When a pharmaceutical company changes an SPC or PIL, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.
Sections 4.4 & 4.8 - Label Update- Pancreatitis
Section 4.8 - Label update vomiting
Sections 4.1, 4.2, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.1, 5.2 - Updated renal impairment information
Add on insulin (II11) Changes to Sections: 4.1, 4.2, 4.4, 4.8, 5.1 4.1 Therapeutic indications For patients with type 2 diabetes mellitus, Januvia is indicated to improve glycaemic control: as monotherapy in patients inadequately controlled by to improve glycaemic control when diet and exercise alone and alone do not provide adequate glycaemic control and whenfor whom metformin is inappropriate due to contraindications or intolerance. as dual oral therapy in combination with to improve glycaemic control in combination with metformin when diet and exercise plus metformin alone do not provide adequate glycaemic control. to improve glycaemic control in combination with a sulphonylurea when diet and exercise plus maximal tolerated dose of a sulphonylurea alone do not provide adequate glycaemic control and when metformin is inappropriate due to contraindications or intolerance. a PPAR g agonist (i.e. a thiazolidinedione) when use of a PPARg agonist is appropriate and when diet and exercise plus the PPARg agonist alone do not provide adequate glycaemic control. as triple oral therapy in combination with to improve glycaemic control in combination with a sulphonylurea and metformin when diet and exercise plus dual therapy with these agents do not provide adequate glycaemic control. a PPAR g agonist and metformin when use of a PPARg agonist is appropriate and when diet and exercise plus dual therapy with these agents do not provide adequate glycaemic control. For patients with type 2 diabetes mellitus in whom use of a PPAR g agonist (i.e. a thiazolidinedione) is appropriate, Januvia is indicated: in combination with the PPAR g agonist when diet and exercise plus the PPARg agonist alone do not provide adequate glycaemic control. in combination with the PPAR g agonist and metformin when diet and exercise plus dual therapy with these agents do not provide adequate glycaemic control. Januvia is also indicated as add-on to insulin (with or without metformin) when diet and exercise plus stable dosage of insulin do not provide adequate glycaemic control. 4.2 Posology and method of administration The dose of Januvia is 100 mg once daily. When sitagliptin Januvia is used in combination with metformin and/or a PPARg agonist, the dosage of metformin and/or PPARg agonist should be maintained, and sitagliptinJanuvia administered concomitantly. When Januvia is 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. (See section 4.4.) 4.4 Special warnings and precautions for use Hypoglycaemia when used in combination with other anti-hyperglycaemic agents In clinical trials of Januvia as monotherapy and as part of combination therapy with agents not known to cause hypoglycaemia (i.e. metformin and/or a PPAR g agonist), rates of hypoglycaemia reported with sitagliptin were similar to rates in patients taking placebo. When sitagliptin was added to a sulphonylurea or to insulin, the incidence of hypoglycaemia was increased over that of placebo (see section 4.8). Therefore, to reduce the risk of hypoglycaemia, a lower dose of sulphonylurea or insulin may be considered (see section 4.2). The use of sitagliptin in combination with insulin has not been adequately studied. 4.8 Undesirable effects In 10 11 large clinical trials of up to 2 years in duration, over 29003200 patients have received treatment with Januvia 100 mg per day alone or in combination with metformin, a sulphonylurea (with or without metformin), insulin (with or without metformin), or a PPARg agent (with or without metformin). In a pooled analysis of 9 of these trials, the rate of discontinuation due to adverse experiences considered drug-related was 0.8 % with 100 mg per day and 1.5 % with other treatments. No adverse reactions considered as drug-related were reported in patients treated with sitagliptin occurring in excess (> 0.2 % and difference > 1 patient) of that in patients treated with control. In an additional combination study with a PPARg agent (rosiglitazone) and metformin, no patients were discontinued due to adverse experiences considered as drug-related. Table 1. The frequency of adverse reactions identified from placebo-controlled clinical studies Adverse Reaction Frequency of adverse reaction by treatment regimen Sitagliptin with Metformin 1 Sitagliptin with a Sulfonylurea Sulphonylurea 2 Sitagliptin with a Sulfonylurea Sulphonylurea and Metformin 3 Sitagliptin with a PPAR g Agent (pioglitazone)4 Sitagliptin with a PPAR g Agent (rosiglitazone) and Metformin5 Sitagliptin with Insulin (+/-) Metformin) 66 Time-point 24-week 24-week 24-week 24-week 18-week 24-week Investigations blood glucose decreased Uncommon Nervous system disorders headache Common Common somnolence Uncommon Gastrointestinal disorders diarrhoea Uncommon Common dry mouth Uncommon nausea Common flatulence Common constipation Common Uncommon upper abdominal pain Uncommon vomiting Common Metabolism and nutrition disorders hypoglycaemia* Common Very common Very common Common Common Common Infections and infestations influenza Common General disorders peripheral oedema Common Common† 5 In this study of sitagliptin 100 mg once daily in combination with rosiglitazone and metformin, which continued through 54 weeks, the incidence of adverse reactions considered as drug-related in patients treated with the sitagliptin combination compared to treatment with the placebo combination was 15.3 % and 10.9 %, respectively. Other drug-related adverse reactions reported in the 54-week analysis (frequency common) in patients treated with the sitagliptin combination occurring in excess (> 0.2 % and difference > 1 patient) of that in patients treated with the placebo combination were: headache, cough, vomiting, hypoglycaemia, fungal skin infection, and upper respiratory tract infection. 6 In this 24-week study of sitagliptin 100 mg once daily as add-on to insulin therapy (with or without metformin), the incidence of adverse reactions considered as drug-related in patients treated with sitagliptin/insulin (with or without metformin) compared to treatment with placebo/insulin (with or without metformin) was 15.5 % and 8.5 %, respectively. In this study 0.9 % of patients treated with sitagliptin/insulin and 0.0 % of patients treated with placebo/insulin were discontinued due to adverse experiences considered as drug-related. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Overall, sitagliptin improved glycaemic control when used as monotherapy or in combination treatment (see Table 2). Overall, sitagliptin improved glycaemic control when given as monotherapy, when used in combination with metformin (initial or add-on therapy), in combination with a sulphonylurea (with or without metformin), in combination with a thiazolidinedione, and in combination with a thiazolidinedione and metformin, as measured by clinically relevant reductions in HbA1c from baseline at study endpoint (see Table 2). A 24-week placebo-controlled study was designed to evaluate the efficacy and safety of sitagliptin (100 mg once daily) added to insulin (at a stable dose for at least 10 weeks) with or without metformin (at least 1500 mg). In patients taking pre-mixed insulin, the mean daily dose was 70.9 U/day. In patients taking non-pre-mixed (intermediate/long-acting) insulin, the mean daily dose was 44.3 U/day. The addition of sitagliptin to insulin provided significant improvements in glycaemic parameters. There was no meaningful change from baseline in body weight in either group. In a 24-week placebo-controlled factorial study of initial therapy, sitagliptin 50 mg twice daily in combination with metformin (500 mg or 1000 mg twice daily) provided significant improvements in glycaemic parameters compared with either monotherapy. The decrease in body weight with the combination of sitagliptin and metformin was similar to that observed with metformin alone or placebo; there was no change from baseline for patients on sitagliptin alone. The incidence of hypoglycaemia was similar across treatment groups. Table 2. HbA1c results in placebo-controlled monotherapy and combination therapy studies* Study Mean baseline HbA1c (%) Mean change from baseline HbA1c (%)† Placebo-corrected mean change in HbA1c (%)† (95 % CI) Monotherapy Studies Sitagliptin 100 mg once daily§ (N= 193) 8.0 -0.5 -0.6 ‡ (-0.8, -0.4) Sitagliptin 100 mg once daily % (N= 229) 8.0 -0.6 -0.8 ‡ (-1.0, -0.6) Combination Therapy Studies Sitagliptin 100 mg once daily added to ongoing metformin therapy % (N=453) 8.0 -0.7 -0.7 ‡ (-0.8, -0.5) Sitagliptin 100 mg once daily added to ongoing pioglitazone therapy % (N=163) 8.1 -0.9 -0.7 ‡ (-0.9, -0.5) Sitagliptin 100 mg once daily added to ongoing glimepiride therapy % (N=102) 8.4 -0.3 -0.6 ‡ (-0.8, -0.3) Sitagliptin 100 mg once daily added to ongoing glimepiride + metformin therapy % (N=115) 8.3 -0.6 -0.9 ‡ (-1.1, -0.7) Sitagliptin 100 mg once daily added to ongoing rosiglitazone + metformin therapy (N=170) Week 18 Week 54 8.8 8.8 -1.0 -1.0 -0.7 ‡ (-0.9, -0.5) -0.8 ‡ (-1.0, -0.5) Initial therapy (twice daily) %: Sitagliptin 50 mg + metformin 500 mg (N=183) 8.8 -1.4 -1.6 ‡ (-1.8, -1.3) Initial therapy (twice daily) %: Sitagliptin 50 mg + metformin 1000 mg (N=178) 8.8 -1.9 -2.1 ‡ (-2.3, -1.8) Sitagliptin 100 mg once daily added to ongoing insulin (+/- metformin) therapy % (N=305) 8.7 -0.6¶ -0.6‡,¶ (-0.7, -0.4) * ALL PATIENTS TREATED POPULATION (AN INTENTION-TO-TREAT ANALYSIS). † LEAST SQUARES MEANS ADJUSTED FOR PRIOR ANTIHYPERGLYCAEMIC THERAPY STATUS AND BASELINE VALUE. ‡ P<0.001 COMPARED TO PLACEBO OR PLACEBO + COMBINATION TREATMENT. § HBA1C (%) AT WEEK 18. % HBA1C (%) AT WEEK 24. ¶ LEAST SQUARES MEAN ADJUSTED FOR METFORMIN USE AT VISIT 1 (YES/NO), INSULIN USE AT VISIT 1 (PRE-MIXED VS. NON-PRE-MIXED [INTERMEDIATE- OR LONG-ACTING]), AND BASELINE VALUE. TREATMENT BY STRATUM (METFORMIN AND INSULIN USE) INTERACTIONS WERE NOT SIGNIFICANT (P > 0.10).
4.1 Therapeutic indications
For patients with type 2 diabetes mellitus, Januvia is indicated
to improve glycaemic control:
as monotherapy
in patients inadequately controlled by
to improve glycaemic control when diet and exercise alone and alone do not provide adequate glycaemic control and whenfor whom metformin is inappropriate due to contraindications or intolerance.
as dual oral therapy in combination with
to improve glycaemic control in combination with metformin when diet and exercise plus metformin alone do not provide adequate glycaemic control.
to improve glycaemic control in combination with a sulphonylurea when diet and exercise plus maximal tolerated dose of a sulphonylurea alone do not provide adequate glycaemic control and when metformin is inappropriate due to contraindications or intolerance.
a PPAR
g agonist (i.e. a thiazolidinedione) when use of a PPARg agonist is appropriate and when diet and exercise plus the PPARg agonist alone do not provide adequate glycaemic control. as triple oral therapy in combination with
as triple oral therapy in combination with
to improve glycaemic control in combination with a sulphonylurea and metformin when diet and exercise plus dual therapy with these agents do not provide adequate glycaemic control.
g agonist and metformin when use of a PPARg agonist is appropriate and when diet and exercise plus dual therapy with these agents do not provide adequate glycaemic control.
For patients with type 2 diabetes mellitus in whom use of a PPAR
g agonist (i.e. a thiazolidinedione) is appropriate, Januvia is indicated: in combination with the PPAR g agonist when diet and exercise plus the PPARg agonist alone do not provide adequate glycaemic control. in combination with the PPAR g agonist and metformin when diet and exercise plus dual therapy with these agents do not provide adequate glycaemic control. Januvia is also indicated as add-on to insulin (with or without metformin) when diet and exercise plus stable dosage of insulin do not provide adequate glycaemic control.
in combination with the PPAR
g agonist when diet and exercise plus the PPARg agonist alone do not provide adequate glycaemic control. in combination with the PPAR
g agonist and metformin when diet and exercise plus dual therapy with these agents do not provide adequate glycaemic control.
Januvia is also indicated as add-on to insulin (with or without metformin) when diet and exercise plus stable dosage of insulin do not provide adequate glycaemic control.
4.2 Posology and method of administration
The dose of Januvia is 100 mg once daily. When sitagliptin
Januvia is used in combination with metformin and/or a PPARg agonist, the dosage of metformin and/or PPARg agonist should be maintained, and sitagliptinJanuvia administered concomitantly. When Januvia is 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. (See section 4.4.) 4.4 Special warnings and precautions for use Hypoglycaemia when used in combination with other anti-hyperglycaemic agents In clinical trials of Januvia as monotherapy and as part of combination therapy with agents not known to cause hypoglycaemia (i.e. metformin and/or a PPAR
When Januvia is 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. (See section 4.4.) 4.4 Special warnings and precautions for use Hypoglycaemia when used in combination with other anti-hyperglycaemic agents In clinical trials of Januvia as monotherapy and as part of combination therapy with agents not known to cause hypoglycaemia (i.e. metformin and/or a PPAR
4.4 Special warnings and precautions for use
Hypoglycaemia when used in combination with other anti-hyperglycaemic agents
In clinical trials of Januvia as monotherapy and as part of combination therapy with agents not known to cause hypoglycaemia (i.e. metformin and/or a PPAR
g agonist), rates of hypoglycaemia reported with sitagliptin were similar to rates in patients taking placebo. When sitagliptin was added to a sulphonylurea or to insulin, the incidence of hypoglycaemia was increased over that of placebo (see section 4.8). Therefore, to reduce the risk of hypoglycaemia, a lower dose of sulphonylurea or insulin may be considered (see section 4.2). The use of sitagliptin in combination with insulin has not been adequately studied. 4.8 Undesirable effects In 10
4.8 Undesirable effects
In 10
11 large clinical trials of up to 2 years in duration, over 29003200 patients have received treatment with Januvia 100 mg per day alone or in combination with metformin, a sulphonylurea (with or without metformin), insulin (with or without metformin), or a PPARg agent (with or without metformin). In a pooled analysis of 9 of these trials, the rate of discontinuation due to adverse experiences considered drug-related was 0.8 % with 100 mg per day and 1.5 % with other treatments. No adverse reactions considered as drug-related were reported in patients treated with sitagliptin occurring in excess (> 0.2 % and difference > 1 patient) of that in patients treated with control. In an additional combination study with a PPARg agent (rosiglitazone) and metformin, no patients were discontinued due to adverse experiences considered as drug-related. Table 1. The frequency of adverse reactions identified from placebo-controlled clinical studies
Table 1. The frequency of adverse reactions identified from placebo-controlled clinical studies
Adverse Reaction
Frequency of adverse reaction by treatment regimen
Sitagliptin with Metformin
1
Sitagliptin with a Sulfonylurea
Sulphonylurea 2
Sulphonylurea
and Metformin
3
Sitagliptin with a PPAR
g Agent (pioglitazone)4
Sitagliptin with a
PPAR
g Agent (rosiglitazone) and Metformin5
and Metformin5
Sitagliptin with Insulin
(+/-) Metformin)
66
Time-point
24-week
18-week
Investigations
blood glucose decreased
Uncommon
Nervous system disorders
headache
Common
somnolence
Gastrointestinal disorders
diarrhoea
dry mouth
nausea
flatulence
constipation
upper abdominal pain
vomiting
Metabolism and nutrition disorders
hypoglycaemia*
Very common
Infections and infestations
influenza
General disorders
peripheral oedema
Common†
5 In this study of sitagliptin 100 mg once daily in combination with rosiglitazone and metformin, which continued through 54 weeks, the incidence of adverse reactions considered as drug-related in patients treated with
the sitagliptin combination compared to treatment with the placebo combination was 15.3 % and 10.9 %, respectively. Other drug-related adverse reactions reported in the 54-week analysis (frequency common) in patients treated with the sitagliptin combination occurring in excess (> 0.2 % and difference > 1 patient) of that in patients treated with the placebo combination were: headache, cough, vomiting, hypoglycaemia, fungal skin infection, and upper respiratory tract infection.
6 In this 24-week study of sitagliptin 100 mg once daily as add-on to insulin therapy (with or without metformin), the incidence of adverse reactions considered as drug-related in patients treated with sitagliptin/insulin (with or without metformin) compared to treatment with placebo/insulin (with or without metformin) was 15.5 % and 8.5 %, respectively. In this study 0.9 % of patients treated with sitagliptin/insulin and 0.0 % of patients treated with placebo/insulin were discontinued due to adverse experiences considered as drug-related.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Overall, sitagliptin improved glycaemic control when used as monotherapy or in combination treatment (see Table 2).
Overall, sitagliptin improved glycaemic control when given as monotherapy, when used in combination with metformin (initial or add-on therapy), in combination with a sulphonylurea (with or without metformin), in combination with a thiazolidinedione, and in combination with a thiazolidinedione and metformin, as measured by clinically relevant reductions in HbA1c from baseline at study endpoint (see Table 2). A 24-week placebo-controlled study was designed to evaluate the efficacy and safety of sitagliptin (100 mg once daily) added to insulin (at a stable dose for at least 10 weeks) with or without metformin (at least 1500 mg). In patients taking pre-mixed insulin, the mean daily dose was 70.9 U/day. In patients taking non-pre-mixed (intermediate/long-acting) insulin, the mean daily dose was 44.3 U/day. The addition of sitagliptin to insulin provided significant improvements in glycaemic parameters. There was no meaningful change from baseline in body weight in either group. In a 24-week placebo-controlled factorial study of initial therapy, sitagliptin 50 mg twice daily in combination with metformin (500 mg or 1000 mg twice daily) provided significant improvements in glycaemic parameters compared with either monotherapy. The decrease in body weight with the combination of sitagliptin and metformin was similar to that observed with metformin alone or placebo; there was no change from baseline for patients on sitagliptin alone. The incidence of hypoglycaemia was similar across treatment groups. Table 2. HbA1c results in placebo-controlled monotherapy and combination therapy studies* Study Mean baseline HbA1c (%) Mean change from baseline HbA1c (%)† Placebo-corrected mean change in HbA1c (%)† (95 % CI) Monotherapy Studies Sitagliptin 100 mg once daily§ (N= 193) 8.0 -0.5 -0.6 ‡ (-0.8, -0.4) Sitagliptin 100 mg once daily % (N= 229) 8.0 -0.6 -0.8 ‡ (-1.0, -0.6) Combination Therapy Studies Sitagliptin 100 mg once daily added to ongoing metformin therapy % (N=453) 8.0 -0.7 -0.7 ‡ (-0.8, -0.5) Sitagliptin 100 mg once daily added to ongoing pioglitazone therapy % (N=163) 8.1 -0.9 -0.7 ‡ (-0.9, -0.5) Sitagliptin 100 mg once daily added to ongoing glimepiride therapy % (N=102) 8.4 -0.3 -0.6 ‡ (-0.8, -0.3) Sitagliptin 100 mg once daily added to ongoing glimepiride + metformin therapy % (N=115) 8.3 -0.6 -0.9 ‡ (-1.1, -0.7) Sitagliptin 100 mg once daily added to ongoing rosiglitazone + metformin therapy (N=170) Week 18 Week 54 8.8 8.8 -1.0 -1.0 -0.7 ‡ (-0.9, -0.5) -0.8 ‡ (-1.0, -0.5) Initial therapy (twice daily) %: Sitagliptin 50 mg + metformin 500 mg (N=183) 8.8 -1.4 -1.6 ‡ (-1.8, -1.3) Initial therapy (twice daily) %: Sitagliptin 50 mg + metformin 1000 mg (N=178) 8.8 -1.9 -2.1 ‡ (-2.3, -1.8) Sitagliptin 100 mg once daily added to ongoing insulin (+/- metformin) therapy % (N=305) 8.7 -0.6¶ -0.6‡,¶ (-0.7, -0.4) * ALL PATIENTS TREATED POPULATION (AN INTENTION-TO-TREAT ANALYSIS). † LEAST SQUARES MEANS ADJUSTED FOR PRIOR ANTIHYPERGLYCAEMIC THERAPY STATUS AND BASELINE VALUE. ‡ P<0.001 COMPARED TO PLACEBO OR PLACEBO + COMBINATION TREATMENT. § HBA1C (%) AT WEEK 18. % HBA1C (%) AT WEEK 24. ¶ LEAST SQUARES MEAN ADJUSTED FOR METFORMIN USE AT VISIT 1 (YES/NO), INSULIN USE AT VISIT 1 (PRE-MIXED VS. NON-PRE-MIXED [INTERMEDIATE- OR LONG-ACTING]), AND BASELINE VALUE. TREATMENT BY STRATUM (METFORMIN AND INSULIN USE) INTERACTIONS WERE NOT SIGNIFICANT (P > 0.10).
A 24-week placebo-controlled study was designed to evaluate the efficacy and safety of sitagliptin (100 mg once daily) added to insulin (at a stable dose for at least 10 weeks) with or without metformin (at least 1500 mg). In patients taking pre-mixed insulin, the mean daily dose was 70.9 U/day. In patients taking non-pre-mixed (intermediate/long-acting) insulin, the mean daily dose was 44.3 U/day. The addition of sitagliptin to insulin provided significant improvements in glycaemic parameters. There was no meaningful change from baseline in body weight in either group.
In a 24-week placebo-controlled factorial study of initial therapy, sitagliptin 50 mg twice daily in combination with metformin (500 mg or 1000 mg twice daily) provided significant improvements in glycaemic parameters compared with either monotherapy. The decrease in body weight with the combination of sitagliptin and metformin was similar to that observed with metformin alone or placebo; there was no change from baseline for patients on sitagliptin alone. The incidence of hypoglycaemia was similar across treatment groups.
Table 2. HbA1c results in placebo-controlled monotherapy and combination therapy studies*
Study
Mean baseline HbA1c (%)
Mean change from baseline HbA1c (%)†
Placebo-corrected mean change in HbA1c (%)†
(95 % CI)
Monotherapy Studies
Sitagliptin 100 mg once daily§
(N= 193)
8.0
-0.5
-0.6
‡
(-0.8, -0.4)
Sitagliptin 100 mg once daily
%
(N= 229)
-0.8
(-1.0, -0.6)
Combination Therapy Studies
Sitagliptin 100 mg once daily added to ongoing metformin therapy
(N=453)
-0.7
(-0.8, -0.5)
Sitagliptin 100 mg once daily added to ongoing pioglitazone therapy
(N=163)
8.1
-0.9
(-0.9, -0.5)
Sitagliptin 100 mg once daily added to ongoing glimepiride therapy
(N=102)
8.4
-0.3
(-0.8, -0.3)
Sitagliptin 100 mg once daily added to ongoing glimepiride + metformin therapy
(N=115)
8.3
(-1.1, -0.7)
Sitagliptin 100 mg once daily added to ongoing rosiglitazone + metformin therapy (N=170)
Week 18
Week 54
8.8
-1.0
(-1.0, -0.5)
Initial therapy (twice daily)
%: Sitagliptin 50 mg + metformin 500 mg (N=183)
Sitagliptin 50 mg + metformin 500 mg
(N=183)
-1.4
-1.6
(-1.8, -1.3)
%: Sitagliptin 50 mg + metformin 1000 mg (N=178)
Sitagliptin 50 mg + metformin 1000 mg
(N=178)
-1.9
-2.1
(-2.3, -1.8)
Sitagliptin 100 mg once daily added to ongoing insulin (+/- metformin) therapy
(N=305)
8.7
-0.6¶
-0.6‡,¶
(-0.7, -0.4)
*
ALL PATIENTS TREATED POPULATION (AN INTENTION-TO-TREAT ANALYSIS).
†
LEAST SQUARES MEANS ADJUSTED FOR PRIOR ANTIHYPERGLYCAEMIC THERAPY STATUS AND BASELINE VALUE.
P<0.001 COMPARED TO PLACEBO OR PLACEBO + COMBINATION TREATMENT.
§
HBA1C (%) AT WEEK 18.
HBA1C (%) AT WEEK 24. ¶ LEAST SQUARES MEAN ADJUSTED FOR METFORMIN USE AT VISIT 1 (YES/NO), INSULIN USE AT VISIT 1 (PRE-MIXED VS. NON-PRE-MIXED [INTERMEDIATE- OR LONG-ACTING]), AND BASELINE VALUE. TREATMENT BY STRATUM (METFORMIN AND INSULIN USE) INTERACTIONS WERE NOT SIGNIFICANT (P > 0.10).
¶
LEAST SQUARES MEAN ADJUSTED FOR METFORMIN USE AT VISIT 1 (YES/NO), INSULIN USE AT VISIT 1 (PRE-MIXED VS. NON-PRE-MIXED [INTERMEDIATE- OR LONG-ACTING]), AND BASELINE VALUE. TREATMENT BY STRATUM (METFORMIN AND INSULIN USE) INTERACTIONS WERE NOT SIGNIFICANT (P > 0.10).
Updated SPC -
additional AE's section 4.8 Addition of 'cutaneous vasculitis' and 'pancreatitis' under Post Marketing Experience in Section 4.8 and date of revision of text.
SECTION 4.1: ADD THE TRIPLE COMBINATION USE Section 4.4 minor text layout change Section 4.8: was updated to reflect the AEs seen as part of the study conducted to support the triple combination use Section 4.9 ad 5.1: updated to describe studies
Updates to sections 4.3, 4.4 and 4.8 of the SPC to include hypersensitivity reactions and exfoliative skin conditions including Stevens-Johnson syndrome
The following sections have been updated 4.1, 4.2, 4.4, 4.8, 5.1, 10.
Section 4.8 has been updated to include Post-marketing Experience.