Talk to your doctor promptly for further instructions

• if you are known to suffer from a genetically inherited disease affecting mitochondria (the energy-producing components within cells) such as MELAS syndrome (Mitochondrial Encephalomyopathy with Lactic acidosis, and Stroke-like episodes) or Maternally Inherited Diabetes and Deafness (MIDD).
• if you have any of these symptoms after starting metformin: seizure, declined cognitive abilities, difficulty with body movements, symptoms indicating nerve damage (e.g. pain or numbness), migraine and deafness.

4.2 – Posology and method of administration

Renal impairment

No dose adjustment is recommended for patients with mild renal impairment (GFR 60-89 mL/min).

 A GFR should be assessed before initiation of treatment with metformin containing products and at least annually thereafter. In patients at increased risk of further progression of renal impairment and in the elderly, renal function should be assessed more frequently, e.g. every 3-6 months. The maximum daily dose of metformin should preferably be divided into 2-3 daily doses. Factors that may increase the risk of lactic acidosis (see section 4.4) should be reviewed before considering initiation of metformin Komboglyze in patients with GFR < 60 mL/min.

4.4 Special warnings and precautions for use

Patients with known or suspected mitochondrial diseases

In patients with known mitochondrial diseases such as Mitochondrial Encephalomyopathy with Lactic Acidosis, and Stroke-like episodes (MELAS) syndrome and Maternally Inherited Diabetes and Deafness (MIDD), metformin is not recommended due to the risk of lactic acidosis exacerbation and neurologic complications which may lead to worsening of the disease.

In case of signs and symptoms suggestive of MELAS syndrome or MIDD after the intake of metformin, treatment with metformin should be withdrawn immediately and prompt diagnostic evaluation should be performed.

......

Change in clinical status of patients with previously controlled type 2 diabetes

As this medicinal product contains metformin, a patient with type 2 diabetes previously well controlled on itKomboglyze who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate, and metformin levels. If acidosis of either form occurs, this medicinal product must be stopped immediately and other appropriate corrective measures initiated.

Use with medicinal products known to cause hypoglycaemia

Insulin and sulphonylureas are known to cause hypoglycaemia. Therefore, a lower dose of insulin or sulphonylurea may be required to reduce the risk of hypoglycaemia when used in combination with this medicinal productKomboglyze.

4.5 Interaction with other medicinal products and other forms of interaction

Alcohol

Alcohol intoxication is associated with an increased risk of lactic acidosis, particularly in the case of fasting, malnutrition or hepatic impairment due to the metformin active substance of this medicinal productKomboglyze (see section 4.4). Consumption of alcohol and medicinal products containing alcohol should be avoided.

4.9 Overdose

No data are available with regard to overdose of the saxagliptin/metformin fixed dose combinationKomboglyze.

5.2 Pharmacokinetic properties

The results of bioequivalence studies in healthy subjects demonstrated that Komboglyze combination tablets are bioequivalent to co-administration of corresponding doses of saxagliptin and metformin hydrochloride as individual tablets.

The following statements reflect the pharmacokinetic properties of the individual active substances of this medicinal productKomboglyze.

Removal of Norther Ireland adverse reporting details

4.      Possible side effects

[...]

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly (see details below). By reporting side effects you can help provide more information on the safety of this medicine.

Ireland

HPRA Pharmacovigilance

Website: www.hpra.ie

Malta

ADR Reporting Website: www.medicinesauthority.gov.mt/adrportal

United Kingdom (Northern Ireland)

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

6.        Contents of the pack and other information

[...]

Marketing Authorisation Holder

AstraZeneca AB

SE‑151 85 Södertälje

Sweden

Manufacturer

AstraZeneca AB

Gärtunavägen

SE-151 85152 57 Södertälje

Sweden

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder:

Ireland

AstraZeneca Pharmaceuticals (Ireland) DAC

Tel: +353 1609 7100

Malta

Associated Drug Co. Ltd

Tel: +356 2277 8000

United Kingdom (Northern Ireland)

AstraZeneca UK Ltd

Tel: +44 1582 836 836

This leaflet was last revised in 11/202105/2023

Inserted text, Deleted text

[..]

4. Possible side effects

[..]

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse.  This includes any possible side effects not listed in this leaflet. You can also report side effects directly (see details below). By reporting side effects you can help provide more information on the safety of this medicine.

[..]

United Kingdom (Northern Ireland)

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

[..]

6. Contents of the pack and other information

[..]

Manufacturer:

[..]

AstraZeneca GmbH

Tinsdaler Weg 183

22880 Wedel

Germany

[..]

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder:

[..]

This leaflet was last revised in 02/2021 11/2021

Inserted text, Deleted text

[..]

4.8         Undesirable effects

[..]

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

[..]

United Kingdom (Northern Ireland)

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

[..]

8.            MARKETING AUTHORISATION NUMBER(S)

Komboglyze 2.5 mg/850 mg film‑coated tablets

EU/1/11/731/001 28 film‑coated tablets

EU/1/11/731/002 56 film‑coated tablets

EU/1/11/731/003 60 film‑coated tablets

EU/1/11/731/004 112 (2 packs of 56) film‑coated tablets

EU/1/11/731/005 196 (7 packs of 28) film‑coated tablets

EU/1/11/731/006 60x1 film‑coated tablets

EU/1/11/731/013 14 film‑coated tablets

Komboglyze 2.5 mg/1,000 mg film‑coated tablets

EU/1/11/731/007 28 film‑coated tablets

EU/1/11/731/008 56 film‑coated tablets

EU/1/11/731/009 60 film‑coated tablets

EU/1/11/731/010 112 (2 packs of 56) film‑coated tablets

EU/1/11/731/011 196 (7 packs of 28) film‑coated tablets

EU/1/11/731/012 60x1 film‑coated tablets

EU/1/11/731/014 14 film‑coated tablets

[..]

10.      DATE OF REVISION OF THE TEXT

12^th March 2020 26^th November 2021

Section 10 was 28^th June 2018 is now 2^nd August 2018

Sections 2 & 3  -  admin/editorial changes

Section 4.2 – saxagliptin dosing for patients with GFR<30 is no longer contraindicated, now max daily dose of 2.5mg.

Section 4.4 – Moderate renal impairment now defined as GFR>30 to <45mL/min.

Section 4.8 – MHRA AE reporting updated

Section 5.2 – Study results for renal impairment patients updated

Sections 6.1 & 8 – admin/editorial changes

Section 4.1- indication re-written to incorporate updated information in section 5.1

Section 4.2  information on ‘For patients inadequately controlled on dual combination therapy of dapagliflozin and metformin, or for patients switching from triple combination therapy of saxagliptin, metformin and dapagliflozin taken as separate tablets’ added and editorial changes.

Section 4.3- editorial changes

Section 4.5 minor editorial changes

Section 4.8 minor editorial changes

Section 5.1 information on ‘ saxagliptin add on to dapagliflozin plus metformin therapy’ added and ‘saxagliptin and dapagliflozin add on to metformin therapy’ added.

Section 5.2 editorial changes

Section 5.3 editorial changes

Section 10 date of revision updated

4.2 inclusion of statement ‘ Adults with normal renal function (GFR  ≥ 90 mL/min) and update to information on renal impairment following article 31 on metformin containing products.

4.3 information on diabeteic ketoacidosis updated to include examples of other acute metabolic acidosis, information on renal impairment updated following article 31 on metformin containing products.

4.4 information on lactic acidosis and renal impairment updated and text on administration of iodinated contrast agents and surgery reworded following article 31 for metformin containing products,

4.5 Repositioning of text, text on alcohol and iodinated contrast agents re-worded. Information on medicinal products which affect renal function/lactic acidosis added following article 31 for metformin containing products and minor editorial changes.

4.6 Minor editorial changes

4.8 minor editorial changes

5.1 Minor editorial changes

5.2 Minor editorial changes

5.3 Minor editorial changes

6.5 minor editorial changes

7 minor editorial changes

10 revision date

Section 2: Minor editorial amendments following renewal

Section 4.1: Minor editorial amendments  following renewal

Section 4.2 Minor editorial amendements following renewal. ‘Komboglyze’ changed to ‘medicinal product’ throughout the section and information on adolescents added to paediatric population

Section 4.3: Minor editorial amendments following renewal

Section 4.4: Removal of information on substitute for insulin, minor editorial amendments following renewal, Komboglyze changed to medicinal product throughout section.

Section 4.5 minor editorial amendments following renewal.

Section 4.6 minor editorial following renewal, Komboglyze changed to medicinal product throughout this section.

Section 4.7 Minor editorial following renewal

Section 4.8 Minor editorial following renewal

Section 5.1 Minor editorial following renewal

Section 5.2 Minor editorial following renewal

Section 5.3: minor editorial following renewal

Section 6.3 minor editorial-change from 36 months to 3 years

Section 6.6 removal of no special requirements

Section 9; minor editorial following renewal

Section 10: date of revision updated

Section 5.1 Savor all cause mortality data included.

Section 10 Revision date updated.

Section 4.4 –updated text on cardiac failure warnings.

Section 4.4 – addition of arthalgia warning.

Section 4.8 – addition of footnote referring to section 4.4 for arthalgia side effect.

Section 10 – date of revision updated.

Section 4.8 addition of constipation as an adverse drug reaction.

Section 10 revision date updated.

- Section 4.2: Elderly populations wording updated in line with SAVOR study.

- Section 4.4: Elderly populations wording updated in line with SAVOR study.

- Section 4.8: Text updated in line with SAVOR study

- Section 4.8: AE reporting wording updated.

- Section 5.1: updated in line with SAVOR study.
- Section 10: updated date of revision

- Section 4.4 Acute Pancreatitis text added
- Section 10 updated date of revision

- Section 4.1 – addition of Triple Oral Therapy indication

- Section 4.2 – posology included for patients inadequately controlled on dual combination therapy of a sulphonylurea and metformin, or for patients switching from triple combination therapy of saxagliptin, metformin and a sulphonylurea taken as separate tablets.

- Section 4.3 – cross reference to section 6.1 included

- Section 4.4 – sulphonylurea added to sub-section regarding use with medicinal products known to cause hypoglycaemia

- Section 4.6 – typographical change

- Section 4.7 – advice included to warn patients of the risk of hypoglycaemia when used in combination with other antidiabetic medicinal products known to cause hypoglycaemia (e.g. insulin, sulphonylureas)

- Section 4.8 – information provided in description of selected adverse reactions when used as an add-on to metformin plus a sulphonylurea; additional information regarding hypoglycaemia

- Section 5.1 additional information regarding Onglyza add-on combination therapy with metformin and sulphonylurea; Additional study data included in Table 4

- Section 6.6 – addition of standard statement regarding disposal of unused product or waste material

- Section 10 – updated date of revision