KOMBOGLYZE 2.5mg / 1000mg tablets medication leaflet

Komboglyze 2.5 mg/850 mg film-coated tablets

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

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 metforminhydrochloride.

For the full list of excipients, see section 6.1.

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 oneside and “4247” printed on the other side, in blue ink.

Komboglyze is indicated in adults with type 2 diabetes mellitus as an adjunct to diet and exercise toimprove 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, inpatients 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 separatetablets.

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 productequivalent to the total daily dose of saxagliptin 5 mg, dosed as 2.5 mg twice daily, plus the dose ofmetformin already being taken.

For patients switching from separate tablets of saxagliptin and metformin

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

For patients inadequately controlled on dual combination therapy of insulin and metformin, or forpatients controlled on triple combination therapy of insulin, and metformin plus saxagliptin asseparate tablets

The dose of this medicinal product should provide saxagliptin 2.5 mg twice daily (5 mg total dailydose) and a dose of metformin similar to the dose already being taken. When this medicinal product isused in combination with insulin, a lower dose of insulin may be required to reduce the risk ofhypoglycaemia (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 asulphonylurea taken as separate tablets

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

For patients inadequately controlled on dual combination therapy of dapagliflozin and metformin, orfor patients switching from triple combination therapy of saxagliptin, metformin and dapagliflozintaken as separate tablets

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

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 atleast annually thereafter. In patients at increased risk of further progression of renal impairment and inthe elderly, renal function should be assessed more frequently, e.g. every 3-6 months. The maximumdaily dose of metformin should preferably be divided into 2-3 daily doses. Factors that may increasethe 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 usedinstead of the fixed dose combination.

Table 1 Dosage in patients with renal impairment

GFR mL/min Metformin Saxagliptin

Maximum daily dose is 3000 mg. Maximum total daily dose is 5 mg.60-89

Dose reduction may be considered inrelation to declining renal function.

Maximum daily dose is 2000 mg.45-59 Maximum total daily dose is 5 mg.

The starting dose is at most half of themaximum dose.

Maximum daily dose is 1000 mg.30-44 Maximum total daily dose is 2.5 mg.

The starting dose is at most half of themaximum dose.

Maximum total daily dose is 2.5 mg.

< 30 Metformin is contraindicated.

This medicinal product must not be used in patients with hepatic impairment (see sections 4.3 and4.5).

As metformin and saxagliptin are excreted by the kidney, this medicinal product should be used withcaution in the elderly. Monitoring of renal function is necessary to prevent metformin-associated lacticacidosis, particularly in the elderly (see sections pct. 4.3, pct. 4.4 and 5.2).

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

Komboglyze should be given twice daily with meals to reduce the gastrointestinal adverse reactionsassociated with metformin.

- Hypersensitivity to the active substances or to any of the excipients listed in section 6.1, orhistory of a serious hypersensitivity reaction, including anaphylactic reaction, anaphylacticshock, and angioedema, to any dipeptidyl peptidase 4 (DPP4) inhibitor (see sections 4.4 and4.8);

- 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, pct. 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).

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

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

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

Lactic acidosis

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

In case of dehydration (severe diarrhoea or vomiting, fever, heat, reduced fluid intake), Komboglyzeshould 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 lacticacidosis are excessive alcohol intake, hepatic insufficiency, inadequately controlled diabetes, ketosis,prolonged fasting and any conditions associated with hypoxia, as well as concomitant use of medicinalproducts 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 ischaracterised by acidotic dyspnoea, abdominal pain, muscle cramps, asthenia and hypothermiafollowed by coma. In case of suspected symptoms, the patient should stop taking Komboglyze andseek 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.

As metformin is excreted by the kidney, renal function should be assessed:

- Before initiation of treatment and regularly thereafter (see sections 4.2, pct. 4.8, 5.1 and 5.2).

- For renal function with GFR levels approaching moderate renal impairment and in elderlypatients, at least 2 to 4 times per year.

- In patients with moderate renal impairment that have GFR ≥ 30 to < 45 mL/min, in the absenceof other conditions that may increase the risk of lactic acidosis, the dose is 2.5 mg/1000 mg or2.5 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 temporarilydiscontinued 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 beexercised in situations where renal function may become impaired, for example when initiatingantihypertensive or diuretic therapy or when starting treatment with a NSAID.

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 nutritionprovided 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 bediscontinued prior to, or at the time of, the imaging procedure and not restarted until at least 48 hoursafter, provided that renal function has been re-evaluated and found to be stable (see sections 4.2 and4.5).

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

Bullous pemphigoid

Postmarketing cases of bullous pemphigoid requiring hospitalisation have been reported with DPP4inhibitor use, including saxagliptin. In reported cases, patients typically responded to topical orsystemic immunosuppressive treatment and discontinuation of the DPP4 inhibitor. If a patientdevelops blisters or erosions while receiving saxagliptin and bullous pemphigoid is suspected, thismedicinal product should be discontinued and referral to a dermatologist should be considered fordiagnosis and appropriate treatment (see section 4.8).

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

During postmarketing experience, including spontaneous reports and clinical trials, the followingadverse reactions have been reported with the use of saxagliptin: serious hypersensitivity reactions,including anaphylactic reaction, anaphylactic shock, and angioedema. If a serious hypersensitivityreaction to saxagliptin is suspected, discontinue this medicinal product, assess for other potentialcauses 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 wellcontrolled on Komboglyze who develops laboratory abnormalities or clinical illness (especially vagueand poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lacticacidosis. 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 medicinalproduct 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 thesaxagliptin treated patients compared to placebo, although a causal relationship has not beenestablished (see section 5.1). Caution is warranted if this medicinal product is used in patients whohave known risk factors for hospitalisation for heart failure, such as a history of heart failure ormoderate to severe renal impairment. Patients should be advised of the characteristic symptoms ofheart failure, and to immediately report such symptoms.

Arthralgia

Joint pain, which may be severe, has been reported in postmarketing reports for DPP4 inhibitors (seesection 4.8). Patients experienced relief of symptoms after discontinuation of the medicinal productand some experienced recurrence of symptoms with reintroduction of the same or another DPP4inhibitor. Onset of symptoms following initiation of drug therapy may be rapid or may occur afterlonger periods of treatment. If a patient presents with severe joint pain, continuation of drug therapyshould be individually assessed.

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

Use with potent CYP3A4 inducers

Using CYP3A4 inducers like carbamazepine, dexamethasone, phenobarbital, phenytoin, andrifampicin 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 orsulphonylurea may be required to reduce the risk of hypoglycaemia when used in combination with

Komboglyze.

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

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

Saxagliptin

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

The metabolism of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5). In invitro 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 healthysubjects, neither the pharmacokinetics of saxagliptin nor its major metabolite, were meaningfullyaltered by metformin, glibenclamide, pioglitazone, digoxin, simvastatin, omeprazole, antacids orfamotidine. In addition, saxagliptin did not meaningfully alter the pharmacokinetics of metformin,glibenclamide, pioglitazone, digoxin, simvastatin, the active components of a combined oralcontraceptive (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 correspondingvalues 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 correspondingvalues for the active metabolite were decreased by 95% and 88%, respectively.

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

The co-administration of saxagliptin and CYP3A4/5 inducers, other than rifampicin (such ascarbamazepine, dexamethasone, phenobarbital and phenytoin) have not been studied and may result indecreased 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 saxagliptinhave not been specifically studied.

Cationic substances that are eliminated by renal tubular secretion (e.g. cimetidine) may interact withmetformin by competing for common renal tubular transport systems. A study conducted in sevennormal healthy volunteers showed that cimetidine, administered as 400 mg twice daily, increasedmetformin systemic exposure (AUC) by 50% and Cmax by 81%. Therefore, close monitoring ofglycaemic control, dose adjustment within the recommended posology and changes in diabetictreatment should be considered when cationic medicinal products that are eliminated by renal tubularsecretion are co-administered.

Alcohol

Alcohol intoxication is associated with an increased risk of lactic acidosis, particularly in the case offasting, malnutrition or hepatic impairment due to the metformin active substance of Komboglyze (seesection 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 bediscontinued prior to, or at the time of the imaging procedure and not restarted until at least 48 hoursafter, provided that renal function has been re-evaluated and found to be stable (see sections 4.2 and4.4).

Combination requiring precautions for use

Glucocorticoids (given by systemic and local routes), beta-2 agonists, and diuretics have intrinsichyperglycaemic activity. The patient should be informed and more frequent blood glucose monitoringperfomed, especially at the beginning of treatment with such medicinal products. If necessary, thedose of the anti-hyperglycaemic medicinal product should be adjusted during therapy with the othermedicinal product and on its discontinuation.

Some medicinal products can adversely affect renal function which may increase the risk of lacticacidosis, 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 suchproducts in combination with metformin, close monitoring of renal function is necessary.

The use of Komboglyze or saxagliptin has not been studied in pregnant women. Studies in animalshave 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 useof 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, embryonicor foetal development, parturition or postnatal development (see section 5.3). This medicinal productshould not be used during pregnancy. If the patient wishes to become pregnant, or if a pregnancyoccurs, treatment with this medicinal product should be discontinued and switched to insulin treatmentas soon as possible.

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 milkin small amounts. This medicinal product must therefore not be used in women who are breast-feeding(see section 4.3).

The effect of saxagliptin on fertility in humans has not been studied. Effects on fertility were observedin male and female rats at high doses producing overt signs of toxicity (see section 5.3). Formetformin, studies in animals have not shown reproductive toxicity (see section 5.3).

Saxagliptin or metformin has a negligible influence on the ability to drive and use machines. Whendriving or using machines, it should be taken into account that dizziness has been reported in studieswith 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 causehypoglycaemia (e.g. insulin, sulphonylureas).

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

Saxagliptin

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 evaluatethe 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 diabeteshave been treated with saxagliptin.

In a pooled analysis of 1,681 patients with type 2 diabetes, including 882 patients treated withsaxagliptin 5 mg, randomised in five double-blind, placebo-controlled clinical safety and efficacystudies 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 comparedto 1.8%).

Adverse reactions reported in ≥ 5% of patients treated with saxagliptin 5 mg and more commonly thanin patients treated with placebo or that were reported in ≥ 2% of patients treated with saxagliptin 5 mgand ≥ 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 definedas 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 availabledata).

Table 2 Frequency of adverse reactions by system organ class

System organ class Frequency of adverse reactions by treatment regimen

Adverse reaction

Saxagliptin with metformin1

Upper respiratory infection Common

Urinary tract infection Common

Gastroenteritis Common

Sinusitis Common

Nasopharyngitis Common2

Headache Common

Vomiting Common1Includes 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 experiencewith saxagliptin. The frequencies are based on the experience from clinical trials.

Table 3 Frequency of additional adverse reactions by system organ class

System organ class

Adverse Reaction Frequency of adverse reactions1

Nausea Common

Pancreatitis Uncommon

Constipation Not known

Hypersensitivity reactions2 (see Uncommonsections 4.3 and 4.4)

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

Angioedema (see sections 4.3 and 4.4) Rare

Dermatitis Uncommon

Pruritus Uncommon

Rash2 Common

Urticaria Uncommon

Bullous pemphigoid Not known1 Frequency estimates are based on the pooled analysis of the saxagliptin monotherapy, add-on to metformin and initialcombination 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 8173patients on placebo. The overall incidence of AEs in patients treated with saxagliptin in this trial wassimilar to placebo (72.5% versus 72.2%, respectively).

The incidence of adjudicated pancreatitis events was 0.3% in both saxagliptin-treated patients andplacebo-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% insubjects treated with saxagliptin and 14.8% among patients treated with placebo. The percent ofsubjects with reported on-treatment events of major hypoglycaemia (defined as an event that requiredassistance of another person) was higher in the saxagliptin group than in the placebo group (2.1% and1.6%, respectively). The increased risk of overall hypoglycaemia and major hypoglycaemia observedin the saxagliptin-treated group occurred primarily in subjects treated with SU at baseline and not insubjects on insulin or metformin monotherapy at baseline. The increased risk of overall and majorhypoglycaemia 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% ofplacebo-treated patients.

Hospitalisation for heart failure, occurred at a greater rate in the saxagliptin group (3.5%) comparedwith 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.

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

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).

Adverse reactions of hypoglycaemia were based on all reports of hypoglycaemia; a concurrent glucosemeasurement was not required. The incidence of reported hypoglycaemia for saxagliptin 5 mg versusplacebo given as add-on therapy to metformin was 5.8% versus 5%. The incidence of reportedhypoglycaemia 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), theoverall 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 reportedhypoglycaemia was 10.1% for saxagliptin 5 mg and 6.3% for placebo.

Across clinical studies, the incidence of laboratory AEs was similar in patients treated with saxagliptin5 mg compared to patients treated with placebo. A small decrease in absolute lymphocyte count wasobserved. From a baseline mean absolute lymphocyte count of approximately 2,200 cells/μL, a meandecrease of approximately 100 cells/μL relative to placebo was observed in the placebo-controlledpooled analysis. Mean absolute lymphocyte counts remained stable with daily dosing up to 102 weeksin duration. The decreases in lymphocyte count were not associated with clinically relevant adversereactions. The clinical significance of this decrease in lymphocyte count relative to placebo is notknown.

Clinical trial data and postmarketing data

Table 4 presents adverse reactions by system organ class and by frequency category. Frequencycategories are based on information available from metformin Summary of Product Characteristicsavailable in the European Union.

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

System organ class Frequency

Adverse reaction

Lactic acidosis Very rare

Vitamin B12 deficiency1 Very rare

Metallic taste Common

Gastrointestinal symptoms2 Very common

Liver function disorders, hepatitis Very rare

Urticaria, erythema, pruritus Very rare1 Long-term treatment with metformin has been associated with a decrease in vitamin B12 absorption which may very rarelyresult 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 frequentlyduring initiation of therapy and resolve spontaneously in most cases.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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 intervalor heart rate at oral doses up to 400 mg daily for 2 weeks (80 times the recommended dose). In theevent of an overdose, appropriate supportive treatment should be initiated as dictated by the patient’sclinical status. Saxagliptin and its major metabolite can be removed by haemodialysis (23% of doseover 4 hours).

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

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

Mechanism of action and pharmacodynamic effects

Komboglyze combines two antihyperglycaemic medicinal products with complementary mechanismsof action to improve glycaemic control in patients with type 2 diabetes: saxagliptin, a dipeptidylpeptidase 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. Inpatients with type 2 diabetes, administration of saxagliptin led to inhibition of DPP4 enzyme activityfor a 24-hour period. After an oral glucose load, this DPP4 inhibition resulted in a 2- to 3-fold increasein circulating levels of active incretin hormones, including glucagon-like peptide-1 (GLP-1) andglucose-dependent insulinotropic polypeptide (GIP), decreased glucagon concentrations and increasedglucose-dependent beta-cell responsiveness, which resulted in higher insulin and C-peptideconcentrations. The rise in insulin from pancreatic beta-cells and the decrease in glucagon frompancreatic alpha-cells were associated with lower fasting glucose concentrations and reduced glucoseexcursion following an oral glucose load or a meal. Saxagliptin improves glycaemic control byreducing fasting and postprandial glucose concentrations in patients with type 2 diabetes.

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

Metformin may act via three mechanisms:

- by reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis inmuscle;

- 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. Metforminincreases 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 lipidmetabolism. This has been shown at therapeutic doses in controlled, medium-term or long-termclinical studies: metformin reduces total cholesterol, LDL-C and triglyceride levels.

In randomised, controlled, double-blind clinical trials (including developmental and postmarketingexperience), 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 diabetesinadequately controlled on metformin alone and in treatment-naive patients inadequately controlled ondiet and exercise alone. Treatment with saxagliptin 5 mg once daily produced clinically relevant andstatistically significant improvements in haemoglobin A1c (HbA1c), fasting plasma glucose (FPG)and postprandial glucose (PPG) compared to placebo in combination with metformin (initial or add-ontherapy). 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 withmetformin was similar to that in the groups given metformin alone. Saxagliptin plus metformin wasnot associated with significant changes from baseline in fasting serum lipids compared to metforminalone.

Saxagliptin add-on to metformin therapy

An add-on to metformin placebo-controlled study of 24-week duration was conducted to evaluate theefficacy and safety of saxagliptin in combination with metformin in patients with inadequateglycaemic control (HbA1c 7-10%) on metformin alone. Saxagliptin (n=186) provided significantimprovements 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 plusmetformin (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 theefficacy and safety of saxagliptin 2.5 mg twice daily in combination with metformin in patients withinadequate glycaemic control (HbA1c 7-10%) on metformin alone. After 12 weeks, the saxagliptingroup (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 thesaxagliptin 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 combinationwith metformin (428 patients) compared with sulphonylurea (glipizide, 5 mg titrated as needed to20 mg, mean dose of 15 mg) in combination with metformin (430 patients) in 858 patients withinadequate glycaemic control (HbA1c 6.5-10%) on metformin alone. The mean metformin dose wasapproximately 1900 mg in each treatment group. After 52 weeks, the saxagliptin and glipizide groupshad 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 showedconsistent results. The reduction in FPG was slightly less in the saxagliptin group and there were morediscontinuations (3.5% vs. 1.2%) due to lack of efficacy based on FPG criteria during the first24 weeks of the study. Saxagliptin also resulted in a significantly lower proportion of patients withhypoglycaemia, 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 weightcompared 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 incombination with metformin (403 patients), compared with sitagliptin 100 mg in combination withmetformin (398 patients) in 801 patients with inadequate glycaemic control on metformin alone. After18 weeks, saxagliptin was non-inferior to sitagliptin in mean reduction from baseline in HbA1c in boththe per-protocol and the full analysis sets. The reductions from baseline in HbA1c respectively forsaxagliptin 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 combinationwith metformin as initial combination therapy in treatment-naive patients with inadequate glycaemiccontrol (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 eithersaxagliptin (n=317) or metformin (n=313) alone as initial therapy. Reductions in HbA1c from baselineto Week 24 were observed in all evaluated subgroups defined by baseline HbA1c, with greaterreductions 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 metforminplus 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 stabledose 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 doseof metformin (n=314). Saxagliptin 5 mg add-on to insulin with or without metformin providedsignificant improvements after 24 weeks in HbA1c and PPG compared with placebo add-on to insulinwith or without metformin. Similar HbA1c reductions versus placebo were achieved for patientsreceiving 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 groupcompared to the placebo add-on to insulin group with or without metformin at Week 52. The HbA1cchange 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) incombination 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 2diabetes 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 completedthe initial 24-week study period were eligible to enter a controlled 28-week long-term study extension(52 weeks).

Individuals treated with saxagliptin added to dapagliflozin and metformin (n=153) achievedstatistically significantly (p-value < 0.0001) greater reductions in HbA1c versus the group withplacebo 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 todapagliflozin plus metformin in the long-term treatment period was consistent with that observed inthe 24-week treatment period in this study and in the trial in which saxagliptin and dapagliflozin weregiven 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 plusdapagliflozin plus metformin group 35.3% (95% CI [28.2, 42.4]) compared to the placebo plusdapagliflozin 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 ofsaxagliptin and metformin

Mean Mean change1 Placebo-correctedbaseline from baseline mean change in

HbA1c HbA1c (%) HbA1c (%) (95%(%) CI)

Add-on/initial combination with metformin studies24-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 combinationwith metformin; Study CV1810393:

Overall population (n=306) 9.4 -2.5 -0.5 (-0.7, -0.4)4

Baseline HbA1c ≥ 10% stratum 10.8 -3.3 -0.6 (-0.9, -0.3)5(n=107)12-weeks

Saxa 2.5 mg twice daily add-on tometformin; 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)224-weeks

Saxa 5 mg daily add-on to metforminplus sulphonylurea;

Study D1680L00006 (n=257) 8.4 -0.7 -0.7 (-0.9, -0.5)2

Saxa 5 mg daily add-on to metforminplus dapagliflozin

Study CV181168 (n=315) 7.9 -0.5 -0.4 (-0.5, -0.2)7n=Randomised patients1 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 onmetformin alone (HbA1c 8%-12%), participated in this 24-week randomised, double-blind, activecomparator-controlled trial to compare the combination of saxagliptin and dapagliflozin addedconcurrently to metformin, versus saxagliptin or dapagliflozin added to metformin. Patients wererandomised to one of three double-blind treatment groups to receive saxagliptin 5 mg anddapagliflozin 10 mg added to metformin, saxagliptin 5 mg and placebo added to metformin, ordapagliflozin 10 mg and placebo added to metformin.

The saxagliptin and dapagliflozin group achieved significantly greater reductions in HbA1c versuseither 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 ofsaxagliptin and dapagliflozin added concurrently to metformin with eithersaxagliptin or dapagliflozin added to metformin

Saxagliptin5 mg+ dapagliflozin Saxagliptin Dapagliflozin

Efficacy parameter10 mg 5 mg 10 mg+ metformin + metformin + metformin

N=1792 N=1762 N=1792

HbA1c (%) at week 241

Baseline (mean) 8.93 9.03 8.87

Change from baseline (adjusted mean3) −1.47 −0.88 −1.20(95% Confidence interval [CI]) (−1.62, −1.31) (−1.03, −0.72) (−1.35, −1.04)

Difference from saxagliptin + metformin(adjusted mean3) −0.594(95% CI) (−0.81, −0.37) - -

Difference from dapagliflozin + metformin(adjusted mean3) −0.275(95% CI) (−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 patientsachieved HbA1c levels of less than 7% compared to 18.3% (95% CI [13.0, 23.5]) of patients in thesaxagliptin 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 withestablished 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. Thestudy population included those ≥ 65 years (n=8561) and ≥ 75 years (n=2330), with normal or mildrenal 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 endpointconsisting 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 saxagliptindoes not increase the cardiovascular risk in patients with type 2 diabetes compared to placebo whenadded to current background therapy.

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

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

Saxagliptin Placebo(N=8280) (N=8212)

Subjects with Event rate Subjects Event rate per Hazardevents per 100 with events 100 Ratio

Endpoint n (%) patient-years n (%) patient-years (95% CI)†

Primary composite 613 3.76 609 3.77 1.00endpoint: MACE (7.4) (7.4) (0.89, 1.12)‡,§, #

Secondary composite 1059 6.72 1034 6.60 1.02endpoint: MACE plus (12.8) (12.6) (0.94, 1.11)¶

All-cause mortality 420 2.50 378 2.26 1.11(5.1) (4.6) (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 overtime.¶ Significance not tested.

One component of the secondary composite endpoint, hospitalisation for heart failure, occurred at agreater rate in the saxagliptin group (3.5%) compared with the placebo group (2.8%), with nominalstatistical significance favouring placebo [HR=1.27; (95% CI 1.07, 1.51); P=0.007]. Clinicallyrelevant factors predictive of increased relative risk with saxagliptin treatment could not bedefinitively identified. Subjects at higher risk for hospitalisation for heart failure, irrespective oftreatment assignment, could be identified by known risk factors for heart failure such as baselinehistory of heart failure or impaired renal function. However, subjects on saxagliptin with a history ofheart failure or impaired renal function at baseline were not at an increased risk relative to placebo forthe 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 groupand 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%) thanplacebo (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.

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

- a significant reduction of the absolute risk of any diabetes-related complication in the metformingroup (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: metformin7.5 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: metformin13.5 events/1,000 patient-years versus diet alone 20.6 events/1,000 patient-years, (p=0.011), andversus the combined sulphonylurea and insulin monotherapy groups18.9 events/1,000 patient-years (p=0.021);

- a significant reduction in the absolute risk of myocardial infarction: metformin11 events/1,000 patient-years, diet alone 18 events/1,000 patient-years, (p=0.01).

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

GENERATION was a 52-week glycaemic control study in 720 elderly patients, the mean age was72.6 years; 433 subjects (60.1%) were < 75 years of age, and 287 subjects (39.9%) were ≥ 75 years ofage. Primary endpoint was the proportion of patients reaching HbA1c < 7% without confirmed orsevere 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 patientsin the saxagliptin group (44.7%) compared to the glimepiride group (54.7%) achieved an HbA1ctarget of 7.0%. A lower proportion of patients in the saxagliptin group (1.1%) compared to theglimepiride group (15.3%), experienced a confirmed or severe hypoglycaemic event.

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 forinformation on paediatric use).

The results of bioequivalence studies in healthy subjects demonstrated that Komboglyze combinationtablets are bioequivalent to co-administration of corresponding doses of saxagliptin and metforminhydrochloride 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 inpatients with type 2 diabetes.

Saxagliptin was rapidly absorbed after oral administration in the fasted state, with maximum plasmaconcentrations (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 increasedproportionally with the increment in the saxagliptin dose, and this dose-proportionality was observedin doses up to 400 mg. Following a 5 mg single oral dose of saxagliptin to healthy subjects, the meanplasma 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. Theintra-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 ofsaxagliptin 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) wasincreased by approximately 0.5 hours with food compared with the fasted state. These changes werenot considered to be clinically meaningful.

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) arenot expected to alter the disposition of saxagliptin.

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 aspotent as saxagliptin.

The mean plasma terminal half-life (t1/2) values for saxagliptin and its major metabolite are 2.5 hoursand 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 of14C-saxagliptin, 24%, 36%, and 75% of the dose was excreted in the urine as saxagliptin, its majormetabolite, 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 werecomparable to estimated glomerular filtration rate. A total of 22% of the administered radioactivitywas recovered in faeces representing the fraction of the saxagliptin dose excreted in bile and/orunabsorbed medicinal product from the gastrointestinal tract.

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

A single-dose, open-label study was conducted to evaluate the pharmacokinetics of a 10 mg oral doseof saxagliptin in subjects with varying degrees of chronic renal impairment compared to subjects withnormal renal function. The study included patients with renal impairment classified on the basis ofcreatinine 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. Theexposures 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 withnormal renal function.

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, thanthose observed in healthy subjects.

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

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

After oral administration, metformin absorption is saturable and incomplete. It is assumed that thepharmacokinetics of metformin absorption is non-linear. At the usual metformin doses and dosingschedules, steady-state plasma concentrations are reached within 24-48 h and are generally less than1 μg/mL. In controlled clinical trials, maximum metformin plasma levels (Cmax) did not exceed4 μg/mL, even at maximum doses.

Interaction with food

Food decreases the extent and slightly delays the absorption of metformin. Following administrationof a dose of 850 mg, a 40% lower plasma peak concentration, a 25% decrease in AUC and a 35 minprolongation of time to peak plasma concentration was observed. The clinical relevance of thisdecrease is unknown.

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

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

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

Co-administration of saxagliptin and metformin

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

Co-administration of saxagliptin and metformin, to pregnant rats and rabbits during the period oforganogenesis, was neither embryolethal nor teratogenic in either species when tested at dosesyielding 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 ofdelayed ossification (“wavy ribs”); associated maternal toxicity was limited to weight decrements of5-6% over the course of gestation days 13 through 18, and related reductions in maternal foodconsumption. In rabbits, co-administration was poorly tolerated in many mothers, resulting in death,moribundity or abortion. However, among surviving mothers with evaluable litters, maternal toxicitywas limited to marginal reductions in body weight over the course of gestation days 21 to 29; andassociated 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. Nocombination toxicity was observed at AUC exposures 68 and 1.5 times the RHDs for saxagliptin andmetformin, respectively.

No animal studies have been conducted with the combination of products in Komboglyze to evaluatecarcinogenesis, mutagenesis, or impairment of fertility. The following data are based on the findingsin 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 metaboliterespectively, 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 inmonkeys have not been observed in human clinical trials of saxagliptin.

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

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

Saxagliptin was not genotoxic in a conventional battery of genotoxicity studies in vitro and in vivo. Nocarcinogenic 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 oftoxicity. 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 decreasedfoetal body weight (in the presence of maternal toxicity), with a NOEL 303 and 30 times the humanexposure for saxagliptin and the major metabolite, respectively, at RHD. In rabbits, the effects ofsaxagliptin were limited to minor skeletal variations observed only at maternally toxic doses (NOEL158 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 atmaternally toxic doses, with NOEL 488 and 45 times the human exposure for saxagliptin and themajor metabolite, respectively at RHD. The effect on offspring body weights were noted untilpostnatal day 92 and 120 in females and males, respectively.

Preclinical data for metformin reveal no special hazard for humans based on conventional studies ofsafety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity toreproduction.

Povidone K30

Magnesium stearate

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)

Shellac

Indigo carmine aluminium lake (E132)

Not applicable.

3 years

Store below 25°C.

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 innon-perforated blisters.60x1 film-coated tablets in perforated unit dose blisters.

Not all pack sizes may be marketed.

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

AstraZeneca AB

SE-151 85 Södertälje

Sweden

Komboglyze 2.5 mg/850 mg film-coated tablets

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Date of first authorisation: 24 November 2011

Date of latest renewal: 15 July 2016

Detailed information on this medicinal product is available on the website of the European Medicines

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