Download Empagliflozin 25 mg

Expanding treatment options for type 2 diabetes:
A review of the clinical efficacy and safety profile of
Jardiance® (empagliflozin)
The Boehringer Ingelheim and Lilly Diabetes Alliance has provided the funding for this sponsored
session, including speaker honoraria and presentation development support. The presentation has
been reviewed for medical accuracy and compliance with applicable laws and regulations.
Boehringer Ingelheim and Lilly Diabetes Alliance products will be discussed during this presentation. Trajenta ® (linagliptin),
Jentadueto®▼ (linagliptin and metformin), Jardiance®▼ (empagliflozin), Synjardy®▼ (empagliflozin and metformin) and
Abasaglar ®▼ (human insulin analogue). Prescribing information can be found at the end of this presentation.
Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard
Adverse events should also be reported to Boehringer Ingelheim Drug Safety on 0800 328 1627 (freephone).
This presentation was developed by the Boehringer Ingelheim and Lilly Diabetes Alliance.
UK/EMP/00264(1) | July 2016
Content
● Mechanism of action of SGLT2 inhibitors
● Licensed indication
● Clinical efficacy
● Impact on weight and blood pressure
● Safety and tolerability profile
● Dosing and administration
UK/EMP/00264(1) | July 2016
Mechanism of action of the sodium glucose
co-transporter 2 (SGLT2) inhibitors
UK/EMP/00264(1) | July 2016
Drug treatments for type 2 diabetes and their sites of action
Glucose absorption
Acarbose
Decreased
glucose
uptake
Increased
glucose
production
Metformin
GLP-1 receptor agonists
DPP-4 inhibitors
Insulin
Hyperglycaemia
Metformin
Pioglitazone
Insulin
Impaired
insulin
secretion
DPP-4, dipeptidyl peptidase-4;
GLP-1, glucagon-like peptide-1;
SGLT2, sodium-glucose co-transporter 2
Reference
Tahrani AA, et al. Lancet. 2011;378:182–197.
Increased
glucose
reabsorption
Insulin
Sulphonylureas
Meglitinides
GLP-1 receptor agonists
DPP-4 inhibitors
SGLT2 inhibitors
UK/EMP/00264(1) | July 2016
Renal glucose re-absorption under healthy conditions1,2
Filtered glucose
load 180 g/day
Virtually all of the
filtered glucose is
re-absorbed in the
proximal tubules
In healthy
through
SGLT2 and
individuals,
SGLT1
with SGLT2
theaccounting
renal glomeruli
for
~180
~ filter
90% in
the gS1
of
glucose
per day
and
S2 segments
and SGLT1
accounting for
~ 10% in the
S3 segment
SGLT2
~ 90%
SGLT1
~ 10%
SGLT, sodium glucose co-transporter.
References
1. Adapted from: Gerich JE. Diabet Med. 2010;27:136–142.
2. Bakris GL, et al. Kidney Int. 2009;75;1272–1277.
UK/EMP/00264(1) | July 2016
Renal glucose re-absorption in patients with diabetes1,2
Filtered glucose
load > 180 g/day
SGLT2
When blood
glucose increases
above the
renal threshold
(~ 11 mmol/l or
190 mg/dL), the
capacity of the
transporters is
exceeded, resulting
in urinary glucose
excretion
~ 90%
SGLT1
~ 10%
SGLT, sodium glucose co-transporter.
References
1. Adapted from: Gerich JE. Diabet Med. 2010;27:136–142.
2. Bakris GL, et al. Kidney Int. 2009;75;1272–1277.
UK/EMP/00264(1) | July 2016
Urinary glucose excretion via SGLT2 inhibition1
Filtered glucose
load > 180 g/day
SGLT2 inhibitors
reduce glucose
re-absorption
in the proximal
tubule, leading to
urinary glucose
excretion* and
osmotic diuresis
SGLT2
SGLT2
inhibitor
SGLT1
SGLT, sodium glucose co-transporter.
* Loss of ~ 78 g of glucose per day2, equating to 240-320 kcal/day.
References
1. Bakris GL, et al. Kidney Int. 2009;75;1272–1277.
2. Jardiance (empagliflozin) Summary of Product Characteristics. Available at: https://www.medicines.org.uk/emc/medicine/28973 (accessed July 2016).
UK/EMP/00264(1) | July 2016
SGLT2 inhibition lowers glycaemia independently of β-cell function
and insulin resistance1–4
SGLT2 inhibition
directly targets glucose
via urinary glucose
excretion
Impaired β-cell
function
Persistent
Persistent
hyperglycaemia
hyperglycaemia
Insulin
resistance
SGLT2, sodium glucose co-transporter 2.
References
1. Adapted from: DeFronzo RA. Diabetes. 2009;58:773–795.
2. Adapted from: Poitout V and Robertson RP. Endocrinology. 2002;143:339–342.
3. Adapted from: DeFronzo RA. Diabetes Obes Metab. 2012;14:5–14.
4. Robertson RP, et al. Diabetes. 2003;52:581–587.
UK/EMP/00264(1) | July 2016
Therapeutic indication
Empagliflozin is indicated for the treatment of type 2 diabetes mellitus to improve
glycaemic control in adults as:
Monotherapy
When diet and exercise alone do not provide adequate glycaemic control in patients for
whom use of metformin is considered inappropriate due to intolerance.
Add-on combination therapy
In combination with other glucose–lowering medicinal products including insulin, when
these, together with diet and exercise, do not provide adequate glycaemic control.
Reference
Jardiance (empagliflozin) Summary of Product Characteristics. Available at: https://www.medicines.org.uk/emc/medicine/28973 (accessed July 2016).
UK/EMP/00264(1) | July 2016
9
NICE Technology Appraisal Guidance (TA336)
In May 2015, NICE issued its Technology Appraisal Guidance (TAG) recommending empagliflozin
for use within the National Health Service (NHS England) in the treatment of type 2 diabetes as
follows:
March 2015, TA336
● 1.1 Empagliflozin in a dual therapy regimen in combination with metformin is recommended
as an option for treating type 2 diabetes, only if:
o a sulfonylurea is contraindicated or not tolerated, or
o the person is at significant risk of hypoglycaemia or its consequences.
● 1.2 Empagliflozin in a triple therapy regimen is recommended as an option for treating type
2 diabetes in combination with:
o metformin and a sulfonylurea or
o metformin and a thiazolidinedione.
● 1.3 Empagliflozin in combination with insulin with or without other antidiabetic drugs is
recommended as an option for treating type 2 diabetes.
● 1.4 People currently receiving treatment initiated within the NHS with empagliflozin that is
not recommended for them by NICE in this guidance should be able to continue treatment
until they and their NHS clinician consider it appropriate to stop.
Reference
National Institute for Health and Care Excellence (NICE), Technology Appraisal Guidance, Empagliflozin in combination therapy for treating type 2 diabetes
Available at: http://www.nice.org.uk/guidance/ta336 (accessed July 2016).
UK/EMP/00264(1) | July 2016
NICE Technology Appraisal Guidance (TA390)
In May 2016, NICE issued another Technology Appraisal Guidance (TAG) recommending
empagliflozin for use within the National Health Service (NHS England) in the treatment of type 2
diabetes as follows:
May 2016, TA390
● 1.1 Canagliflozin, dapagliflozin and empagliflozin as monotherapies are recommended as
options for treating type 2 diabetes in adults for whom metformin is contraindicated or not
tolerated and when diet and exercise alone do not provide adequate glycaemic control, only
if:
o a dipeptidyl peptidase-4 (DPP-4) inhibitor would otherwise be prescribed and
o a sulfonylurea or pioglitazone is not appropriate.
● 1.2 Adults whose treatment with canagliflozin, dapagliflozin or empagliflozin as
monotherapy is not recommended in this NICE guidance, but was started within the NHS
before this guidance was published, should be able to continue treatment until they and
their NHS clinician consider it appropriate to stop.
Reference
National Institute for Health and Care Excellence (NICE), Technology Appraisal Guidance, Canagliflozin, dapagliflozin and empagliflozin as monotherapies for treating type 2
diabetes. Available at: https://www.nice.org.uk/guidance/ta390 (accessed July 2016).
UK/EMP/00264(1) | July 2016
Empagliflozin clinical pharmacokinetics
Tablet intake:
10 mg once daily /
25 mg once daily
Absorption:
Peak levels at 1.5 hours
after dosing
No clinically relevant food effect
Half-life:
Estimated to be 12.4 hours,
steady state reached by ~ Day 5
Metabolism:
No active metabolite
Target organ
Selectivity:
5,000 x more selective for
SGLT2 vs SGLT1
Reference
Jardiance (empagliflozin) Summary of Product Characteristics. Available at: https://www.medicines.org.uk/emc/medicine/28973 (accessed July 2016).
UK/EMP/00264(1) | July 2016
Empagliflozin clinical study programme across the treatment pathway
Add-on to metformin
● versus placebo (EMPA-REG MET™)
● versus glimepiride (EMPA-REG H2H-SU™)
Add-on to TZD
Add-on to metformin + SU
● versus placebo (EMPA-REG PIO™)*
● versus placebo (EMPA-REG METSU™)
Add-on to metformin + TZD
● versus placebo (EMPA-REG PIO™)*
Diet and
exercise
Start with OAD
Start dual OAD
combination
Start triple OAD
combination
Insulin-based
therapies
Add-on to basal insulin
● versus placebo (EMPA-REG BASAL™)
Add-on to Multiple Daily Injection of insulin
● versus placebo (EMPA-REG MDI™)
>4,300 empagliflozin patients
*These data will not be shown in the presentation
OAD, oral antidiabetic; SU, sulphonylurea; TZD, thiazolidinedione
Reference
Jardiance (empagliflozin) Summary of Product Characteristics. Available at: https://www.medicines.org.uk/emc/medicine/28973 (accessed July 2016).
UK/EMP/00264(1) | July 2016
13
Efficacy Analysis
UK/EMP/00264(1) | July 2016
In combination with other therapies, empagliflozin provides significant HbA1c
reductions
Mean (SE) placebo-adjusted change
from baseline in HbA1c (%)
Change in HbA1c was a primary endpoint in clinical trials
0.00
Add on to MET
24 weeks
Empagliflozin 25 mg
Empagliflozin 10 mg
Add on to MET+SU
24 weeks
Add on to Basal Insulin
18 weeks
-0.10
-0.20
-0.30
-0.40
-0.50
-0.60
-0.70
-0.57
-0.64
-0.80
-0.90
-0.64
-0.59
-0.6
-0.7
p<0.001
vs. placebo
p<0.001
vs. placebo
p<0.001
vs. placebo
Patients, n
217
213
225
216
132
117
BL HbA1c, %
7.94
7.86
8.07
8.10
8.3
8.3
BL, baseline; MET, metformin; SE, standard error; SU, sulphonylurea.
References
Adapted from: Häring H-U, et al., Diabetes Care 2014; [Epub ahead of print]:doi:10.2337/dc13-2105; Häring H-U, et al. Diabetes Care 2013;36:3396-3404;
Rosenstock J, et al. Poster 1102-P, presented at American Diabetes Association (ADA) 73rd Scientific Sessions, 21-25 June 2013, Chicago, IL, USA.
UK/EMP/00264(1) | July 2016
In combination with other therapies, empagliflozin provides significant
FPG (mmol/L) reductions
Mean (SE) placebo-adjusted change
from baseline in FPG (mmol/l)
Change in FPG was an exploratory endpoint in clinical trials
0.00
Add on to MET
24 weeks
Empagliflozin 25 mg
Empagliflozin 10 mg
Add on to MET+SU
24 weeks
Add on to Basal Insulin
18 weeks
-0.20
-0.40
-0.60
-0.80
-1.00
-1.20
-1.40
-1.60
-1.80
-1.47
-2.00
-1.59
-1.60
p<0.001
vs. placebo
-1.60
p<0.001
vs. placebo
-1.57
-1.64
p<0.001
vs. placebo
Patients, n
216
213
225
216
169
155
BL FPG, mmol/l
8.58
8.29
8.38
8.69
7.68
8.13
FPG, fasting plasma glucose; BL, baseline; MET, metformin; SE, standard error; SU, sulphonylurea.
References
Adapted from: Häring H-U, et al., Diabetes Care 2014; [Epub ahead of print]:doi:10.2337/dc13-2105; (Supplementary data); Häring H-U, et al. Diabetes Care 2013;36:3396-3404;
(Supplementary data); Rosenstock J, et al. Poster 1102-P, presented at American Diabetes Association (ADA) 73rd Scientific Sessions, 21-25 June 2013, Chicago, IL, USA.
UK/EMP/00264(1) | July 2016
Adding empagliflozin can provide the secondary benefit of weight loss
Weight change was a secondary endpoint in clinical trials
Empagliflozin is not indicated for weight loss
Empagliflozin 25 mg
Mean (SE) placebo-adjusted change
from baseline in body weight (kg)
Empagliflozin 10 mg
0.00
Add on to MET
24 weeks
Add on to MET+SU
24 weeks
Add on to Basal Insulin
18 weeks
-0.50
-1.00
-0.9
-1.50
-2.00
-1.63
-2.01
-2.50
-1.7
-1.76
p<0.001
vs. placebo
-1.99
p<0.001
vs. placebo
p=0.035
p=0.293
vs. placebo vs. placebo
Patients, n
217
213
225
216
169
155
BL weight, kg
81.6
82.2
77.1
77.5
91.6
94.7
BL, baseline; MET, metformin; SE, standard error; SU, sulphonylurea.
References
Adapted from: Häring H-U, et al., Diabetes Care 2014; [Epub ahead of print]:doi:10.2337/dc13-2105; Häring H-U, et al. Diabetes Care 2013;36:3396-3404;
Rosenstock J, et al. Poster 1102-P, presented at American Diabetes Association (ADA) 73rd Scientific Sessions, 21-25 June 2013, Chicago, IL, USA.
UK/EMP/00264(1) | July 2016
Adding empagliflozin can provide the secondary benefit of reduction in
Systolic Blood Pressure (SBP)
Mean (SE) placebo-adjusted change
from baseline in SBP (mmHg)
Change in SBP was an exploratory endpoint in clinical trials
Empagliflozin is not indicated for blood pressure control
0.00
Add on to MET
24 weeks
Empagliflozin 25 mg
Empagliflozin 10 mg
Add on to MET+SU
24 weeks
Add on to Basal Insulin
18 weeks
-1.00
-2.00
-2.10
-3.00
-2.70
-4.00
-5.00
-6.00
Patients, n
BL SBP, mmHg
-3.4
-4.10
-3.0
-4.80
p<0.001
vs. placebo
p=0.032
p<0.005
vs. placebo vs. placebo
p=0.011
p=0.027
vs. placebo vs. placebo
217
213
225
216
169
155
129.6
130.0
128.7
129.3
132.4
132.8
BL, baseline; MET, metformin; SE, standard error; SU, sulphonylurea.
References
Adapted from: Häring H-U, et al., Diabetes Care 2014; [Epub ahead of print]:doi:10.2337/dc13-2105; Häring H-U, et al. Diabetes Care 2013;36:3396-3404;
Rosenstock J, et al. Poster 1102-P, presented at American Diabetes Association (ADA) 73rd Scientific Sessions, 21-25 June 2013, Chicago, IL, USA.
UK/EMP/00264(1) | July 2016
As an add-on to metformin, empagliflozin 25 mg demonstrated superior
reduction in HbA1c over glimepiride at 24 months
Change from baseline in HbA1c after 104 weeks of treatment
Mean baseline values for both treatment groups = 7.92%
Empagliflozin 25 mg
Glimepiride 1-4 mg
n = 765
n = 780
Mean change from baseline
in HbA1c (%)
0
-0.25
-0.5
-0.55
-0.75
-1
-1.25
-0.66
Between groups difference = -0.11%
p<0.0001 for non-inferiority
p=0.0153 for superiority
Recommended starting dose of empagliflozin is 10mg
Reference
Adapted from Ridderstrale M et al., Lancet Diabetes Endocrinol 2014; [epub ahead of print]:doi: 10.1016/S2213-8587(14)
UK/EMP/00264(1) | July 2016
As an add-on to metformin, empagliflozin 25 mg demonstrated superior
reduction in HbA1c over glimepiride at 24 months
Change from baseline in HbA1c by visit over time was an exploratory endpoint*
Glimepiride 1–4 mg
Mean (SE) change from baseline
in HbA1c (%) over time
0.0
Empagliflozin 25 mg
-0.1
-0.2
-0.3
-0.4
-0.5
-0.6
-0.7
-0.8
-0.9
0 4
12
28
40
52
65
78
91
Study week
104
Glimepiride
761 758
738
699
660
609
562
524
494
461
Empagliflozin
759 751
734
702
672
646
624
593
568
548
*Data are based on the full analysis set, observed cases analyses by Mixed Model Repeated Measures
Recommended starting dose of empagliflozin is 10mg
Reference
Boehringer Ingelheim Ltd., Data on File EMP14-01.
UK/EMP/00264(1) | July 2016
20
As an add-on to metformin, Empagliflozin 25 mg demonstrated superior weight
loss over glimepiride at 24 months
Weight change was a secondary endpoint in clinical trials
Empagliflozin is not indicated for weight loss
Glimepiride 1–4 mg (n=780)
Adjusted mean (SE) change
from baseline in body weight (kg)
Empagliflozin 25 mg (n=765)
2.0
1.5
1.0
0.5
0.0
-0.5
-1.0
-1.5
-2.0
-2.5
-3.0
-3.5
1.34
Mean baseline:
83.03
-4.46
p<0.0001
-3.12
82.52
Recommended starting dose of empagliflozin is 10mg
Reference
Boehringer Ingelheim Ltd., Data on File EMP14-01.
UK/EMP/00264(1) | July 2016
As an add-on to metformin, empagliflozin 25 mg demonstrated superior weight
loss over glimepiride at 24 months
Change in bodyweight over time was an additional exploratory endpoint*
Adjusted mean (SE) change from
baseline in body weight (kg)
Empagliflozin is not indicated for weight loss
2
1
Glimepiride 1–4 mg
Empagliflozin 25 mg
0
-1
-2
-3
-4
BL
12
28
52
Study Week
78
104
Glimepiride
745
743
703
610
526
462
Empagliflozin
739
737
706
643
595
555
*Data are based on the full analysis set, observed cases analyses by Mixed Model Repeated Measures
Recommended starting dose of empagliflozin is 10mg
Reference
Boehringer Ingelheim Ltd., Data on File EMP14-01.
UK/EMP/00264(1) | July 2016
22
In younger, overweight/obese patients with HbA1c ≥8%, empagliflozin
significantly reduced HbA1c and body weight*
Empagliflozin 10 mg
Weight change was a secondary endpoint in clinical trials
Empagliflozin is not indicated for weight loss
Empagliflozin 25 mg
Placebo
(n=193)
(n=179)
(n=188)
0
-0.25
-0.17
-0.5
-0.75
-1
-1.05
-1.25
-1.15
24 weeks
(Mean baseline = 79.1/79.5/79.6 kg)
Adjusted mean change from baseline
weight (kg)
Adjusted mean change from baseline
in HbA1c (%)
24 weeks
(Mean baseline = 8.72/8.73/8.72%)
(n=193)
(n=179)
(n=188)
0
-0.3
-0.5
-1
-1.5
-2
-1.9
-2.3
-2.5
p<0.001 vs placebo
p<0.001 vs placebo
In this pooled subgroup post-hoc analysis, adverse events were consistent with other studies
Patients were treated with empagliflozin as monotherapy, add-on to metformin, add-on to metformin + sulphonylurea or
add-on to metformin + pioglitazone. Empagliflozin is indicated as monotherapy when metformin is not tolerated.
* post-hoc analysis of patients aged <65 years with BMI ≥25 to <35kg/m2
Reference
Merker L et al. Poster 1079P presented at 74th Scientific Session of American Diabetes Association, 13-17 June 2014, San Francisco, CA, USA
UK/EMP/00264(1) | July 2016
Safety Profile
UK/EMP/00264(1) | July 2016
Empagliflozin safety profile
Safety data reported in placebo-controlled studies by absolute frequency
System organ
class
Very common
(≥1/10)
Skin and
subcutaneous
disorders
Hypoglycaemia
(when used
with SU or
insulin)
Rare
(≥1/10,000 to
<1/1,000)
Diabetic
Ketoacidosis*
Pruritis
(generalised)
Vascular
disorders
Renal and
urinary disorders
Uncommon
(≥1/1,000 to
<1/100)
Vaginal moniliasis,
vulvovaginitis, balanitis and
other genital infection
Urinary tract infection
Infections and
infestations
Metabolism and
nutrition
disorders
Common
(≥1/100 to <1/10)
Volume
depletion
Increased
urination
Dysuria
In a prospective, pre-specified meta-analysis of phase II and III clinical studies involving 10,036
patients with type 2 diabetes, empagliflozin did not increase cardiovascular risk
*derived from post-marketing experience
Reference
Jardiance (empagliflozin) Summary of Product Characteristics. Available at: https://www.medicines.org.uk/emc/medicine/28973 (accessed July 2016).
UK/EMP/00264(1) | July 2016
Empagliflozin safety profile
Safety data reported in placebo controlled studies
Frequency of common adverse events1
Event
Placebo
Empagliflozin 10 mg
Empagliflozin 25 mg
Vaginal moniliasis,
vulvovaginitis, balanitis and other
genital infection
0.9%
4.1%
3.7%
Increased urination
(including the predefined
terms pollakiurea, polyuria,
and nocturia)
1.0%
3.4%
3.2%
Urinary tract infection (UTI)
7.6%
9.3%
7.6%
● UTI was reported more frequently in females than in males1
● Genital tract infections were mild or moderate in intensity and were reported more frequently in females
than in males1
● The frequency of reported nocturia for empagliflozin was <1%1
● Discontinuations due to UTI were low (0.1 – 0.2%)2
The majority of patients who experienced a UTI or genital infection reported a single event2
References
1. Jardiance (empagliflozin) Summary of Product Characteristics. Available at: https://www.medicines.org.uk/emc/medicine/28973 (accessed July 2016).
2. Kim G, et al. Poster 74-LB, presented at 73rd Scientific Session of American Diabetes Association; June 21–25, 2013; Chicago, IL
UK/EMP/00264(1) | July 2016
26
Phase III trials pooled* safety and tolerability analysis
Events consistent with UTI
Empagliflozin
Number of episodes per patient, n (%)
0
1
2
≥3
Placebo (n = 825)
10 mg OD (n = 830)
25 mg OD (n = 822)
757 (91.8)
62 (7.5)
6 (0.7)
0
753 (90.7)
65 (7.8)
10 (1.2)
2 (0.2)
760 (92.5)
56 (6.8)
6 (0.7)
0
OD, once daily; UTI, urinary tract infection. *Pooled analysis includes a proportion of monotherapy-treated patients
Reference
Kim G, et al. Poster 74-LB, presented at 73rd Scientific Session of American Diabetes Association; June 21–25, 2013; Chicago, IL
UK/EMP/00264(1) | July 2016
Overall incidences of hypoglycaemic events
Monotherapy1
Add-on to metformin2
Add-on to metformin + SU3
Add-on to insulin +/- metformin/SU4
Placebo
(n=229)
Empagliflozin 10 mg
(n=224)
Empagliflozin 25 mg
(n=223)
<1%
<1%
<1%
Placebo
(n=206)
Empagliflozin 10 mg
(n=217)
Empagliflozin 25 mg
(n=214)
<1%
<2%
<1.5%
Placebo
(n=225)
Empagliflozin 10 mg
(n=224)
Empagliflozin 25 mg
(n=217)
8.4%
16.1%
11.5%
Placebo
(n=170)
Empagliflozin 10mg
(n=169)
Empagliflozin 25 mg
(n=155)
35%
36%
36%
● A lower dose of insulin or insulin secretagogues (eg, SUs) may be needed to reduce the risk of
hypoglycaemia when empagliflozin is used in combination with these agents5
SU, sulphonylurea
References
1.Roden M, et al. Lancet Diabetes Endocrinol 2013;1:208-19
2. Häring HU, et al.. Diabetes Care 2014; [Epub ahead of print]: doi:10.2337/dc13-2105
3. Häring HU, et al. Diabetes Care 2013;36:3396–3404
4. Rosenstock J, et al. Poster 1102-P, presented at American Diabetes Association (ADA) 73rd Scientific Sessions, 21-25 June 2013, Chicago, IL, USA
5. Jardiance (empagliflozin) Summary of Product Characteristics. Available at: https://www.medicines.org.uk/emc/medicine/28973 (accessed July 2016).
UK/EMP/00264(1) | July 2016
28
Diabetic ketoacidosis (DKA)
● Rare cases of DKA, including life-threatening cases, have been reported in
clinical trials and post-marketing in patients treated with SGLT2 inhibitors,
including empagliflozin.
● Empagliflozin should not be used in patients with type 1 diabetes as safety and
efficacy have not been established. Limited data from clinical trials suggest that
DKA occurs with common frequency when patients with type 1 diabetes are
treated with SGLT2 inhibitors
● Consider the risk of DKA in the event of non-specific symptoms such as nausea,
vomiting, anorexia, abdominal pain, excessive thirst, difficulty breathing,
confusion, unusual fatigue or sleepiness and assess patients for ketoacidosis
immediately, regardless of blood glucose level.
DKA: Diabetic Ketoacidosis
Reference
Jardiance (empagliflozin) Summary of Product Characteristics. Available at: https://www.medicines.org.uk/emc/medicine/28973 (accessed July 2016).
UK/EMP/00264(1) | July 2016
Diabetic ketoacidosis (DKA)
● Before initiating empagliflozin, consider factors in the patient history that may
predispose to ketoacidosis. Use with caution in patients who may be at higher
risk of DKA.
● Treatment with empagliflozin for patients who are hospitalised for major
surgical procedures or acute serious medical illnesses should be interrupted
and may be restarted once the patient’s condition has stabilised
● If DKA is suspected or diagnosed, treatment with empagliflozin should be
discontinued immediately
DKA: Diabetic Ketoacidosis
Reference
Jardiance (empagliflozin) Summary of Product Characteristics. Available at: https://www.medicines.org.uk/emc/medicine/28973 (accessed July 2016).
UK/EMP/00264(1) | July 2016
Empagliflozin dosing and administration
● Recommended starting dose 10 mg once daily
● For patients who tolerate 10 mg and need further glycaemic control, their dose can be increased to
25 mg once daily
● Can be taken with/without food, at any time of day
● Can be used alone or in combination with other common therapies
– No clinically meaningful interactions were observed when empagliflozin was co-administered with other
commonly used medications, including pioglitazone
– A lower dose of insulin or insulin secretagogues (eg, sulphonylureas) may be needed to reduce the risk of
hypoglycaemia when empagliflozin is used in combination with these agents
● Should not be initiated in patients with an eGFR <60 ml/min/1.73m2
● In patients tolerating empagliflozin whose eGFR falls persistently below 60 ml/min/1.73m2 the
dose of empagliflozin should be adjusted to or maintained at 10 mg once daily
● Empagliflozin should be discontinued when eGFR is persistently below 45 ml/min/1.73 m2 or CrCl
persistently below 45 ml/min
Reference
Jardiance (empagliflozin) Summary of Product Characteristics. Available at: https://www.medicines.org.uk/emc/medicine/28973 (accessed July 2016).
UK/EMP/00264(1) | July 2016
31
For the treatment of type 2 diabetes
Clinical considerations when prescribing empagliflozin
● Empagliflozin should be prescribed with caution in patients aged ≥75 years and is not
recommended in patients over 85 years old
● Caution should be exercised in patients for whom a empagliflozin induced drop in blood pressure
could pose a risk, such as patients with known cardiovascular disease, or patients on
anti-hypertensive therapy such as loop diuretics or thiazides or with a history of hypotension
● Assessment of renal function is recommended prior to empagliflozin initiation and periodically
during treatment, i.e. at least yearly, and prior to the initiation of any concomitant medication that
may have a negative impact on renal function
● No significant drug-drug interactions were observed when empagliflozin was co-administered with
other commonly used medications
● Empagliflozin is not recommended for use in patients with severe hepatic impairment
Reference
Jardiance (empagliflozin) Summary of Product Characteristics. Available at: https://www.medicines.org.uk/emc/medicine/28973 (accessed July 2016).
UK/EMP/00264(1) | July 2016
32
In summary
● Empagliflozin is indicated for the treatment of type 2 diabetes mellitus to improve
glycaemic control in adults as:
– Monotherapy
• When diet and exercise alone do not provide adequate glycaemic control in patients for
whom use of metformin is considered inappropriate due to intolerance.
– Add-on combination therapy
• In combination with other glucose–lowering medicinal products including insulin, when
these, together with diet and exercise, do not provide adequate glycaemic control.
● Empagliflozin can provide your patients with:
– Significant placebo-adjusted HbA1c reductions: up to 0.64%
– Secondary benefit of significant placebo-adjusted weight reduction of around 2 kg
– Significant glycaemic efficacy in combination with a range of background treatment including insulin
● The most frequently reported adverse reaction was hypoglycaemia when used with a sulphonylurea or
insulin
● The incidence of genital tract infections was greater in patients receiving empagliflozin than placebo
● When used in combination with empagliflozin, a lower dose of sulphonylurea or insulin should be
considered to reduce the risk of hypoglycaemia
● Convenient once-daily oral dosing.
Jardiance (empagliflozin) Summary of Product Characteristics. Available at: https://www.medicines.org.uk/emc/medicine/28973 (accessed July 2016).
UK/EMP/00264(1) | July 2016
33
▼Jardiance® (empagliflozin) 10mg and 25mg film-coated tablets
Film-coated tablets containing 10 mg or 25 mg empagliflozin.
Indication: Treatment of type 2 diabetes mellitus to improve
glycaemic control in adults: As monotherapy when diet and
exercise alone do not provide adequate glycaemic control in
patients for whom use of metformin is considered inappropriate
due to intolerance; as add-on combination therapy with other
glucose–lowering medicinal products including insulin when
these together with diet and exercise do not provide adequate
glycaemic control. Dose and Administration: Monotherapy or
add-on combination: The recommended starting dose is 10mg
once daily. In patients tolerating empagliflozin 10 mg once daily
who have eGFR ≥ 60 ml/min/1.73m2 and need tighter glycaemic
control, the dose can be increased to 25 mg once daily. The
maximum daily dose is 25 mg. When used with sulphonylurea or
insulin a lower dose of these may be considered to reduce the
risk of hypoglycaemia. Renal impairment: Efficacy is dependent
on renal function. No dose adjustment is required for patients
with an eGFR ≥60 ml/min/1.73m2 or CrCl ≥60 ml/min. Do not
initiate in patients with an eGFR <60 ml/min/1.73m2 or
CrCl <60 ml/min. In patients tolerating empagliflozin whose eGFR
falls persistently below 60 ml/min/1.73m2 or CrCl below
60 ml/min, the dose of empagliflozin should be adjusted to or
maintained at 10 mg once daily. Discontinue when eGFR is
persistently below 45 ml/min/1.73m2 or CrCl persistently below
45 ml/min. Not for use in patients with end stage renal disease
(ESRD) or on dialysis. Hepatic impairment: No dose adjustment is
required for patients with hepatic impairment. Not
recommended in severe hepatic impairment. Elderly patients:
No dose adjustment is recommended based on age. In patients
75 years and older, an increased risk for volume depletion should
be taken into account. Not recommended in patients 85 years or
older. Paediatric population: No data are available. Method of
administration: The tablets can be taken with or without food,
swallowed whole with water. 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.
Contraindications:
Hypersensitivity to the active substance or to any of the
excipients. Warnings and Precautions: Not to be used in
patients with type 1 diabetes or for the treatment of diabetic
ketoacidosis (DKA). Rare cases of DKA, including life-threatening
cases, have been reported in clinical trials and post-marketing in
patients treated with SGLT2 inhibitors, including empagliflozin.
Consider the risk of DKA in the event of non-specific symptoms
such as nausea, vomiting, anorexia, abdominal pain, excessive
thirst, difficulty breathing, confusion, unusual fatigue or
sleepiness and assess patients for ketoacidosis immediately,
regardless of blood glucose level. Interrupt treatment for
patients hospitalised for major surgical procedures or acute
serious medical illnesses. In patients where DKA is suspected or
diagnosed, treatment should be discontinued immediately.
Before initiating empagliflozin, consider factors in the patient
history that may predispose to ketoacidosis. Use with caution in
patients who may be at higher risk of DKA. Renal impairment and
elderly patients: See under Dose and Administration. Monitor
renal function prior to initiation and at least annually. Cases of
hepatic injury have been reported with empagliflozin in clinical
trials. A causal relationship between empagliflozin and hepatic
injury has not been established. Osmotic diuresis accompanying
therapeutic glucosuria may lead to a modest decrease in blood
pressure. Therefore, caution should be exercised in patients with
known cardiovascular disease, patients on anti-hypertensive
therapy with a history of hypotension or patients aged 75 years
and older. In case of conditions that may lead to fluid loss (e.g.
gastrointestinal illness), careful monitoring of volume status and
electrolytes is recommended. Temporary interruption of
treatment with empagliflozin should be considered until the fluid
loss is corrected. Temporary interruption of empagliflozin should
be considered in patients with complicated urinary tract
infections. Experience in New York Heart Association (NYHA)
class I-II is limited, and there is no experience in clinical studies
with empagliflozin in NYHA class III-IV. Due to its mechanism of
action, patients taking Jardiance will test positive for glucose in
their urine.The tablets contain lactose and should not be used in
patients with rare hereditary problems of galactose intolerance,
the Lapp lactase deficiency, or glucose-galactose malabsorption.
Interactions: Use with diuretics may increase the risk of
dehydration and hypotension. Insulin and insulin secretagogues
may increase the risk of hypoglycaemia therefore, a lower dose
of insulin or an insulin secretagogue may be required. The effect
of UGT induction on empagliflozin has not been studied. Comedication with known inducers of UGT enzymes should be
avoided due to a potential risk of decreased efficacy. Interaction
UK/EMP/00264(1) | July 2016
studies conducted in healthy volunteers suggest that the
pharmacokinetics of empagliflozin were not influenced by
coadministration with metformin, glimepiride, pioglitazone,
sitagliptin, linagliptin, warfarin, verapamil, ramipril, simvastatin,
torasemide and hydrochlorothiazide. Interaction studies
conducted in healthy volunteers suggest that empagliflozin had
no clinically relevant effect on the pharmacokinetics of
metformin, glimepiride, pioglitazone, sitagliptin, linagliptin,
simvastatin, warfarin, ramipril, digoxin, diuretics and oral
contraceptives. Fertility, pregnancy and lactation: There are no
data from the use of empagliflozin in pregnant women. Use
should be avoided avoid during early pregnancy and is not
recommended during the second and third trimester of
pregnancy. No data in humans are available on excretion of
empagliflozin into milk. Jardiance should not be used during
breast-feeding. No studies on the effect on human fertility have
been conducted for Jardiance. Undesirable effects: Frequencies
are defined as very common (≥1/10), common (≥1/100 to <1/10),
uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000).
Very common: Hypoglycaemia (when used with sulphonylurea or
insulin). Common: Vaginal moniliasis, vulvovaginitis, balanitis
and other genital infections, urinary tract infection, pruritus
(generalised), increased urination. Uncommon: Volume
depletion,dysuria. Rare: DKA. Prescribers should consult the
Summary of Product Characteristics for further information on
side effects. Pack sizes and NHS price: 10 mg; 28 tablets £36.59,
25 mg: 28 tablets £36.59.
Legal category: POM
MA
numbers:10 mg/28 tablets EU/1/14/930/013; 25 mg/28 tablets
EU/1/14/930/004. Marketing Authorisation Holder: Boehringer
Ingelheim International GmbH, D-55216 Ingelheim am Rhein,
Germany. Prescribers should consult the Summary of Product
Characteristics for full prescribing information. Prepared in May
2016.
Adverse events should be reported. Reporting
forms and information can be found at
www.mhra.gov.uk/yellowcard. Adverse events
should also be reported to Boehringer Ingelheim
Drug Safety on 0800 328 1627 (freephone).
▼Synjardy® (empagliflozin and metformin hydrochloride)
5 mg/850 mg, 5 mg/1000 mg, 12.5 mg/850 mg or 12.5 mg/1000 mg film coated tablets
Film-coated tablets containing 5 mg empagliflozin and 850 mg
metformin hydrochloride, 5 mg empagliflozin and 1000 mg metformin
hydrochloride, 12.5 mg empagliflozin and 850 mg metformin
hydrochloride or 12.5 mg empagliflozin and 1000 mg metformin
hydrochloride. Indication: Synjardy is indicated in adults aged 18 years
and older with type 2 diabetes mellitus as an adjunct to diet and
exercise to improve glycaemic control in certain patient groups. These
include patients inadequately controlled on their maximally tolerated
dose of metformin alone, in patients inadequately controlled with
metformin in combination with other glucose-lowering medicinal
products including insulin, and in patients already being treated with the
combination of empagliflozin and metformin as separate tablets. Dose
and Administration: Recommended dose: one tablet twice daily. The
dosage should be individualised on the basis of the patient’s current
regimen, effectiveness, and tolerability using the recommended daily
dose of 10 mg or 25 mg of empagliflozin, while not exceeding maximum
recommended daily dose of metformin. For patients inadequately
controlled on metformin monotherapy or in combination with other
glucose-lowering medicinal products, including insulin, the
recommended starting dose of Synjardy should provide empagliflozin
5 mg twice daily (10 mg daily dose) and the dose of metformin similar to
the dose already being taken. In patients tolerating a total daily dose of
empagliflozin 10 mg and who need tighter glycaemic control, the dose
can be increased to a total daily dose of empagliflozin 25 mg. When
used in combination with insulin and/or an insulin secretagogue such as
sulphonylurea, a lower dose of the insulin and/or insulin secretagogue
may be required. Patients switching from separate tablets of
empagliflozin (10 mg or 25 mg total daily dose) and metformin to
Synjardy should receive the same daily dose of these already being
taken or the nearest therapeutically appropriate dose of metformin.
Hepatic impairment: Not to be used in patients with hepatic
impairment. Renal impairment: No dose adjustment is recommended
for patients with mild renal impairment. Synjardy must not be used in
patients with moderate or severe renal impairment (creatinine
clearance <60 ml/min). Elderly: Decreased renal function will result in
reduced efficacy of empagliflozin. Metformin is excreted by the kidney
and therefore caution should be used in elderly patients due to
decreased renal function in the elderly population. Monitoring of renal
function is necessary to aid in prevention of metformin-associated lactic
acidosis, particularly in elderly patients. In patients 75 years and older,
an increased risk for volume depletion should be taken into account.
Not recommended in patients 85 years or older. Paediatric population:
No data are available. Method of administration: Synjardy should be
taken twice daily with meals. If a dose is missed, it should be taken as
soon as the patient remembers. However, a double dose should not be
taken at the same time. In that case, the missed dose should be skipped.
Contraindications: Hypersensitivity to the active substances or to any of
the excipients. Diabetic ketoacidosis (DKA), diabetic pre coma. Renal
failure or renal dysfunction (creatinine clearance <60 ml/min). Acute
conditions with the potential to alter renal function such as:
dehydration, severe infection, shock. Disease which may cause tissue
hypoxia (especially acute disease, or worsening of chronic disease) such
as: decompensated heart failure, respiratory failure, recent myocardial
infarction, shock. Hepatic impairment, acute alcohol intoxication,
alcoholism. Warnings and Precautions: Not to be used in patients with
type 1 diabetes or in paediatric populations. Rare cases of DKA,
including life-threatening cases, have been reported in clinical trials and
post-marketing in patients treated with SGLT2 inhibitors, including
empagliflozin. Consider the risk of DKA in the event of non-specific
symptoms such as nausea, vomiting, anorexia, abdominal pain,
excessive thirst, difficulty breathing, confusion, unusual fatigue or
sleepiness and assess patients for ketoacidosis immediately, regardless
of blood glucose level. Interrupt treatment for patients hospitalised for
major surgical procedures or acute serious medical illnesses. In patients
where DKA is suspected or diagnosed, treatment should be discontinued
immediately. Before initiating empagliflozin, consider factors in the
patient history that may predispose to ketoacidosis. Use with caution in
patients who may be at higher risk of DKA. Lactic acidosis can occur due
to metformin accumulation and occurs primarily in patients with renal
failure or acute worsening of renal function. In the case of lactic acidosis
the patient should be hospitalised immediately. Treatment should be
temporarily discontinued in situations where renal function may
become impaired, e.g. in case of dehydration (severe diarrhoea or
vomiting), or when initiating antihypertensive therapy or diuretic
therapy and when starting therapy with a non-steroidal antiinflammatory drug (NSAID). Other risk factors should be considered such
as poorly controlled diabetes, ketosis, prolonged fasting, excessive
alcohol intake, hepatic impairment and any condition associated with
hypoxia (such as decompensated cardiac failure, acute myocardial
infarction). Risk of lactic acidosis must also be considered, and
treatment temporarily discontinued, in the event of non-specific signs
e.g. muscle cramps and digestive disorders such as abdominal pain and
severe asthenia. Physicians should alert patients on the risk and
symptoms of lactic acidosis. Determine serum creatinine levels before
treatment and at least annually (with normal renal function) or at least
two to four times a year (with serum creatinine levels at the upper limit
of normal and in elderly subjects). Renal function should be checked
before initiating treatment with metformin. Patients with heart failure
are more at risk of hypoxia and renal insufficiency. In patients with
stable chronic heart failure, Synjardy may be used with a regular
monitoring of cardiac and renal function. Synjardy must be discontinued
prior to, or at the time of intravascular administration of iodinated
contrast materials in radiologic studies and must not be reinstituted
until at least 48 hours afterwards, and only after renal function has been
re-evaluated and has not deteriorated further. Synjardy must be
discontinued 48 hours before elective surgery with general, spinal or
peridural anaesthesia and not be resumed earlier than 48 hours and
after renal function has been re-evaluated and found to be normal.
Exercise caution in patients with known cardiovascular disease, patients
on anti-hypertensive therapy with a history of hypotension or patients
aged 75 years and older. In case of conditions that may lead to fluid loss
(e.g. gastrointestinal illness), careful monitoring of volume status and
electrolytes is recommended. Temporary interruption of treatment
should be considered until the fluid loss is corrected. Temporary
interruption of treatment should be considered in patients with
complicated urinary tract infections. Patients aged 75 years and older
may be at an increased risk of volume depletion. Experience in New York
Heart Association (NYHA) class I-II is limited, and there is no experience
in clinical studies with empagliflozin in NYHA class III-IV. Patients taking
Synjardy will test positive for glucose in their urine. Interactions: No
interaction studies have been performed for Synjardy. Interactions for
Empagliflozin: Use with diuretics may increase the risk of dehydration
and hypotension. Insulin and insulin secretagogues may increase the risk
of hypoglycaemia therefore, a lower dose of insulin or an insulin
secretagogue may be required. The effect of UGT induction on
empagliflozin has not been studied. Co-medication with known inducers
of UGT enzymes should be avoided due to a potential risk of decreased
efficacy. Interaction studies conducted in healthy volunteers suggest
UK/EMP/00264(1) | July 2016
that the pharmacokinetics of empagliflozin were not influenced by
coadministration with metformin, glimepiride, pioglitazone, sitagliptin,
linagliptin, warfarin, verapamil, ramipril, simvastatin, torasemide and
hydrochlorothiazide. Interaction studies conducted in healthy
volunteers suggest that empagliflozin had no clinically relevant effect on
the pharmacokinetics of metformin, glimepiride, pioglitazone,
sitagliptin, linagliptin, simvastatin, warfarin, ramipril, digoxin, diuretics
and oral contraceptives. Interactions for Metformin: There is increased
risk of lactic acidosis in acute alcohol intoxication (particularly in the
case of fasting, malnutrition or hepatic impairment due to the
metformin active substance). Consumption of alcohol and medicinal
products containing alcohol should be avoided. Cationic substances that
are eliminated by renal tubular secretion (e.g. cimetidine) may interact
with metformin by competing for common renal tubular transport
systems. The intravascular administration of iodinated contrast agents
in radiological studies may lead to lactic acidosis (refer to Warnings and
Precautions). Glucocorticoids (given by systemic and local routes),
beta-2-agonists, and diuretics have intrinsic hyperglycaemic activity. The
patient should be informed and more frequent blood glucose
monitoring performed, especially at the beginning of treatment with
such medicinal products. Insulin and insulin secretagogues, such as
sulphonylureas, may increase the risk of hypoglycaemia. Fertility,
Pregnancy and Lactation: There are no data from the use of Synjardy or
empagliflozin in pregnant women. When the patient plans to become
pregnant, and during pregnancy, it is recommended that diabetes is not
treated with this medicinal product, but insulin be used to maintain
blood glucose levels as close to normal as possible, to reduce the risk of
malformations of the foetus. Synjardy should not be used during breast
feeding. No studies on the effect on human fertility have been
conducted for Synjardy or empagliflozin. Undesirable effects:
Frequencies are defined as very common (≥1/10), common (≥1/100 to
<1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000),
very rare (<1/10,000), and not known (cannot be estimated from the
available data). Very common: hypoglycaemia (when used with
sulphonylurea or insulin), gastrointestinal symptoms. Common: vaginal
moniliasis, vulvovaginitis, balanitis and other genital infections, urinary
tract infection, taste disturbance, pruritus (generalised), increased
urination. Uncommon: volume depletion, dysuria. Rare: DKA. Very rare:
lactic acidosis, vitamin B12 deficiency, liver function tests abnormalities,
hepatitis, erythema, urticaria. Prescribers should consult the Summary
of Product Characteristics for further information on side effects. Pack
sizes and NHS price: 56 x 1 film-coated tablets; 5 mg/850 mg: £36.59,
5 mg/1000 mg: £36.59, 12.5 mg/850 mg: £36.59 and 12.5 mg/1000 mg:
£36.59. Legal category: POM.
MA numbers: 5 mg/850 mg:
EU/1/15/1003/004;
5
mg/1000
mg:
EU/1/15/1003/013;
12.5 mg/850 mg: EU/1/15/1003/22; 12.5 mg/1000 mg:
EU/1/15/1003/031. Marketing Authorisation Holder: Boehringer
Ingelheim International GmbH, Binger Strasse 173, D-55216 Ingelheim
am Rhein, Germany. Prescribers should consult the Summary of Product
Characteristics for full prescribing information. Prepared in May 2016
Adverse events should be reported. Reporting
forms and information can be found at
www.mhra.gov.uk/yellowcard. Adverse events
should also be reported to Boehringer Ingelheim
Drug Safety on 0800 328 1627 (freephone).
Trajenta® (linagliptin) 5 mg film-coated tablets
Film-coated tablets containing 5 mg linagliptin. Indication:
Trajenta is indicated in the treatment of type 2 diabetes
mellitus to improve glycaemic control in adults: as
monotherapy: - in patients inadequately controlled by diet
and exercise alone and for whom metformin is
inappropriate due to intolerance, or contraindicated due
to renal impairment; as combination therapy: - in
combination with metformin when diet and exercise plus
metformin alone do not provide adequate glycaemic
control; - in combination with a sulphonylurea and
metformin when diet and exercise plus dual therapy with
these medicinal products do not provide adequate
glycaemic control; - in combination with insulin with or
without metformin, when this regimen alone, with diet
and exercise, does not provide adequate glycaemic
control. Dose and Administration: 5 mg once daily. If
added to metformin, the dose of metformin should be
maintained and linagliptin administered concomitantly.
When used in combination with a sulphonylurea or with
insulin, a lower dose of the sulphonylurea or insulin, may
be considered to reduce the risk of hypoglycaemia. Renal
impairment: no dose adjustment required. Hepatic
impairment: pharmacokinetic studies suggest that no dose
adjustment is required for patients with hepatic
impairment but clinical experience in such patients is
lacking. Elderly: no dose adjustment is necessary based on
age however, clinical experience in patients > 80 years of
age is limited and caution should be exercised when
treating this population. Paediatric population: the safety
and efficacy of linagliptin in children and adolescents has
not yet been established. No data are available. Take the
tablets with or without a meal at any time of the day. If a
dose is missed, it should be taken as soon as possible but a
double dose should not be taken on the same day.
Contraindications: Hypersensitivity to the active
substance or to any of the excipients. Warnings and
Precautions: Linagliptin should not be used in patients
with type 1 diabetes or for the treatment of diabetic
ketoacidosis. Caution is advised when linagliptin is used in
combination with a sulphonylurea and/or insulin; a dose
reduction of the sulphonylurea or insulin may be
considered. Acute pancreatitis: In post-marketing
experience of linagliptin there have been spontaneously
reported adverse reactions of acute pancreatitis. Patients
should be informed of the characteristic symptoms of
acute pancreatitis. If pancreatitis is suspected, Trajenta
should be discontinued; if acute pancreatitis is confirmed,
Trajenta should not be restarted. Caution should be
exercised in patients with a history of pancreatitis.
Interactions: 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 low potency. Based on these results and in
vivo interaction studies, linagliptin is considered unlikely
to cause interactions with other P-gp substrates. The risk
for clinically meaningful interactions by other medicinal
products on linagliptin is low and in clinical studies
linagliptin had no clinically relevant effect on the
pharmacokinetics
of
metformin,
glibenclamide,
simvastatin, warfarin, digoxin or oral contraceptives
(please refer to Summary of Product Characteristics for
information on clinical data). Fertility, pregnancy and
lactation: Avoid use during pregnancy. A risk to the breastfed child cannot be excluded. A decision must be made
whether to discontinue breast-feeding or to
discontinue/abstain from linagliptin therapy taking into
account the benefit of breast-feeding for the child and the
benefit of therapy for the woman. No studies on the
effect on human fertility have been conducted for
linagliptin. Undesirable effects: Adverse reactions
reported in patients who received linagliptin 5 mg daily as
monotherapy or as add-on therapies (frequencies
identified from pooled analysis of placebo-controlled
studies) in clinical trial and from post-marketing
experience. The adverse reactions are listed by absolute
frequency. Frequencies are defined as very common
(≥1/10), common (≥1/100 to <1/10), uncommon (≥ 1/1,000
to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare
(<1/10,000) or not known (cannot be estimated from the
available
data).
Very
common:
hypoglycaemia
(combination
with/add-on
to
metformin
and
sulphonylurea).
Uncommon:
nasopharyngitis
(monotherapy; combination with/add-on to metformin;
combination with/add-on to insulin); hypersensitivity e.g.
UK/EMP/00264(1) | July 2016
bronchial hyperreactivity (monotherapy; combination
with/add-on to metformin; combination with/add-on to
metformin and sulphonylurea; combination with/add-on
to insulin); cough (monotherapy; combination with/addon to metformin; combination with/add-on to insulin);
pancreatitis (combination with/add-on to insulin);
constipation (combination with/add-on to insulin); rash
(monotherapy; combination with/add-on to metformin;
combination
with/add-on
to
metformin
and
sulphonylurea; combination with/add-on to insulin);
amylase increased (combination with/add-on to
metformin; combination with/add-on to metformin and
sulphonylurea). Rare: angioedema (monotherapy;
combination with/add-on to metformin; combination
with/add-on
to
metformin
and
sulphonylurea;
combination
with/add-on
to
insulin);
urticaria
(monotherapy; combination with/add-on to metformin;
combination
with/add-on
to
metformin
and
sulphonylurea; combination with/add-on to insulin);
amylase increased (monotherapy). Not known:
nasopharyngitis (combination with/add-on to metformin
and sulphonylurea); cough (combination with/add-on to
metformin
and
sulphonylurea);
pancreatitis
(monotherapy; combination with/add-on to metformin;
combination
with/add-on
to
metformin
and
sulphonylurea); bullous pemphigoid (monotherapy;
combination with/add-on to metformin; combination
with/add-on
to
metformin
and
sulphonylurea;
combination with/add-on to insulin); amylase increased
(combination with/add-on to insulin). Prescribers should
consult the Summary of Product Characteristics for further
information on side effects. Pack sizes and NHS price: 28
tablets £33.26. Legal category: POM. MA number:
EU/1/11/707/003. Marketing Authorisation Holder:
Boehringer Ingelheim International GmbH, D-55216
Ingelheim am Rhein, Germany. Prescribers should consult
the Summary of Product Characteristics for full prescribing
information. Prepared in June 2016.
Adverse events should be reported. Reporting
forms and information can be found at
www.mhra.gov.uk/yellowcard. Adverse events
should also be reported to Boehringer Ingelheim
Drug Safety on 0800 328 1627 (freephone).
▼Jentadueto® (linagliptin and metformin hydrochloride)
2.5 mg/850 mg film-coated tablets and 2.5 mg/1,000 mg film-coated tablets
Film-coated tablets containing 2.5 mg linagliptin and 850 mg metformin
hydrochloride or 2.5 mg linagliptin and 1,000 mg metformin
hydrochloride. Indication: Treatment of adult patients with type 2
diabetes mellitus: as an adjunct to diet and exercise to improve
glycaemic control in adult patients inadequately controlled on their
maximal tolerated dose of metformin alone, or those already being
treated with the combination of linagliptin and metformin; in combination
with a sulphonylurea (i.e. triple combination therapy) as an adjunct to diet
and exercise in adult patients inadequately controlled on their maximal
tolerated dose of metformin and a sulphonylurea; in combination with
insulin (i.e. triple combination therapy) as an adjunct to diet and exercise
to improve glycaemic control in adult patients when insulin and metformin
alone do not provide adequate glycaemic control. Dose and
Administration: The dose should be individualised based on the
patient’s current regimen, effectiveness and tolerability, not exceeding
the maximum recommended daily dose of 5 mg linagliptin plus 2,000 mg
metformin hydrochloride. Patients inadequately controlled on maximal
tolerated dose of metformin monotherapy: the usual starting dose should
provide linagliptin 2.5 mg twice daily (5 mg total daily dose) plus the
current metformin dose. Patients switching from co-administration of
linagliptin and metformin: Initiate at the dose of linagliptin and metformin
already being taken. Patients inadequately controlled on dual
combination of the maximal tolerated dose of metformin and a
sulphonylurea: The dose should provide linagliptin 2.5 mg twice daily
(5 mg total daily dose) and a metformin dose similar to the dose already
being taken. When linagliptin plus metformin hydrochloride is used in
combination with a sulphonylurea, a lower dose of the sulphonylurea may
be required to reduce the risk of hypoglycaemia. Patients inadequately
controlled on dual combination with insulin and the maximal tolerated
dose of metformin: The dose should provide linagliptin 2.5 mg twice daily
(5 mg total daily dose) and a metformin dose similar to the dose already
being taken. When linagliptin plus metformin hydrochloride is used in
combination with insulin, a lower dose of insulin may be required to
reduce the risk of hypoglycaemia. Elderly: As metformin is excreted by
the kidney, use with caution as age increases. Monitoring of renal
function is necessary. Exercise caution in patients 80 years and older as
clinical experience in this age group is limited. Renal impairment:
Jentadueto must not be used in patients with moderate or severe renal
impairment (creatinine clearance < 60 ml/min). Hepatic impairment: Not
recommended. Clinical experience in patients with hepatic impairment is
lacking. Paediatric population: Safety and efficacy in children and
adolescents (aged 0 to 18 years) have not been established. No data are
available. Taking Jentadueto: To be taken twice daily with meals. All
patients should continue their diet with an adequate distribution of
carbohydrate intake during the day. Overweight patients should continue
their energy-restricted diet. If a dose is missed, it should be taken as
soon as the patient remembers. However, a double dose should not be
taken at the same time (the missed dose should be skipped).
Contraindications: Hypersensitivity to the active substances or to any of
the excipients; diabetic ketoacidosis, diabetic pre-coma; renal failure or
renal dysfunction (creatinine clearance < 60 ml/min); acute conditions
with the potential to alter renal function such as dehydration, severe
infection, shock; disease which may cause tissue hypoxia (especially
acute disease, or worsening of chronic disease) such as decompensated
heart failure, respiratory failure, recent myocardial infarction, shock;
hepatic impairment, acute alcohol intoxication, alcoholism. Warnings
and Precautions: Not to be used in patients with type 1 diabetes or for
the treatment of diabetic ketoacidosis. Caution is advised when
Jentadueto is used in combination with a sulphonylurea and/or insulin
due to increased incidence of hypoglycaemia. Lactic acidosis can occur
due to metformin accumulation. If diagnosed the patient should be
hospitalised immediately. Treatment should be temporarily discontinued
in situations where renal function may become impaired e.g. dehydration
(severe diarrhoea or vomiting), initiation of antihypertensive therapy,
diuretic therapy or therapy with a non-steroidal anti-inflammatory drug
(NSAID). Risk of lactic acidosis must also be considered, and treatment
temporarily discontinued, in the event of non-specific signs e.g. muscle
cramps and digestive disorders such as abdominal pain and severe
asthenia. Patients should be alerted to the risk and symptoms of lactic
acidosis. Serum creatinine levels should be determined before initiating
treatment and regularly thereafter. Decreased renal function in older
subjects is frequent and asymptomatic. Special caution should be
exercised in situations where renal function may become impaired. Renal
function should be checked before initiating treatment with metformin.
Patients with heart failure are more at risk of hypoxia and renal
impairment. In patients with stable chronic heart failure Jentadueto may
be used with regular monitoring of cardiac and renal function. Treatment
must be discontinued 48 hours before elective surgery with general,
spinal or epidural anaesthesia, or prior to, or at the time of intravascular
administration of iodinated contrast agents in radiologic studies. Therapy
should usually not be resumed earlier than 48 hours following surgery or
must not be reinstituted until at least 48 hours after the test and only after
renal function has been re-evaluated and found to be normal (surgery) or
has not deteriorated further (radiologic studies). A patient with previously
well controlled type 2 diabetes on Jentadueto who develops laboratory
abnormalities or clinical illness (especially vague and poorly defined
illness) should be evaluated promptly for evidence of ketoacidosis or
lactic acidosis. If acidosis of either form occurs, stop treatment
immediately and initiate other appropriate corrective measures. There
have been spontaneously reported adverse reactions of acute
pancreatitis with linagliptin. If pancreatitis is suspected, Jentadueto
should be discontinued; if confirmed, treatment should not be restarted.
Patients should be informed of the characteristic symptoms of acute
pancreatitis. Exercise caution in patients with a history of pancreatitis.
Interactions: Combination requiring precautions for use: glucocorticoids
(given by systemic and local routes), beta-2-agonists, and diuretics. More
frequent blood glucose monitoring should be performed, especially at the
beginning of treatment with such medicinal products. If necessary, adjust
the dose of Jentadueto during therapy with the other medicinal product
and on its discontinuation. Combinations not recommended: Avoid
consumption of alcohol and medicinal products containing alcohol due to
increased risk of lactic acidosis in acute alcohol intoxication. Cationic
substances that are eliminated by renal tubular secretion e.g. cimetidine.
The intravascular administration of iodinated contrast agents in
radiological studies may lead to renal failure, resulting in metformin
accumulation and a risk of lactic acidosis (see above). Fertility,
UK/EMP/00264(1) | July 2016
pregnancy and lactation: Jentadueto should not be used during
pregnancy. If the patient plans to become pregnant, or if pregnancy
occurs, discontinue treatment and switch to insulin treatment as soon as
possible in order to lower the risk of foetal malformations associated with
abnormal blood glucose levels. A decision must be made whether to
discontinue breast-feeding or to discontinue/abstain from Jentadueto
therapy taking into account the benefit of breast-feeding for the child and
the benefit of therapy for the woman. No studies on the effect on human
fertility have been conducted for Jentadueto. Undesirable effects:
Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to
< 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000),
very rare (< 1/10,000) and not known (cannot be estimated from the
available data). Adverse reactions reported with the fixed dose
combination: Common: diarrhoea; Uncommon: nasopharyngitis;
hypersensitivity e.g. bronchial hyperreactivity; cough; decreased appetite;
nausea; vomiting; rash; pruritus; blood amylase increased. Rare:
angioedema; urticaria. Not known: pancreatitis, bullous pemphigoid.
Adverse reactions known to occur with each active substance given
singly but which have not been seen in clinical trials with Jentadueto,
may occur during treatment with this medicinal product. Additional
adverse reactions reported when linagliptin and metformin were
combined with sulphonylurea: very common: hypoglycaemia. Additional
reactions reported when linagliptin and metformin were combined with
insulin: Uncommon: constipation; liver function disorders. Additional
information on individual components: Adverse reactions previously
reported with one of the individual active substances may be potential
adverse reactions with Jentadueto, even if not observed in clinical trials.
Linagliptin: All identified adverse reactions of linagliptin monotherapy are
also described for Jentadueto. Metformin: Known adverse reactions that
were not reported in patients who received Jentadueto. Very common:
abdominal pain. Common: taste disturbance. Very rare: lactic acidosis;
vitamin B12 deficiency; hepatitis; skin reactions. Prescribers should
consult the Summary of Product Characteristics for further information on
side effects. Pack sizes and NHS price: 2.5 mg/850 mg 56 tablets
£33.26; 2.5 mg/1,000 mg 56 tablets £33.26. Legal category: POM. MA
numbers: 2.5 mg/850 mg (56 tablets) EU/1/12/780/005; 2.5 mg/1,000
mg (56 tablets) EU/1/12/780/019. Marketing Authorisation Holder:
Boehringer Ingelheim International GmbH, D-55216 Ingelheim am Rhein,
Germany. Prescribers should consult the Summary of Product
Characteristics for full prescribing information. Prepared in June 2016.
Adverse events should be reported. Reporting forms
and information can be found at
www.mhra.gov.uk/yellowcard Adverse events
should also be reported to Boehringer Ingelheim
Drug Safety on 0800 328 1627 (freephone).
▼ ABASAGLAR® CARTRIDGE AND KWIKPEN™ ABBREVIATED PRESCRIBING INFORMATION
ABASAGLAR IS INSULIN GLARGINE (human insulin analogue)
Presentation Abasaglar is a clear, colourless, sterile solution of
100 units/ml (equivalent to 3.64mg) insulin glargine (rDNA
origin), available as either 3ml cartridge or 3ml KwikPen. Each
cartridge/pen contains 300 units of insulin glargine in 3ml
solution. Uses Treatment of diabetes mellitus in adults,
adolescents, and children aged 2 years and above. Dosage and
Administration The dose regimen (dose and timing) should be
individually adjusted. In patients with Type 2 diabetes
mellitus, Abasaglar can also been given together with orally
active antidiabetic medication. Abasaglar has a prolonged
duration of action, and should be administered once daily at
any time, but at the same time each day. It should only be
given by subcutaneous injection and should not be
administered intravenously. Injection sites must be rotated
within a given injection area from one injection to the next.
Abasaglar must not be mixed with any other insulin or diluted.
When changing from another intermediate or long-acting
insulin treatment regimen to Abasaglar, a change of the dose
of the basal insulin may be required and the concomitant
antidiabetic treatment may need to be adjusted (dose and
timing of additional regular insulins or fast-acting insulin
analogues, or the dose of oral antidiabetic medicinal
products). Contraindications Hypersensitivity to insulin
glargine or any of the excipients. Warnings and Special
Precautions Abasaglar is not the insulin of choice for the
treatment of diabetic ketoacidosis. In case of insufficient
glucose control, or tendency to hyper- or hypoglycaemic
episodes, other relevant factors must be reviewed before dose
adjustment is considered. Transferring a patient to another
type or brand of insulin should be done under strict medical
supervision. Changes in strength, brand, type, origin, and/or
method of manufacture may result in the need for a change in
dose. In rare cases, insulin antibodies may necessitate dose
adjustment. The time of occurrence of hypoglycaemia may
change when the insulin regimen is changed, depending on
the action profile of the insulins used. Caution and intensified
glucose monitoring are advised in patients for whom
hypoglycaemia might be of particular clinical relevance.
Patients should be aware that warning symptoms of
hypoglycaemia may be changed, less pronounced, or absent in
certain circumstances, including: markedly improved
glycaemic control; when hypoglycaemia develops gradually; in
the elderly; after transfer from animal to human insulin;
autonomic neuropathy; long history of diabetes; psychiatric
illness; use of certain medications such as beta-blockers. This
may result in severe hypoglycaemia. The prolonged effect of
insulin glargine may delay recovery from hypoglycaemia. If
HbA1c is low, consider possibility of recurrent, unrecognised
hypoglycaemia. Adherence of the patient to the dose and
dietary regimen, correct insulin administration, and awareness
of hypoglycaemia symptoms are essential to reduce risk of
hypoglycaemia. Factors increasing risk of hypoglycaemia
require particularly close monitoring and may necessitate dose
adjustment. Intercurrent illness requires intensified
monitoring. Testing for ketones and dose adjustment may be
necessary. Patients with Type 1 diabetes must continue to
consume at least small amounts of carbohydrate and must
never omit insulin entirely. The cartridges should only be used
in a pen recommended for the use with Lilly insulin cartridges.
The insulin label must always be checked before each injection
to avoid medication errors. Cases of cardiac failure have been
reported when pioglitazone was used in combination with
insulin. If the combination is used, patients should be
observed for signs and symptoms of heart failure and
pioglitazone discontinued if any deterioration occurs.
Pregnancy and Lactation No clinical data from controlled
studies are available. Data from >1,000 pregnancy outcomes
indicate no specific adverse effects of insulin glargine on
pregnancy and no specific malformative nor feto/neonatal
toxicity. The use of Abasaglar may be considered during
pregnancy, if necessary. Insulin requirements may decrease
during the first trimester and generally increase during the
second and third trimesters. Immediately after delivery,
insulin requirements decline rapidly. Careful monitoring of
UK/EMP/00264(1) | July 2016
glucose control is essential. Driving, etc The patient’s ability to
concentrate and react may be impaired as a result of hypo- or
hyperglycaemia, or visual impairment. This may constitute a
risk in situations where these abilities are of special
importance (eg, driving a car or operating machines).
Undesirable Effects Hypoglycaemia is very common. Injection
site reactions and lipohypertrophy are common. Immediatetype allergic reactions are rare, but may be life-threatening.
For full details of these and other side-effects, please see the
Summary of Product Characteristics, which is available at
http://www.medicines.org.uk/emc/. Legal Category
POM
Marketing Authorisation
Numbers EU/1/14/944/003,
EU/1/14/944/007 Basic NHS Cost £35.28 - 5 X 3ml cartridges,
£35.28 - 5 X 3ml KwikPens Date of Preparation or Last Review
May 2015 Full Prescribing Information is Available From Eli
Lilly and Company Limited, Lilly House, Priestley Road,
Basingstoke, Hampshire, RG24 9NL Telephone: Basingstoke
(01256) 315 000
E-mail: [email protected] Website:
www.lillypro.co.uk
ABASAGLAR® (insulin glargine) is a registered trademark of Eli
Lilly and Company.
KWIKPEN™ is a trademark of Eli Lilly and Company.
Adverse events should be reported. Reporting forms
and information can be found at:
www.mhra.gov.uk/yellowcard
Adverse events and product complaints should also be
reported to Lilly:
please call Lilly UK on 01256 315000