TRAJENTA

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

The dispensing of this medicine requires a doctor’s prescription

Trajenta

®

5 mg film-coated tablets

Each film-coated tablet of Trajenta 5 mg contains: 5 mg linagliptin.

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?

In addition to diet and physical activity, Trajenta is intended for controlling blood sugar levels in adults

with type 2 diabetes. Trajenta may be given as monotherapy or in combination with additional

medicinal products to reduce blood sugar levels.

Limitation of use: Do not use Trajenta to treat type 1 diabetes or diabetic ketoacidosis, because

Trajenta is not effective with these conditions.

Trajenta has not been studied in patients who have previously had pancreatitis (inflammation of the

pancreas). It is not known whether patients who have previously suffered from pancreatitis are at an

increased risk of developing pancreatitis during the treatment with Trajenta.

Therapeutic group: DPP-4 (dipeptidyl peptidase-4) inhibitors.

2. Before using this medicine

Do not use this medicine if:

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

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

allergy to Trajenta 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.

Special warnings about using this medicine

Before using Trajenta, tell your doctor if:

You are taking additional medicines to lower your blood sugar level: especially medicines called

sulfonylurea (such as glimepiride) or insulin. Combining these medicines with Trajenta increases

the risk of a drop in blood sugar level (hypoglycemia). Your doctor may want to reduce your dose of

sulfonylurea or insulin. See further details in Section 4: 'Side effects’.

You have, or have ever had pancreatitis, gall stones, alcohol dependence, high levels of

triglycerides in the blood, or any other medical problem.

You 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 lying down

swelling or fluid retention, especially in your feet, ankles, or legs

an unusually fast increase in weight

unusual tiredness

These may be symptoms of heart failure. Heart failure means that your heart does not pump blood

well enough.

You are breastfeeding or planning to breastfeed. It is not known if Trajenta passes into your breast

milk. Consult your doctor about the best way to feed your baby if you are taking Trajenta.

You are pregnant or plan to become pregnant. It is not known if Trajenta can harm your unborn

baby. If you are pregnant, talk to your doctor about the best way to control your sugar levels during

this time.

Pancreatitis (see Section 4: 'Side effects') may occur in patients treated with Trajenta, it may be

severe and even life threatening. Certain medical problems may increase the risk of pancreatitis.

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

pain. You may experience pain which passes from your abdomen to your back. The pain may appear

with or without vomiting. These may be symptoms of pancreatitis.

Other medicines and Trajenta

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

and nutritional supplements, tell your doctor or pharmacist. Particularly if you are taking:

Rifampicin (an antibiotics for treating tuberculosis): this combination may reduce the efficacy of

Trajenta.

Other blood sugar lowering medicines. When your body is under stress, such as fever, trauma (for

example, a road accident), infection or surgery, the dosage of blood sugar-lowering medicine that

you need may change. Consult your doctor right away if you have any of these conditions and

follow your doctor’s instructions.

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.

Stay on your diet and exercise program while taking Trajenta.

Your doctor will monitor your diabetes with regular blood tests, including your blood sugar and your

glycated hemoglobin (HbA1C) levels.

Ask your doctor to advise you how to prevent, identify and treat low blood sugar levels

(hypoglycemia), high blood sugar levels (hyperglycemia), and diabetes complications.

Using the medicine and food

The medicine can be taken with or without food.

Pregnancy, breastfeeding, and fertility

If you are pregnant, plan to become pregnant or are breastfeeding, consult a doctor before taking this

medicine.

There is no information about the effect of this medicine on the 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.

Elderly patients, patients with renal insufficiency or liver insufficiency

No dose adjustment is necessary in these populations.

3.

How to use this medicine?

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 the medicine.

The recommended dose is usually one film-coated tablet, once a day. Do not exceed the

recommended dose.

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

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.

Persist with the treatment as recommended by the 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 the

pharmacist.

4. Side effects

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

this list of side effects. You may not experience any of them.

Serious side effects that require immediate medical attention:

Pancreatitis (unknown frequency):

Acute pancreatitis may rarely occur in patients treated with Trajenta; it may be severe and even life

threatening (see also section 2 'Special warnings about using this medicine').

Stop taking Trajenta and contact a doctor immediately if you develop persistent severe abdominal

pain. The pain may radiate to your back and may appear with or without vomiting. These may be

symptoms of pancreatitis.

Joint pain (common):

Certain patients who take DPP-4 inhibitors, such as Trajenta, may develop joint pain which may be

severe and disabling (arthralgia). Consult your doctor immediately.

Skin reactions (unknown frequency):

Certain patients who take DPP-4 inhibitors, such as Trajenta, may develop a skin reaction called

bullous pemphigoid, which may require treatment in hospital. See a doctor immediately if you develop

blisters or sores on the outer layer of your skin (erosions). Your doctor may advise you to stop taking

Trajenta.

Allergic reactions (hypersensitivity) (unknown frequency):

Severe allergic reactions may occur after taking the first dose or up to 3 months after starting treatment

with Trajenta. 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 your skin).

rash, itch, peeling of the skin.

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

go to a hospital emergency room right away.

Low blood sugar levels (hypoglycemia) (common side effect):

If you are taking Trajenta with other medicines that lower blood sugar levels, such as sulfonylurea or

insulin, the risk of low blood sugar levels increases. Signs and symptoms of low blood sugar level may

include the following: headache, drowsiness, weakness, dizziness, confusion, agitation, hunger, rapid

heartbeats, sweating, irritability. If you notice one or more of these signs, check your blood sugar level,

treat it if it is low and contact a doctor.

Common side effects, effects that occur in 1-10 users in 100:

Stuffy or runny nose and sore throat, diarrhea, cough, urinary tract infection, high blood levels of fats

(lipids or triglycerides), weight gain, constipation, joint pain, back pain, headache, infection in the upper

airways, pain in the extremities, in laboratory test: increased level of uric acid, increased level of

enzymes that break up fats (lipase).

Side effects of unknown frequency (side effects whose frequently is still unknown):

Muscle pain.

Mouth ulcers, inflammation of the mouth.

Skin reactions in the form of blisters and/or sores (bullous pemphigoid).

Breakdown of skeletal muscle (rhabdomyolysis).

The side effects listed above occurred when Trajenta was used on its own or together with other

medicines for balancing sugar.

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 ingredient this medicine also contains the following inactive ingredients:

mannitol, pregelatinized starch, maize starch, copovidone, magnesium stearate, hypromellose,

titanium dioxide, talc, polyethylene glycol, red ferric oxide.

What the medicine looks like and what are the contents of the package:

Trajenta is a round, light red, convex, film-coated tablet, with a sharp beveled edge. D5 is imprinted on

one side and the logo of Boehringer Ingelheim is imprinted on the other.

Tablets are packaged in blister trays of 30 film-coated tablets. Each package contains 30 or 90 film-

coated tablets.

Not all pack sizes may be marketed.

Registration holder's name and address: Boehringer Ingelheim Israel Ltd., 89 Medinat HaYehudim St.,

P.O.B. 4124, Herzeliya Pituach 4676672.

Manufacturer name: West Ward Columbus Inc., Columbus, Ohio, USA.

Registration number of the medicine in the National Drug Registry of the Ministry of Health: 149-96-

33738-00.

This leaflet was reviewed and approved by the Ministry of Health in March 2017 and revised in August

2019 in accordance with Ministry of Health guidelines

Trajenta

Updated Prescribing Information

File coated tablets 5 mg

May 2020

TRAJENTA

Linagliptin 5 mg

FILM COATED TABLETS

PRESCRIBING INFORMATION

1.

NAME OF THE MEDICINAL PRODUCT

Trajenta

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

The active ingredient is linagliptin 5 mg.

For the full list of excipients, see section "DESCRIPTION" below.

3.

PHARMACEUTICAL FORM

Film coated tablets.

4.

INDICATIONS AND USAGE

4.1.

Monotherapy and Combination Therapy

TRAJENTA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type

2 diabetes mellitus [see Clinical Studies (16.1)].

4.2.

Important Limitations of Use

TRAJENTA 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 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 [see Warnings and Precautions (8.1)].

5.

DOSAGE AND ADMINISTRATION

5.1.

Recommended Dosing

The recommended dose of TRAJENTA is 5 mg once daily.

TRAJENTA tablets can be taken with or without food.

5.2.

Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin

When TRAJENTA is used in combination with an insulin secretagogue (e.g., sulfonylurea) or with insulin,

a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia

[see Warnings and Precautions (8.2)].

Trajenta

Updated Prescribing Information

File coated tablets 5 mg

May 2020

6.

DOSAGE FORMS AND STRENGTHS

TRAJENTA (linagliptin) 5 mg tablets are light red, round, biconvex, bevel-edged, film-coated tablets with

“D5” debossed on one side and the Boehringer Ingelheim logo debossed on the other side.

7.

CONTRAINDICATIONS

TRAJENTA is contraindicated in patients with hypersensitivity to linagliptin or any of the excipients in

Trajenta, reactions such as anaphylaxis, angioedema, exfoliative skin conditions, urticaria, or bronchial

hyperreactivity have occured [see Warnings and Precautions (8.

) and Adverse Reactions (9)].

8.

WARNINGS AND PRECAUTIONS

8.1.

Pancreatitis

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

the CARMELINA trial [see Clinical Studies (16.2)], acute pancreatitis was reported in 9 (0.3%) patients

treated with TRAJENTA and in 5 (0.1%) patients treated with placebo. Two patients treated with

TRAJENTA in the CARMELINA trial had acute pancreatitis with a fatal outcome. There have been

postmarketing reports of acute pancreatitis, including fatal pancreatitis, in patients treated with

TRAJENTA. Take careful notice of potential signs and symptoms of pancreatitis. If pancreatitis is

suspected, promptly discontinue TRAJENTA 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.

8.2.

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 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.

8.3.

Use with Medications Known to Cause Hypoglycemia

Insulin secretagogues and insulin are known to cause hypoglycemia. The use of TRAJENTA 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)]. The use of

TRAJENTA in combination with insulin in subjects with severe renal impairment was associated with a

higher rate of hypoglycemia [see Adverse Reactions (9.1)]. 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.

8.4.

Hypersensitivity Reactions

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

TRAJENTA. 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

TRAJENTA, with some reports occurring after the first dose. If a serious hypersensitivity reaction is

suspected, discontinue TRAJENTA, assess for other potential causes for the event, and institute

alternative treatment for diabetes.

Trajenta

Updated Prescribing Information

File coated tablets 5 mg

May 2020

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.

8.5.

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.

8.6.

Bullous Pemphigoid

Bullous pemphigoid was reported in 7 (0.2%) patients treated with TRAJENTA 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. If

bullous pemphigoid is suspected, TRAJENTA 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:

Pancreatitis [see Warnings and Precautions (8.1)]

Heart Failure [see Warnings and Precautions (8.2)]

Use with Medications Known to Cause Hypoglycemia [see Warnings and Precautions (8.3)]

Hypersensitivity Reactions [see Warnings and Precautions (8.4)]

Severe and Disabling Arthralgia [see Warnings and Precautions (8.5)]

Bullous Pemphigoid [see Warnings and Precautions (8.6)]

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.

The safety evaluation of TRAJENTA 5 mg once daily in patients with type 2 diabetes is based on 14

placebo-controlled trials, 1 active-controlled study, and one study in patients with severe renal

impairment. In the 14 placebo-controlled studies, a total of 3625 patients were randomized and treated

with TRAJENTA 5 mg daily and 2176 with placebo. The mean exposure in patients treated with

TRAJENTA across studies was 29.6 weeks. The maximum follow-up was 78 weeks.

TRAJENTA 5 mg once daily was studied as monotherapy in three placebo-controlled trials of 18 and 24

weeks’ duration and in five additional placebo-controlled studies lasting

18 weeks. The use of

TRAJENTA in combination with other antihyperglycemic agents was studied in six placebo-controlled

trials: two with metformin (12 and 24 weeks’ treatment duration); one with a sulfonylurea (18 weeks’

treatment duration); one with metformin and sulfonylurea (24 weeks’ treatment duration); one with

pioglitazone (24 weeks’ treatment duration); and one with insulin (primary endpoint at 24 weeks).

In a pooled dataset of 14 placebo-controlled clinical trials, adverse reactions that occurred in

2% of

patients receiving TRAJENTA (n = 3625) and more commonly than in patients given placebo (n = 2176),

are shown in Table 1. The overall incidence of adverse events with TRAJENTA were similar to placebo.

Trajenta

Updated Prescribing Information

File coated tablets 5 mg

May 2020

Table 1 Adverse Reactions Reported in

2% of Patients Treated with TRAJENTA and Greater than

Placebo in Placebo-Controlled Clinical Studies of TRAJENTA Monotherapy or Combination Therapy

Number (%) of Patients

TRAJENTA 5mg

n = 3625

Placebo

n = 2176

Nasopharyngitis

254 (7.0)

132 (6.1)

Diarrhea

119 (3.3)

65 (3.0)

Cough

76 (2.1)

30 (1.4)

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

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

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

(2.7% vs 0.8%) and weight increased (2.3% vs 0.8%) when TRAJENTA was used as add-on to pioglitazone;

and constipation (2.1% vs 1%) when TRAJENTA was used as add-on to basal insulin therapy. Other

adverse reactions reported in clinical studies with treatment of TRAJENTA were hypersensitivity (e.g.,

urticaria, angioedema, localized skin exfoliation, or bronchial hyperreactivity) and myalgia.

Following 104 weeks’ treatment in a controlled study comparing TRAJENTA with glimepiride in which

all patients were also receiving metformin, adverse reactions reported in

5% of patients treated with

TRAJENTA (n = 776) and more frequently than in patients treated with a sulfonylurea (n = 775) were

back pain (9.1% vs 8.4%), arthralgia (8.1% vs 6.1%), upper respiratory tract infection (8.0% vs 7.6%),

headache (6.4% vs 5.2%), cough (6.1% vs 4.9%), and pain in extremity (5.3% vs 3.9%).

In the clinical trial program, pancreatitis was reported in 15.2 cases per 10,000 patient year exposure

while being treated with TRAJENTA 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.

Hypoglycemia

Table 2 summarizes the incidence of hypoglycemia in placebo-controlled studies of TRAJENTA. The

incidence of hypoglycemia increased when TRAJENTA was administered with sulfonylurea or insulin.

Table 2: Incidence (%) of Hypoglycemia in Placebo-Controlled Clinical Studies of TRAJENTA in

Patients with Type 2 Diabetes Mellitus

Add-on to Sulfonylurea (18

Weeks)

Placebo (N=84)

TRAJENTA (N=161)

Hypoglycemia with plasma

glucose <54 mg/dL

1.2%

1.9%

Severe* hypoglycemia (%)

Add-on to Metformin and

Sulfonylurea (24 Weeks)

Placebo (N=263)

TRAJENTA (N=792)

Hypoglycemia with plasma

glucose <54 mg/dL

5.3%

8.1%

Severe* hypoglycemia (%)

0.8%

0.6%

Add-on to Basal Insulin (52

Weeks)

Placebo (N=630)

TRAJENTA (N=631)

Hypoglycemia with plasma

21.6%

19.8%

Trajenta

Updated Prescribing Information

File coated tablets 5 mg

May 2020

glucose <54 mg/dL

Severe* hypoglycemia (%)

1.1%

1.7%

*Hypoglycemia requiring assistance of another person to actively administer carbohydrate, glucagon, or

other resuscitative actions.

In an active-controlled (glimepiride) cardiovascular safety study with TRAJENTA (CAROLINA) with

median time on treatment of 5.9 years, the incidence of severe hypoglycemia was 0.3% in the TRAJENTA

group (N=3014) and 2.2% in glimepiride group (N=3000).

Use in Renal Impairment

TRAJENTA was compared to placebo as add-on to pre-existing antidiabetic therapy over 52 weeks in 133

patients with severe renal impairment (estimated GFR <30 mL/min). For the initial 12 weeks of the study,

background antidiabetic therapy was kept stable and included insulin, sulfonylurea, glinides, and

pioglitazone. For the remainder of the trial, dose adjustments in antidiabetic background therapy were

allowed.

In general, the incidence of adverse events including severe hypoglycemia was similar to those reported in

other TRAJENTA trials. The observed incidence of hypoglycemia was higher (TRAJENTA, 63% compared

to placebo, 49%) due to an increase in asymptomatic hypoglycemic events especially during the first 12

weeks when background glycemic therapies were kept stable. Ten TRAJENTA-treated patients (15%) and

11 placebo-treated patients (17%) reported at least one episode of confirmed symptomatic hypoglycemia

(accompanying finger stick glucose

54 mg/dL). During the same time period, severe hypoglycemic

events, defined as an event requiring the assistance of another person to actively administer carbohydrate,

glucagon or other resuscitative actions, were reported in 3 (4.4%) TRAJENTA-treated patients and 3

(4.6%) placebo-treated patients. Events that were considered life-threatening or required hospitalization

were reported in 2 (2.9%) patients on TRAJENTA and 1 (1.5%) patient on placebo. Renal function as

measured by mean eGFR and creatinine clearance did not change over 52 weeks’ treatment compared to

placebo.

Laboratory Tests

Changes in laboratory findings were similar in patients treated with TRAJENTA 5 mg compared to

patients treated with placebo.

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

group and

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

2.7% in the TRAJENTA group).

Increase in Lipase: In a placebo-controlled clinical trial with TRAJENTA 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 TRAJENTA 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

TRAJENTA and placebo arms, respectively.

Increase in Amylase: In a cardiovascular safety study comparing TRAJENTA 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 TRAJENTA and glimepiride arms, respectively.

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

of potential signs and symptoms of pancreatitis [see Warnings and Precautions (8.1)].

Trajenta

Updated Prescribing Information

File coated tablets 5 mg

May 2020

Vital signs

No clinically meaningful changes in vital signs were observed in patients treated with TRAJENTA.

9.2.

Postmarketing Experience

Additional adverse reactions have been identified during postapproval use of TRAJENTA. 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.

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

Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions Severe

and disabling arthralgia

Bullous pemphigoid

Rash

Mouth ulceration, stomatitis

Rhabdomyolysis

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/

10.

DRUG INTERACTIONS

Inducers of P-glycoprotein or CYP3A4 Enzymes

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

when administered in combination with a strong P-gp or CYP3A4 inducer. Therefore, use of alternative

treatments is strongly recommended when linagliptin is to be administered with a strong P-gp or CYP3A4

inducer [see Clinical Pharmacology (14.3)].

11.

USE IN SPECIFIC POPULATIONS

11.1.

Pregnancy

Risk Summary

The limited data with TRAJENTA use in pregnant women are not sufficient to inform of drug-associated risk for

major birth defects and miscarriage. 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 linagliptin 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 to25% 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

Trajenta

Updated Prescribing Information

File coated tablets 5 mg

May 2020

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

Animal Data

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.

11.2.

Lactation

Risk Summary

There is no information regarding the presence of linagliptin in human milk, the effects on the breastfed infant, or the

effects on milk production. However, linagliptin

is present in rat milk. Therefore, the developmental and health

benefits of breastfeeding should be considered along with the mother’s clinical need for TRAJENTA and any potential

adverse effects on the breastfed child from TRAJENTA or from the underlying maternal condition.

11.3.

Pediatric Use

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

established.

11.4.

Geriatric Use

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.

11.5.

Renal Impairment

No dose adjustment is recommended for patients with renal impairment [see Clinical Pharmacology

(14.3)].

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

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

). Approximately 20% of the population had

eGFR

45 to <60 mL/min/1.73 m

, 28% of the population had eGFR

30 to <45 mL/min/1.73 m

and 15%

had eGFR <30 mL/min/1.73 m

. The overall incidence of adverse reactions were generally similar

between the TRAJENTA and placebo treatment arms.

11.6.

Hepatic Impairment

No dose adjustment is recommended for patients with hepatic impairment [see Clinical Pharmacology

(14.3)].

12.

OVERDOSAGE

In the event of an overdose with TRAJENTA, contact your doctor immediately. Removal of linagliptin by

hemodialysis or peritoneal dialysis is unlikely.

13.

DESCRIPTION

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TRAJENTA (linagliptin) tablets contain, as the active ingredient, 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).

Each film-coated tablet of TRAJENTA contains 5 mg of linagliptin free base and the following inactive

ingredients: mannitol, pregelatinized starch, corn starch, copovidone, and magnesium stearate. In

addition, the film coating contains the following inactive ingredients: hypromellose, titanium dioxide,

talc, polyethylene glycol, and red ferric oxide.

14.

CLINICAL PHARMACOLOGY

14.1.

Mechanism of Action

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.

14.2.

Pharmacodynamics

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

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

thus resulting in better regulation of 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

The pharmacokinetics of linagliptin has been characterized in healthy subjects and patients with type 2

diabetes. After oral administration of a single 5-mg dose to healthy subjects, peak plasma concentrations

of linagliptin occurred at approximately 1.5 hours post dose (T

); the mean plasma area under the curve

(AUC) was 139 nmol*h/L and maximum concentration (C

) was 8.9 nmol/L.

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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. The prolonged elimination phase

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 steady state compared with the first dose.

The intra-subject and inter-subject coefficients of variation for linagliptin AUC were small (12.6% and

28.5%, respectively). 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.

Absorption

The absolute bioavailability of linagliptin is approximately 30%. A high-fat meal reduced C

by 15%

and increased AUC by 4%; this effect is not clinically relevant. TRAJENTA may be administered with or

without food.

Distribution

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%-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.

Elimination

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.

Metabolism

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 linagliptin is

metabolized to a pharmacologically inactive metabolite, which shows a steady-state exposure of 13.3%

relative to linagliptin.

Excretion

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. Specific Populations

Renal Impairment

An open-label pharmacokinetic study evaluated the pharmacokinetics of linagliptin 5 mg in male and

female patients with varying degrees of chronic renal impairment. The study included 6 healthy subjects

with normal renal function (creatinine clearance [CrCl]

80 mL/min), 6 patients with mild renal

impairment (CrCl 50 to <80 mL/min), 6 patients with moderate renal impairment (CrCl 30 to <50

mL/min), 10 patients with type 2 diabetes mellitus and severe renal impairment (CrCl <30 mL/min), and

11 patients with type 2 diabetes mellitus and normal renal function. Creatinine clearance was measured

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by 24-hour urinary creatinine clearance measurements or estimated from serum creatinine based on the

Cockcroft-Gault formula.

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.

These findings were further supported by the results of population pharmacokinetic analyses.

Hepatic Impairment

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

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.

Body Mass Index (BMI)/Weight

No dose adjustment is necessary based on BMI/weight. BMI/weight had no clinically meaningful effect on

the pharmacokinetics of linagliptin based on a population pharmacokinetic analysis.

Gender

No dose adjustment is necessary based on gender. Gender had no clinically meaningful effect on the

pharmacokinetics of linagliptin based on a population pharmacokinetic analysis.

Geriatric

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

population pharmacokinetic analysis.

Pediatric

Studies characterizing the pharmacokinetics of linagliptin in pediatric patients have not yet been

performed.

Race

No dose adjustment is necessary based on race. 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.

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Drug Interactions

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 organic

cationic transporter (OCT).

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Table 3

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

Cmax

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

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 (10.1)].

#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

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Table 4

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

Cmax

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-

metabolite M-

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

simvasta

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

and levonorgestrel

ethinylestradiol 0.03

mg and levonorgestrel

0.150 mg QD

5 mg QD

ethinylestradi

levonorgestrel

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 Cmax=Emax for pharmacodynamic end points

INR = International Normalized Ratio

PT = Prothrombin Time

QD = once daily

TID = three times daily

15.

NONCLINICAL TOXICOLOGY

15.1.

Carcinogenesis, Mutagenesis, Impairment of Fertility

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).

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16.

CLINICAL STUDIES

16.1 Glycemic Control Trials

TRAJENTA has been studied as monotherapy and in combination with metformin, sulfonylurea,

pioglitazone, and insulin. TRAJENTA has also been studied in patients with type 2 diabetes and severe

chronic renal impairment.

In patients with type 2 diabetes, treatment with TRAJENTA produced clinically significant

improvements in hemoglobin A1c (A1C), fasting plasma glucose (FPG), and 2-hour post-prandial glucose

(PPG) compared with placebo.

Monotherapy

A total of 730 patients with type 2 diabetes participated in 2 double-blind, placebo-controlled studies, one

of 18 weeks’ and another of 24 weeks’ duration, to evaluate the efficacy and safety of TRAJENTA

monotherapy. In both monotherapy studies, patients currently on an antihyperglycemic agent

discontinued the agent and underwent a diet, exercise, and drug washout period of about 6 weeks that

included an open-label placebo run-in during the last 2 weeks. Patients with inadequate glycemic control

(A1C 7% to 10%) after the washout period were randomized; patients not currently on antihyperglycemic

agents (off therapy for at least 8 weeks) with inadequate glycemic control (A1C 7% to 10%) were

randomized after completing the 2-week, open-label, placebo run-in period. In the 18-week study, only

patients ineligible for metformin were recruited. In the 18-week study, 76 patients were randomized to

placebo and 151 to TRAJENTA 5 mg; in the 24-week study, 167 patients were randomized to placebo and

336 to TRAJENTA 5 mg. Patients who failed to meet specific glycemic goals during the 18-week study

received rescue therapy with pioglitazone and/or insulin; metformin rescue therapy was used in the 24-

week trial.

Treatment with TRAJENTA 5 mg daily provided statistically significant improvements in A1C, FPG, and

2-hour PPG compared with placebo (Table 5). In the 18-week study, 12% of patients receiving

TRAJENTA 5 mg and 18% who received placebo required rescue therapy. In the 24-week study, 10.2% of

patients receiving TRAJENTA 5 mg and 20.9% of patients receiving placebo required rescue therapy. The

improvement in A1C compared with placebo was not affected by gender, age, race, prior

antihyperglycemic therapy, baseline BMI, or a standard index of insulin resistance (HOMA-IR). As is

typical for trials of agents to treat type 2 diabetes, the mean reduction in A1C with TRAJENTA appears to

be related to the degree of A1C elevation at baseline. In these 18- and 24-week studies, the changes from

baseline in A1C were -0.4% and -0.4%, respectively, for those given TRAJENTA , and 0.1% and 0.3%,

respectively, for those given placebo. Change from baseline in body weight did not differ significantly

between the groups.

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Table 5

Glycemic Parameters in Placebo-Controlled Monotherapy Studies of TRAJENTA *

18-Week Study

24-Week Study

TRAJENTA

5 mg

Placebo

TRAJENTA

5 mg

Placebo

A1C (%)

Number of patients

n = 147

n = 73

n = 333

n = 163

Baseline (mean)

Change from baseline (adjusted

mean***)

-0.4

-0.4

Difference from placebo

(adjusted mean) (95% CI)

-0.6 (-0.9, -0.3)

-0.7 (-0.9, -0.5)

Patients

(%)] achieving

<7%**

32 (23.5)

8 (11.8)

77 (25)

17 (12)

FPG (mg/dL)

Number of patients

n = 138

n = 66

n = 318

n = 149

Baseline (mean)

Change from baseline (adjusted

mean***)

Difference

from

placebo

(adjusted mean) (95% CI)

-21 (-31, -10)

-23 (-30, -16)

2-hour PPG (mg/dL)

Number of patients

Data not

available

Data not

available

n = 67

n = 24

Baseline (mean)

Change from baseline (adjusted

mean***)

Difference from placebo

(adjusted mean) (95% CI)

-58 (-82, -34)

*Full analysis population using last observation on study

**18-week study: Placebo, n=68; TRAJENTA, n=136

24-week study: Placebo, n=147; TRAJENTA, n=306

***18-week study. HbA1c: ANCOVA model included treatment, reason for metformin intolerance and

number of prior oral anti-diabetic medicine(s) (OADs) as class-effects, as well as baseline HbA1c as

continuous covariates. FPG: ANCOVA model included treatment, reason for metformin intolerance and

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

covariates.

24-week 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. 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.

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 TRAJENTA in combination with metformin. Patients

already on metformin (n = 491) at a dose of at least 1500 mg per day were 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 TRAJENTA 5

mg or placebo, administered once daily. Patients who failed to meet specific glycemic goals during the

studies were treated with glimepiride rescue.

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In combination with metformin, TRAJENTA provided statistically significant improvements in A1C, FPG,

and 2-hour PPG compared with placebo (Table 6). Rescue glycemic therapy was used in 7.8% of patients

treated with TRAJENTA 5 mg and in 18.9% of patients treated with placebo. A similar decrease in body

weight was observed for both treatment groups.

Table 6

Glycemic Parameters in Placebo-Controlled Study for TRAJENTA in Combination

with Metformin*

TRAJENTA 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

**TRAJENTA 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.

Initial Combination Therapy with 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 TRAJENTA 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

TRAJENTA 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.

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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 7).

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 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 TRAJENTA 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 TRAJENTA 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 7

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**

Placeb

o

TRAJENT

A 5 mg

Once

Daily*

Metformi

n

500 mg

Twice

Daily

Linaglipti

n

2.5 mg

Twice

Daily*

+

Metformi

n

500 mg

Twice

Daily

Metformi

n

1000 mg

Twice

Daily

Linaglipti

n

2.5 mg

Twice

Daily*

+

Metformi

n

1000 mg

Twice

Daily

A1C (%)

Number of 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 of 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 TRAJENTA 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 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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Active-Controlled Study vs Glimepiride in Combination with Metformin

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

inferiority study in patients with type 2 diabetes 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/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 TRAJENTA 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 and 104 weeks, TRAJENTA and glimepiride both had reductions from baseline in A1C (52 weeks:

-0.4% for TRAJENTA, -0.6% for glimepiride; 104 weeks: -0.2% for TRAJENTA, -0.4% for glimepiride)

from a baseline mean of 7.7% (Table 8). 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 8

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

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

Week 52

Week 104

TRAJENTA 5

mg +

Metformin

Glimepiride +

Metformin

(mean

Glimepiride

dose 3 mg)

TRAJENTA 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****)

Hypoglycemia incidence

(%)***

Number of patients

n = 776

n = 775

n = 776

n = 775

Incidence****

5.3 *

31.1

7.5 *

36.1

*p<0.0001 vs glimepiride;

p=0.0012 vs glimepiride

**Full analysis population using last observation on study

***Hypoglycemic incidence included both asymptomatic events (not accompanied by typical symptoms

and plasma glucose concentration of

70 mg/dL) and symptomatic events with typical symptoms of

hypoglycemia and plasma glucose concentration of

70 mg/dL.

****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.

Hypoglycemia incidence (%): Cochran-Mantel-Haenszel test was performed on the patient population

contained in the treated set, to compare the proportion of patients with hypoglycemic events between

patients treated with linagliptin and patients treated with glimepiride.

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 Pioglitazone

A total of 389 patients with type 2 diabetes participated in a 24-week, randomized, double-blind, placebo-

controlled study designed to assess the efficacy of TRAJENTA in combination with pioglitazone. Therapy

was stopped in patients on oral antihyperglycemic therapy for a period of 6 weeks (4 weeks followed by a

2-week, open-label, placebo run-in period). Drug-naïve patients entered directly into the 2-week placebo

run-in period. After the run-in period, patients were randomized to receive either TRAJENTA 5 mg or

placebo, both in addition to pioglitazone 30 mg daily. Patients who failed to meet specific glycemic goals

during the studies were treated with metformin rescue. Glycemic endpoints measured were A1C and FPG.

In initial combination with pioglitazone 30 mg, TRAJENTA 5 mg provided statistically significant

improvements in A1C and FPG compared to placebo with pioglitazone (Table 9). Rescue therapy was

used in 7.9% of patients treated with TRAJENTA 5 mg/pioglitazone 30 mg and 14.1% of patients treated

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with placebo/pioglitazone 30 mg. Patient weight increased in both groups during the study with an

adjusted mean change from baseline of 2.3 kg and 1.2 kg in the TRAJENTA 5 mg/pioglitazone 30 mg and

placebo/pioglitazone 30 mg groups, respectively (p = 0.0141).

Table 9

Glycemic Parameters in Placebo-Controlled Study for TRAJENTA in Combination

Therapy with Pioglitazone*

TRAJENTA 5 mg +

Pioglitazone

Placebo + Pioglitazone

A1C (%)

Number of patients

n = 252

n = 128

Baseline (mean)

Change from baseline (adjusted mean**)

-1.1

-0.6

Difference from placebo + pioglitazone

(adjusted mean) (95% CI)

-0.5 (-0.7, -0.3)

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

108 (42.9)

39 (30.5)

FPG (mg/dL)

Number of patients

n = 243

n = 122

Baseline (mean)

Change from baseline (adjusted mean**)

Difference from placebo + pioglitazone

(adjusted mean) (95% CI)

-14 (-21, -7)

*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.

Add-On Combination with Sulfonylureas

A total of 245 patients with type 2 diabetes participated in an 18-week, randomized, double-blind,

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

(SU). Patients on sulfonylurea monotherapy (n = 142) were randomized after completing a 2-week, single-

blind, placebo run-in period. Patients on a sulfonylurea plus one additional oral antihyperglycemic agent

(n = 103) were randomized after a wash-out period of 4 weeks and a 2-week, single-blind, placebo run-in

period. Patients were randomized to the addition of TRAJENTA 5 mg or to placebo, each administered

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

metformin rescue. Glycemic endpoints measured included A1C and FPG.

In combination with a sulfonylurea, TRAJENTA provided statistically significant improvements in A1C

compared with placebo following 18 weeks’ treatment; the improvements in FPG observed with

TRAJENTA were not statistically significant compared with placebo (Table 10). Rescue therapy was used

in 7.6% of patients treated with TRAJENTA 5 mg and 15.9% of patients treated with placebo. There was

no significant difference between TRAJENTA and placebo in body weight.

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Table 10

Glycemic Parameters in Placebo-Controlled Study for TRAJENTA in Combination

with Sulfonylurea*

TRAJENTA 5 mg + SU

Placebo + SU

A1C (%)

Number of patients

n = 158

n = 82

Baseline (mean)

Change from baseline (adjusted mean***)

-0.5

-0.1

Difference from placebo + SU (adjusted mean)

(95% CI)

-0.5 (-0.7, -0.2)

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

23 (14.7)

3 (3.7)

FPG (mg/dL)

Number of patients

n = 155

n = 78

Baseline (mean)

Change from baseline (adjusted mean***)

Difference from placebo + SU (adjusted mean)

(95% CI)

-6 (-17, 4)

SU = sulfonylurea

*Full analysis population using last observation on study

**TRAJENTA 5 mg + SU, n=156; Placebo + SU, n=82

***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

Add-On Combination Therapy with Metformin and a Sulfonylurea

A total of 1058 patients with type 2 diabetes participated in a 24-week, randomized, double-blind,

placebo-controlled study designed to assess the efficacy of TRAJENTA 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 TRAJENTA 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 endpoints measured included A1C and FPG.

In combination with a sulfonylurea and metformin, TRAJENTA provided statistically significant

improvements in A1C and FPG compared with placebo (Table 11). In the entire study population (patients

on TRAJENTA in combination with 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 TRAJENTA 5 mg and in 13% of patients treated with placebo. Change from

baseline in body weight did not differ significantly between the groups.

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Table 11

Glycemic Parameters in Placebo-Controlled Study for TRAJENTA in Combination with

Metformin and Sulfonylurea*

TRAJENTA 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%

-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%

-13 (-18, -7)

SU = sulfonylurea

*Full analysis population using last observation on study

**TRAJENTA 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.

Add-On Combination Therapy with Insulin

A total of 1261 patients with type 2 diabetes inadequately controlled on basal insulin alone or basal

insulin in combination with oral drugs participated in a randomized, double-blind placebo-controlled

trial designed to evaluate the efficacy of TRAJENTA as add-on therapy to basal insulin over 24 weeks.

Randomization was stratified by baseline HbA1c (<8.5% vs

8.5%), renal function impairment status

(based on baseline eGFR), and concomitant use of oral antidiabetic drugs (none, metformin only,

pioglitazone only, metformin + pioglitazone). Patients with a baseline A1C of >7% and <10% were

included in the study including 709 patients with renal impairment (eGFR <90 mL/min), most of whom

(n=575) were categorized as mild renal impairment (eGFR 60 to <90 mL/min). Patients entered a 2 week

placebo run-in period on basal insulin (e.g., insulin glargine, insulin detemir, or NPH insulin) with or

without metformin and/or pioglitazone background therapy. Following the run-in period, patients with

inadequate glycemic control were randomized to the addition of either 5 mg of TRAJENTA or placebo,

administered once daily. Patients were maintained on a stable dose of insulin prior to enrollment, during

the run-in period, and during the first 24 weeks of treatment. Patients who failed to meet specific

glycemic goals during the double-blind treatment period were rescued by increasing background insulin

dose.

TRAJENTA used in combination with insulin (with or without metformin and/or pioglitazone), provided

statistically significant improvements in A1C and FPG compared to placebo (Table 12) after 24 weeks of

treatment. The mean total daily insulin dose at baseline was 42 units for patients treated with

TRAJENTA and 40 units for patients treated with placebo. Background baseline diabetes therapy

included use of: insulin alone (16.1%), insulin combined with metformin only (75.5%), insulin combined

with metformin and pioglitazone (7.4%), and insulin combined with pioglitazone only (1%). The mean

change from baseline to Week 24 in the daily dose of insulin was +1.3 IU in the placebo group and +0.6 IU

in the TRAJENTA group. The mean change in body weight from baseline to Week 24 was similar in the

two treatment groups.

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Table 12

Glycemic Parameters in Placebo-Controlled Study for TRAJENTA in Combination with

Insulin*

TRAJENTA 5 mg +

Insulin

Placebo + Insulin

A1C (%)

Number of patients

n = 618

n = 617

Baseline (mean)

Change from baseline (adjusted mean***)

-0.6

Difference from placebo (adjusted mean) (95%

-0.7 (-0.7, -0.6)

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

116 (19.5)

48 (8.1)

FPG (mg/dL)

Number of patients

n = 613

n = 608

Baseline (mean)

Change from baseline (adjusted mean***)

Difference from placebo (adjusted mean) (95%

-11 (-16, -6)

*Full analysis population using last observation carried forward (LOCF) method on study

**TRAJENTA+Insulin, N=595; Placebo+Insulin, N=593

***HbA1c: ANCOVA model included treatment, categorical renal function impairment status and

concomitant OADs as class-effects, as well as baseline HbA1c as continuous covariates. FPG: ANCOVA

model included treatment, categorical renal function impairment status and concomitant OADs as class-

effects, as well as baseline HbA1c and baseline FPG as continuous covariates.

The difference between treatment with linagliptin and placebo in terms of adjusted mean change from

baseline in HbA1c after 24 weeks was comparable for patients with no renal impairment (eGFR

mL/min, n=539), with mild renal impairment (eGFR 60 to <90 mL/min, n= 565), or with moderate renal

impairment (eGFR 30 to <60 mL/min, n=124).

Renal Impairment

A total of 133 patients with type 2 diabetes participated in a 52 week, double-blind, randomized, placebo-

controlled trial designed to evaluate the efficacy and safety of TRAJENTA in patients with both type 2

diabetes and severe chronic renal impairment. Participants with an estimated (based on the four variables

modified diet in renal disease [MDRD] equation) GFR value of <30 mL/min were eligible to participate in

the study. Randomization was stratified by baseline HbA1c (

8% and >8%) and background antidiabetic

therapy (insulin or any combination with insulin, SU or glinides as monotherapy and pioglitazone or any

other antidiabetics excluding any other DPP-4 inhibitors). For the initial 12 weeks of the study,

background antidiabetic therapy was kept stable and included insulin, sulfonylurea, glinides, and

pioglitazone. For the remainder of the trial, dose adjustments in antidiabetic background therapy were

allowed. At baseline in this trial, 62.5% of patients were receiving insulin alone as background diabetes

therapy, and 12.5% were receiving sulfonylurea alone.

After 12 weeks of treatment, TRAJENTA 5 mg provided statistically significant improvement in A1C

compared to placebo, with an adjusted mean change of -0.6% compared to placebo (95% confidence

interval -0.9, -0.3) based on the analysis using last observation carried forward (LOCF). With adjustments

in antidiabetic background therapy after the initial 12 weeks, efficacy was maintained for 52 weeks, with

an adjusted mean change from baseline in A1C of -0.7% compared to placebo (95% confidence interval -

1.0, -0.4) based on analysis using LOCF.

14.2 Cardiovascular Safety Trials

CARMELINA

The cardiovascular risk of TRAJENTA was evaluated in CARMELINA, a multi-national, multi-center,

placebo-controlled, double-blind, parallel group trial comparing TRAJENTA (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

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TRAJENTA 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.

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/1.73m

. The mean eGFR was 55 mL/min/1.73m

and 27% of patients had mild renal

impairment (eGFR 60 to 90 mL/min/1.73m

), 47% of patients had moderate renal impairment (eGFR 30

to <60 mL/min/1.73 m

) and 15% of patients had severe renal impairment (eGFR <30 mL/min/1.73 m

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 13. The estimated hazard ratio for MACE associated with TRAJENTA

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 1.

Table 13

Major Adverse Cardiovascular Events (MACE) by Treatment Group in the

CARMELINA Trial

TRAJENTA 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)

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 1

Kaplan-Meier: Time to First Occurrence of MACE in the CARMELINA Trial

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CAROLINA

The cardiovascular risk of TRAJENTA was evaluated in CAROLINA, a multi-center, multi-national, randomized,

double-blind, parallel group trial comparing TRAJENTA (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 TRAJENTA 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, age ≥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/1.73m

. 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.

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The results of CAROLINA, including the contribution of each component to the primary composite endpoint, are

shown in Table 14. The Kaplan-Meier curve depicting time to first occurrence of MACE is shown in Figure 2.

Table 14

Major Adverse Cardiovascular Events (MACE) by Treatment Group in the CAROLINA Study

TRAJENTA 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)

356 (11.8)

20.7

362 (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 2 Time to First Occurrence of 3P-MACE in CAROLINA

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17.

HOW SUPPLIED/STORAGE AND HANDLING

TRAJENTA tablets are available as light red, round, biconvex, bevel-edged, film-coated tablets containing

5 mg of linagliptin. TRAJENTA tablets are debossed with “D5” on one side and the Boehringer Ingelheim

logo on the other side.

They are supplied as blister packs of 30 and 90 film-coated tablets.

Not all the pack sizes may be marketed.

Shelf life

The expiry date of the product is indicated on the packaging materials.

Storage

Store below 25°C.

18.

MANUFACTURER

West Ward Columbus Inc.

Colombus, Ohio

19.

REGISTRATION HOLDER

Boehringer Ingelheim Israel Ltd

89 Medinat Ha-Yehudim st.

P.O.B 4124

Herzeliya Pituach 4676672

Registration number: 149-96-33738-00

Revised in May 2020