these patients [see

Warnings and Precautions (8.1) and Clinical Pharmacology (14.3)].

Drugs that Reduce Metformin Clearance

Concomitant use of drugs that interfere with common renal tubular transport systems involved in

the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2] / multidrug and

toxin extrusion [MATE] inhibitors such as ranolazine, vandetanib, dolutegravir, and cimetidine)

could increase systemic exposure to metformin and may increase the risk for lactic acidosis [see

Clinical Pharmacology (14.3)]. Consider the benefits and risks of concomitant use.

Alcohol

Alcohol is known to potentiate the effect of metformin on lactate metabolism. Warn patients

against excessive alcohol intake while receiving TRAJENTA DUO.

10.2 Drug Interactions With Linagliptin

Inducers of P-glycoprotein and CYP3A4 Enzymes

Rifampin decreased linagliptin exposure, suggesting that the efficacy of linagliptin may be reduced

when administered in combination with a strong P-gp inducer or CYP 3A4 inducer. As TRAJENTA

DUO is a fixed-dose combination of linagliptin and metformin, use of alternative treatments (not

containing linagliptin) is strongly recommended when concomitant treatment with a strong P-gp or

CYP 3A4 inducer is necessary [see Clinical Pharmacology (14.3)].

10.3 Insulin Secretagogues or Insulin

Co-administration of TRAJENTA DUO with an insulin secretagogue (e.g., sulfonylurea) or insulin

may require lower doses of the insulin secretagogue or insulin to reduce the risk of hypoglycemia

[see

Warnings and Precautions (8.4)].

10.4 Drugs Affecting Glycemic Control

Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs

include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products,

estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel

blocking drugs, and isoniazid. When such drugs are administered to a patient receiving TRAJENTA

DUO, the patient should be closely observed to maintain adequate glycemic control [see Clinical

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Pharmacology (14.3)]. When such drugs are withdrawn from a patient receiving TRAJENTA DUO,

the patient should be observed closely for hypoglycemia.

11

USE IN SPECIFIC POPULATIONS

11.1 Pregnancy

Risk Summary

The limited data with TRAJENTA DUO and linagliptin use in pregnant women are not sufficient to

inform a TRAJENTA DUO-associated or linagliptin-associated risk for major birth defects and

miscarriage. Published studies with metformin use during pregnancy have not reported a clear

association with metformin and major birth defect or miscarriage risk [see Data]. There are risks to

the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical

Considerations].

In animal reproduction studies, no adverse developmental effects were observed when the

combination of linagliptin and metformin was administered to pregnant rats during the period of

organogenesis at doses similar to the maximum recommended clinical dose, based on exposure [see

Data].

The estimated background risk of major birth defects is 6 to 10% in women with pre-gestational

diabetes with a HbA1c>7 and has been reported to be as high as 20 to 25% in women with

HbA1c>10. The estimated background risk of miscarriage for the indicated population is unknown.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage

in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-

eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled

diabetes increases the fetal risk for major birth defects, still birth, and macrosomia- related

morbidity.

Data

Human Data

Published data from post-marketing studies have not reported a clear association with metformin

and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was

used during pregnancy. However, these studies cannot definitely establish the absence of any

metformin-associated risk because of methodological limitations, including small sample size and

inconsistent comparator groups.

Animal Data

Linagliptin and metformin, the components of TRAJENTA DUO, were coadministered to pregnant

Wistar Han rats during the period of organogenesis. No adverse developmental outcome was

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observed at doses similar to the maximum recommended clinical dose, based on exposure. At higher

doses associated with maternal toxicity, the metformin component of the combination was

associated with an increased incidence of fetal rib and scapula malformations at

9-times a 2000

mg clinical dose, based on exposure.

Linagliptin

No adverse developmental outcome was observed when linagliptin was administered to pregnant

Wistar Han rats and Himalayan rabbits during the period of organogenesis at doses up to 240 mg/kg

and 150 mg/kg, respectively. These doses represent approximately 943 times (rats) and 1943 times

(rabbits) the 5 mg clinical dose, based on exposure. No adverse functional, behavioral, or

reproductive outcome was observed in offspring following administration of linagliptin to Wistar

Han rats from gestation day 6 to lactation day 21 at a dose 49 times the 5 mg clinical dose, based on

exposure.

Metformin Hydrochloride

Metformin hydrochloride did not cause adverse developmental effects when administered to

pregnant rabbits up to 600 mg/kg/day during the period of organogenesis. This represents an

exposure of approximately 6-times a clinical dose of 2000 mg, based on body surface area.

11.2 Lactation

Risk Summary

There is no information regarding the presence of TRAJENTA DUO or linagliptin in human milk,

the effects on the breastfed infant, or the effects on milk production. However, linagliptin is present

in rat milk. Limited published studies report that metformin is present in human milk [see Data].

However, there is insufficient information to determine the effects of metformin on the breastfed

infant and no available information on the effects of metformin on milk production. Therefore, the

developmental and health benefits of breastfeeding should be considered along with the mother’s

clinical need for TRAJENTA DUO and any potential adverse effects on the breastfed child from

TRAJENTA DUO or from the underlying maternal condition.

Data

Published clinical lactation studies report that metformin is present in human milk which resulted

in infant doses approximately 0.11% to 1% of the maternal weight-adjusted dosage and a

milk/plasma ratio ranging between 0.13 and 1. However, the studies were not designed to definitely

establish the risk of use of metformin during lactation because of small sample size and limited

adverse event data collected in infants.

11.3 Females and Males of Reproductive Potential

Discuss the potential for unintended pregnancy with premenopausal women as therapy with

metformin may result in ovulation in some anovulatory women.

11.4 Pediatric Use

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Safety and effectiveness of TRAJENTA DUO in pediatric patients under 18 years of age have not

been established.

11.5 Geriatric Use

Linagliptin is minimally excreted by the kidney; however, metformin is substantially excreted by the

kidney [see Warnings and Precautions (8.1) and Clinical Pharmacology (14.3)].

Linagliptin

In the 15 type 2 diabetes studies with linagliptin, 1085 linagliptin-treated patients were 65 years of

age and older (including 131 linagliptin-treated patients 75 years of age and older). Of these 15

studies, 12 were double-blind placebo-controlled. In these 12 studies, 591 linagliptin-treated

patients were 65 years of age and older (including 82 linagliptin-treated patients 75 years of age and

older). In these linagliptin studies, no overall differences in safety or effectiveness of linagliptin

were observed between geriatric patients and younger adult patients.

Metformin

Controlled clinical studies of metformin did not include sufficient numbers of elderly patients to

determine whether they respond differently from younger patients.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of

the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function,

and of concomitant disease or other drug therapy and the higher risk of lactic acidosis. Assess renal

function more frequently in elderly patients [see Contraindications (7), Warnings and Precautions

(8.1), and Clinical Pharmacology (14.3)].

11.6 Renal Impairment

Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and

lactic acidosis increases with the degree of renal impairment. TRAJENTA DUO is contraindicated in

severe renal impairment, patients with an estimated glomerular filtration rate (eGFR) below 30

mL/min/1.73 m

[see Dosage and Administration (5.2), Contraindications (7), Warnings and

Precautions (8.1), and Clinical Pharmacology (14.3)].

If TRAJENTA DUO is discontinued due to evidence of renal impairment, linagliptin may be

continued as a single entity tablet at the same total daily dose of 5 mg. No dose adjustment of

linagliptin is recommended in patients with renal impairment.

In the linagliptin treatment arm of the CARMELINA trial [see Clinical Studies (16.2)], 2200 (63%)

patients had renal impairment (eGFR <60 mL/min/1.73m

). Approximately 20% of the population

had eGFR

45 to <60 mL/min/1.73 m2, 28% of the population had eGFR

30 to <45 mL/min/1.73

m2 and 15% had eGFR <30 mL/min/1.73 m2. The overall incidence of adverse reactions were

generally similar between the linagliptin and placebo treatment arms.

11.7 Hepatic Impairment

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Use of metformin in patients with hepatic impairment has been associated with some cases of lactic

acidosis. TRAJENTA DUO is not recommended in patients with hepatic impairment [see Warnings

and Precautions (8.1)].

12

OVERDOSAGE

In the event of an overdose with TRAJENTA DUO contact your doctor immediately. Removal of

linagliptin by hemodialysis or peritoneal dialysis is unlikely. However, metformin is dialyzable with

a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis

may be useful partly for removal of accumulated metformin from patients in whom TRAJENTA

DUO overdosage is suspected.

Metformin

Overdose of metformin has occurred, including ingestion of amounts greater than 50 grams.

Hypoglycemia was reported in approximately 10% of cases, but no causal association with

metformin has been established. Lactic acidosis has been reported in approximately 32% of

metformin overdose cases [see Boxed Warning and Warnings and Precautions (8.1)].

13

DESCRIPTION

TRAJENTA DUO tablets contain 2 oral antihyperglycemic drugs used in the management of type 2

diabetes mellitus: linagliptin and metformin hydrochloride.

Linagliptin

Linagliptin is an orally-active inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme.

Linagliptin is described chemically as 1H-Purine-2,6-dione, 8-[(3R)-3-amino-1-piperidinyl]-7-(2-

butyn-1-yl)-3,7-dihydro-3-methyl-1-[(4-methyl-2-quinazolinyl)methyl]-

The empirical formula is C

and the molecular weight is 472.54 g/mol. The structural

formula is:

Linagliptin is a white to yellowish, not or only slightly hygroscopic solid substance. It is very slightly

soluble in water (0.9 mg/mL). Linagliptin is soluble in methanol (ca. 60 mg/mL), sparingly soluble

in ethanol (ca. 10 mg/mL), very slightly soluble in isopropanol (<1 mg/mL), and very slightly soluble

in acetone (ca. 1 mg/mL).

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Metformin Hydrochloride

Metformin hydrochloride (N,N-dimethylimidodicarbonimidic diamide hydrochloride) is not

chemically or pharmacologically related to any other classes of oral antihyperglycemic agents.

Metformin hydrochloride is a white to off-white crystalline compound with a molecular formula of

HCl and a molecular weight of 165.63 g/mol. Metformin hydrochloride is freely soluble in

water and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4.

The pH of a 1% aqueous solution of metformin hydrochloride is 6.68. The structural formula is:

TRAJENTA DUO

TRAJENTA DUO is available for oral administration as tablets containing 2.5 mg linagliptin and

500 mg metformin hydrochloride (TRAJENTA DUO 2.5 mg/500 mg), 850 mg metformin

hydrochloride (TRAJENTA DUO 2.5 mg/850 mg) or 1000 mg metformin hydrochloride (TRAJENTA

DUO 2.5 mg/1000 mg). Each film-coated tablet of TRAJENTA DUO contains the following inactive

ingredients: arginine, maize starch, copovidone, silica colloidal anhydrous, magnesium stearate,

hypromellose, propylene glycol, titanium dioxide, , talc, yellow ferric oxide (2.5 mg/500 mg; 2.5

mg/850 mg) and/or red ferric oxide (2.5 mg/850 mg; 2.5 mg/1000 mg).

14

CLINICAL PHARMACOLOGY

14.1 Mechanism of Action

TRAJENTA DUO

TRAJENTA DUO combines 2 antihyperglycemic agents with complementary mechanisms of action

to improve glycemic control in patients with type 2 diabetes mellitus: linagliptin, a dipeptidyl

peptidase-4 (DPP-4) inhibitor, and metformin, a member of the biguanide class.

Linagliptin

Linagliptin is an inhibitor of DPP-4, an enzyme that degrades the incretin hormones glucagon-like

peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Thus, linagliptin

increases the concentrations of active incretin hormones, stimulating the release of insulin in a

glucose-dependent manner and decreasing the levels of glucagon in the circulation. Both incretin

hormones are involved in the physiological regulation of glucose homeostasis. Incretin hormones

are secreted at a low basal level throughout the day and levels rise immediately after meal intake.

GLP-1 and GIP increase insulin biosynthesis and secretion from pancreatic beta cells in the presence

of normal and elevated blood glucose levels. Furthermore, GLP-1 also reduces glucagon secretion

from pancreatic alpha cells, resulting in a reduction in hepatic glucose output.

Metformin

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Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2

diabetes mellitus, lowering both basal and postprandial plasma glucose. Metformin decreases

hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin

sensitivity by increasing peripheral glucose uptake and utilization. With metformin therapy, insulin

secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may

actually decrease.

14.2 Pharmacodynamics

Linagliptin

Linagliptin binds to DPP-4 in a reversible manner and increases the concentrations of incretin

hormones. Linagliptin glucose-dependently increases insulin secretion and lowers glucagon

secretion, thus resulting in a better regulation of the glucose homeostasis. Linagliptin binds

selectively to DPP-4 and selectively inhibits DPP-4, but not DPP-8 or DPP-9 activity in vitro at

concentrations approximating therapeutic exposures.

Cardiac Electrophysiology

In a randomized, placebo-controlled, active-comparator, 4-way crossover study, 36 healthy subjects

were administered a single oral dose of linagliptin 5 mg, linagliptin 100 mg (20 times the

recommended dose), moxifloxacin, and placebo. No increase in QTc was observed with either the

recommended dose of 5 mg or the 100-mg dose. At the 100-mg dose, peak linagliptin plasma

concentrations were approximately 38-fold higher than the peak concentrations following a 5-mg

dose.

14.3 Pharmacokinetics

TRAJENTA DUO

The results of a bioequivalence study in healthy subjects demonstrated that TRAJENTA DUO

(linagliptin/metformin hydrochloride) 2.5 mg/500 mg, 2.5 mg/850 mg, and 2.5 mg/1000 mg

combination tablets are bioequivalent to coadministration of corresponding doses of linagliptin and

metformin as individual tablets. Administration of linagliptin 2.5 mg/metformin hydrochloride

1000 mg fixed-dose combination with food resulted in no change in overall exposure of linagliptin.

There was no change in metformin AUC; however, mean peak serum concentration of metformin

was decreased by 18% when administered with food. A delayed time-to-peak serum concentrations

by 2 hours was observed for metformin under fed conditions. These changes are not likely to be

clinically significant.

Absorption

Linagliptin

The absolute bioavailability of linagliptin is approximately 30%. Following oral administration,

plasma concentrations of linagliptin decline in at least a biphasic manner with a long terminal half-

life (>100 hours), related to the saturable binding of linagliptin to DPP-4. However, the prolonged

elimination does not contribute to the accumulation of the drug. The effective half-life for

accumulation of linagliptin, as determined from oral administration of multiple doses of linagliptin

5 mg, is approximately 12 hours. After once-daily dosing, steady state plasma concentrations of

linagliptin 5 mg are reached by the third dose, and C

and AUC increased by a factor of 1.3 at

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steady-state compared with the first dose. Plasma AUC of linagliptin increased in a less than dose-

proportional manner in the dose range of 1 to 10 mg. The pharmacokinetics of linagliptin is similar

in healthy subjects and in patients with type 2 diabetes.

Metformin

The absolute bioavailability of a metformin hydrochloride 500 mg tablet given under fasting

conditions is approximately 50% to 60%. Studies using single oral doses of metformin tablets 500

mg to 1500 mg, and 850 mg to 2550 mg, indicate that there is a lack of dose proportionality with

increasing doses, which is due to decreased absorption rather than an alteration in elimination.

Distribution

Linagliptin

The mean apparent volume of distribution at steady state following a single intravenous dose of

linagliptin 5 mg to healthy subjects is approximately 1110 L, indicating that linagliptin extensively

distributes to the tissues. Plasma protein binding of linagliptin is concentration-dependent

decreasing from about 99% at 1 nmol/L to 75% to 89% at

30 nmol/L, reflecting saturation of

binding to DPP-4 with increasing concentration of linagliptin. At high concentrations, where DPP-4

is fully saturated, 70% to 80% of linagliptin remains bound to plasma proteins and 20% to 30% is

unbound in plasma. Plasma binding is not altered in patients with renal or hepatic impairment.

Metformin

The apparent volume of distribution (V/F) of metformin following single oral doses of immediate-

release metformin hydrochloride tablets 850 mg averaged 654±358 L. Metformin is negligibly

bound to plasma proteins, in contrast to SUs, which are more than 90% protein bound. Metformin

partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing

schedules of metformin tablets, steady-state plasma concentrations of metformin are reached

within 24 to 48 hours and are generally <1 mcg/mL. During controlled clinical trials of metformin,

maximum metformin plasma levels did not exceed 5 mcg/mL, even at maximum doses.

Elimination

Linagliptin

Linagliptin has a terminal half-life of about 200 hours at steady-state, though the accumulation

half-life is about 11 hours. Renal clearance at steady-state was approximately 70 mL/min.

Metformin

Metformin has a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination

half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment

of distribution.

Metabolism

Linagliptin

Following oral administration, the majority (about 90%) of linagliptin is excreted unchanged,

indicating that metabolism represents a minor elimination pathway. A small fraction of absorbed

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linagliptin is metabolized to a pharmacologically inactive metabolite, which shows a steady-state

exposure of 13.3% relative to linagliptin.

Metformin

Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted

unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been

identified in humans) nor biliary excretion.

Excretion

Linagliptin

Following administration of an oral [

C]linagliptin dose to healthy subjects, approximately 85% of

the administered radioactivity was eliminated via the enterohepatic system (80%) or urine (5%)

within 4 days of dosing.

Metformin

Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that

tubular secretion is the major route of metformin elimination. Following oral administration,

approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours,

with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is

approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of

distribution.

Specific Populations

Renal Impairment

TRAJENTA DUO: Studies characterizing the pharmacokinetics of linagliptin and metformin after

administration of TRAJENTA DUO in renally impaired patients have not been performed[see

Contraindications (7) and Warnings and Precautions (8.1)].

Linagliptin: Under steady-state conditions, linagliptin exposure in patients with mild renal

impairment was comparable to healthy subjects. In patients with moderate renal impairment under

steady-state conditions, mean exposure of linagliptin increased (AUC

by 71% and C

by 46%)

compared with healthy subjects. This increase was not associated with a prolonged accumulation

half-life, terminal half-life, or an increased accumulation factor. Renal excretion of linagliptin was

below 5% of the administered dose and was not affected by decreased renal function.

Patients with type 2 diabetes mellitus and severe renal impairment showed steady-state exposure

approximately 40% higher than that of patients with type 2 diabetes mellitus and normal renal

function (increase in AUC by 42% and C

by 35%). For both type 2 diabetes mellitus groups, renal

excretion was below 7% of the administered dose.

Metformin: In patients with decreased renal function, the plasma and blood half-life of metformin

is prolonged and the renal clearance is decreased [see Contraindications (7) and Warnings and

Precautions (8.1)].

Hepatic Impairment

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TRAJENTA DUO: Studies characterizing the pharmacokinetics of linagliptin and metformin after

administration of TRAJENTA DUO in hepatically impaired patients have not been performed [see

Warnings and Precautions (8.4)].

Linagliptin: In patients with mild hepatic impairment (Child-Pugh class A) steady-state exposure

(AUC

) of linagliptin was approximately 25% lower and C

max,ss

was approximately 36% lower than

in healthy subjects. In patients with moderate hepatic impairment (Child-Pugh class B), AUC

, of

linagliptin was about 14% lower and C

max,ss

was approximately 8% lower than in healthy subjects.

Patients with severe hepatic impairment (Child-Pugh class C) had comparable exposure of

linagliptin in terms of AUC

0-24

and approximately 23% lower C

compared with healthy subjects.

Reductions in the pharmacokinetic parameters seen in patients with hepatic impairment did not

result in reductions in DPP-4 inhibition.

Metformin hydrochloride: No pharmacokinetic studies of metformin have been conducted in

patients with hepatic impairment.

Body Mass Index (BMI)/Weight

Linagliptin: BMI/Weight had no clinically meaningful effect on the pharmacokinetics of linagliptin

based on a population pharmacokinetic analysis.

Gender

Linagliptin: Gender had no clinically meaningful effect on the pharmacokinetics of linagliptin

based on a population pharmacokinetic analysis.

Metformin hydrochloride: Metformin pharmacokinetic parameters did not differ significantly

between normal subjects and patients with type 2 diabetes mellitus when analyzed according to

gender. Similarly, in controlled clinical studies in patients with type 2 diabetes mellitus, the

antihyperglycemic effect of metformin was comparable in males and females.

Geriatric

TRAJENTA DUO: Studies characterizing the pharmacokinetics of linagliptin and metformin after

administration of TRAJENTA DUO in geriatric patients have not been performed. [see Warnings

and Precautions (8.1) and Use in Specific Populations (11.5)].

Linagliptin: Age did not have a clinically meaningful impact on the pharmacokinetics of linagliptin

based on a population pharmacokinetic analysis.

Metformin hydrochloride: Limited data from controlled pharmacokinetic studies of metformin in

healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life

is prolonged, and C

is increased, compared with healthy young subjects. From these data, it

appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a

change in renal function.

Pediatric

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Studies characterizing the pharmacokinetics of linagliptin and metformin after administration of

TRAJENTA DUO in pediatric patients have not yet been performed.

Race

Linagliptin: Race had no clinically meaningful effect on the pharmacokinetics of linagliptin based

on available pharmacokinetic data, including subjects of White, Hispanic, Black, and Asian racial

groups.

Metformin hydrochloride: No studies of metformin pharmacokinetic parameters according to race

have been performed. In controlled clinical studies of metformin in patients with type 2 diabetes

mellitus, the antihyperglycemic effect was comparable in Caucasians (n=249), Blacks (n=51), and

Hispanics (n=24).

Drug Interactions

Pharmacokinetic drug interaction studies with TRAJENTA DUO have not been performed;

however, such studies have been conducted with the individual components of TRAJENTA DUO

(linagliptin and metformin hydrochloride).

Linagliptin

In vitro Assessment of Drug Interactions

Linagliptin is a weak to moderate inhibitor of CYP isozyme CYP3A4, but does not inhibit other CYP

isozymes and is not an inducer of CYP isozymes, including CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19,

2D6, 2E1, and 4A11.

Linagliptin is a P-glycoprotein (P-gp) substrate, and inhibits P-gp mediated transport of digoxin at

high concentrations. Based on these results and in vivo drug interaction studies, linagliptin is

considered unlikely to cause interactions with other P-gp substrates at therapeutic concentrations.

In vivo Assessment of Drug Interactions

Strong inducers of CYP3A4 or P-gp (e.g., rifampin) decrease exposure to linagliptin to

subtherapeutic and likely ineffective concentrations[see Drug Interactions (10)].. In vivo studies

indicated evidence of a low propensity for causing drug interactions with substrates of CYP3A4,

CYP2C9, CYP2C8, P-gp, and OCT.

Table 2 Effect of Coadministered Drugs on Systemic Exposure of Linagliptin

Coadministered

Drug

Dosing of

Coadministered

Drug*

Dosing of

Linagliptin*

Geometric Mean Ratio

(ratio with/without

coadministered drug)

No effect=1.0

Metformin

850 mg TID

10 mg QD

1.20

1.03

Glyburide

1.75 mg

5 mg QD

1.02

1.01

Pioglitazone

45 mg QD

10 mg QD

1.13

1.07

Ritonavir

200 mg BID

5 mg

2.01

2.96

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Rifampin**

600 mg QD

5 mg QD

0.60

0.56

*Multiple dose (steady state) unless otherwise noted

**For information regarding clinical recommendations [see Drug Interactions (10.2)].

Single dose

†AUC = AUC(0 to 24 hours) for single-dose treatments and AUC = AUC(TAU) for multiple-dose treatments

QD = once daily

BID = twice daily

TID = three times daily

Table 3 Effect of Linagliptin on Systemic Exposure of Coadministered Drugs

Coadministered

Drug

Dosing of

Coadministered

Drug*

Dosing of

Linagliptin*

Geometric Mean Ratio

(ratio with/without

coadministered drug)

No effect=1.0

Metformin

850 mg TID

10 mg QD

metformin

1.01

0.89

Glyburide

1.75 mg

5 mg QD

glyburide

0.86

0.86

Pioglitazone

45 mg QD

10 mg QD

pioglitazone

metabolite

M-III

metabolite

M-IV

0.94

0.98

1.04

0.86

0.96

1.05

Digoxin

0.25 mg QD

5 mg QD

digoxin

1.02

0.94

Simvastatin

40 mg QD

10 mg QD

simvastatin

simvastatin

acid

1.34

1.33

1.10

1.21

Warfarin

10 mg

5 mg QD

R-warfarin

S-warfarin

0.99

1.03

0.93**

1.03**

1.00

1.01

1.04**

1.15**

Ethinylestradiol

levonorgestrel

ethinylestradiol 0.03

mg and

levonorgestrel 0.150

mg QD

5 mg QD

ethinylestrad

levonorgestr

1.01

1.09

1.08

1.13

* Multiple dose (steady state) unless otherwise noted

Single dose

†AUC = AUC(INF) for single-dose treatments and AUC = AUC(TAU) for multiple-dose treatments

**AUC=AUC(0-168) and C

for pharmacodynamic end points

INR = International Normalized Ratio

PT = Prothrombin Time

QD = once daily

TID = three times daily

Metformin hydrochloride

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Table 4 Effect of Coadministered Drug on Plasma Metformin Systemic Exposure

Coadministered

Drug

Dosing of

Coadministered

Drug*

Dosing of

Metformin*

Geometric Mean Ratio

(ratio with/without

coadministered drug)

No effect=1.0

Glyburide

5 mg

850 mg

metformin

0.91‡

0.93‡

Furosemide

40 mg

850 mg

metformin

1.09‡

1.22‡

Nifedipine

10 mg

850 mg

metformin

1.16

1.21

Propranolol

40 mg

850 mg

metformin

0.90

0.94

Ibuprofen

400 mg

850 mg

metformin

1.05‡

1.07‡

Cationic drugs eliminated by renal tubular secretion may reduce metformin elimination

[see

Drug Interactions (10.1)].

Cimetidine

400 mg

850 mg

metformin

1.40

1.61

Carbonic anhydrase inhibitors may cause metabolic acidosis

[see

Drug Interactions (10.1)]

.

Topiramate**

100 mg

500 mg

metformin

1.25

1.17

* All metformin and coadministered drugs were given as single doses

† AUC = AUC(INF)

‡ Ratio of arithmetic means

**At steady state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours; AUC = AUC0-12h

Table 5 Effect of Metformin on Coadministered Drug Systemic Exposure

Coadministered

Drug

Dosing of

Coadministered

Drug*

Dosing of

Metformin*

Geometric Mean Ratio

(ratio with/without metformin)

No effect=1.0

Glyburide

5 mg

850 mg§

glyburide

0.78‡

0.63‡

Furosemide

40 mg

850 mg

furosemide

0.87‡

0.69‡

Nifedipine

10 mg

850 mg

nifedipine

1.10§

1.08

Propranolol

40 mg

850 mg

propranolol

1.01§

1.020

Ibuprofen

400 mg

850 mg

ibuprofen

0.97¶

1.01¶

Cimetidine

400 mg

850 mg

cimetidine

0.95§

1.01

* All metformin and coadministered drugs were given as single doses

† AUC = AUC(INF) unless otherwise noted

‡ Ratio of arithmetic means, p-value of difference <0.05

§ AUC(0-24 hours) reported

¶ Ratio of arithmetic means

15 NONCLINICAL TOXICOLOGY

15.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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TRAJENTA DUO

No animal studies have been conducted with the combined products in TRAJENTA DUO to

evaluate carcinogenesis, mutagenesis, or impairment of fertility. General toxicity studies in rats up

to 13 weeks were performed with TRAJENTA DUO.

The following data are based on the findings in studies with linagliptin and metformin individually.

Linagliptin

Linagliptin did not increase the incidence of tumors in male and female rats in a 2-year study at

doses of 6, 18, and 60 mg/kg. The highest dose of 60 mg/kg is approximately 418 times the clinical

dose of 5 mg/day based on AUC exposure. Linagliptin did not increase the incidence of tumors in

mice in a 2-year study at doses up to 80 mg/kg (males) and 25 mg/kg (females), or approximately 35

and 270 times the clinical dose based on AUC exposure. Higher doses of linagliptin in female mice

(80 mg/kg) increased the incidence of lymphoma at approximately 215 times the clinical dose based

on AUC exposure.

Linagliptin was not mutagenic or clastogenic with or without metabolic activation in the Ames

bacterial mutagenicity assay, a chromosomal aberration test in human lymphocytes, and an in vivo

micronucleus assay.

In fertility studies in rats, linagliptin had no adverse effects on early embryonic development,

mating, fertility, or bearing live young up to the highest dose of 240 mg/kg (approximately 943

times the clinical dose based on AUC exposure).

Metformin Hydrochloride

Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and

mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1500

mg/kg/day, respectively. These doses are both approximately 4 times the maximum recommended

human daily dose of 2000 mg/kg/day based on body surface area comparisons. No evidence of

carcinogenicity with metformin was found in either male or female mice. Similarly, there was no

tumorigenic potential observed with metformin in male rats. There was, however, an increased

incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day.

There was no evidence of a mutagenic potential of metformin in the following in vitro tests: Ames

test (Salmonella typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal

aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also

negative.

Fertility of male or female rats was unaffected by metformin when administered at doses as high as

600 mg/kg/day, which is approximately 2 times the MRHD based on body surface area

comparisons.

16

CLINICAL STUDIES

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The coadministration of linagliptin and metformin has been studied in patients with type 2 diabetes

mellitus inadequately controlled on diet and exercise and in combination with sulfonylurea.

There have been no clinical efficacy studies conducted with TRAJENTA DUO; however,

bioequivalence of TRAJENTA DUO to linagliptin and metformin coadministered as individual

tablets was demonstrated in healthy subjects.

16.1 Glycemic Control Trials

Initial Combination Therapy with Linagliptin and Metformin

A total of 791 patients with type 2 diabetes mellitus and inadequate glycemic control on diet and

exercise participated in the 24-week, randomized, double-blind, portion of this placebo-controlled

factorial study designed to assess the efficacy of linagliptin as initial therapy with metformin.

Patients on an antihyperglycemic agent (52%) underwent a drug washout period of 4 weeks’

duration. After the washout period and after completing a 2-week single-blind placebo run-in

period, patients with inadequate glycemic control (A1C

7.0% to

10.5%) were randomized. Patients

with inadequate glycemic control (A1C

7.5% to <11.0%) not on antihyperglycemic agents at study

entry (48%) immediately entered the 2-week single-blind placebo run-in period and then were

randomized. Randomization was stratified by baseline A1C (<8.5% vs

8.5%) and use of a prior oral

antidiabetic drug (none vs monotherapy). Patients were randomized in a 1:2:2:2:2:2 ratio to either

placebo or one of 5 active-treatment arms. Approximately equal numbers of patients were

randomized to receive initial therapy with 5 mg of linagliptin once daily, 500 mg or 1000 mg of

metformin twice daily, or 2.5 mg of linagliptin twice daily in combination with 500 mg or 1000 mg

of metformin twice daily. Patients who failed to meet specific glycemic goals during the study were

treated with sulfonylurea, thiazolidinedione, or insulin rescue therapy.

Initial therapy with the combination of linagliptin and metformin provided significant

improvements in A1C, and fasting plasma glucose (FPG) compared to placebo, to metformin alone,

and to linagliptin alone (Table 6, Figure 1). The adjusted mean treatment difference in A1C from

baseline to week 24 (LOCF) was -0.5% (95% CI -0.7, -0.3; p<0.0001) for linagliptin 2.5

mg/metformin 1000 mg twice daily compared to metformin 1000 mg twice daily; -1.1% (95% CI -

1.4, -0.9; p<0.0001) for linagliptin 2.5 mg/metformin 1000 mg twice daily compared to linagliptin 5

mg once daily; -0.6% (95% CI -0.8, -0.4; p<0.0001) for linagliptin 2.5 mg/metformin 500 mg twice

daily compared to metformin 500 mg twice daily; and -0.8% (95% CI -1.0, -0. 6; p<0.0001) for

linagliptin 2.5 mg/metformin 500 mg twice daily compared to linagliptin 5 mg once daily.

Lipid effects were generally neutral. No meaningful change in body weight was noted in any of the

6 treatment groups.

Table 6 Glycemic Parameters at Final Visit (24-Week Study) for Linagliptin and Metformin,

Alone and in Combination in Randomized Patients with Type 2 Diabetes Mellitus

Inadequately Controlled on Diet and Exercise**

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Placebo

Linagliptin

5 mg Once

Daily*

Metformin

500 mg

Twice

Daily

Linagliptin

2.5 mg

Twice

Daily* +

Metformin

500 mg

Twice

Daily

Metformin

1000 mg

Twice

Daily

Linagliptin

2.5 mg

Twice

Daily* +

Metformin

1000 mg

Twice Daily

A1C (%)

Number

patients

n=65

n=135

n=141

n=137

n=138

n=140

Baseline (mean)

Change from

baseline (adjusted

mean****)

-0.5

-0.6

-1.2

-1.1

-1.6

Difference from

placebo (adjusted

mean) (95% CI)

-0.6 (-0.9, -

0.3)

-0.8 (-1.0, -

0.5)

-1.3 (-1.6, -

1.1)

-1.2 (-1.5, -

0.9)

-1.7 (-2.0, -

1.4)

Patients [n (%)]

achieving A1C

<7% ***

7 (10.8)

14 (10.4)

26 (18.6)

41 (30.1)

42 (30.7)

74 (53.6)

Patients (%)

receiving rescue

medication

29.2

11.1

13.5

FPG (mg/dL)

Number

patients

n=61

n=134

n=136

n=135

n=132

n=136

Baseline (mean)

Change from

baseline (adjusted

mean****)

Difference from

placebo (adjusted

mean) (95% CI)

-19 (-31, -

-26 (-38, -

-43 (-56, -

-42 (-55, -

-60 (-72, -

* Total daily dose of linagliptin is equal to 5 mg

** Full analysis population using last observation on study

*** Metformin 500 mg twice daily, n=140; Linagliptin 2.5 mg twice daily + Metformin 500 mg twice

daily, n=136; Metformin 1000 mg twice daily, n=137; Linagliptin 2.5 mg twice daily + Metformin

1000 mg twice daily, n=138.

**** HbA1c: ANCOVA model included treatment and number of prior OADs as class-effects, as well

as baseline HbA1c as continuous covariates. FPG: ANCOVA model included treatment and number

of prior OADs as class-effects, as well as baseline HbA1c and baseline FPG as continuous covariates.

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Figure 1

Adjusted Mean Change from Baseline for A1C (%) over 24 Weeks with Linagliptin

and Metformin, Alone and in Combination in Patients with Type 2 Diabetes Mellitus

Inadequately Controlled with Diet and Exercise - FAS completers.

Initial Combination Therapy with Linagliptin and Metformin vs Linagliptin in Treatment-Naïve

Patients

A total of 316 patients with type 2 diabetes diagnosed within the previous 12 months and

treatment-naïve (no antidiabetic therapy for 12 weeks prior to randomization) and inadequate

glycemic control (A1C

8.5% to

12.0%) participated in a 24-week, randomized, double-blind, study

designed to assess the efficacy of linagliptin in combination with metformin vs linagliptin. Patients

were randomized (1:1), after a 2-week run-in period, to either linagliptin 5 mg plus metformin (1500

to 2000 mg per day, n=159) or linagliptin 5 mg plus placebo, (n=157) administered once daily.

Patients in the linagliptin and metformin treatment group were up-titrated to a maximum tolerated

dose of metformin (1000 to 2000 mg per day) over a three-week period.

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Initial therapy with the combination of linagliptin and metformin provided statistically significant

improvements in A1C compared to linagliptin (Table 7). The mean difference between groups in

A1C change from baseline was -0.8% with 2-sided 95% confidence interval (-1.23%, -0.45%).

Table 7 Glycemic Parameters at 24 Weeks in Study Comparing Linagliptin in Combination with

Metformin to Linagliptin in Treatment-Naïve Patients*

Linagliptin 5 mg +

Metformin

Linagliptin 5 mg +

Placebo

A1C (%) *

Number of patients

n=153

n=150

Baseline (mean)

Change from baseline (adjusted mean)

-2.9

Difference from linagliptin (adjusted

mean**) (95% CI)

-0.84 (-1.23, -0.45)

Patients [n (%)] achieving A1C <7% *

82 (53.6)

45 (30)

FPG (mg/dL) *

Number of patients

n=153

n=150

Baseline (mean)

Change from baseline (adjusted mean)

Difference from linagliptin (adjusted

mean**) (95% CI)

-18†† (-31, -5.5)

†p<0.0001 compared to linagliptin, ††p=0.0054 compared to linagliptin

*Full analysis set population

**A1C: MMRM model included treatment, continuous baseline A1C, baseline A1C by visit

interaction, visit by treatment interaction, baseline renal impairment by treatment interaction and

baseline renal impairment by treatment by visit interaction. FPG: MMRM model included

treatment, continuous baseline A1C, continuous baseline FPG, baseline FPG by visit interaction,

visit by treatment interaction, baseline renal impairment by treatment interaction and baseline renal

impairment by treatment by visit interaction.

The adjusted mean changes for A1C (%) from baseline over time for linagliptin and metformin as

compared to linagliptin alone were maintained throughout the 24 week treatment period. Using the

completers analysis the respective adjusted means for A1C (%) changes from baseline for linagliptin

and metformin as compared to linagliptin alone were -1.9 and -1.3 at week 6, -2.6 and -1.8 at week

12, -2.7 and -1.9 at week 18, and -2.7 and -1.9 at week 24.

Changes in body weight from baseline were not clinically significant in either treatment group.

Add-On Combination Therapy With Metformin

A total of 701 patients with type 2 diabetes participated in a 24-week, randomized, double-blind,

placebo-controlled study designed to assess the efficacy of linagliptin in combination with

metformin. Patients already on metformin (n=491) at a dose of at least 1500 mg per day were

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randomized after completing a 2-week open-label placebo run-in period. Patients on metformin

and another antihyperglycemic agent (n=207) were randomized after a run-in period of

approximately 6 weeks on metformin (at a dose of at least 1500 mg per day) in monotherapy.

Patients were randomized to the addition of either linagliptin 5 mg or placebo, administered once

daily. Patients who failed to meet specific glycemic goals during the studies were treated with

glimepiride rescue.

In combination with metformin, linagliptin provided statistically significant improvements in A1C,

FPG, and 2-hour PPG compared with placebo (Table 8). Rescue glycemic therapy was used in 7.8%

of patients treated with linagliptin 5 mg and in 18.9% of patients treated with placebo. A similar

decrease in body weight was observed for both treatment groups.

Table 8 Glycemic Parameters in Placebo-Controlled Study for Linagliptin in Combination with

Metformin*

Linagliptin 5 mg +

Metformin

Placebo + Metformin

A1C (%)

Number of patients

n=513

n=175

Baseline (mean)

Change from baseline (adjusted mean***)

-0.5

0.15

Difference from placebo + metformin

(adjusted mean) (95% CI)

-0.6 (-0.8, -0.5)

Patients [n (%)] achieving A1C <7% **

127 (26.2)

15 (9.2)

FPG (mg/dL)

Number of patients

n=495

n=159

Baseline (mean)

Change from baseline (adjusted mean***)

Difference from placebo + metformin

(adjusted mean) (95% CI)

-21 (-27, -15)

2-hour PPG (mg/dL)

Number of patients

n=78

n=21

Baseline (mean)

Change from baseline (adjusted mean***)

Difference from placebo + metformin

(adjusted mean) (95% CI)

-67 (-95, -40)

* Full analysis population using last observation on study

** Linagliptin 5 mg + Metformin, n=485; Placebo + Metformin, n=163.

*** HbA1c: ANCOVA model included treatment and number of prior oral OADs as class-effects, as

well as baseline HbA1c as continuous covariates. FPG: ANCOVA model included treatment and

number of prior OADs as class-effects, as well as baseline HbA1c and baseline FPG as continuous

covariates. PPG: ANCOVA model included treatment and number of prior OADs as class-effects, as

well as baseline HbA1c and baseline postprandial glucose after two hours as covariate.

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Active-Controlled Study vs Glimepiride in Combination With Metformin

The efficacy of linagliptin was evaluated in a 104-week double-blind, glimepiride-controlled non-

inferiority study in type 2 diabetic patients with insufficient glycemic control despite metformin

therapy. Patients being treated with metformin only entered a run-in period of 2 weeks’ duration,

whereas patients pretreated with metformin and one additional antihyperglycemic agent entered a

run-in treatment period of 6 weeks’ duration with metformin monotherapy (dose of

1500 mg per

day) and washout of the other agent. After an additional 2-week placebo run-in period, those with

inadequate glycemic control (A1C 6.5% to 10%) were randomized 1:1 to the addition of linagliptin 5

mg once daily or glimepiride. Randomization was stratified by baseline HbA1c (<8.5% vs

8.5%),

and the previous use of antidiabetic drugs (metformin alone vs metformin plus one other OAD).

Patients receiving glimepiride were given an initial dose of 1 mg/day and then electively titrated

over the next 12 weeks to a maximum dose of 4 mg/day as needed to optimize glycemic control.

Thereafter, the glimepiride dose was to be kept constant, except for down-titration to prevent

hypoglycemia.

After 52 weeks and 104 weeks, linagliptin and glimepiride both had reductions from baseline in

A1C (52 weeks: -0.4% for linagliptin, -0.6% for glimepiride; 104 weeks: -0.2% for linagliptin, -0.4%

for glimepiride) from a baseline mean of 7.7% (Table 9). The mean difference between groups in

A1C change from baseline was 0.2% with 2-sided 97.5% confidence interval (0.1%, 0.3%) for the

intent-to-treat population using last observation carried forward. These results were consistent with

the completers analysis.

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Table 9

Glycemic Parameters at 52 and 104 Weeks in Study Comparing Linagliptin to

Glimepiride as Add-On Therapy in Patients Inadequately Controlled on Metformin**

Week 52

Week 104

Linagliptin

5 mg +

Metformin

Glimepiride

+ Metformin

(mean

glimepiride

dose 3 mg)

Linagliptin

5 mg +

Metformin

Glimepiride

+ Metformin

(mean

glimepiride

dose 3 mg)

A1C (%)

Number of patients

n=764

n=755

n=764

n=755

Baseline (mean)

Change from baseline (adjusted

mean****)

-0.4

-0.6

-0.2

-0.4

Difference from glimepiride

(adjusted mean) (97.5% CI)

0.2 (0.1, 0.3)

0.2 (0.1, 0.3)

FPG (mg/dL)

Number of patients

n=733

n=725

n=733

n=725

Baseline (mean)

Change from baseline (adjusted

mean****)

-2†

* p<0.0001 vs glimepiride

p=0.0012 vs glimepiride

** Full analysis population using last observation on study

**** HbA1c: ANCOVA model included treatment and number of prior OADs as class-effects, as well

as baseline HbA1c as continuous covariates. FPG: ANCOVA model included treatment and number

of prior OADs as class-effects, as well as baseline HbA1c and baseline FPG as continuous covariates.

Patients treated with linagliptin had a mean baseline body weight of 86 kg and were observed to

have an adjusted mean decrease in body weight of 1.1 kg at 52 weeks and 1.4 kg at 104 weeks.

Patients on glimepiride had a mean baseline body weight of 87 kg and were observed to have an

adjusted mean increase from baseline in body weight of 1.4 kg at 52 weeks and 1.3 kg at 104 weeks

(treatment difference p<0.0001 for both timepoints).

Add-On Combination Therapy With Metformin and a Sulfonylurea

A total of 1058 patients with type 2 diabetes mellitus participated in a 24-week, randomized,

double-blind, placebo-controlled study designed to assess the efficacy of linagliptin in combination

with a sulfonylurea and metformin. The most common sulfonylureas used by patients in the study

were glimepiride (31%), glibenclamide (26%), and gliclazide (26% [not available in the United

States]). Patients on a sulfonylurea and metformin were randomized to receive linagliptin 5 mg or

placebo, each administered once daily. Patients who failed to meet specific glycemic goals during

the study were treated with pioglitazone rescue. Glycemic end points measured included A1C and

FPG.

In combination with a sulfonylurea and metformin, linagliptin provided statistically significant

improvements in A1C and FPG compared with placebo (Table 10). In the entire study population

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(patients on linagliptin in combination with a sulfonylurea and metformin), a mean reduction from

baseline relative to placebo in A1C of

-0.6% and in FPG of -13 mg/dL was seen. Rescue therapy was used in 5.4% of patients treated with

linagliptin 5 mg and in 13% of patients treated with placebo. Change from baseline in body weight

did not differ significantly between the groups.

Table 10 Glycemic Parameters at Final Visit (24-Week Study) for Linagliptin in Combination

With Metformin and Sulfonylurea*

Linagliptin 5 mg +

Metformin + SU

Placebo + Metformin

+ SU

A1C (%)

Number of patients

n=778

n=262

Baseline (mean)

Change from baseline (adjusted mean***)

-0.7

-0.1

Difference from placebo (adjusted mean)

(95% CI)

-0.6 (-0.7, -0.5)

Patients [n (%)] achieving A1C <7% **

217 (29.2)

20 (8.1)

FPG (mg/dL)

Number of patients

n=739

n=248

Baseline (mean)

Change from baseline (adjusted mean***)

Difference from placebo (adjusted mean)

(95% CI)

-13 (-18, -7)

SU=sulfonylurea

* Full analysis population using last observation on study

** Linagliptin 5 mg + Metformin + SU, n=742; Placebo + Metformin + SU, n=247

*** HbA1c: ANCOVA model included treatment as class-effects and baseline HbA1c as continuous

covariates. FPG: ANCOVA model included treatment as class effects, as well as baseline HbA1c and

baseline FPG as continuous covariates.

16.2 Linagliptin Cardiovascular Safety Trial

CARMELINA

The cardiovascular risk of linagliptin was evaluated in CARMELINA, a multi-national, multi-

center, placebo-controlled, double-blind, parallel group trial comparing linagliptin (N=3494) to

placebo (N=3485) in adult patients with type 2 diabetes mellitus and a history of established

macrovascular and/or renal disease. The trial compared the risk of major adverse cardiovascular

events (MACE) between linagliptin and placebo when these were added to standard of care

treatments for diabetes and other cardiovascular risk factors. The trial was event driven, the median

duration of follow-up was 2.2 years and vital status was obtained for 99.7% of patients.

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Patients were eligible to enter the trial if they were adults with type 2 diabetes, with HbA1c of 6.5%

to 10%, and had either albuminuria and previous macrovascular disease (39% of enrolled

population), or evidence of impaired renal function by eGFR and Urinary Albumin Creatinine Ratio

(UACR) criteria (42% of enrolled population), or both (18% of enrolled population).

At baseline the mean age was 66 years and the population was 63% male, 80% Caucasian, 9% Asian,

and 6% Black. Mean HbA1c was 8.0% and mean duration of type 2 diabetes mellitus was 15 years.

The trial population included 17% patients

75 years of age and 62% patients with renal

impairment defined as eGFR <60 mL/min/1.73 m2. The mean eGFR was 55 mL/min/1.73 m2 and

27% of patients had mild renal impairment (eGFR 60 to 90 mL/min/1.73 m2), 47% of patients had

moderate renal impairment (eGFR 30 to <60 mL/min/1.73 m2) and 15% of patients had severe renal

impairment (eGFR <30 mL/min/1.73 m2). Patients were taking at least one antidiabetic drug (97%),

and the most common were insulin and analogues (57%), metformin (54%) and sulfonylurea (32%).

Patients were also taking antihypertensives (96%), lipid lowering drugs (76%) with 72% on statin,

and aspirin (62%).

The primary endpoint, MACE, was the time to first occurrence of one of three composite outcomes

which included cardiovascular death, nonfatal myocardial infarction or nonfatal stroke. The study

was designed as a non-inferiority trial with a pre-specified risk margin of 1.3 for the hazard ratio of

MACE.

The results of CARMELINA, including the contribution of each component to the primary

composite endpoint, are shown in Table 11. The estimated hazard ratio for MACE associated with

linagliptin relative to placebo was 1.02 with a 95% confidence interval of (0.89, 1.17). The upper

bound of this confidence interval, 1.17, excluded the risk margin of 1.3. The Kaplan-Meier curve

depicting time to first occurrence of MACE is shown in Figure 2.

Table 11

Major Adverse Cardiovascular Events (MACE) by Treatment Group in the

CARMELINA Trial

Linagliptin 5 mg

n = 3494

Placebo

n = 3485

Hazard

Ratio

Number

of

Subjects

(%)

Incidence

Rate per

1000 PY*

Number of

Subjects

(%)

Incidence

Rate per

1000 PY*

(95% CI)

Composite of first event of

CV death, non-fatal

myocardial infarction

(MI), or non-fatal stroke

(MACE)

434 (12.4)

57.7

420 (12.1)

56.3

1.02 (0.89,

1.17)

CV death**

255 (7.3)

32.6

264 (7.6)

34.0

0.96 (0.81,

1.14)

Non-fatal MI**

156 (4.5)

20.6

135 (3.9)

18.0

1.15 (0.91,

1.45)

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Non-fatal stroke**

65 (1.9)

73 (2.1)

0.88 (0.63,

1.23)

*PY=patient years

**A patient may have experienced more than one component; therefore, the sum of the components is larger than the

number of patients who experienced the composite outcome.

Figure 2

Kaplan-Meier: Time to First Occurrence of MACE in the CARMELINA Trial

CAROLINA

The cardiovascular risk of linagliptin was evaluated in CAROLINA, a multi-center, multi-national,

randomized, double-blind, parallel group trial comparing linagliptin (N=3023) to glimepiride

(N=3010) in adult patients with type 2 diabetes mellitus and a history of established cardiovascular

disease and/or multiple cardiovascular risk factors. The trial compared the risk of major adverse

cardiovascular events (MACE) between linagliptin and glimepiride when these were added to

standard of care treatments for diabetes and other cardiovascular risk factors. The trial was event

driven, the median duration of follow-up was 6.23 years and vital status was obtained for 99.3% of

patients.

Patients were eligible to enter the trial if they were adults with type 2 diabetes with insufficient

glycemic control (defined as HbA1c of 6.5% to 8.5% or 6.5% to 7.5% depending on whether

treatment-naïve, on monotherapy or on combination therapy), and were defined to be at high

cardiovascular risk with previous vascular disease, evidence of vascular related end-organ damage,

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70 years, and/or two cardiovascular risk factors (duration of diabetes >10 years, systolic blood

pressure >140 mmHg, current smoker, LDL cholesterol

135 mg/dL).

At baseline, the mean age was 64 years and the population was 60% male, 73% Caucasian, 18%

Asian, and 5% Black. The mean HbA1c was 7.15% and mean duration of type 2 diabetes was 7.6

years. The trial population included 34% patients

70 years of age and 19% patients with renal

impairment defined as eGFR <60 mL/min/1.73 m

. The mean eGFR was 77 mL/min/1.73 m

Patients were taking at least one antidiabetic drug (91%) and the most common were metformin

(83%) and sulfonylurea (28%). Patients were also taking antihypertensives (89%), lipid lowering

drugs (70%) with 65% on statin, and aspirin (47%).

The primary endpoint, MACE, was the time to first occurrence of one of three composite outcomes

which included cardiovascular death, non-fatal myocardial infarction or non-fatal stroke. The

study was designed as a non-inferiority trial with a pre-specified risk margin of 1.3 for the upper

bound of the 95% CI for the hazard ratio of MACE.

The results of CAROLINA, including the contribution of each component to the primary composite

endpoint, are shown in Table 12. The Kaplan-Meier curve depicting time to first occurrence of

MACE is shown in Figure 3.

Table 12

Major Adverse Cardiovascular Events (MACE) by Treatment Group in the

CAROLINA Study

Linagliptin 5 mg

n=3023

Glimepiride (1 mg to

4 mg)

n=3010

Hazard

Ratio

Number

of

Subjects

(%)

Incidence

Rate per

1000 PY*

Number

of

Subjects

(%)

Incidence

Rate per

1000 PY*

(95% CI)

Composite of first event of CV death,

non-fatal myocardial infarction

(MI), or non-fatal stroke (MACE)

(11.8)

20.7

(12.0)

21.2

0.98 (0.84,

1.14)

CV death**

169 (5.6)

168 (5.6)

1.00 (0.81,

1.24)

Non-fatal MI**

145 (4.8)

142 (4.7)

1.01 (0.80,

1.28)

Non-fatal stroke**

91 (3.0)

104 (3.5)

0.87 (0.66,

1.15)

*PY=patient years

**A patient may have experienced more than one component; therefore, the sum of the components

is larger than the number of patients who experienced the composite outcome

Figure 3

Time to First Occurrence of 3P-MACE in CAROLINA

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17

HOW SUPPLIED/STORAGE AND HANDLING

Blister packs are available with 14 and 60 film-coated tablets.

Not all the pack sizes may be marketed.

Storage

Store below 25°C.

The expiry date of the product is indicated on the packaging materials.

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18

MANUFACTURER

Boehringer Ingelheim Pharma GmbH & Co. KG

Binger Straße 173

55216 Ingelheim am Rhein

GERMANY

Boehringer Ingelheim Ellas A.E., Koropi, Greece

Dragenopharm Apotheker Puschl GmbH, Germany

Goollstrasse 1, 84529 Tittmoning, Germany

19

REGISTRATION HOLDER / NUMBER

Boehringer Ingelheim Israel Ltd.,

Medinat Ha-Yehudim 89 St.; P.O.B 4124, Herzeliya Pituach 4676672

Registration numbers:

Trajenta Duo

Tablets

2.5mg/500mg

150-17-33739

Trajenta Duo

Tablets

2.5mg/850mg

150-18-33740

Trajenta Duo

Tablets

2.5mg/1,000mg

150-19-33741

Revised in May 2020

רבמטפס

2019

,ה/רקי ה/אפור

ה/רקי ת/חקור

וכדע :ןודנה

ן

ולע

ן

רישכתה לש

Duo

rajenta

T

Trajenta duo

2.5mg/500mg film-coated tablets (linagliptin/metformin)

Trajenta duo

2.5mg/850mg film-coated tablets (linagliptin /metformin)

Trajenta duo

2.5mg/1000mg film-coated tablets (linagliptin /metformin)

תרבח

םייהלגניא רגנירוב םכעידוהל תשקבמ מ"עב לארשי וכדע לע

ןולעב ןכרצל אפורלו לש

.ןודנב רישכתה

יוותה

מושרה

לארשיב רישכתל

TRAJENTA DUO is indicated as an adjunct to diet and exercise to improve glycemic

control in adults with type 2 diabetes mellitus when treatment with both linagliptin and

metformin is appropriate.

TRAJENTA-DUO should not be used in patients with type 1 diabetes or for the

treatment of diabetic ketoacidosis, as it would not be effective in these settings.

TRAJENTA-DUO has not been studied in patients with a history of pancreatitis.

It is unknown whether patients with a history of pancreatitis are at an increased risk for

the development of pancreatitis while using TRAJENTA-DUO.

םייונישה ולעב רתויב םייתועמשמה

ונמוס הטמ

ולעה

כדועמה

לשנ

תואירבה דרשמ רתאבש תופורתה רגאמב םוסרפל

,ןכ ומכ

לבקל ןתינ

לע

:םושירה לעבל היינפ ידי

םידוהיה תנידמ 'חר ,מ"עב לארשי םייהלגניא רגנירוב

חותיפ הילצרה

בו ןופלט

09-9730500

ה כ ר ב ב

ח ירימ ןז

הנוממ תחקור

לארשי םייהלגניא רגנירוב

ל ןולעב םינוכדע אפור

:

8 Warnings and precautions

[…]

8.3 Heart Failure

An association between DPP-4 inhibitor treatment and heart failure has been observed in cardiovascular

outcomes trials for two other members of the DPP-4 inhibitor class. These trials evaluated patients with

type 2 diabetes mellitus and atherosclerotic cardiovascular disease.

Consider the risks and benefits of TRAJENTA DUO prior to initiating treatment in patients at risk for

heart failure, such as those with a prior history of heart failure and a history of renal impairment, and

observe these patients for signs and symptoms of heart failure during therapy. Advise patients of the

characteristic symptoms of heart failure and to immediately report such symptoms. If heart failure

develops, evaluate and manage according to current standards of care and consider discontinuation of

TRAJENTA DUO.

[…]

8.7 Severe and Disabling Arthralgia

There have been postmarketing reports of severe and disabling arthralgia in patients taking DPP-4

inhibitors. The time to onset of symptoms following initiation of drug therapy varied from one day to

years. Patients experienced relief of symptoms upon discontinuation of the medication. A subset of

patients experienced a recurrence of symptoms when restarting the same drug or a different DPP-4

inhibitor. Consider DPP-4 inhibitors as a possible cause for severe joint pain and discontinue drug if

appropriate.

8.8 Bullous Pemphigoid

Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP-4

inhibitor use. In reported cases, patients typically recovered with topical or systemic immunosuppressive

treatment and discontinuation of the DPP-4 inhibitor. Tell patients to report development of blisters or

erosions while receiving TRAJENTA DUO. If bullous pemphigoid is suspected, TRAJENTA DUO

should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate

treatment.

[…]

9

ADVERSE REACTIONS

Laboratory Tests

Linagliptin

Increase in Uric Acid:

Changes in laboratory values that occurred more frequently in the linagliptin group

and ≥1% more than in the placebo group were increases in uric acid (1.3% in the placebo group, 2.7% in

the linagliptin group).

controlled clinical trial with linagliptin in type 2 diabetes mellitus

In a placebo

Increase in Lipase:

albuminuria, a mean increase of 30% in lipase concentrations from baseline

or macro

patients with micro

to 24 weeks was observed in the linagliptin arm compared to a mean decrease of 2% in the placebo arm.

1.7% patients in the

Lipase levels above 3 times upper limit of normal were seen in 8.2% compared to

linagliptin and placebo arms, respectively

[…]

9.2 Postmarketing Experience

Linagliptin

[see Indications and Usage (4.2) and Warnings

Acute pancreatitis, including fatal pancreatitis

and Precautions (8.2

ns including anaphylaxis, angioedema, and exfoliative skin

Hypersensitivity reactio

[see Warnings and Precautions (8.5)]

conditions

Severe and disabling arthralgia

[see Warnings and Precautions (8.7)]

Rash

Bullous pemphigoid

[see Warnings and Precautions (8.8

Mouth ulceration, stomatitis

Rhabdomyolysis

Metformin

Cholestatic, hepatocellular, and mixed hepatocellular liver injury

11

USE IN SPECIFIC POPULATIONS

11.3 Females and Males of Reproductive Potential

Discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin

may result in ovulation in some anovulatory women.

:ןכרצל ןולעב םינוכדע

2

.

הפורתב שומישה ינפל

םא הפורתב שמתשהל ןיא

:

(ךלש יתיילכה דוקפתב העיגפה תמר יהמ רידגי ךלש אפורה) רומח ןפואב דורי יתיילכ דוקפתמ לבוס ךניה

ויעבמ לבוס ךניה .תוילכב תורומח ת

:הפורתב שומישל תועגונה תודחוימ תורהזא

[...]

:בל תקיפס יא

לופיטה ינפל

גרט

ואוד הטנ

םא אפורל רפס

וא בל תקיפס יאמ רבעב תלבס וא לבוס ךנה :םיאבה םינימסתהמ דחא הווח ךנהו הדימב דימ אפורב ץעוויה .תוילכב תויעבמ

,המישנ יישק וא רבגתמ המישנ רצוק ;הביכשב דוחייב

;םיילגרה וא םיילוסרקה ,םיילגרה תופכב דוחייב ,םילזונ תריצא וא תוחפנתה

לקשמב הליגר יתלבו הריהמ היילע

.הליגר יתלב תופייע

.בל תקיפס יא לש םינימסת תויהל םילולע הלא לכ

בל תקיפס יא

םד םירזמ וניא ךלש בלה ובש בצמ וניה .תקפסמ תומכב

לופיטה ינפל

ב

רט

ג

ואוד הטנ

,

םא אפורל רפס

:

תויעבמ לבוס ךנה תורומח

הילכב

ךניה

לוה

קירז לבקל

דוגינ וא עבצ רמוח ךרוצל

תא קיספהל ךרוצ היהיש ןכתי .ןגטנר םוליצ תליטנ

גרט הטנ' ואוד

ןמזל רצק

ץעווה

אפורב

לפטמה

ךלש

יבגל

תליטנ תקספה דעומ גרט הטנ' ואוד

דעומ

תלחתה

התליטנ

תינשב

,ןוירה תננכתמ ךניאו הדימב .ללכ רוזחמ הווח הניאש וא רידס יתלב רוזחמ תלעב ,רבעמה םורט ליגב השיא ךניה יחווד .תורהל יוכיסה תא ריבגהל הלולע ואוד הטנ'גרטש ןוויכ ,העינמ יעצמא תריחב יבגל ךלש לפטמה אפורב יצעווה רטב לופיטה ךלהמב תירהו הדימב דימ ךלש אפורל .ואוד הטנ'ג

ואוד הטנ'גרט תלטונ ךניה םא .םא בלחב תרבוע ואוד בטנ'גרט םא עודי אל .קינהל תננכתמ וא הקינמ ךניה .ךקונית תא ליכאהל רתויב הבוטה ךרדה יבגל ךלש לפטמה אפורב יצעווה

םא ךנה

רפס ,הנוזת יפסותו םשרמ אלל תופורת ללוכ תורחא תופורת ,הנורחאל תחקל םא וא ,חקול ךכ לע חקורל וא אפורל

ןידיטמיסו ריוורגטולוד,בינטדנאו ,ןיזלונר לולע בולישה : גרט יביכרממ דחא) ןימרופטמ תומר תא תולעהל

הטנ (ואוד םדב

תיטקל תצמחל ןוכיס תולעהלו

(םייטפליפא םיפקתהב לופיטל הפורת) טאמאריפוט דימנפרולכיד וא דימלוזטצא ,דימאסינוז, לולע בולישה : תולעהל תיטקל תצמחל ןוכיסה תא

3

.

?הפורתב שמתשת דציכ

[...]

.רתוי ךומנ ןונימ ךל םושרי אפורהו ןכתיי ,תוילכ ידוקפתב הדירי ךל שיו הדימב

4

.

יאוול תועפות

:םיקרפמ יבאכ

יבכעמ תצובקמ תופורת ולטנ רשא םימיוסמ םילפוטמ

DPP4

יבאכ חתפל םילולע ,ואוד הטנ'גרטב םיביכרמה דחא , ולעש םיקרפמ .םירומח םיקרפ יבאכ לבוס ךנהו הדימב אפורל הנפ .(היגלרתרא) םיליבגמו םירומח תויהל םיל

:תוירוע תובוגת

יבכעמ תצובקמ תופורת ולטנ רשא םימיוסמ םילפוטמ

DPP4

חתפל םילולע ,ואוד הטנ'גרטב םיביכרמה דחא , תארקנה תירוע הבוגת

bullous pemphigoid

תיבב לופיט שורדל הלולע רשא ,

הדימב דימ אפורל הנפ .םילוח לופיט תקספה לע ץילמי לפטמה אפורהו ןכתיי .(תויזורא) רועה לש ינוציחה קלחב םיעצפ וא תויחופלש תוחתפתמו .ואוד הטנ'גרטב

ב תועיפומ) תוחיכש יאוול תועפות

10-1

םישמתשמ

ךותמ

100

:(

ףא

םותס

וא

תלזנ יבאכ ,

לושלשו ןורג

[...]

ש יאוול תועפות ,לועיש :(ןימרופטמ/ןיטפילגניל) ואוד הטנ'גרט לש םיביכרמה דחאב שומישמ האצותכ ופצנ

תוריצע

,תירואה הצמוחב היילע

ןימטיו תומרב הדיריו (זאפיל) ןמוש םיקרפמה םימיזנאב היילע

ב תועיפומ) תוחיכש ןניאש יאוול תועפות

1-10

ךותמ םישמתשמ

1000

:(

תי תושיגר ,ןובאיתב הדירי

,הליחב האקה

ידבכ קזנ .החירפ, תועפות

יאוול

תורידנ

תועיפומה)

ב

10

-

1

םישמתשמ

ךותמ

10000

:(

תוירוע תובוגת ) םיעצפ וא/ו תויחופלש תרוצב

Bullous pemphigoid

הפב םיביכ

תועפות

יאוול

:העבקנ םרט ןתוחיכשש ,תופסונ

דרג ,בלבל תקלד , יע יבאכ ,השלוח ,תוחיפנ ,םירירש יבאכ ,לוכ שאר יבאכו תינטב תוחונ יא

הפורתה קוויש רחאל םיינטנופס םיחווידב

לש םיביכרמה דחאב שומישמ האצותכ יאוול תועפות לע םיחוויד ויה .החירפ:(ןימרופטמ/ןיטפילגניל) ואוד הטנ'גרט

.תוומל הליבוה ףאש הפירח בלבל תקלד

רתי תושיגר

םיליבגמו םירומח םיקרפמ יבאכ

לד ,הפב םיביכ הפב תק

) םיעצפ וא/ו תויחופלש תרוצב תוירוע תובוגת

Bullous pemphigoid

ידבכ קזנ

רירש סמת

rhabdomyolysis

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