Bristol Myers Squibb-AstraZeneca EEIG

Section 4.4

Additional Text

Pancreatitis

In post-marketing experience there have been spontaneously reported adverse reactions of acute pancreatitis. Patients should be informed of the characteristic symptom of acute pancreatitis: persistent, severe abdominal pain. Resolution of pancreatitis has been observed after discontinuation of saxagliptin. If pancreatitis is suspected, Onglyza and other potentially suspect medicinal products should be discontinued.

Section 4.8

Table 2           Frequency of additional adverse reactions by system organ class

Addition of:

Gastrointestinal disorders

Nausea                                    Common

Pancreatitis                             Uncommon

Dermatitis                                Uncommon

Pruritus                                    Uncommon

Section 10

Date of revision changed to 22^nd December 2011

Section 4.1

New paragraph added

 
·         in combination with insulin (with or without metformin), when this regimen alone, with diet and exercise, does not provide adequate glycaemic control.

Section 4.2

Addition of word insulin to first paragraph.

Section 4.4

General

New paragraph added.

 Onglyza is not a substitute for insulin in insulin‑requiring patients.

Hepatic impairment

Text amended to:

Use with medicinal products known to cause hypoglycaemia

Sulphonylureas and insulin are known to cause hypoglycaemia. Therefore, a lower dose of sulphonylurea or insulin may be required to reduce the risk of hypoglycaemia when used in combination with Onglyza.  

Section 4.8

New Paragraph added before “Investigations” paragraph

When used as add‑on to insulin (with or without metformin), the overall incidence of reported hypoglycaemia was 18.4% for Onglyza 5 mg and 19.9% for placebo.

Section 5.1

New paragraph added after paragraph 10

Saxagliptin add‑on combination therapy with insulin (with or without metformin)

A total of 455 patients with type 2 diabetes participated in a 24‑week randomised, double‑blind, placebo‑controlled study to evaluate the efficacy and safety of saxagliptin in combination with a stable dose of insulin (baseline mean: 54.2 Units) in patients with inadequate glycaemic control (HbA1c ≥ 7.5% and ≤ 11%) on insulin alone (n=141) or on insulin in combination with a stable dose of metformin (n=314). Saxagliptin 5 mg add‑on to insulin with or without metformin provided significant improvements after 24 weeks in HbA1c and PPG compared with placebo add‑on to insulin with or without metformin. Similar HbA1c reductions versus placebo were achieved for patients receiving saxagliptin 5 mg add‑on to insulin regardless of metformin use (−0.4% for both subgroups). Improvements from baseline HbA1c were sustained in the saxagliptin add‑on to insulin group compared to the placebo add‑on to insulin group with or without metformin at Week 52. The HbA1c change for the saxagliptin group (n=244) compared to placebo (n=124) was ‑0.4% at Week 52.

Paragraph 12 Text amended to:

Patients with renal impairment

A 12 week, multi-centre, randomised, double-blind, placebo controlled study was conducted to evaluate the treatment effect of saxagliptin 2.5 mg once daily compared with placebo in 170 patients (85 patients on saxagliptin and 85 on placebo) with type 2 diabetes (HbA1c 7.0-11%) and renal impairment (moderate [n=90]; severe [n=41]; or ESRD [n=39]). In this study, 98.2% of the patients received other antihyperglycaemic treatments (75.3% on insulin and 31.2% on oral antihyperglycaemics; some received both). Saxagliptin significantly decreased HbA1c compared with placebo; the HbA1c change for saxagliptin was -0.9% at Week 12 (HbA1c change of -0.4% for placebo). Improvements in HbA1c following treatment with saxagliptin 2.5 mg were sustained up to Week 52, however the number of patients who completed 52 weeks without modification of other antihyperglycaemic treatments was low (26 subjects in the saxagliptin group versus 34 subjects in the placebo group). The incidence of confirmed hypoglycaemic events was somewhat higher in the saxagliptin group (9.4%) versus placebo group (4.7%) although the number of subjects with any hypoglycaemic event did not differ between the treatment groups. There was no adverse effect on renal function as determined by estimated glomerular filtration rate or CrCL at Week 12 and Week 52.

Table 3

Add-on Combination Studies updated.

New Paragraph at end of Section 5.1

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with Onglyza in one or more subsets of the paediatric population in the treatment of type 2 diabetes mellitus (see section 4.2 for information on paediatric use).

Section 10

Date of revision changed to 22^nd November 2011

European Medicines Agency website address updated.

Section 4.3

 Additional text.

SPC Changes Onglyza 2.5mg & 5mg film coated tablets

Section 1

Addition of 2.5mg dose, now reads as,

“Onglyza▼2.5 mg film‑coated tablets

Onglyza▼5 mg film‑coated tablets”

Section 2

Addition of details for 2.5mg dose, now reads as,

” Each tablet contains 2.5 mg saxagliptin (as hydrochloride).

Each tablet contains 5 mg saxagliptin (as hydrochloride).

Excipients:

Each tablet contains 99 mg lactose monohydrate.

For a full list of excipients, see section 6.1.”

Section 3

Additional of 2.5mg dose, now reads as,

” Film‑coated tablet (tablet).

Onglyza 2.5 mg tablets are pale yellow to light yellow, biconvex, round, film-coated tablets, with “2.5” printed on one side and “4214” printed on the other side, in blue ink.

Onglyza 5 mg tablets are pink  , biconvex, round, film‑coated tablet, with “5” printed on one side and “4215” printed on the other side, in blue ink.”

Section 4.2

Text changes to Special populations, renal impairment, Elderly and Paediatric population, now reads as,

“Posology

Add‑on combination therapy

The recommended dose of Onglyza is 5 mg once daily as add‑on combination therapy with metformin, a thiazolidinedione or a sulphonylurea. 

The safety and efficacy of saxagliptin as triple oral therapy in combination with metformin and a thiazolidinedione, or with metformin and a sulphonylurea, has not been established.

Special populations

Elderly (≥65 years)

No dose adjustment is recommended based solely on age. Experience in patients aged 75 years and older is very limited and caution should be exercised when treating this population (see also sections 4.4, 5.1 and 5.2.

Renal impairment

No dose adjustment is recommended for patients with mild renal impairment.  

The dose of Onglyza should be reduced to 2.5 mg once daily in patients with moderate or severe renal impairment.

The experience in patients with severe renal impairment is very limited. Therefore, saxagliptin should be used with caution in this population. Onglyza is not recommended for patients with end-stage renal disease (ESRD) requiring haemodialysis (see section 4.4).

Because the dose of Onglyza should be limited to 2.5 mg based upon renal function, assessment of renal function is recommended prior to initiation of Onglyza, and, in keeping with routine care, renal assessment should be done periodically thereafter (see sections 4.4 and 5.2).

Hepatic impairment

No dose adjustment is necessary for patients with mild or moderate hepatic impairment (see section 5.2). Saxagliptin should be used with caution in patients with moderate hepatic impairment, and is not recommended for use in patients with severe hepatic impairment (see section 4.4).

Paediatric population

The safety and efficacy of Onglyza in children aged birth to < 18 years have not yet been established.No data are available.

Method of administration

Onglyza can be taken with or without a meal at any time of the day. If a dose is missed, it should be taken as soon as the patient remembers. A double dose should not be taken on the same day. ”

Section 4.4

Change to first paragraph and addtiional second paragraph, ”Renal impairment”, these paragraphs now reads as,

” General

Onglyza should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.

Renal impairment

A single dosage adjustment is recommended in patients with moderate or severe renal impairment. Saxagliptin should be used with caution in patients with severe renal impairment, and is not recommended for use in patients with end-stage renal disease (ESRD) requiring haemodialysis. Assessment of renal function is recommended prior to initiation of Onglyza, and, in keeping with routine care, renal assessment should be done periodically thereafter (see sections 4.2 and 5.2).”

Section 4.7

Second paragraph, second line, word ”operating” now ”using”.

Section 4.8

Under paragraph, Tabulated list of adverse reactions, changes made to first paragraph, now reads as,

” Tabulated list of adverse reactions

Adverse reactions reported in ≥5% of patients treated with saxagliptin 5 mg and more commonly than in patients treated with placebo or that were reported in ≥2% of patients treated with saxagliptin 5 mg and ≥1% more frequently compared to placebo are shown in Table 1.

The adverse reactions are listed by system organ class and absolute frequency. Frequencies are defined as Very common (³ 1/10), Common (³ 1/100 to <1/10), Uncommon (³ 1/1,000 to 1/100), Rare (³ 1/10,000 to 1/1,000), or Very rare (<1/10,000), not known (cannot be estimated from the available data).”

Table 1:  Heading change from General disorders to, ”General disorders and administration site conditions

Paragraph heading Laboratory tests now ”Invstigations”

Section 5.1

Text changes to first paragraph, now reads as,

” Pharmacotherapeutic group: Drugs used in diabetes. Dipeptidyl peptidase 4 (DPP‑4) inhibitors, ATC code: A10BH03”

New heading and text, Patients with renal impairment, reads as,

” Patients with renal impairment

A 12 week, multi-centre, randomised, double-blind, placebo controlled study was conducted to evaluate the treatment effect of saxagliptin 2.5 mg once daily compared with placebo in 170 patients (85 patients on saxagliptin and 85 on placebo) with type 2 diabetes (HbA1c 7.0-11%) and renal impairment (moderate [N=90]; severe [N=41]; or ESRD [N=39]). In this study, 98.2% of the patients were treated with other antihyperglycaemic medication (75.3% on insulin and 31.2% on oral antihyperglycaemic drugs; some received both). Saxagliptin significantly decreased HbA1c compared with placebo; the HbA1c change for saxagliptin was -0.9% at Week 12 (HbA1c change of -0.4% for placebo). Improvements in HbA1c following treatment with saxagliptin 2.5 mg were sustained up to Week 52, however the number of patients who completed 52 weeks without modification of other antihyperglycaemic medications was low (26 subjects in the saxagliptin group versus 34 subjects in the placebo group). The incidence of confirmed hypoglycaemic events was somewhat higher in the saxagliptin group (9.4%) versus placebo group (4.7%) although the number of subjects with any hypoglycaemic event did not differ between the treatment groups. There was no adverse effect on renal function as determined by estimated glomerular filtration rate or CrCL at Week 12 and Week 52.”

Section 6.1

Additional text to film coating, now reads as,

Film coating:
Polyvinyl alcohol
Macrogol/3350
Titanium dioxide (E171)
Talc (E553b)
Iron oxide red (E172) 5 mg Tablets only

Iron oxide yellow (E172) 2.5 mg Tablets only

Printing ink:

Shellac

Indigo carmine aluminium lake (E132)”

Section 6.5

Additional information for 2.5mg dose, reads as,

” 2.5 mg Tablets

Alu/Alu blister.

Pack sizes of 14, 28, and 98 film‑coated tablets in non‑perforated calendar blisters.

Pack sizes of 30x1 and 90x1 film‑coated tablets in perforated unit dose blisters.

Not all pack sizes may be marketed.”

Section 8

New first paragraph for 2.5mg dose, now reads as,

” EU/1/09/545/012 - Onglyza 2.5 mg film-coated tablet oral use non-perforated calendar blister (Alu/Alu)-28 tablets”

Section 9

Now reads as,

“5 mg Tablets- 1^st October 2009

2.5 mg Tablets – 2^nd March 2011”

Section 10

Now reads as,

“2^nd March 2011”

SPC Changes – Onglyza 5mg Tablets

Section 5.1

Two new paragraphs (6^th and 7^th) in sub-section ‘Clinical safety and efficacy’ reads as,

”Saxagliptin add-on to metformin compared with SU add-on to metformin

A 52‑week study was conducted to evaluate the efficacy and safety of saxagliptin 5 mg in combination with metformin (428 patients) compared with sulphonylurea (glipizide, 5 mg titrated as needed to 20 mg, mean dose of 15 mg) in combination with metformin (430 patients) in 858 patients with inadequate glycaemic control (HbA1c 6.5%‑10%) on metformin alone. The mean metformin dose was approximately 1900 mg in each treatment group. After 52 weeks, the saxagliptin and glipizide groups had similar mean reductions from baseline in HbA1c in the per-protocol analysis (‑0.7% vs. –0.8%, respectively, mean baseline HbA1c of 7.5% for both groups). The intent-to-treat analysis showed consistent results. The reduction in FPG was slightly less in the saxagliptin-group and there were more discontinuations (3.5% vs. 1.2%) due to lack of efficacy based on FPG criteria during the first 24 weeks of the study. Saxagliptin also resulted in a significantly lower proportion of patients with hypoglycaemia, 3% (19 events in 13 subjects) vs. 36.3% (750 events in 156 patients) for glipizide. Patients treated with saxagliptin exhibited a significant decrease from baseline in body weight compared to a weight gain in patients administered glipizide (-1.1 vs. +1.1 kg).

Saxagliptin add-on to metformin compared with sitagliptin add-on to metformin

An 18‑week study was conducted to evaluate the efficacy and safety of saxagliptin 5 mg in combination with metformin (403 patients), compared with sitagliptin 100 mg in combination with metformin (398 patients) in 801 patients with inadequate glycaemic control on metformin alone. After 18 weeks, saxagliptin was non-inferior to sitagliptin in mean reduction from baseline in HbA1c in both the per-protocol and the full analysis sets . The reductions from baseline in HbA1c respectively for saxagliptin and sitagliptin in the primary per-protocol analysis were ‑0.5% (mean and median) and ‑0.6% (mean and median). In the confirmatory full analysis set, mean reductions were ‑0.4% and ‑0.6% respectively for saxagliptin and sitagliptin, with median reductions of ‑0.5% for both groups.”

Section 10, Date of revision of text

6th September 2010

Section 4.1

Additional text ‘aged 18 years and older’

Add‑on combination therapy

Onglyza is indicated in adult patients aged 18 years and older with type 2 diabetes mellitus to improve glycaemic control:

Section 4.2

Change of text under heading  ‘Paediatric population’:

The safety and efficacy of Onglyza in children aged birth to < 18 years have not yet been established: no data are available.

Section 4.6

Change of text under heading ‘Pregnancy’:

The use of saxagliptin has not been studied in pregnant women. Studies in animals have shown reproductive toxicity at high doses (see section 5.3). The potential risk for humans is unknown. Onglyza should not be used during pregnancy unless clearly necessary.

New sub heading  and text for ‘Fertility’

Fertility

The effect of saxagliptin on fertility in humans has not been studied. Effects on fertility were observed in male and female rats at high doses producing overt signs of toxicity (see section 5.3).

Section 4.7

Additional text:

Onglyza may have a negligible influence on the ability to drive and use machines.

Section 5.1

updated to include the addition of the long-term data for the following trials:
- Saxagliptin add on to metformin therapy
- Saxagliptin in combination with metformin as initial therapy
- Saxagliptin add on to glibenclamide therapy
- Saxagliptin add on to thiazolidinedione therapy

Section 10

New revision date of text: 2^nd July 2010