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, 4.5, 4.6, 4.7, 4.8, 4.9, 5.1, - Updated renal impairment information. New individual SPCs to replace previous combined versions.
Update section 4.1, 4.2, 4.4, 4.7, 4.8 & 5.1 of the SPC regarding the use of Janumet in combination with insulin: 4.1 Therapeutic indications Janumet is also indicated as add-on to insulin (i.e., triple combination therapy) as an adjunct to diet and exercise to improve glycaemic control in patients when stable dosage of insulin and metformin alone do not provide adequate glycaemic control.
4.2 Posology and method of administration
For patients inadequately controlled on dual combination therapy with insulin and the maximal tolerated dose of metformin The dose of Janumet should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose) and a dose of metformin similar to the dose already being taken. When Janumet is used in combination with insulin, a lower dose of insulin may be required to reduce the risk of hypoglycaemia (see section 4.4). 4.4 Special warnings and precautions for use Hypoglycaemia Patients receiving Janumet in combination with a sulphonylurea or with insulin may be at risk for hypoglycaemia. Therefore, a reduction in the dose of the sulphonylurea or insulin may be necessary may be necessary. 4.7 Effects on ability to drive and use machines In addition, patients should be alerted to the risk of hypoglycaemia when Janumet is used in combination with other sulfonylurea agents In addition, patients should be alerted to the risk of hypoglycaemia when Janumet is used in combination with other sulfonylurea agents or with insulin. 4.8 Undesirable effects Table 1. The frequency of adverse reactions identified from placebo-controlled clinical studies Adverse Reaction Frequency of adverse reaction by treatment regimen Sitagliptin with Metformin1 Sitagliptin with Metformin and a Sulphonylurea2 Sitagliptin with Metformin and a PPARγ Agent (rosiglitazone) 3 Sitagliptin with Metformin and Insulin4 Time-point 24-week 24-week 18-week 24-week Investigations blood glucose decreased Uncommon Nervous system disorders headache Common Uncommon somnolence Uncommon Gastrointestinal disorders diarrhoea Uncommon Common nausea Common constipation Common upper abdominal pain Uncommon vomiting Common dry mouth Uncommon Metabolism and nutrition disorders hypoglycaemia* Very common Common Very common General disorders peripheral oedema Common † 4 In this 24-week placebo-controlled study of sitagliptin 100 mg once daily as add-on to insulin and metformin, the incidence of adverse reactions considered as drug-related in patients treated with sitagliptin in combination with insulin/metformin compared to treatment with placebo in combination with insulin/metformin was 16.2 % and 9.0 %, respectively. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Overall, sitagliptin improved glycaemic control when used as monotherapy or in combination treatment. Study of sitagliptin in combination with metformin and insulin 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. Data from the 73 % of patients who were taking metformin are presented in Table 3. 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. Table 3: HbA1c results in placebo-controlled combination therapy studies of sitagliptin and metformin* * Study Mean baseline HbA1c (%) Mean change from baseline HbA1c (%)† Placebo-corrected mean change in HbA1c (%)† (95 % CI) 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 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) Sitagliptin 100 mg once daily added to ongoing insulin + metformin therapy % (N=223) 8.7 -0.7 § -0.5 §,‡ (-0.7, -0.4) 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 1,000 mg (N=178) 8.8 -1.9 -2.1 ‡ (-2.3, -1.8) * 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 24. § Least squares mean adjusted for insulin use at Visit 1 (pre-mixed vs. non-pre-mixed [intermediate- or long-acting]), and baseline value.
The dose of Janumet should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose) and a dose of metformin similar to the dose already being taken. When Janumet is used in combination with insulin, a lower dose of insulin may be required to reduce the risk of hypoglycaemia (see section 4.4).
4.4 Special warnings and precautions for use Hypoglycaemia Patients receiving Janumet in combination with a sulphonylurea
or with insulin may be at risk for hypoglycaemia. Therefore, a reduction in the dose of the sulphonylurea or insulin may be necessary may be necessary. 4.7 Effects on ability to drive and use machines In addition, patients should be alerted to the risk of hypoglycaemia when Janumet is used in combination with other sulfonylurea agents In addition, patients should be alerted to the risk of hypoglycaemia when Janumet is used in combination with other sulfonylurea agents or with insulin. 4.8 Undesirable effects Table 1. The frequency of adverse reactions identified from placebo-controlled clinical studies Adverse Reaction Frequency of adverse reaction by treatment regimen Sitagliptin with Metformin1 Sitagliptin with Metformin and a Sulphonylurea2 Sitagliptin with Metformin and a PPARγ Agent (rosiglitazone) 3 Sitagliptin with Metformin and Insulin4 Time-point 24-week 24-week 18-week 24-week Investigations blood glucose decreased Uncommon Nervous system disorders headache Common Uncommon somnolence Uncommon Gastrointestinal disorders diarrhoea Uncommon Common nausea Common constipation Common upper abdominal pain Uncommon vomiting Common dry mouth Uncommon Metabolism and nutrition disorders hypoglycaemia* Very common Common Very common General disorders peripheral oedema Common † 4 In this 24-week placebo-controlled study of sitagliptin 100 mg once daily as add-on to insulin and metformin, the incidence of adverse reactions considered as drug-related in patients treated with sitagliptin in combination with insulin/metformin compared to treatment with placebo in combination with insulin/metformin was 16.2 % and 9.0 %, respectively. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Overall, sitagliptin improved glycaemic control when used as monotherapy or in combination treatment. Study of sitagliptin in combination with metformin and insulin 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. Data from the 73 % of patients who were taking metformin are presented in Table 3. 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. Table 3: HbA1c results in placebo-controlled combination therapy studies of sitagliptin and metformin* * Study Mean baseline HbA1c (%) Mean change from baseline HbA1c (%)† Placebo-corrected mean change in HbA1c (%)† (95 % CI) 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 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) Sitagliptin 100 mg once daily added to ongoing insulin + metformin therapy % (N=223) 8.7 -0.7 § -0.5 §,‡ (-0.7, -0.4) 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 1,000 mg (N=178) 8.8 -1.9 -2.1 ‡ (-2.3, -1.8) * 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 24. § Least squares mean adjusted for insulin use at Visit 1 (pre-mixed vs. non-pre-mixed [intermediate- or long-acting]), and baseline value.
4.7 Effects on ability to drive and use machines In addition, patients should be alerted to the risk of hypoglycaemia when Janumet is used in combination with other sulfonylurea agents In addition, patients should be alerted to the risk of hypoglycaemia when Janumet is used in combination with other sulfonylurea agents
or with insulin. 4.8 Undesirable effects Table 1. The frequency of adverse reactions identified from placebo-controlled clinical studies
Adverse Reaction
Frequency of adverse reaction by treatment regimen
Sitagliptin with Metformin1
Sitagliptin with Metformin and a Sulphonylurea2
Sitagliptin with Metformin and a PPARγ Agent (rosiglitazone)
3
Sitagliptin with Metformin and Insulin4
Time-point
24-week
18-week
Investigations
blood glucose decreased
Uncommon
Nervous system disorders
headache
Common
somnolence
Gastrointestinal disorders
diarrhoea
nausea
constipation
upper abdominal pain
vomiting
dry mouth
Metabolism and nutrition disorders
hypoglycaemia*
Very common
General disorders
peripheral oedema
†
4 In this 24-week placebo-controlled study of sitagliptin 100 mg once daily as add-on to insulin and metformin, the incidence of adverse reactions considered as drug-related in patients treated with sitagliptin in combination with insulin/metformin compared to treatment with placebo in combination with insulin/metformin was 16.2 % and 9.0 %, respectively. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties
Overall, sitagliptin improved glycaemic control when used as monotherapy or in combination treatment.
Study of sitagliptin in combination with metformin and insulin 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. Data from the 73 % of patients who were taking metformin are presented in Table 3. 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.
Table 3: HbA1c results in placebo-controlled combination therapy studies of sitagliptin and metformin* *
Study
Mean baseline HbA1c (%)
Mean change from baseline HbA1c (%)†
Placebo-corrected mean change in HbA1c (%)†
(95 % CI)
Sitagliptin 100 mg once daily added to ongoing metformin therapy
%
(N=453)
8.0
-0.7
‡
(-0.8, -0.5)
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
-1.0
(-0.9, -0.5)
-0.8
(-1.0, -0.5)
Sitagliptin 100 mg once daily added to ongoing insulin + metformin therapy
(N=223)
8.7
§
-0.5
§,‡
(-0.7, -0.4)
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 1,000 mg (N=178)
Sitagliptin 50 mg + metformin 1,000 mg
(N=178)
-1.9
-2.1
(-2.3, -1.8)
*
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.
‡ p< 0.001 compared to placebo or placebo + combination treatment.
HbA1c (%) at week 24.
§ Least squares mean adjusted for insulin use at Visit 1 (pre-mixed vs. non-pre-mixed [intermediate- or long-acting]), and baseline value.
Section 4.8 Undesirable effects, Section 10. Date of revision To include cutaneous vasculitis and pancreatitis in Section 4.8 and to update date of revision isn Section 10
inclusion of 'multi-packs containing 196 (2 packs of 98)'
Section 4.1: add the triple combination use. 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.
Section 8 has been amended.