Komboglyze

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS



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1. NAME OF THE MEDICINAL PRODUCT

Komboglyze 2.5 mg/850 mg film-coated tablets
Komboglyze 2.5 mg/1,000 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Komboglyze 2.5 mg/850 mg film-coated tablets
Each tablet contains 2.5 mg of saxagliptin (as hydrochloride) and 850 mg of metformin hydrochloride.

Komboglyze 2.5 mg/1,000 mg film-coated tablets
Each tablet contains 2.5 mg of saxagliptin (as hydrochloride) and 1,000 mg of metformin 
hydrochloride.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet (tablet).

Komboglyze 2.5 mg/850 mg film-coated tablets
Light brown to brown, biconvex, round, film-coated tablets, with “2.5/850” printed on one side and 
“4246” printed on the other side, in blue ink.

Komboglyze 2.5 mg/1,000 mg film-coated tablets
Pale yellow to light yellow, biconvex, oval shaped, film-coated tablets, with “2.5/1000” printed on one 
side and “4247” printed on the other side, in blue ink.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Komboglyze is indicated in adults with type 2 diabetes mellitus as an adjunct to diet and exercise to 
improve glycaemic control:

 in patients inadequately controlled on their maximally tolerated dose of metformin alone

 in combination with other medicinal products for the treatment of diabetes, including insulin, in 
patients inadequately controlled with metformin and these medicinal products (see sections 4.4, 
4.5 and 5.1 for available data on different combinations)

 in patients already being treated with the combination of saxagliptin and metformin as separate 
tablets.

4.2 Posology and method of administration

Posology
Adults with normal renal function (GFR ≥ 90 mL/min)

For patients inadequately controlled on maximal tolerated dose of metformin monotherapy
Patients not adequately controlled on metformin alone should receive a dose of this medicinal product 
equivalent to the total daily dose of saxagliptin 5 mg, dosed as 2.5 mg twice daily, plus the dose of 
metformin already being taken.



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For patients switching from separate tablets of saxagliptin and metformin
Patients switching from separate tablets of saxagliptin and metformin should receive the doses of 
saxagliptin and metformin already being taken.

For patients inadequately controlled on dual combination therapy of insulin and metformin, or for 
patients controlled on triple combination therapy of insulin, and metformin plus saxagliptin as 
separate tablets
The dose of this medicinal product should provide saxagliptin 2.5 mg twice daily (5 mg total daily 
dose) and a dose of metformin similar to the dose already being taken. When this medicinal product is 
used in combination with insulin, a lower dose of insulin may be required to reduce the risk of 
hypoglycaemia (see section 4.4).

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
The dose of this medicinal product should provide saxagliptin 2.5 mg twice daily (5 mg total daily 
dose), and a dose of metformin similar to the dose already being taken. When this medicinal product is 
used in combination with a sulphonylurea, a lower dose of the sulphonylurea may be required to 
reduce the risk of hypoglycaemia (see section 4.4).

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
The dose of this medicinal product should provide saxagliptin 2.5 mg twice daily (5 mg total daily 
dose), and a dose of metformin similar to the dose already being taken.

Special populations
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 
Komboglyze in patients with GFR < 60 mL/min.

If no adequate strength of Komboglyze is available, individual monocomponents should be used 
instead of the fixed dose combination.

Table 1 Dosage in patients with renal impairment

GFR mL/min Metformin Saxagliptin

60-89
Maximum daily dose is 3000 mg.

Dose reduction may be considered in 
relation to declining renal function.

Maximum total daily dose is 5 mg.

45-59
Maximum daily dose is 2000 mg.

The starting dose is at most half of the 
maximum dose.

Maximum total daily dose is 5 mg.

30-44
Maximum daily dose is 1000 mg.
The starting dose is at most half of the 
maximum dose.

Maximum total daily dose is 2.5 mg.

< 30 Metformin is contraindicated.

Maximum total daily dose is 2.5 mg.



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Hepatic impairment
This medicinal product must not be used in patients with hepatic impairment (see sections 4.3 and 
4.5). 

Elderly (≥ 65 years)
As metformin and saxagliptin are excreted by the kidney, this medicinal product should be used with 
caution in the elderly. Monitoring of renal function is necessary to prevent metformin-associated lactic 
acidosis, particularly in the elderly (see sections 4.3, 4.4 and 5.2). 

Paediatric population
The safety and efficacy of this medicinal product in children and adolescents from birth to < 18 years 
of age have not been established. No data are available.

Method of administration
Komboglyze should be given twice daily with meals to reduce the gastrointestinal adverse reactions 
associated with metformin.

4.3 Contraindications

- Hypersensitivity to the active substances or to any of the excipients listed in section 6.1, or 
history of a serious hypersensitivity reaction, including anaphylactic reaction, anaphylactic 
shock, and angioedema, to any dipeptidyl peptidase 4 (DPP4) inhibitor (see sections 4.4 and 
4.8); 

- Any type of acute metabolic acidosis (such as lactic acidosis, diabetic ketoacidosis);
- Diabetic pre-coma;
- Severe renal failure (GFR < 30 mL/min) (see sections 4.2, 4.4 and 5.2);
- Acute conditions with the potential to alter renal function such as:

- dehydration,
- severe infection,
- shock;

- Acute or chronic disease which may cause tissue hypoxia such as:
- cardiac or respiratory failure,
- recent myocardial infarction,
- shock;

- Hepatic impairment (see sections 4.2 and 4.5);
- Acute alcohol intoxication, alcoholism (see section 4.5);
- Breast-feeding (see section 4.6).

4.4 Special warnings and precautions for use

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

Acute pancreatitis
Use of DPP4 inhibitors has been associated with a risk of developing acute pancreatitis. Patients 
should be informed of the characteristic symptoms of acute pancreatitis; persistent, severe abdominal 
pain. If pancreatitis is suspected, this medicinal product should be discontinued; if acute pancreatitis is 
confirmed, this medicinal product should not be restarted. Caution should be exercised in patients with 
a history of pancreatitis.

In postmarketing experience of saxagliptin, there have been spontaneously reported adverse reactions 
of acute pancreatitis. 



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Lactic acidosis
Lactic acidosis, a very rare but serious metabolic complication, most often occurs at acute worsening 
of renal function or cardiorespiratory illness or sepsis. Metformin accumulation occurs at acute 
worsening of renal function and increases the risk of lactic acidosis.

In case of dehydration (severe diarrhoea or vomiting, fever, heat, reduced fluid intake), Komboglyze 
should be temporarily discontinued and contact with a health care professional is recommended.

Medicinal products that can acutely impair renal function (such as antihypertensives, diuretics and 
NSAIDs) should be initiated with caution in metformin-treated patients. Other risk factors for lactic 
acidosis are excessive alcohol intake, hepatic insufficiency, inadequately controlled diabetes, ketosis, 
prolonged fasting and any conditions associated with hypoxia, as well as concomitant use of medicinal 
products that may cause lactic acidosis (see sections 4.3 and 4.5).

Patients and/or care-givers should be informed on the risk of lactic acidosis. Lactic acidosis is 
characterised by acidotic dyspnoea, abdominal pain, muscle cramps, asthenia and hypothermia 
followed by coma. In case of suspected symptoms, the patient should stop taking Komboglyze and 
seek immediate medical attention. Diagnostic laboratory findings are decreased blood pH (< 7.35), 
increased plasma lactate levels above 5 mmol/L, and an increased anion gap and lactate/pyruvate ratio. 

Renal function
As metformin is excreted by the kidney, renal function should be assessed:
- Before initiation of treatment and regularly thereafter (see sections 4.2, 4.8, 5.1 and 5.2).
- For renal function with GFR levels approaching moderate renal impairment and in elderly 

patients, at least 2 to 4 times per year.
- In patients with moderate renal impairment that have GFR ≥ 30 to < 45 mL/min, in the absence 

of other conditions that may increase the risk of lactic acidosis, the dose is 2.5 mg/1000 mg or 
2.5 mg/850 mg once daily. It is not recommended to initiate treatment in these patients. 
Treatment may be continued in the well-informed patients with close monitoring.

- Metformin is contraindicated in patients with a GFR < 30 mL/min and should be temporarily 
discontinued in the presence of conditions that alter renal function (see section 4.3).

Decreased renal function in elderly patients is frequent and asymptomatic. Special caution should be 
exercised in situations where renal function may become impaired, for example when initiating 
antihypertensive or diuretic therapy or when starting treatment with a NSAID.

Surgery
Komboglyze must be discontinued at the time of surgery with general, spinal or epidural anaesthesia. 
Therapy may be restarted no earlier than 48 hours following surgery or resumption of oral nutrition 
provided that renal function has been re-evaluated and found to be stable.

Administration of iodinated contrast agents 
Intravascular administration of iodinated contrast agents may lead to contrast induced nephropathy, 
resulting in metformin accumulation and increased risk of lactic acidosis. Komboglyze should be
discontinued prior to, or at the time of, the imaging procedure and not restarted until at least 48 hours 
after, provided that renal function has been re-evaluated and found to be stable (see sections 4.2 and 
4.5).

Skin disorders
Ulcerative and necrotic skin lesions have been reported in extremities of monkeys in non-clinical 
toxicology studies for saxagliptin (see section 5.3). Skin lesions were not observed at an increased 
incidence in clinical trials. Postmarketing reports of rash have been described in the DPP4 inhibitor 
class. Rash is also noted as an adverse event (AE) for saxagliptin (see section 4.8). Therefore, in 
keeping with routine care of the diabetic patient, monitoring for skin disorders, such as blistering, 
ulceration or rash, is recommended.



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Bullous pemphigoid
Postmarketing cases of bullous pemphigoid requiring hospitalisation have been reported with DPP4 
inhibitor use, including saxagliptin. In reported cases, patients typically responded to topical or 
systemic immunosuppressive treatment and discontinuation of the DPP4 inhibitor. If a patient 
develops blisters or erosions while receiving saxagliptin and bullous pemphigoid is suspected, this 
medicinal product should be discontinued and referral to a dermatologist should be considered for 
diagnosis and appropriate treatment (see section 4.8).

Hypersensitivity reactions
As this medicinal product contains saxagliptin, it should not be used in patients who have had any 
serious hypersensitivity reaction to a dipeptidyl peptidase 4 (DPP4) inhibitor.

During postmarketing experience, including spontaneous reports and clinical trials, the following 
adverse reactions have been reported with the use of saxagliptin: serious hypersensitivity reactions, 
including anaphylactic reaction, anaphylactic shock, and angioedema. If a serious hypersensitivity 
reaction to saxagliptin is suspected, discontinue this medicinal product, assess for other potential 
causes for the event, and institute alternative treatment for diabetes (see sections 4.3 and 4.8).

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 Komboglyze 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.

Cardiac failure
In the SAVOR trial a small increase in the rate for hospitalisation for heart failure was observed in the 
saxagliptin treated patients compared to placebo, although a causal relationship has not been 
established (see section 5.1). Caution is warranted if this medicinal product is used in patients who 
have known risk factors for hospitalisation for heart failure, such as a history of heart failure or 
moderate to severe renal impairment. Patients should be advised of the characteristic symptoms of 
heart failure, and to immediately report such symptoms.

Arthralgia
Joint pain, which may be severe, has been reported in postmarketing reports for DPP4 inhibitors (see 
section 4.8). Patients experienced relief of symptoms after discontinuation of the medicinal product 
and some experienced recurrence of symptoms with reintroduction of the same or another DPP4 
inhibitor. Onset of symptoms following initiation of drug therapy may be rapid or may occur after 
longer periods of treatment. If a patient presents with severe joint pain, continuation of drug therapy 
should be individually assessed.

Immunocompromised patients
Immunocompromised patients, such as patients who have undergone organ transplantation or patients 
diagnosed with human immunodeficiency syndrome, have not been studied in the saxagliptin clinical 
program. Therefore, the efficacy and safety profile of saxagliptin in these patients has not been 
established. 

Use with potent CYP3A4 inducers
Using CYP3A4 inducers like carbamazepine, dexamethasone, phenobarbital, phenytoin, and 
rifampicin may reduce the glycaemic lowering effect of saxagliptin (see section 4.5). 

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 
Komboglyze.



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4.5 Interaction with other medicinal products and other forms of interaction

Co-administration of multiple doses of saxagliptin (2.5 mg twice daily) and metformin (1,000 mg 
twice daily) did not meaningfully alter the pharmacokinetics of either saxagliptin or metformin in 
patients with type 2 diabetes.

There have been no formal interaction studies for Komboglyze. The following statements reflect the 
information available on the individual active substances.

Saxagliptin
Clinical data described below suggest that the risk for clinically meaningful interactions with 
co-administered medicinal products is low. 

The metabolism of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5). In in 
vitro studies, saxagliptin and its major metabolite neither inhibited CYP1A2, 2A6, 2B6, 2C8, 2C9, 
2C19, 2D6, 2E1, or 3A4, nor induced CYP1A2, 2B6, 2C9, or 3A4. In studies conducted in healthy 
subjects, neither the pharmacokinetics of saxagliptin nor its major metabolite, were meaningfully 
altered by metformin, glibenclamide, pioglitazone, digoxin, simvastatin, omeprazole, antacids or 
famotidine. In addition, saxagliptin did not meaningfully alter the pharmacokinetics of metformin, 
glibenclamide, pioglitazone, digoxin, simvastatin, the active components of a combined oral 
contraceptive (ethinyl estradiol and norgestimate), diltiazem or ketoconazole.

Concomitant administration of saxagliptin with the moderate inhibitor of CYP3A4/5 diltiazem, 
increased the Cmax and AUC of saxagliptin by 63% and 2.1-fold, respectively, and the corresponding 
values for the active metabolite were decreased by 44% and 34%, respectively.

Concomitant administration of saxagliptin with the potent inhibitor of CYP3A4/5 ketoconazole, 
increased the Cmax and AUC of saxagliptin by 62% and 2.5-fold, respectively, and the corresponding 
values for the active metabolite were decreased by 95% and 88%, respectively.

Concomitant administration of saxagliptin with the potent CYP3A4/5 inducer rifampicin, reduced Cmax
and AUC of saxagliptin by 53% and 76%, respectively. The exposure of the active metabolite and the 
plasma DPP4 activity inhibition over a dose interval were not influenced by rifampicin (see 
section 4.4).

The co-administration of saxagliptin and CYP3A4/5 inducers, other than rifampicin (such as 
carbamazepine, dexamethasone, phenobarbital and phenytoin) have not been studied and may result in 
decreased plasma concentration of saxagliptin and increased concentration of its major metabolite. 
Glycaemic control should be carefully assessed when saxagliptin is used concomitantly with a potent 
CYP3A4 inducer.

The effects of smoking, diet, herbal products, and alcohol use on the pharmacokinetics of saxagliptin 
have not been specifically studied.

Metformin
Concomitant use not recommended
Cationic substances that are eliminated by renal tubular secretion (e.g. cimetidine) may interact with 
metformin by competing for common renal tubular transport systems. A study conducted in seven 
normal healthy volunteers showed that cimetidine, administered as 400 mg twice daily, increased 
metformin systemic exposure (AUC) by 50% and Cmax by 81%. Therefore, close monitoring of 
glycaemic control, dose adjustment within the recommended posology and changes in diabetic 
treatment should be considered when cationic medicinal products that are eliminated by renal tubular 
secretion are co-administered.



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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 Komboglyze (see 
section 4.4). Consumption of alcohol and medicinal products containing alcohol should be avoided.

Iodinated contrast agents
Intravascular administration of iodinated contrast agents may lead to contrast induced nephropathy, 
resulting in metformin accumulation and increased risk of lactic acidosis. Komboglyze must be 
discontinued prior to, or at the time of the imaging procedure and not restarted until at least 48 hours 
after, provided that renal function has been re-evaluated and found to be stable (see sections 4.2 and 
4.4).

Combination requiring precautions for use
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 
perfomed, especially at the beginning of treatment with such medicinal products. If necessary, the 
dose of the anti-hyperglycaemic medicinal product should be adjusted during therapy with the other 
medicinal product and on its discontinuation.

Some medicinal products can adversely affect renal function which may increase the risk of lactic 
acidosis, e.g. NSAIDs, including selective cyclo-oxygenase (COX) II inhibitors, ACE inhibitors, 
angiotensin II receptor antagonists and diuretics, especially loop diuretics. When starting or using such 
products in combination with metformin, close monitoring of renal function is necessary.

4.6 Fertility, pregnancy and lactation

Pregnancy
The use of Komboglyze or saxagliptin has not been studied in pregnant women. Studies in animals 
have shown reproductive toxicity at high doses of saxagliptin alone or in combination with metformin 
(see section 5.3). The potential risk for humans is unknown. A limited amount of data suggest the use 
of metformin in pregnant women is not associated with an increased risk of congenital malformations. 
Animal studies with metformin do not indicate harmful effects with respect to pregnancy, embryonic 
or foetal development, parturition or postnatal development (see section 5.3). This medicinal product
should not be used during pregnancy. If the patient wishes to become pregnant, or if a pregnancy 
occurs, treatment with this medicinal product should be discontinued and switched to insulin treatment 
as soon as possible.

Breast-feeding
Studies in animals have shown excretion of both saxagliptin and/or metabolite and metformin in milk. 
It is unknown whether saxagliptin is excreted in human milk, but metformin is excreted in human milk 
in small amounts. This medicinal product must therefore not be used in women who are breast-feeding 
(see section 4.3).

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). For 
metformin, studies in animals have not shown reproductive toxicity (see section 5.3).

4.7 Effects on ability to drive and use machines

Saxagliptin or metformin has a negligible influence on the ability to drive and use machines. When 
driving or using machines, it should be taken into account that dizziness has been reported in studies 
with saxagliptin. In addition, patients should be alerted to the risk of hypoglycaemia when 
Komboglyze is used in combination with other antidiabetic medicinal products known to cause 
hypoglycaemia (e.g. insulin, sulphonylureas).



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4.8 Undesirable effects

There have been no therapeutic clinical trials conducted with Komboglyze tablets, however,
bioequivalence of Komboglyze with co-administered saxagliptin and metformin has been 
demonstrated (see section 5.2).

Saxagliptin
Summary of the safety profile
There were 4,148 patients with type 2 diabetes, including 3,021 patients treated with saxagliptin, 
randomised in six double-blind, controlled clinical safety and efficacy studies conducted to evaluate 
the effects of saxagliptin on glycaemic control. In randomised, controlled, double-blind clinical trials 
(including developmental and postmarketing experience), over 17,000 patients with type 2 diabetes 
have been treated with saxagliptin.

In a pooled analysis of 1,681 patients with type 2 diabetes, including 882 patients treated with 
saxagliptin 5 mg, randomised in five double-blind, placebo-controlled clinical safety and efficacy 
studies conducted to evaluate the effects of saxagliptin on glycaemic control, the overall incidence of 
AEs in patients treated with saxagliptin 5 mg was similar to placebo. Discontinuation of therapy due to 
AEs was higher in patients who received saxagliptin 5 mg as compared to placebo (3.3% as compared 
to 1.8%).

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 2.

The adverse reactions are listed by system organ class and 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), or very rare (< 1/10,000), not known (cannot be estimated from the available 
data).

Table 2 Frequency of adverse reactions by system organ class

System organ class
Adverse reaction

Frequency of adverse reactions by treatment regimen

Saxagliptin with metformin1

Infections and infestations
Upper respiratory infection Common
Urinary tract infection Common
Gastroenteritis Common
Sinusitis Common
Nasopharyngitis Common2

Nervous system disorders
Headache Common
Gastrointestinal disorders
Vomiting Common
1Includes saxagliptin in add-on to metformin and initial combination with metformin.
2Only in the initial combination therapy.

Postmarketing experience from clinical trials and spontaneous reports
Table 3 shows additional adverse reactions which have been reported in postmarketing experience 
with saxagliptin. The frequencies are based on the experience from clinical trials.



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Table 3 Frequency of additional adverse reactions by system organ class

System organ class
Adverse Reaction Frequency of adverse reactions1

Gastrointestinal disorders
Nausea Common
Pancreatitis Uncommon
Constipation Not known
Immune system disorders
Hypersensitivity reactions2 (see
sections 4.3 and 4.4)

Uncommon

Anaphylactic reactions including anaphylactic 
shock (see sections 4.3 and 4.4)

Rare

Skin and subcutaneous tissue disorders
Angioedema (see sections 4.3 and 4.4) Rare
Dermatitis Uncommon
Pruritus Uncommon
Rash2 Common
Urticaria Uncommon
Bullous pemphigoid Not known
1 Frequency estimates are based on the pooled analysis of the saxagliptin monotherapy, add-on to metformin and initial 
combination with metformin, add-on to sulphonylurea and add-on to thiazolidinedione clinical trials.
2 These reactions were also identified in the pre-approval clinical trials, but do not meet the criteria for Table 2.

SAVOR trial results
The SAVOR trial included 8240 patients treated with saxagliptin 5 mg or 2.5 mg once daily and 8173 
patients on placebo. The overall incidence of AEs in patients treated with saxagliptin in this trial was 
similar to placebo (72.5% versus 72.2%, respectively).

The incidence of adjudicated pancreatitis events was 0.3% in both saxagliptin-treated patients and
placebo-treated patients in the intent-to-treat population.

The incidence of hypersensitivity reactions was 1.1% in both saxagliptin-treated patients and placebo-
treated patients.

The overall incidence of reported hypoglycaemia (recorded in daily patient diaries) was 17.1% in 
subjects treated with saxagliptin and 14.8% among patients treated with placebo. The percent of 
subjects with reported on-treatment events of major hypoglycaemia (defined as an event that required 
assistance of another person) was higher in the saxagliptin group than in the placebo group (2.1% and 
1.6%, respectively). The increased risk of overall hypoglycaemia and major hypoglycaemia observed 
in the saxagliptin-treated group occurred primarily in subjects treated with SU at baseline and not in 
subjects on insulin or metformin monotherapy at baseline. The increased risk of overall and major 
hypoglycaemia was primarily observed in subjects with A1C < 7% at baseline.

Decreased lymphocyte counts were reported in 0.5% of saxagliptin-treated patients and 0.4% of 
placebo-treated patients.

Hospitalisation for heart failure, occurred at a greater rate in the saxagliptin group (3.5%) compared 
with the placebo group (2.8%), with nominal statistical significance favouring placebo [HR = 1.27; 
95% CI 1.07, 1.51); P = 0.007]. See also section 5.1.

Description of selected adverse reactions

AEs, considered by the investigator to be at least possibly drug-related and reported in at least two 
more patients treated with saxagliptin 5 mg compared to control, are described below by treatment 
regimen.



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As monotherapy: dizziness (common) and fatigue (common).

As add-on to metformin: dyspepsia (common) and myalgia (common).

As initial combination with metformin: gastritis (common), arthralgia* (uncommon), myalgia 
(uncommon), and erectile dysfunction (uncommon).

As add-on to metformin and a sulphonylurea: dizziness (common), fatigue (common) and flatulence 
(common).

*Arthralgia has also been reported during postmarketing surveillance (see section 4.4).

Hypoglycaemia
Adverse reactions of hypoglycaemia were based on all reports of hypoglycaemia; a concurrent glucose 
measurement was not required. The incidence of reported hypoglycaemia for saxagliptin 5 mg versus 
placebo given as add-on therapy to metformin was 5.8% versus 5%. The incidence of reported 
hypoglycaemia was 3.4% in treatment-naive patients given saxagliptin 5 mg plus metformin and 4.0% 
in patients given metformin alone. When used as add-on to insulin (with or without metformin), the 
overall incidence of reported hypoglycaemia was 18.4% for saxagliptin 5 mg and 19.9% for placebo.

When used as add-on to metformin plus a sulphonylurea, the overall incidence of reported 
hypoglycaemia was 10.1% for saxagliptin 5 mg and 6.3% for placebo.

Investigations
Across clinical studies, the incidence of laboratory AEs was similar in patients treated with saxagliptin 
5 mg compared to patients treated with placebo. A small decrease in absolute lymphocyte count was 
observed. From a baseline mean absolute lymphocyte count of approximately 2,200 cells/μL, a mean 
decrease of approximately 100 cells/μL relative to placebo was observed in the placebo-controlled
pooled analysis. Mean absolute lymphocyte counts remained stable with daily dosing up to 102 weeks 
in duration. The decreases in lymphocyte count were not associated with clinically relevant adverse 
reactions. The clinical significance of this decrease in lymphocyte count relative to placebo is not 
known.

Metformin
Clinical trial data and postmarketing data
Table 4 presents adverse reactions by system organ class and by frequency category. Frequency 
categories are based on information available from metformin Summary of Product Characteristics 
available in the European Union.

Table 4 The frequency of metformin adverse reactions identified from clinical trial and 
postmarketing data

System organ class
Adverse reaction

Frequency 

Metabolism and nutrition disorders
Lactic acidosis Very rare
Vitamin B12 deficiency1 Very rare
Nervous system disorders 
Metallic taste Common
Gastrointestinal disorders
Gastrointestinal symptoms2 Very common
Hepatobiliary disorders
Liver function disorders, hepatitis Very rare



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Skin and subcutaneous tissue disorders
Urticaria, erythema, pruritus Very rare
1 Long-term treatment with metformin has been associated with a decrease in vitamin B12 absorption which may very rarely 
result in clinically significant vitamin B12 deficiency (e.g. megaloblastic anaemia).
2 Gastrointestinal symptoms such as nausea, vomiting, diarrhoea, abdominal pain and loss of appetite occur most frequently 
during initiation of therapy and resolve spontaneously in most cases.

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 the national reporting system 
listed in Appendix V.

4.9 Overdose

No data are available with regard to overdose of Komboglyze.

Saxagliptin
Saxagliptin has been shown to be well-tolerated with no clinically meaningful effect on QTc interval 
or heart rate at oral doses up to 400 mg daily for 2 weeks (80 times the recommended dose). In the 
event of an overdose, appropriate supportive treatment should be initiated as dictated by the patient’s 
clinical status. Saxagliptin and its major metabolite can be removed by haemodialysis (23% of dose 
over 4 hours).

Metformin
High overdose or concomitant risks of metformin may lead to lactic acidosis. Lactic acidosis is a 
medical emergency and must be treated in hospital. The most effective method to remove lactate and 
metformin is haemodialysis.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Drugs used in diabetes, Combinations of oral blood glucose lowering 
drugs, ATC code: A10BD10.

Mechanism of action and pharmacodynamic effects
Komboglyze combines two antihyperglycaemic medicinal products with complementary mechanisms 
of action to improve glycaemic control in patients with type 2 diabetes: saxagliptin, a dipeptidyl 
peptidase 4 (DPP4) inhibitor, and metformin hydrochloride, a member of the biguanide class.

Saxagliptin
Saxagliptin is a highly potent (Ki: 1.3 nM), selective, reversible, competitive, DPP4 inhibitor. In 
patients with type 2 diabetes, administration of saxagliptin led to inhibition of DPP4 enzyme activity 
for a 24-hour period. After an oral glucose load, this DPP4 inhibition resulted in a 2- to 3-fold increase 
in circulating levels of active incretin hormones, including glucagon-like peptide-1 (GLP-1) and 
glucose-dependent insulinotropic polypeptide (GIP), decreased glucagon concentrations and increased 
glucose-dependent beta-cell responsiveness, which resulted in higher insulin and C-peptide 
concentrations. The rise in insulin from pancreatic beta-cells and the decrease in glucagon from 
pancreatic alpha-cells were associated with lower fasting glucose concentrations and reduced glucose 
excursion following an oral glucose load or a meal. Saxagliptin improves glycaemic control by 
reducing fasting and postprandial glucose concentrations in patients with type 2 diabetes. 

Metformin
Metformin is a biguanide with antihyperglycaemic effects, lowering both basal and postprandial 
plasma glucose. It does not stimulate insulin secretion and therefore does not produce hypoglycaemia. 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


13

Metformin may act via three mechanisms:
- by reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis in 

muscle;
- by modestly increasing insulin sensitivity, improving peripheral glucose uptake and utilisation;
- by delaying intestinal glucose absorption.

Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase. Metformin 
increases the transport capacity of specific types of membrane glucose transporters (GLUT-1 and 
GLUT-4).

In humans, independently of its action on glycaemia, metformin has favourable effects on lipid 
metabolism. This has been shown at therapeutic doses in controlled, medium-term or long-term 
clinical studies: metformin reduces total cholesterol, LDL-C and triglyceride levels.

Clinical efficacy and safety
In randomised, controlled, double-blind clinical trials (including developmental and postmarketing 
experience), over 17,000 patients with type 2 diabetes have been treated with saxagliptin.

Saxagliptin in combination with metformin for glycaemic control
The co-administration of saxagliptin and metformin has been studied in patients with type 2 diabetes 
inadequately controlled on metformin alone and in treatment-naive patients inadequately controlled on 
diet and exercise alone. Treatment with saxagliptin 5 mg once daily produced clinically relevant and 
statistically significant improvements in haemoglobin A1c (HbA1c), fasting plasma glucose (FPG) 
and postprandial glucose (PPG) compared to placebo in combination with metformin (initial or add-on 
therapy). Reductions in A1c were seen across subgroups including gender, age, race, and baseline 
BMI. Decrease in body weight in the treatment groups given saxagliptin in combination with 
metformin was similar to that in the groups given metformin alone. Saxagliptin plus metformin was 
not associated with significant changes from baseline in fasting serum lipids compared to metformin 
alone.

Saxagliptin add-on to metformin therapy
An add-on to metformin placebo-controlled study of 24-week duration was conducted to evaluate the 
efficacy and safety of saxagliptin in combination with metformin in patients with inadequate 
glycaemic control (HbA1c 7-10%) on metformin alone. Saxagliptin (n=186) provided significant 
improvements in HbA1c, FPG, and PPG compared to placebo (n=175). Improvements in HbA1c, 
PPG, and FPG following treatment with saxagliptin 5 mg plus metformin were sustained up to 
Week 102. The HbA1c change for saxagliptin 5 mg plus metformin (n=31) compared to placebo plus 
metformin (n=15) was -0.8% at Week 102.

Saxagliptin twice daily add-on to metformin therapy
An add-on to metformin placebo-controlled study of 12-week duration was conducted to evaluate the 
efficacy and safety of saxagliptin 2.5 mg twice daily in combination with metformin in patients with 
inadequate glycaemic control (HbA1c 7-10%) on metformin alone. After 12 weeks, the saxagliptin 
group (n=74) had a greater HbA1c mean reduction from baseline than the placebo group (n=86) 
(-0.6% vs. -0.2%, respectively, difference of -0.34%, from a mean baseline HbA1c of 7.9% for the 
saxagliptin group and 8.0% for the placebo group), and a greater FPG reduction (-13.73 mg/dL versus 
-4.22 mg/dL) but without statistical significance (p=0.12, 95% CI [-21.68; 2.66]).

Saxagliptin add-on to metformin compared with sulphonylurea 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 



14

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.

Saxagliptin in combination with metformin as initial therapy
A 24-week study was conducted to evaluate the efficacy and safety of saxagliptin 5 mg in combination 
with metformin as initial combination therapy in treatment-naive patients with inadequate glycaemic 
control (HbA1c 8-12%). Initial therapy with the combination of saxagliptin 5 mg plus metformin 
(n=306) provided significant improvements in HbA1c, FPG, and PPG compared to with either 
saxagliptin (n=317) or metformin (n=313) alone as initial therapy. Reductions in HbA1c from baseline 
to Week 24 were observed in all evaluated subgroups defined by baseline HbA1c, with greater 
reductions observed in patients with a baseline HbA1c ≥ 10% (see Table 5). Improvements in HbA1c, 
PPG, and FPG following initial therapy with saxagliptin 5 mg plus metformin were sustained up to 
Week 76. The HbA1c change for saxagliptin 5 mg plus metformin (n=177) compared to metformin 
plus placebo (n=147) was -0.5% at Week 76.

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.

Saxagliptin add-on combination therapy with metformin and sulphonylurea
A total of 257 patients with type 2 diabetes participated in a 24-week randomised, double-blind, 
placebo-controlled study to evaluate the efficacy and safety of saxagliptin (5 mg once daily) in 
combination with metformin plus sulphonylurea (SU) in patients with inadequate glycaemic control 
(HbA1c ≥ 7% and ≤ 10%). Saxagliptin (n=127) provided significant improvements in HbA1c and 
PPG compared with the placebo (n=128). The HbA1c change for saxagliptin compared to placebo was 
-0.7% at Week 24.

Saxagliptin add-on to dapagliflozin plus metformin therapy
A 24-week randomised, double-blind, placebo-controlled study conducted in patients with type 2 
diabetes mellitus compared saxagliptin 5 mg with placebo as add-on therapy in individuals with 
HbA1c 7-10.5% treated with dapagliflozin (SGLT2-inhibtor) and metformin. Patients who completed 
the initial 24-week study period were eligible to enter a controlled 28-week long-term study extension 
(52 weeks). 



15

Individuals treated with saxagliptin added to dapagliflozin and metformin (n=153) achieved 
statistically significantly (p-value < 0.0001) greater reductions in HbA1c versus the group with 
placebo added to dapagliflozin plus metformin (n=162) at 24 weeks (see Table 5). The effect on 
HbA1c observed at Week 24 was sustained at Week 52. The safety profile of saxagliptin added to 
dapagliflozin plus metformin in the long-term treatment period was consistent with that observed in 
the 24-week treatment period in this study and in the trial in which saxagliptin and dapagliflozin were 
given concomitantly as add-on therapy to patients treated with metformin (described below).

Proportion of patients achieving HbA1c < 7%
The proportion of patients achieving HbA1c < 7% at Week 24 was higher in the saxagliptin 5 mg plus 
dapagliflozin plus metformin group 35.3% (95% CI [28.2, 42.4]) compared to the placebo plus 
dapagliflozin plus metformin group 23.1% (95% CI [16.9, 29.3]). The effect in HbA1c observed at 
Week 24 was sustained at Week 52.

Table 5 Key efficacy results in placebo-controlled, combination therapy studies of 
saxagliptin and metformin

Mean 
baseline 
HbA1c 

(%)

Mean change1

from baseline 
HbA1c (%)

Placebo-corrected 
mean change in 

HbA1c (%) (95% 
CI)

Add-on/initial combination with metformin studies
24-weeks 

Saxa 5 mg daily add-on to metformin; 
Study CV181014 (n=186) 8.1 -0.7 -0.8 (-1.0, -0.6)2

Saxa 5 mg daily initial combination 
with metformin; Study CV1810393:

Overall population (n=306)
Baseline HbA1c ≥ 10% stratum 
(n=107)

9.4
10.8

-2.5
-3.3

-0.5 (-0.7, -0.4)4

-0.6 (-0.9, -0.3)5

12-weeks
Saxa 2.5 mg twice daily add-on to 
metformin; Study CV181080 (n=74) 7.9 -0.6 -0.3 (-0.6,-0.1)6

Add-on/combination studies with additional therapies
Add-on to insulin (+/- metformin)

Saxa 5 mg daily, Study CV181057: 
Overall population (n=300) 8.7 -0.7 -0.4 (-0.6, -0.2)2

24-weeks
Saxa 5 mg daily add-on to metformin 
plus sulphonylurea;
Study D1680L00006 (n=257) 8.4 -0.7 -0.7 (-0.9, -0.5)2

Saxa 5 mg daily add-on to metformin 
plus dapagliflozin
Study CV181168 (n=315) 7.9 -0.5 -0.4 (-0.5, -0.2)7

n=Randomised patients
1 Adjusted mean change from baseline adjusted for baseline value (ANCOVA).
2 p< 0.0001 compared to placebo.
3 Metformin was uptitrated from 500 to 2000 mg per day as tolerated.
4 Mean HbA1c change is the difference between the saxagliptin 5 mg + metformin and metformin alone groups (p< 0.0001).
5 Mean HbA1c change is the difference between the saxagliptin 5 mg + metformin and metformin alone groups.
6 p-value = 0.0063 (between group comparisons significant at α = 0.05).
7 Mean HbA1c change is the difference between the saxagliptin 5 mg + dapagliflozin + metformin and dapagliflozin + 

metformin groups (p< 0.0001).

Saxagliptin and dapagliflozin add-on to metformin therapy
A total of 534 adult patients with type 2 diabetes mellitus and inadequate glycaemic control on 
metformin alone (HbA1c 8%-12%), participated in this 24-week randomised, double-blind, active 
comparator-controlled trial to compare the combination of saxagliptin and dapagliflozin added 



16

concurrently to metformin, versus saxagliptin or dapagliflozin added to metformin. Patients were 
randomised to one of three double-blind treatment groups to receive saxagliptin 5 mg and 
dapagliflozin 10 mg added to metformin, saxagliptin 5 mg and placebo added to metformin, or 
dapagliflozin 10 mg and placebo added to metformin.

The saxagliptin and dapagliflozin group achieved significantly greater reductions in HbA1c versus 
either the saxagliptin group or dapagliflozin group at 24 weeks (see Table 6).

Table 6 HbA1c at Week 24 in active-controlled study comparing the combination of 
saxagliptin and dapagliflozin added concurrently to metformin with either 
saxagliptin or dapagliflozin added to metformin

Efficacy parameter

Saxagliptin 
5 mg

+ dapagliflozin 
10 mg 

+ metformin
N=1792

Saxagliptin 
5 mg 

+ metformin
N=1762

Dapagliflozin 
10 mg

+ metformin
N=1792

HbA1c (%) at week 241

Baseline (mean) 8.93 9.03 8.87

Change from baseline (adjusted mean3)
(95% Confidence interval [CI])

−1.47
(−1.62, −1.31)

−0.88
(−1.03, −0.72)

−1.20
(−1.35, −1.04)

Difference from saxagliptin + metformin 
(adjusted mean3)
(95% CI)

−0.594

(−0.81, −0.37) - -

Difference from dapagliflozin + metformin 
(adjusted mean3)
(95% CI)

−0.275

(−0.48, −0.05) - -

1 LRM = Longitudinal repeated measures (using values prior to rescue).
2 Randomised and treated patients with baseline and at least 1 post-baseline efficacy measurement.
3 Least squares mean adjusted for baseline value.
4 p-value < 0.0001.
5 p-value=0.0166.

Proportion of patients achieving HbA1c < 7%
In the saxagliptin and dapagliflozin combination group, 41.4% (95% CI [34.5, 48.2]) of patients 
achieved HbA1c levels of less than 7% compared to 18.3% (95% CI [13.0, 23.5]) of patients in the 
saxagliptin group and 22.2% (95% CI [16.1, 28.3]) of patients in the dapagliflozin group.

Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-
Thrombolysis in Myocardial Infarction (SAVOR) Study 
SAVOR was a CV outcome trial in 16,492 patients with HbA1c ≥ 6.5% and < 12% (12959 with 
established CV disease; 3533 with multiple risk factors only) who were randomised to saxagliptin 
(n=8280) or placebo (n=8212) added to regional standards of care for HbA1c and CV risk factors. The 
study population included those ≥ 65 years (n=8561) and ≥ 75 years (n=2330), with normal or mild 
renal impairment (n=13916) as well as moderate (n=2240) or severe (n=336) renal impairment.

The primary safety (noninferiority) and efficacy (superiority) endpoint was a composite endpoint 
consisting of the time-to-first occurrence of any of the following major adverse CV events (MACE): 
CV death, nonfatal myocardial infarction, or nonfatal ischaemic stroke.

After a mean follow up of 2 years, the trial met its primary safety endpoint demonstrating saxagliptin 
does not increase the cardiovascular risk in patients with type 2 diabetes compared to placebo when 
added to current background therapy.



17

No benefit was observed for MACE or all-cause mortality.

Table 7 Primary and secondary clinical endpoints by treatment group in the SAVOR study*

Endpoint

Saxagliptin
(N=8280)

Placebo
(N=8212)

Hazard 
Ratio 

(95% CI)†

Subjects with 
events
n (%)

Event rate 
per 100 

patient-years

Subjects 
with events

n (%)

Event rate per 
100 

patient-years

Primary composite 
endpoint: MACE

613
(7.4)

3.76 609
(7.4)

3.77 1.00
(0.89, 1.12)‡,§, #

Secondary composite 
endpoint: MACE plus

1059
(12.8)

6.72 1034
(12.6)

6.60 1.02
(0.94, 1.11)¶

All-cause mortality 420
(5.1)

2.50 378
(4.6)

2.26 1.11
(0.96, 1.27)¶

* Intent-to-treat population
† Hazard ratio adjusted for baseline renal function category and baseline CVD risk category.
‡ p-value < 0.001 for noninferiority (based on HR < 1.3) compared to placebo.
§ p-value = 0.99 for superiority (based on HR < 1.0) compared to placebo.
# Events accumulated consistently over time, and the event rates for saxagliptin and placebo did not diverge notably over 

time.
¶ Significance not tested.

One component of the secondary composite endpoint, hospitalisation for heart failure, occurred at a 
greater rate in the saxagliptin group (3.5%) compared with the placebo group (2.8%), with nominal 
statistical significance favouring placebo [HR=1.27; (95% CI 1.07, 1.51); P=0.007]. Clinically 
relevant factors predictive of increased relative risk with saxagliptin treatment could not be 
definitively identified. Subjects at higher risk for hospitalisation for heart failure, irrespective of 
treatment assignment, could be identified by known risk factors for heart failure such as baseline 
history of heart failure or impaired renal function. However, subjects on saxagliptin with a history of 
heart failure or impaired renal function at baseline were not at an increased risk relative to placebo for 
the primary or secondary composite endpoints or all-cause mortality.

Another secondary endpoint, all-cause mortality, occurred at a rate of 5.1% in the saxagliptin group 
and 4.6% in the placebo group (see Table 7). CV deaths were balanced across the treatment groups. 
There was a numerical imbalance in non-CV death, with more events on saxagliptin (1.8%) than 
placebo (1.4%) [HR = 1.27; (95% CI 1.00, 1.62); P = 0.051].

A1c was lower with saxagliptin compared to placebo in an exploratory analysis.

Metformin
The prospective randomised (UKPDS) study has established the long-term benefit of intensive blood 
glucose control in type 2 diabetes. Analysis of the results for overweight patients treated with 
metformin after failure of diet alone showed:

- a significant reduction of the absolute risk of any diabetes-related complication in the metformin 
group (29.8 events/1,000 patient-years) versus diet alone (43.3 events/1,000 patient-years), 
p=0.0023, and versus the combined sulphonylurea and insulin monotherapy groups 
(40.1 events/1,000 patient-years), p=0.0034;

- a significant reduction of the absolute risk of any diabetes-related mortality: metformin 
7.5 events/1,000 patient-years, diet alone 12.7 events/1,000 patient-years, p=0.017;

- a significant reduction of the absolute risk of overall mortality: metformin 
13.5 events/1,000 patient-years versus diet alone 20.6 events/1,000 patient-years, (p=0.011), and 
versus the combined sulphonylurea and insulin monotherapy groups 
18.9 events/1,000 patient-years (p=0.021);

- a significant reduction in the absolute risk of myocardial infarction: metformin 
11 events/1,000 patient-years, diet alone 18 events/1,000 patient-years, (p=0.01).



18

Elderly population
In the SAVOR study subgroups over 65 and over 75 years of age, efficacy and safety were consistent 
with the overall study population.

GENERATION was a 52-week glycaemic control study in 720 elderly patients, the mean age was 
72.6 years; 433 subjects (60.1%) were < 75 years of age, and 287 subjects (39.9%) were ≥ 75 years of 
age. Primary endpoint was the proportion of patients reaching HbA1c < 7% without confirmed or 
severe hypoglycaemia. There appeared to be no difference in percentage responders: 37.9% 
(saxagliptin) and 38.2% (glimepiride) achieved the primary endpoint. A lower proportion of patients 
in the saxagliptin group (44.7%) compared to the glimepiride group (54.7%) achieved an HbA1c 
target of 7.0%. A lower proportion of patients in the saxagliptin group (1.1%) compared to the 
glimepiride group (15.3%), experienced a confirmed or severe hypoglycaemic event.

Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with 
Komboglyze in all subsets of the paediatric population in type 2 diabetes mellitus (see section 4.2 for 
information on paediatric use).

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 
Komboglyze.

Saxagliptin
The pharmacokinetics of saxagliptin and its major metabolite were similar in healthy subjects and in 
patients with type 2 diabetes. 

Absorption
Saxagliptin was rapidly absorbed after oral administration in the fasted state, with maximum plasma 
concentrations (Cmax) of saxagliptin and its major metabolite attained within 2 and 4 hours (Tmax), 
respectively. The Cmax and AUC values of saxagliptin and its major metabolite increased 
proportionally with the increment in the saxagliptin dose, and this dose-proportionality was observed 
in doses up to 400 mg. Following a 5 mg single oral dose of saxagliptin to healthy subjects, the mean 
plasma AUC values for saxagliptin and its major metabolite were 78 ng·h/mL and 214 ng·h/mL, 
respectively. The corresponding plasma Cmax values were 24 ng/mL and 47 ng/mL, respectively. The 
intra-subject coefficients of variation for saxagliptin Cmax and AUC were less than 12%. 

The inhibition of plasma DPP4 activity by saxagliptin for at least 24 hours after oral administration of 
saxagliptin is due to high potency, high affinity, and extended binding to the active site.

Interaction with food
Food had relatively modest effects on the pharmacokinetics of saxagliptin in healthy subjects. 
Administration with food (a high-fat meal) resulted in no change in saxagliptin Cmax and a 27% 
increase in AUC compared with the fasted state. The time for saxagliptin to reach Cmax (Tmax) was 
increased by approximately 0.5 hours with food compared with the fasted state. These changes were 
not considered to be clinically meaningful.

Distribution
The in vitro protein binding of saxagliptin and its major metabolite in human serum is negligible.
Thus, changes in blood protein levels in various disease states (e.g. renal or hepatic impairment) are 
not expected to alter the disposition of saxagliptin.



19

Biotransformation
The biotransformation of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5).
The major metabolite of saxagliptin is also a selective, reversible, competitive DPP4 inhibitor, half as 
potent as saxagliptin.

Elimination
The mean plasma terminal half-life (t1/2) values for saxagliptin and its major metabolite are 2.5 hours 
and 3.1 hours respectively, and the mean t1/2 value for plasma DPP4 inhibition was 26.9 hours. 
Saxagliptin is eliminated by both renal and hepatic pathways. Following a single 50 mg dose of 
14C-saxagliptin, 24%, 36%, and 75% of the dose was excreted in the urine as saxagliptin, its major 
metabolite, and total radioactivity respectively. The average renal clearance of saxagliptin 
(230 mL/min) was greater than the average estimated glomerular filtration rate (120 mL/min), 
suggesting some active renal excretion. For the major metabolite, renal clearance values were 
comparable to estimated glomerular filtration rate. A total of 22% of the administered radioactivity 
was recovered in faeces representing the fraction of the saxagliptin dose excreted in bile and/or 
unabsorbed medicinal product from the gastrointestinal tract.

Linearity
The Cmax and AUC of saxagliptin and its major metabolite increased proportionally to the saxagliptin 
dose. No appreciable accumulation of either saxagliptin or its major metabolite was observed with 
repeated once-daily dosing at any dose level. No dose- and time-dependence was observed in the 
clearance of saxagliptin and its major metabolite over 14 days of once-daily dosing with saxagliptin at 
doses ranging from 2.5 mg to 400 mg.

Special populations
Renal impairment
A single-dose, open-label study was conducted to evaluate the pharmacokinetics of a 10 mg oral dose 
of saxagliptin in subjects with varying degrees of chronic renal impairment compared to subjects with 
normal renal function. The study included patients with renal impairment classified on the basis of 
creatinine clearance as mild (approximately GFR ≥ 45 to < 90 mL/min), moderate (approximately 
GFR ≥ 30 to < 45 mL/min), or severe (approximately GFR < 30 mL/min) renal impairment. The 
exposures to saxagliptin were 1.2-, 1.4- and 2.1-fold higher, respectively, and the exposures to 
BMS-510849 were 1.7-, 2.9- and 4.5-fold higher, respectively, than those observed in subjects with 
normal renal function.

Hepatic impairment
In subjects with mild (Child-Pugh Class A), moderate (Child-Pugh Class B), or severe (Child-Pugh 
Class C) hepatic impairment the exposures to saxagliptin were 1.1-, 1.4- and 1.8-fold higher, 
respectively, and the exposures to BMS-510849 were 22%, 7%, and 33% lower, respectively, than 
those observed in healthy subjects.

Elderly (≥ 65 years)
Elderly patients (65-80 years) had about 60% higher saxagliptin AUC than young patients (18-40 
years). This is not considered clinically meaningful, therefore, no dose adjustment for this medicinal 
product is recommended on the basis of age alone.

Metformin
Absorption
After an oral dose of metformin, tmax is reached in 2.5 h. Absolute bioavailability of a 500 mg 
metformin tablet is approximately 50-60% in healthy subjects. After an oral dose, the non-absorbed 
fraction recovered in faeces was 20-30%.

After oral administration, metformin absorption is saturable and incomplete. It is assumed that the 
pharmacokinetics of metformin absorption is non-linear. At the usual metformin doses and dosing 
schedules, steady-state plasma concentrations are reached within 24-48 h and are generally less than 
1 μg/mL. In controlled clinical trials, maximum metformin plasma levels (Cmax) did not exceed 
4 μg/mL, even at maximum doses.



20

Interaction with food
Food decreases the extent and slightly delays the absorption of metformin. Following administration 
of a dose of 850 mg, a 40% lower plasma peak concentration, a 25% decrease in AUC and a 35 min 
prolongation of time to peak plasma concentration was observed. The clinical relevance of this 
decrease is unknown.

Distribution
Plasma protein binding is negligible. Metformin partitions into erythrocytes. The blood peak is lower 
than the plasma peak and appears at approximately the same time. The red blood cells most likely 
represent a secondary compartment of distribution. The mean Vd ranged between 63-276 L.

Biotransformation
Metformin is excreted unchanged in the urine. No metabolites have been identified in humans.

Elimination
Renal clearance of metformin is > 400 mL/min, indicating that metformin is eliminated by glomerular 
filtration and tubular secretion. Following an oral dose, the apparent terminal elimination half-life is 
approximately 6.5 h. When renal function is impaired, renal clearance is decreased in proportion to 
that of creatinine and thus the elimination half-life is prolonged, leading to increased levels of 
metformin in plasma.

5.3 Preclinical safety data

Co-administration of saxagliptin and metformin
A 3-month dog study and embryo-foetal development studies in rats and rabbits have been conducted 
with the combination of saxagliptin and metformin. 

Co-administration of saxagliptin and metformin, to pregnant rats and rabbits during the period of 
organogenesis, was neither embryolethal nor teratogenic in either species when tested at doses 
yielding systemic exposures (AUC) up to 100 and 10 times the maximum recommended human doses 
(RHD; 5 mg saxagliptin and 2000 mg metformin), respectively, in rats; and 249 and 1.1 times the 
RHDs in rabbits. In rats, minor developmental toxicity was limited to an increased incidence of 
delayed ossification (“wavy ribs”); associated maternal toxicity was limited to weight decrements of 
5-6% over the course of gestation days 13 through 18, and related reductions in maternal food 
consumption. In rabbits, co-administration was poorly tolerated in many mothers, resulting in death, 
moribundity or abortion. However, among surviving mothers with evaluable litters, maternal toxicity 
was limited to marginal reductions in body weight over the course of gestation days 21 to 29; and 
associated developmental toxicity in these litters was limited to foetal body weight decrements of 7%, 
and a low incidence of delayed ossification of the foetal hyoid.

A 3-month dog study was conducted with the combination of saxagliptin and metformin. No 
combination toxicity was observed at AUC exposures 68 and 1.5 times the RHDs for saxagliptin and 
metformin, respectively.

No animal studies have been conducted with the combination of products in Komboglyze to evaluate 
carcinogenesis, mutagenesis, or impairment of fertility. The following data are based on the findings 
in the studies with saxagliptin and metformin individually.

Saxagliptin
In cynomolgus monkeys saxagliptin produced reversible skin lesions (scabs, ulcerations and necrosis) 
in extremities (tail, digits, scrotum and/or nose) at doses ≥ 3 mg/kg/day. The no effect level (NOEL) 
for the lesions is 1 and 2 times the human exposure of saxagliptin and the major metabolite 
respectively, at the recommended human dose (RHD) of 5 mg/day. 

The clinical relevance of the skin lesions is not known, however, clinical correlates to skin lesions in 
monkeys have not been observed in human clinical trials of saxagliptin.



21

Immune related findings of minimal, nonprogressive, lymphoid hyperplasia in spleen, lymph nodes 
and bone marrow with no adverse sequelae have been reported in all species tested at exposures 
starting from 7 times the RHD.

Saxagliptin produced gastrointestinal toxicity in dogs, including bloody/mucoid faeces and 
enteropathy at higher doses with a NOEL 4 and 2 times the human exposure for saxagliptin and the 
major metabolite, respectively, at RHD.

Saxagliptin was not genotoxic in a conventional battery of genotoxicity studies in vitro and in vivo. No 
carcinogenic potential was observed in two-year carcinogenicity assays with mice and rats.

Effects on fertility were observed in male and female rats at high doses producing overt signs of 
toxicity. Saxagliptin was not teratogenic at any doses evaluated in rats or rabbits. At high doses in rats, 
saxagliptin caused reduced ossification (a developmental delay) of the foetal pelvis and decreased 
foetal body weight (in the presence of maternal toxicity), with a NOEL 303 and 30 times the human 
exposure for saxagliptin and the major metabolite, respectively, at RHD. In rabbits, the effects of 
saxagliptin were limited to minor skeletal variations observed only at maternally toxic doses (NOEL 
158 and 224 times the human exposure for saxagliptin and the major metabolite, respectively at RHD). 
In a pre- and post-natal developmental study in rats, saxagliptin caused decreased pup weight at 
maternally toxic doses, with NOEL 488 and 45 times the human exposure for saxagliptin and the
major metabolite, respectively at RHD. The effect on offspring body weights were noted until 
postnatal day 92 and 120 in females and males, respectively.

Metformin
Preclinical data for metformin reveal no special hazard for humans based on conventional studies of 
safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to 
reproduction.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core
Povidone K30
Magnesium stearate

Film coating
Komboglyze 2.5 mg/850 mg film-coated tablets
Polyvinyl alcohol
Macrogol 3350
Titanium dioxide (E171)
Talc (E553b)
Iron oxide red (E172)
Iron oxide yellow (E172)

Komboglyze 2.5 mg/1,000 mg film-coated tablets
Polyvinyl alcohol
Macrogol 3350
Titanium dioxide (E171)
Talc (E553b)
Iron oxide yellow (E172)

Printing ink
Shellac
Indigo carmine aluminium lake (E132)



22

6.2 Incompatibilities

Not applicable.

6.3 Shelf life 

3 years

6.4 Special precautions for storage 

Store below 25°C.

6.5 Nature and contents of container 

Alu/Alu blister.

Pack sizes of 14, 28, 56 and 60 film-coated tablets in non-perforated blisters.
Multipacks containing 112 (2 packs of 56) and 196 (7 packs of 28) film-coated tablets in 
non-perforated blisters.
60x1 film-coated tablets in perforated unit dose blisters.
Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements.

7. MARKETING AUTHORISATION HOLDER

AstraZeneca AB
SE-151 85 Södertälje
Sweden

8. MARKETING AUTHORISATION NUMBER(S)

Komboglyze 2.5 mg/850 mg film-coated tablets
EU/1/11/731/001
EU/1/11/731/002
EU/1/11/731/003
EU/1/11/731/004
EU/1/11/731/005
EU/1/11/731/006
EU/1/11/731/013

Komboglyze 2.5 mg/1,000 mg film-coated tablets
EU/1/11/731/007
EU/1/11/731/008
EU/1/11/731/009
EU/1/11/731/010
EU/1/11/731/011
EU/1/11/731/012
EU/1/11/731/014



23

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 24 November 2011
Date of latest renewal: 15 July 2016

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu.

http://www.ema.europa.eu/


24

ANNEX II

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH 
RELEASE

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 
AND USE

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 
THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT



25

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer(s) responsible for batch release

AstraZeneca GmbH
Tinsdaler Weg 183
22880 Wedel
Germany

AstraZeneca UK Limited
Silk Road Business Park
Macclesfield
Cheshire
SK10 2NA
United Kingdom

Bristol-Myers Squibb S.r.l.
Contrada Fontana del Ceraso
IT-03012 Anagni (FR)
Italy

The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch.

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

Medicinal product subject to medical prescription.

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION 

 Periodic Safety Update Reports

The requirements for submission of periodic safety update reports for this medicinal product are 
set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of 
Directive 2001/83/EC and any subsequent updates published on the European medicines 
web-portal.

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT

 Risk Management Plan (RMP)

The MAH shall perform the required pharmacovigilance activities and interventions detailed in 
the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed 
subsequent updates of the RMP.

An updated RMP should be submitted:
 At the request of the European Medicines Agency;
 Whenever the risk management system is modified, especially as the result of new 

information being received that may lead to a significant change to the benefit/risk profile 
or as the result of an important (pharmacovigilance or risk minimisation) milestone being 
reached.



26

ANNEX III

LABELLING AND PACKAGE LEAFLET



27

A. LABELLING



28

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

CARTON 

1. NAME OF THE MEDICINAL PRODUCT

Komboglyze 2.5 mg/850 mg film-coated tablets
saxagliptin/metformin hydrochloride

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each tablet contains 2.5 mg of saxagliptin (as hydrochloride) and 850 mg of metformin hydrochloride.

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

14 film-coated tablets
28 film-coated tablets
56 film-coated tablets
60 film-coated tablets
Multipack: 112 (2 packs of 56) film-coated tablets
Multipack: 196 (7 packs of 28) film-coated tablets
60x1 film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store below 25°C.



29

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

AstraZeneca AB
SE-151 85 Södertälje
Sweden

12. MARKETING AUTHORISATION NUMBER(S) 

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

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

Medicinal product subject to medical prescription.

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Komboglyze 2.5 mg/850 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

PC
SN
NN



30

PARTICULARS TO APPEAR ON THE INTERMEDIATE PACKAGING

CARTON 

1. NAME OF THE MEDICINAL PRODUCT

Komboglyze 2.5 mg/850 mg film-coated tablets
saxagliptin/metformin hydrochloride

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each tablet contains 2.5 mg of saxagliptin (as hydrochloride) and 850 mg of metformin hydrochloride.

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

56 film-coated tablets. Component of a multipack, can’t be sold separately.
28 film-coated tablets. Component of a multipack, can’t be sold separately.

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store below 25°C.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE



31

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

AstraZeneca AB
SE-151 85 Södertälje
Sweden

12. MARKETING AUTHORISATION NUMBER(S) 

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

Medicinal product subject to medical prescription.

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Komboglyze 2.5 mg/850 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA



32

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

BLISTERS (PERFORATED/NON-PERFORATED) 

1. NAME OF THE MEDICINAL PRODUCT

Komboglyze 2.5 mg/850 mg tablets
saxagliptin/metformin HCl

2. NAME OF THE MARKETING AUTHORISATION HOLDER

AstraZeneca AB

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER



33

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

CARTON 

1. NAME OF THE MEDICINAL PRODUCT

Komboglyze 2.5 mg/1,000 mg film-coated tablets
saxagliptin/metformin hydrochloride

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each tablet contains 2.5 mg of saxagliptin (as hydrochloride) and 1,000 mg of metformin 
hydrochloride.

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

14 film-coated tablets
28 film-coated tablets
56 film-coated tablets
60 film-coated tablets
Multipack: 112 (2 packs of 56) film-coated tablets
Multipack: 196 (7 packs of 28) film-coated tablets
60x1 film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store below 25°C.



34

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

AstraZeneca AB
SE-151 85 Södertälje
Sweden

12. MARKETING AUTHORISATION NUMBER(S) 

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

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

Medicinal product subject to medical prescription.

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Komboglyze 2.5 mg/1,000 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

PC
SN
NN



35

PARTICULARS TO APPEAR ON THE INTERMEDIATE PACKAGING

CARTON 

1. NAME OF THE MEDICINAL PRODUCT

Komboglyze 2.5 mg/1000 mg film-coated tablets
saxagliptin/metformin hydrochloride

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each tablet contains 2.5 mg of saxagliptin (as hydrochloride) and 1000 mg of metformin 
hydrochloride.

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

56 film-coated tablets. Component of a multipack, can’t be sold separately.
28 film-coated tablets. Component of a multipack, can’t be sold separately.

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store below 25°C.



36

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

AstraZeneca AB
SE-151 85 Södertälje
Sweden

12. MARKETING AUTHORISATION NUMBER(S) 

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

Medicinal product subject to medical prescription.

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Komboglyze 2.5 mg/1000 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA



37

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

BLISTERS (PERFORATED/NON-PERFORATED) 

1. NAME OF THE MEDICINAL PRODUCT

Komboglyze 2.5 mg/1,000 mg tablets
saxagliptin/metformin HCl

2. NAME OF THE MARKETING AUTHORISATION HOLDER

AstraZeneca AB

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER



38

B. PACKAGE LEAFLET



39

Package leaflet: Information for the patient

Komboglyze 2.5 mg/850 mg film-coated tablets
saxagliptin/metformin hydrochloride

Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor, pharmacist or nurse.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.
- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4.

What is in this leaflet: 

1. What Komboglyze is and what it is used for
2. What you need to know before you take Komboglyze
3. How to take Komboglyze
4. Possible side effects
5. How to store Komboglyze
6. Contents of the pack and other information

1. What Komboglyze is and what it is used for

This medicine contains two different substances called:

saxagliptin, part of a class of medicines called DPP-4 inhibitors (dipeptidyl peptidase-4 inhibitors), 
and metformin, part of a class of medicines called biguanides.

Both belong to a group of medicines called oral anti-diabetics. 

What Komboglyze is used for
This medicine is used to treat a type of diabetes called ‘type 2 diabetes’.

How Komboglyze works
Saxagliptin and metformin work together to control your blood sugar. They increase the levels of 
insulin after a meal. They also lower the amount of sugar made by your body. Along with diet and 
exercise, this helps lower your blood sugar. This medicine can be used alone or together with other
antidiabetic medicines, including insulin.

To control your diabetes, you still need to diet and exercise, even when you are taking this medicine. 
So it is important to keep following the advice about diet and exercise from your doctor or nurse.

2. What you need to know before you take Komboglyze

Do not take Komboglyze
- If you are allergic to saxagliptin, metformin or any of the other ingredients of this medicine 

(listed in section 6);
- If you have had a serious allergic (hypersensitive) reaction to any other similar medications that 

you take to control your blood sugar.
Symptoms of a serious allergic reaction may include:

- Rash
- Raised red patches on your skin (hives)



40

- Swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or 
swallowing.

If you have these symptoms, stop taking this medicine and call your doctor or nurse right 
away.

 If you have ever had a diabetic coma;
 If you have uncontrolled diabetes, with, for example, severe hyperglycaemia (high blood 

glucose), nausea, vomiting, diarrhoea, rapid weight loss, lactic acidosis (see “Risk of lactic 
acidosis” below) or ketoacidosis. Ketoacidosis is a condition in which substances called ‘ketone 
bodies’ accumulate in the blood and which can lead to a diabetic pre-coma. Symptoms include 
stomach pain, fast and deep breathing, sleepiness or your breath developing an unusual fruity 
smell;

 If you have severely reduced kidney function or problems with your liver;
 If you have recently had a heart attack or if you have heart failure or serious problems with your 

blood circulation or difficulties in breathing which could be a sign of heart problems;
 If you have a severe infection or are dehydrated (have lost a lot of water from your body);
 If you are breast-feeding (see also “Pregnancy and breast-feeding”);
 If you drink a large amount of alcohol (either every day or only from time to time) (please see 

section “Komboglyze with alcohol”);

Do not take this medicine if any of the above apply to you. If you are not sure, talk to your doctor or 
pharmacist before taking this medicine.

Warnings and precautions:
Risk of lactic acidosis
Komboglyze may cause a very rare, but very serious side effect called lactic acidosis, particularly if 
your kidneys are not working properly. The risk of developing lactic acidosis is also increased with 
uncontrolled diabetes, serious infections, prolonged fasting or alcohol intake, dehydration (see further 
information below), liver problems and any medical conditions in which a part of the body has a 
reduced supply of oxygen (such as acute severe heart disease).
If any of the above apply to you, talk to your doctor for further instructions.

Stop taking Komboglyze for a short time if you have a condition that may be associated with 
dehydration (significant loss of body fluids) such as severe vomiting, diarrhoea, fever, exposure to 
heat or if you drink less fluid than normal. Talk to your doctor for further instructions.

Stop taking Komboglyze and contact a doctor or the nearest hospital immediately if you 
experience some of the symptoms of lactic acidosis, as this condition may lead to coma. 
Symptoms of lactic acidosis include:

 vomiting
 stomach ache (abdominal pain)
 muscle cramps
 a general feeling of not being well with severe tiredness
 difficulty in breathing
 reduced body temperature and heartbeat

Lactic acidosis is a medical emergency and must be treated in a hospital.

Talk to your doctor or pharmacist before taking Komboglyze
 If you have type 1 diabetes (your body does not produce any insulin). This medicine should not 

be used to treat this condition;
 If you have or have had a disease of the pancreas;
 If you are taking insulin or an antidiabetic medicine known as ‘sulphonylurea’, your doctor may 

want to reduce your dose of insulin or the sulphonylurea when you take either of them together 
with this medicine, in order to avoid low blood sugar;

 If you have had allergic reactions to any other medicines that you take to control the amount of 
sugar in your blood;

 If you have a problem or take a medicine that can lower your body’s defence against infections; 



41

 If you have ever had heart failure or you have other risk factors for developing heart failure such 
as problems with your kidneys. Your doctor will advise you of the signs and symptoms of heart 
failure. You should call your doctor, pharmacist or nurse immediately if you experience any of 
these symptoms. Symptoms can include, but are not limited to, increasing shortness of breath, 
rapid increase in weight and swelling of the feet (pedal oedema);

If you need to have major surgery, you must stop taking Komboglyze during and for some time after 
the procedure. Your doctor will decide when you must stop and when to restart your treatment with 
Komboglyze.

Diabetic skin lesions are a common complication of diabetes. Rash has been seen with saxagliptin and 
with certain anti-diabetic medicines in the same class as saxagliptin. Follow the recommendations for 
skin and foot care that your doctor or nurse gave you. Contact your doctor if you encounter blistering 
of the skin, as it may be a sign for a condition called bullous pemphigoid. Your doctor may ask you to
stop Komboglyze.

If any of the above apply to you, or if you are not sure, talk to your doctor or pharmacist before taking 
this medicine.

Kidney tests or checks
During treatment with this medicine, your doctor will check your kidney function at least once a year 
or more frequently if you are elderly and/or if you have worsening kidney function.

Children and adolescents
Komboglyze is not recommended for use in children and adolescents under 18 years. It is not known if 
this medicine is safe and effective when used in children and adolescents under 18 years of age.

Other medicines and Komboglyze
If you need to have an injection of contrast medium that contains iodine into your bloodstream, for 
example in the context of an X-ray or scan, you must stop taking Komboglyze before or at the time of 
the injection. Your doctor will decide when you can restart your treatment with Komboglyze.

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. You may need more frequent blood glucose and kidney function tests, or your doctor may 
adjust the dosage of Komboglyze. It is especially important to mention the following:
 cimetidine, a medicine used to treat stomach problems
 ketoconazole which is used to treat fungal infections
 bronchodilators (beta-2 agonists) which are used to treat asthma
 diltiazem which is used for high blood pressure 
 rifampicin, an antibiotic used to treat infections such as tuberculosis 
 corticosteroids, which are used to treat inflammation in diseases like asthma and arthritis
 carbamazepine, phenobarbital or phenytoin, which are used to control fits (seizures) or 

long-term pain
 medicines which increase urine production (diuretics)
 medicines used to treat pain and inflammation (NSAID and COX-2-inhibitors, such as ibuprofen 

and celecoxib)
 certain medicines for the treatment of high blood pressure (ACE inhibitors and angiotensin II 

receptor antagonists).

If any of the above apply to you, or if you are not sure, talk to your doctor or pharmacist before taking 
this medicine.

Komboglyze with alcohol
Avoid excessive alcohol intake while taking Komboglyze since this may increase the risk of lactic 
acidosis (see “Warnings and precautions”).



42

Pregnancy and breast-feeding
Do not take this medicine if you are pregnant or might become pregnant. This is because it may affect 
the baby.

Do not take this medicine if you are breast-feeding or plan to breast-feed. This is because metformin 
passes into human milk in small amounts.

Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines
Saxagliptin and metformin have a negligible influence on the ability to drive and use machines.
Hypoglycaemia may affect your ability to drive and use machines or work with safe foothold and there 
is a risk of hypoglycaemia when taking this medicine in combination with medicines known to cause 
hypoglycaemia such as insulin and sulphonylureas.

3. How to take Komboglyze

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure. 

If your doctor prescribes this medicine together with a sulphonylurea or insulin, remember to take this 
other medicine as directed by your doctor to achieve the best results for your health.

How much to take
 The amount of this medicine that you will take varies depending on your condition and the doses 

you currently take of metformin and/or individual tablets of saxagliptin and metformin. Your 
doctor will tell you exactly the dose of this medicine to take.

 The recommended dosing is one tablet twice a day. 
If you have reduced kidney function, your doctor may prescribe a lower dose.

How to take this medicine
 Take this medicine by mouth.
 Take with a meal to lower your chance of getting an upset stomach.

Diet and exercise
To control your diabetes, you still need to diet and exercise, even when you are taking this medicine. 
So it is important to keep following the advice about diet and exercise from your doctor or nurse. In 
particular, if you are following a diabetic weight control diet, keep on with this while you are taking 
this medicine. 

If you take more Komboglyze than you should
If you take more Komboglyze tablets than you should, talk to a doctor or go to a hospital straight 
away. Take the medicine pack with you.

If you forget to take Komboglyze
 If you forget to take a dose of this medicine, take it as soon as you remember. However, if it is 

time for your next dose, skip the missed dose and take your next dose at the usual time. 
 Do not take a double dose of this medicine to make up for a forgotten dose. 

If you stop taking Komboglyze
Keep taking this medicine until your doctor tells you to stop. This is to help keep your blood sugar 
under control.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.



43

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Stop taking Komboglyze and contact a doctor immediately if you notice any of the following 
serious side effects:
 Lactic acidosis, Komboglyze may cause a very rare (may affect up to 1 user in 10,000), but very 

serious side effect called lactic acidosis (see section “Warnings and precautions”). If this happens 
you must stop taking Komboglyze and contact a doctor or the nearest hospital immediately, 
as lactic acidosis may lead to coma.

 Severe and persistent pain in the abdomen (stomach area) which might reach through to your 
back, as well as nausea and vomiting, as it could be a sign of an inflamed pancreas (pancreatitis).

You should call your doctor if you experience the following side effects:
 severe joint pain.

Other side effects of Komboglyze include:
Common (may affect up to 1 in 10 people)
 headache 
 muscle pain (myalgia)
 being sick or indigestion (dyspepsia)
 infection of the structures that carry urine (urinary tract infection)
 infection of the upper airways
 inflamed nose or throat such as with a cold or sore throat
 inflamed stomach (gastritis) or gut, sometimes caused by an infection (gastroenteritis)
 infection of your sinuses, sometimes with a feeling of pain and fullness behind your cheeks and 

eyes (sinusitis)
 flatulence
 dizziness
 tiredness (fatigue).

Uncommon (may affect up to 1 in 100 people)
 joint pain (arthralgia)
 difficulties in getting or maintaining an erection (erectile dysfunction).

Side effects seen when taking saxagliptin alone: 
Common
 dizziness
 tiredness (fatigue).

Side effects seen when taking saxagliptin alone or in combination: 
Not known (frequency cannot be estimated from the available data): 
 constipation 
 blistering of the skin (bullous pemphigoid)

Some patients have had a small reduction in the number of one type of white blood cells 
(lymphocytes) shown in a blood test when saxagliptin was used alone or in combination. In addition,
some patients have reported rash and skin reactions (hypersensitivity) while taking saxagliptin.

During post-approval use of saxagliptin, additional side effects have been reported that include serious 
allergic reactions (anaphylaxis), and swelling of the face, lips, tongue, and throat that may cause 
difficulty in breathing or swallowing. If you have an allergic reaction, stop taking this medicine and 
call your doctor right away. Your doctor may prescribe a medicine to treat your allergic reaction and a 
different medicine for your diabetes.



44

Side effects seen when taking metformin alone:
Very common (may affect more than 1 in 10 people)
 nausea, vomiting
 diarrhoea or stomach pain
 loss of appetite.

Common
 a metallic taste in your mouth.

Very rare
 decreased vitamin B12 levels
 liver problems (hepatitis)
 redness of the skin (rash) or itching.

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 via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine.

5. How to store Komboglyze

Keep this medicine out of the sight and reach of children. 

Do not use this medicine after the expiry date which is stated on the blister and the carton after EXP. 
The expiry date refers to the last day of that month. 

Store below 25°C.

Do not use this medicine if the package is damaged or shows signs of tampering. 

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help to protect the environment. 

6. Contents of the pack and other information

What Komboglyze contains
The active substances are saxagliptin and metformin hydrochloride. Each film-coated tablet contains 
2.5 mg saxagliptin (as hydrochloride) and 850 mg metformin hydrochloride.

The other ingredients (excipients) are:
 Tablet core: povidone K30, magnesium stearate.
 Film-coating: polyvinyl alcohol, macrogol 3350, titanium dioxide (E171), talc (E553b), iron 

oxide red (E172), iron oxide yellow (E172).
 Printing ink: shellac, indigo carmine aluminium lake (E132).

What Komboglyze looks like and contents of the pack
 Komboglyze 2.5 mg/850 mg film-coated tablets (‘tablets’) are light brown to brown and round, 

with “2.5/850” printed on one side and “4246” printed on the other side, in blue ink.
 Komboglyze is available in aluminium foil blister. The pack sizes are 14, 28, 56 and 60 

film-coated tablets in non-perforated blisters, multipacks containing 112 (2 packs of 56) and 
196 (7 packs of 28) film-coated tablets in non-perforated blisters and 60 x1 film-coated tablets 
in perforated unit dose blisters.

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


45

Not all pack sizes may be marketed in your country.

Marketing Authorisation Holder

AstraZeneca AB
SE-151 85 Södertälje
Sweden

Manufacturer

AstraZeneca GmbH
Tinsdaler Weg 183
22880 Wedel
Germany

AstraZeneca UK Limited
Silk Road Business Park
Macclesfield
Cheshire
SK10 2NA
United Kingdom

Bristol-Myers Squibb Company
Contrada Fontana del Ceraso 
IT-03012 Anagni (FR)
Italy

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

België/Belgique/Belgien
AstraZeneca S.A./N.V.
Tel: +32 2 370 48 11

Lietuva
UAB AstraZeneca Lietuva
Tel: +370 5 2660550

България
АстраЗенека България ЕООД
Тел.: +359 (2) 44 55 000

Luxembourg/Luxemburg
AstraZeneca S.A./N.V.
Tél/Tel: +32 2 370 48 11

Česká republika
AstraZeneca Czech Republic s.r.o.
Tel: +420 222 807 111

Magyarország
AstraZeneca Kft.
Tel.: +36 1 883 6500

Danmark
AstraZeneca A/S
Tlf: +45 43 66 64 62

Malta
Associated Drug Co. Ltd
Tel: +356 2277 8000

Deutschland
AstraZeneca GmbH
Tel: +49 41 03 7080

Nederland
AstraZeneca BV
Tel: +31 79 363 2222

Eesti
AstraZeneca 
Tel: +372 6549 600

Norge
AstraZeneca AS
Tlf: +47 21 00 64 00



46

Ελλάδα
AstraZeneca A.E.
Τηλ: +30 2 106871500

Österreich
AstraZeneca Österreich GmbH
Tel: +43 1 711 31 0

España
AstraZeneca Farmacéutica Spain, S.A.
Tel: +34 91 301 91 00

Polska
AstraZeneca Pharma Poland Sp. z o.o.
Tel.: +48 22 245 73 00

France
AstraZeneca
Tél: +33 1 41 29 40 00

Portugal
AstraZeneca Produtos Farmacêuticos, Lda.
Tel: +351 21 434 61 00

Hrvatska 
AstraZeneca d.o.o.
Tel: +385 1 4628 000

România
AstraZeneca Pharma SRL
Tel: +40 21 317 60 41

Ireland
AstraZeneca Pharmaceuticals (Ireland) DAC
Tel: +353 1609 7100

Slovenija
AstraZeneca UK Limited
Tel: +386 1 51 35 600

Ísland
Vistor hf.
Sími: +354 535 7000

Slovenská republika
AstraZeneca AB, o.z.
Tel: +421 2 5737 7777

Italia
AstraZeneca S.p.A.
Tel: +39 02 9801 1

Suomi/Finland
AstraZeneca Oy
Puh/Tel: +358 10 23 010

Κύπρος
Αλέκτωρ Φαρµακευτική Λτδ
Τηλ: +357 22490305

Sverige
AstraZeneca AB
Tel: +46 8 553 26 000

Latvija
SIA AstraZeneca Latvija
Tel: +371 67377100

United Kingdom
AstraZeneca UK Ltd
Tel: +44 1582 836 836

This leaflet was last revised in

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.

http://www.ema.europa.eu/


47

Package leaflet: Information for the patient

Komboglyze 2.5 mg/1,000 mg film-coated tablets
saxagliptin/metformin hydrochloride

Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor, pharmacist or nurse.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.
- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4.

What is in this leaflet: 

1. What Komboglyze is and what it is used for
2. What you need to know before you take Komboglyze
3. How to take Komboglyze
4. Possible side effects
5. How to store Komboglyze
6. Contents of the pack and other information

1. What Komboglyze is and what it is used for

This medicine contains two different substances called:

saxagliptin, part of a class of medicines called DPP-4 inhibitors (dipeptidyl peptidase-4 inhibitors), 
and metformin, part of a class of medicines called biguanides.

Both belong to a group of medicines called oral anti-diabetics. 

What Komboglyze is used for
This medicine is used to treat a type of diabetes called ‘type 2 diabetes’.

How Komboglyze works
Saxagliptin and metformin work together to control your blood sugar. They increase the levels of 
insulin after a meal. They also lower the amount of sugar made by your body. Along with diet and 
exercise, this helps lower your blood sugar. This medicine can be used alone or together with other
antidiabetic medicines, including insulin.

To control your diabetes, you still need to diet and exercise, even when you are taking this medicine. 
So it is important to keep following the advice about diet and exercise from your doctor or nurse.

2. What you need to know before you take Komboglyze

Do not take Komboglyze
- If you are allergic to saxagliptin, metformin or any of the other ingredients of this medicine 

(listed in section 6);
- If you have had a serious allergic (hypersensitive) reaction to any other similar medications that 

you take to control your blood sugar.
Symptoms of a serious allergic reaction may include:

- Rash
- Raised red patches on your skin (hives)



48

- Swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or 
swallowing.

If you have these symptoms, stop taking this medicine and call your doctor or nurse right 
away.

 If you have ever had a diabetic coma;
 If you have uncontrolled diabetes, with, for example, severe hyperglycaemia (high blood 

glucose), nausea, vomiting, diarrhoea, rapid weight loss, lactic acidosis (see “Risk of lactic 
acidosis” below) or ketoacidosis. Ketoacidosis is a condition in which substances called ‘ketone 
bodies’ accumulate in the blood and which can lead to a diabetic pre-coma. Symptoms include 
stomach pain, fast and deep breathing, sleepiness or your breath developing an unusual fruity 
smell;

 If you have severely reduced kidney function or problems with your liver;
 If you have recently had a heart attack or if you have heart failure or serious problems with your 

blood circulation or difficulties in breathing which could be a sign of heart problems;
 If you have a severe infection or are dehydrated (have lost a lot of water from your body);
 If you are breast-feeding (see also “Pregnancy and breast-feeding”);
 If you drink a large amount of alcohol (either every day or only from time to time) (please see 

section “Komboglyze with alcohol”);

Do not take this medicine if any of the above apply to you. If you are not sure, talk to your doctor or 
pharmacist before taking this medicine.

Warnings and precautions:
Risk of lactic acidosis
Komboglyze may cause a very rare, but very serious side effect called lactic acidosis, particularly if 
your kidneys are not working properly. The risk of developing lactic acidosis is also increased with 
uncontrolled diabetes, serious infections, prolonged fasting or alcohol intake, dehydration (see further 
information below), liver problems and any medical conditions in which a part of the body has a 
reduced supply of oxygen (such as acute severe heart disease).
If any of the above apply to you, talk to your doctor for further instructions.

Stop taking Komboglyze for a short time if you have a condition that may be associated with 
dehydration (significant loss of body fluids) such as severe vomiting, diarrhoea, fever, exposure to 
heat or if you drink less fluid than normal. Talk to your doctor for further instructions.

Stop taking Komboglyze and contact a doctor or the nearest hospital immediately if you 
experience some of the symptoms of lactic acidosis, as this condition may lead to coma. 
Symptoms of lactic acidosis include:

 vomiting
 stomach ache (abdominal pain)
 muscle cramps
 a general feeling of not being well with severe tiredness
 difficulty in breathing
 reduced body temperature and heartbeat

Lactic acidosis is a medical emergency and must be treated in a hospital.

Talk to your doctor or pharmacist before taking Komboglyze
 If you have type 1 diabetes (your body does not produce any insulin). This medicine should not 

be used to treat this condition;
 If you have or have had a disease of the pancreas;
 If you are taking insulin or an antidiabetic medicine known as ‘sulphonylurea’, your doctor may 

want to reduce your dose of insulin or the sulphonylurea when you take either of them together 
with this medicine, in order to avoid low blood sugar;

 If you have had allergic reactions to any other medicines that you take to control the amount of 
sugar in your blood;

 If you have a problem or take a medicine that can lower your body’s defence against infections; 



49

 If you have ever had heart failure or you have other risk factors for developing heart failure such 
as problems with your kidneys. Your doctor will advise you of the signs and symptoms of heart 
failure. You should call your doctor, pharmacist or nurse immediately if you experience any of 
these symptoms. Symptoms can include, but are not limited to, increasing shortness of breath, 
rapid increase in weight and swelling of the feet (pedal oedema);

If you need to have major surgery, you must stop taking Komboglyze during and for some time after 
the procedure. Your doctor will decide when you must stop and when to restart your treatment with 
Komboglyze.

Diabetic skin lesions are a common complication of diabetes. Rash has been seen with saxagliptin and 
with certain anti-diabetic medicines in the same class as saxagliptin. Follow the recommendations for 
skin and foot care that your doctor or nurse gave you. Contact your doctor if you encounter blistering 
of the skin, as it may be a sign for a condition called bullous pemphigoid. Your doctor may ask you to 
stop Komboglyze.

If any of the above apply to you, or if you are not sure, talk to your doctor or pharmacist before taking 
this medicine.

Kidney tests or checks
During treatment with this medicine, your doctor will check your kidney function at least once a year 
or more frequently if you are elderly and/or if you have worsening kidney function.

Children and adolescents
Komboglyze is not recommended for use in children and adolescents under 18 years. It is not known if 
this medicine is safe and effective when used in children and adolescents under 18 years of age.

Other medicines and Komboglyze
If you need to have an injection of contrast medium that contains iodine into your bloodstream, for 
example in the context of an X-ray or scan, you must stop taking Komboglyze before or at the time of 
the injection. Your doctor will decide when you can restart your treatment with Komboglyze.

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. You may need more frequent blood glucose and kidney function tests, or your doctor may 
adjust the dosage of Komboglyze. It is especially important to mention the following:
 cimetidine, a medicine used to treat stomach problems
 ketoconazole which is used to treat fungal infections
 bronchodilators (beta-2 agonists) which are used to treat asthma
 diltiazem which is used for high blood pressure 
 rifampicin, an antibiotic used to treat infections such as tuberculosis 
 corticosteroids, which are used to treat inflammation in diseases like asthma and arthritis
 carbamazepine, phenobarbital or phenytoin, which are used to control fits (seizures) or 

long-term pain
 medicines which increase urine production (diuretics)
 medicines used to treat pain and inflammation (NSAID and COX-2-inhibitors, such as ibuprofen 

and celecoxib)
 certain medicines for the treatment of high blood pressure (ACE inhibitors and angiotensin II 

receptor antagonists).

If any of the above apply to you, or if you are not sure, talk to your doctor or pharmacist before taking 
this medicine.

Komboglyze with alcohol
Avoid excessive alcohol intake while taking Komboglyze since this may increase the risk of lactic 
acidosis (see “Warnings and precautions”).



50

Pregnancy and breast-feeding
Do not take this medicine if you are pregnant or might become pregnant. This is because it may affect 
the baby.

Do not take this medicine if you are breast-feeding or plan to breast-feed. This is because metformin 
passes into human milk in small amounts.

Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines
Saxagliptin and metformin have a negligible influence on the ability to drive and use machines. 
Hypoglycaemia may affect your ability to drive and use machines or work with safe foothold and there 
is a risk of hypoglycaemia when taking this medicine in combination with medicines known to cause 
hypoglycaemia such as insulin and sulphonylureas.

3. How to take Komboglyze

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure. 

If your doctor prescribes this medicine together with a sulphonylurea or insulin, remember to take this 
other medicine as directed by your doctor to achieve the best results for your health.

How much to take
 The amount of this medicine that you will take varies depending on your condition and the doses 

you currently take of metformin and/or individual tablets of saxagliptin and metformin. Your 
doctor will tell you exactly the dose of this medicine to take.

 The recommended dosing is one tablet twice a day. 
If you have reduced kidney function, your doctor may prescribe a lower dose.

How to take this medicine
 Take this medicine by mouth.
 Take with a meal to lower your chance of getting an upset stomach.

Diet and exercise
To control your diabetes, you still need to diet and exercise, even when you are taking this medicine. 
So it is important to keep following the advice about diet and exercise from your doctor or nurse. In 
particular, if you are following a diabetic weight control diet, keep on with this while you are taking 
this medicine. 

If you take more Komboglyze than you should
If you take more Komboglyze tablets than you should, talk to a doctor or go to a hospital straight 
away. Take the medicine pack with you.

If you forget to take Komboglyze
 If you forget to take a dose of this medicine, take it as soon as you remember. However, if it is 

time for your next dose, skip the missed dose and take your next dose at the usual time. 
 Do not take a double dose of this medicine to make up for a forgotten dose. 

If you stop taking Komboglyze
Keep taking this medicine until your doctor tells you to stop. This is to help keep your blood sugar 
under control.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.



51

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Stop taking Komboglyze and contact a doctor immediately if you notice any of the following 
serious side effects:
 Lactic acidosis, Komboglyze may cause a very rare (may affect up to 1 user in 10,000), but very 

serious side effect called lactic acidosis (see section “Warnings and precautions”). If this happens 
you must stop taking Komboglyze and contact a doctor or the nearest hospital immediately, 
as lactic acidosis may lead to coma.

 Severe and persistent pain in the abdomen (stomach area) which might reach through to your 
back, as well as nausea and vomiting, as it could be a sign of an inflamed pancreas (pancreatitis).

You should call your doctor if you experience the following side effect:
 severe joint pain.

Other side effects of Komboglyze include:
Common (may affect up to 1 in 10 people)
 headache 
 muscle pain (myalgia)
 being sick or indigestion (dyspepsia)
 infection of the structures that carry urine (urinary tract infection)
 infection of the upper airways
 inflamed nose or throat such as with a cold or sore throat
 inflamed stomach (gastritis) or gut, sometimes caused by an infection (gastroenteritis)
 infection of your sinuses, sometimes with a feeling of pain and fullness behind your cheeks and 

eyes (sinusitis)
 flatulence
 dizziness
 tiredness (fatigue).

Uncommon (may affect up to 1 in 100 people)
 joint pain (arthralgia)
 difficulties in getting or maintaining an erection (erectile dysfunction).

Side effects seen when taking saxagliptin alone:
Common
 dizziness
 tiredness (fatigue).

Side effects seen when taking saxagliptin alone or in combination: 
Not known (frequency cannot be estimated from the available data): 
 constipation 
 blistering of the skin (bullous pemphigoid)

Some patients have had a small reduction in the number of one type of white blood cells 
(lymphocytes) shown in a blood test when saxagliptin was used alone or in combination. In addition, 
some patients have reported rash and skin reactions (hypersensitivity) while taking saxagliptin.

During post-approval use of saxagliptin, additional side effects have been reported that include serious 
allergic reactions (anaphylaxis), and swelling of the face, lips, tongue, and throat that may cause 
difficulty in breathing or swallowing. If you have an allergic reaction, stop taking this medicine and 
call your doctor right away. Your doctor may prescribe a medicine to treat your allergic reaction and a 
different medicine for your diabetes.



52

Side effects seen when taking metformin alone:
Very common (may affect more than 1 in 10 people)
 nausea, vomiting
 diarrhoea or stomach pain
 loss of appetite.

Common
 a metallic taste in your mouth.

Very rare
 decreased vitamin B12 levels
 liver problems (hepatitis)
 redness of the skin (rash) or itching.

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 via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine.

5. How to store Komboglyze

Keep this medicine out of the sight and reach of children. 

Do not use this medicine after the expiry date which is stated on the blister and the carton after EXP. 
The expiry date refers to the last day of that month. 

Store below 25°C.

Do not use this medicine if the package is damaged or shows signs of tampering. 

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help to protect the environment. 

6. Contents of the pack and other information

What Komboglyze contains
The active substances are saxagliptin and metformin hydrochloride. Each film-coated tablet contains 
2.5 mg saxagliptin (as hydrochloride) and 1,000 mg metformin hydrochloride.

The other ingredients (excipients) are:
 Tablet core: povidone K30, magnesium stearate.
 Film-coating: polyvinyl alcohol, macrogol 3350, titanium dioxide (E171), talc (E553b), iron 

oxide yellow (E172).
 Printing ink: shellac, indigo carmine aluminium lake (E132).

What Komboglyze looks like and contents of the pack
 Komboglyze 2.5 mg/1,000 mg film-coated tablets (‘tablets’) are pale yellow to light yellow and 

oval, with “2.5/1000” printed on one side and “4247” printed on the other side, in blue ink.
 Komboglyze is available in aluminium foil blister. The pack sizes are 14, 28, 56 and 60 

film-coated tablets in non-perforated blisters, multipacks containing 112 (2 packs of 56) and 
196 (7 packs of 28) film-coated tablets in non-perforated blisters and 60 x1 film-coated tablets 
in perforated unit dose blisters.

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


53

Not all pack sizes may be marketed in your country.

Marketing Authorisation Holder

AstraZeneca AB
SE-151 85 Södertälje
Sweden

Manufacturer

AstraZeneca GmbH
Tinsdaler Weg 183
22880 Wedel
Germany

AstraZeneca UK Limited
Silk Road Business Park
Macclesfield
Cheshire
SK10 2NA
United Kingdom

Bristol-Myers Squibb Company
Contrada Fontana del Ceraso 
IT-03012 Anagni (FR)
Italy

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

België/Belgique/Belgien
AstraZeneca S.A./N.V.
Tel: +32 2 370 48 11

Lietuva
UAB AstraZeneca Lietuva
Tel: +370 5 2660550

България
АстраЗенека България ЕООД
Тел.: +359 (2) 44 55 000

Luxembourg/Luxemburg
AstraZeneca S.A./N.V.
Tél/Tel: +32 2 370 48 11

Česká republika
AstraZeneca Czech Republic s.r.o.
Tel: +420 222 807 111

Magyarország
AstraZeneca Kft.
Tel.: +36 1 883 6500

Danmark
AstraZeneca A/S
Tlf: +45 43 66 64 62

Malta
Associated Drug Co. Ltd
Tel: +356 2277 8000

Deutschland
AstraZeneca GmbH
Tel: +49 41 03 7080

Nederland
AstraZeneca BV
Tel: +31 79 363 2222

Eesti
AstraZeneca 
Tel: +372 6549 600

Norge
AstraZeneca AS
Tlf: +47 21 00 64 00



54

Ελλάδα
AstraZeneca A.E.
Τηλ: +30 2 106871500

Österreich
AstraZeneca Österreich GmbH
Tel: +43 1 711 31 0

España
AstraZeneca Farmacéutica Spain, S.A.
Tel: +34 91 301 91 00

Polska
AstraZeneca Pharma Poland Sp. z o.o.
Tel.: +48 22 245 73 00

France
AstraZeneca
Tél: +33 1 41 29 40 00

Portugal
AstraZeneca Produtos Farmacêuticos, Lda.
Tel: +351 21 434 61 00

Hrvatska 
AstraZeneca d.o.o.
Tel: +385 1 4628 000

România
AstraZeneca Pharma SRL
Tel: +40 21 317 60 41

Ireland
AstraZeneca Pharmaceuticals (Ireland) DAC
Tel: +353 1609 7100

Slovenija
AstraZeneca UK Limited
Tel: +386 1 51 35 600

Ísland
Vistor hf.
Sími: +354 535 7000

Slovenská republika
AstraZeneca AB, o.z.
Tel: +421 2 5737 7777

Italia
AstraZeneca S.p.A.
Tel: +39 02 9801 1

Suomi/Finland
AstraZeneca Oy
Puh/Tel: +358 10 23 010

Κύπρος
Αλέκτωρ Φαρµακευτική Λτδ
Τηλ: +357 22490305

Sverige
AstraZeneca AB
Tel: +46 8 553 26 000

Latvija
SIA AstraZeneca Latvija
Tel: +371 67377100

United Kingdom
AstraZeneca UK Ltd
Tel: +44 1582 836 836

This leaflet was last revised in

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.

http://www.ema.europa.eu/

	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING  AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET