1. NAME OF THE MEDICINAL
TRAJENTA 5 mg film-coated tablets
2. QUALITATIVE AND QUANTITATIVE
Each tablet contains 5 mg of
For a full list of excipents, see
3. PHARMACEUTICAL FORM
Film-coated tablet (tablet)
8 mm diameter round, light red
film-coated tablet debossed with "D5" on one side and the Boehringer
Ingelheim logo on the other.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Linagliptin is indicated in adult
patients with type 2 diabetes mellitus (T2DM) to improve glycaemic control
in conjunction with diet and exercise, as monotherapy or as add on to
metformin, sulphonylureas, or metformin plus sulphonylureas.
4.2 Posology and method of
The dose of linagliptin is 5 mg
once daily. When linagliptin is added to metformin, the dose of metformin
should be maintained, and linagliptin administered concomitantly.
When linagliptin is used in
combination with a sulphonylurea, a lower dose of the sulphonylurea may be
considered to reduce the risk of hypoglycaemia (see section 4.4)
For patients with renal
impairment, no dose adjustment for TRAJENTA is required.
Pharmacokinetic studies suggest
that no dose adjustment is required for patients with hepatic impairment but
clinical experience in such patients is lacking.
No dose adjustment is necessary
based on age.
However, clinical experience in
patients > 75 years of age is limited.
The safety and efficacy of
linagliptin in paediatric population has not yet been established. No data
Method of administration
TRAJENTA can be taken with or
without a meal at any time of the day. If a dose is missed, it should be
taken as soon as the patient remembers. A double dose should not be taken on
the same day.
Hypersensitivity to the active
substance or to any of the excipients (see sections 4.8 and 6.1)
4.4 Special warnings and
precautions for use
TRAJENTA should not be used in
patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
There have been post-marketing
reports of acute pancreatitis in patients taking linagliptin. If
pancreatitis is suspected, TRAJENTA should be discontinued.
Linagliptin alone showed a
comparable incidence of hypoglycaemia to placebo.
In clinical trials of linagliptin
as part of combination therapy with medicinal products not known to cause
hypoglycaemia (metformin, thiazolidinediones)rates of hypoglycaemia reported
with linagliptin were similar to rates in patients taking placebo.
When linagliptin was added to a
sulphonylurea (on a background of metformin), the incidence of hypoglycaemia
was increased over that of placebo (see section 4.8).
Sulphonylureas are known to cause
hypoglycaemia. Therefore, caution is advised when linagliptin is used in
combination with a sulphonylurea. A dose reduction of the sulphonylurea may
be considered (see section 4.2).
4.5 Interaction with other
medicinal products and other forms of interaction
In vitro assessment of
Linagliptin is a weak competitive
and a weak to moderate mechanism-based inhibitor of CYP isozyme CYP3A4, but
does not inhibit other CYP isozymes. It is not an inducer of CYP isozymes.
Linagliptin is a P-glycoprotein
substrate, and inhibits P-glycoprotein mediated transport of digoxin with
Based on these results and in
vivo interaction studies, linagliptin is considered unlikely to cause
interactions with other P-gp substrates.
In vivo assessment of
Effects of other medicinal
products on linagliptin
Clinical data described below
suggest that the risk for clinically meaningful interactions by
coadministered medicinal products is low.
co-administration of multiple three times daily doses of 850 mg metformin
with 10 mg linagliptin once daily did not clinical meaningfully alter the
pharmacokinetics of linagliptin in healthy volunteers.
steady-state pharmacokinetics of 5 mg linagliptin was not changed by
concomitant administration of a single 1.75 mg dose glibenclamide (glyburide).
Co-administration of multiple daily doses of 10 mg linagliptin (supratherapeutic)
with multiple daily doses of 45 mg pioglitazone, a CYP2C8 and CYP3A4
substrate, had no clinically relevant effect on the pharmacokinetics of
either linagliptin or pioglitazone or the active metabolites of pioglitazone,
indicating that linagliptin is not an inhibitor of CYP2C8-mediated
metabolism in vivo and supporting the conclusion that the in vivo
inhibition of CYP3A4 by linagliptin is negligible.
co-administration of a single 5 mg oral dose of linagliptin and multiple 200
mg oral doses of ritonavir, a potent inhibitor of P-glycoprotein and CYP3A4,
increased the AUC and Cmax of linagliptin approximately twofold and
threefold, respectively. The unbound concentrations, which are usually less
than 1% at the therapeutic dose of linagliptin, were increased 4-5-fold
after coadministration with ritanovir. Simulations of steady-state plasma
concentrations of linagliptin with and without ritonavir indicated that the
increase in exposure will be not associated with an increased accumulation.
These changes in linagliptin pharmacokinetics were not considered to be
clinically relevant. Therefore, clinically relevant interactions would not
be expected with other Pglycoprotein/CYP3A4 inhibitors.
Rifampicin: multiple co-administration of 5 mg linagliptin
with rifampicin, a potent inductor of P-glycoprotein and CYP3A4, resulted in
a 39.6% and 43.8% decreased linagliptin steady-state AUC and Cmax,
respectively, and about 30% decreased DPP-4 inhibition at trough. Thus, full
efficacy of linagliptin in combination with strong P-gp inducers might not
be achieved, particularly if these are administered long-term.
Co-administration with other potent inducers of P-glycoprotein and CYP3A4,
such as carbamazepine, phenobarbital and phenytoin has not been studied.
Effects of linagliptin on other medicinal products
In clinical studies, as described below, linagliptin had no clinically
relevant effect on the pharmacokinetics of metformin, glyburide, simvastatin,
warfarin, digoxin or oral contraceptives providing in vivo evidence of a low
propensity for causing medicinal product interactions with substrates of
CYP3A4, CYP2C9, CYP2C8, P-glycoprotein, and organic cationic transporter
Metformin: co-administration of multiple daily doses of 10 mg
linagliptin with 850 mg metformin, an OCT substrate, had no relevant effect
on the pharmacokinetics of metformin in healthy volunteers.
Therefore, linagliptin is not an inhibitor of OCT mediated transport.
Sulphonylureas: co-administration of multiple oral doses of 5
mg linagliptin and a single oral dose of 1.75 mg glibenclamide (glyburide)
resulted in clinically not relevant reduction of 14% of both AUC and Cmax of
glibenclamide. Because glibenclamide is primarily metabolised by CYP2C9,
these data also support the conclusion that linagliptin is not a CYP2C9
inhibitor. Clinically meaningful interactions would not be expected with
other sulfonylureas (e.g., glipizide, tolbutamide, and glimepiride) which,
like glibenclamide, are primarily eliminated by CYP2C9.
Digoxin: co-administration of multiple of 5 mg linagliptin
with multiple doses of 0.25 mg digoxin had no effect on the pharmacokinetics
of digoxin in healthy volunteers. Therefore, linagliptin is not an inhibitor
of P-glycoprotein-mediated transport in vivo.
daily doses of 5 mg linagliptin did not alter the pharmacokinetics of S(-)
or R(+) warfarin, a CYP2C9 substrate, administered in a single dose.
multiple daily doses of linagliptin had a minimal effect on the steady state
pharmacokinetics of simvastatin, a senstivie CYP3A4 substrate, in healthy
volunteers. Following administration of a supratherapeutic dose of 10 mg
linagliptin concomitantly with 40 mg of simvastatin daily for 6 days, the
plasma AUC of simvastatin was increased by 34%, and the plasma Cmax by 10%.
co-administration with 5 mg linagliptin did not alter the steady-state
pharmacokinetics of levonorgestrel or ethinylestradiol.