Komboglyze 2.5 mg/850 mg film-coated tablets

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

2.5 mg/850 mg:

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

For a full list of excipients, see section 6.1.

2.5 mg/1,000 mg:

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.

Film-coated tablet (tablet).

2.5 mg/850 mg:

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.

2.5 mg/1,000 mg:

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.

Komboglyze is indicated as an adjunct to diet and exercise to improve glycaemic control in adult patients aged 18 years and older with type 2 diabetes mellitus inadequately controlled on their maximally tolerated dose of metformin alone or those already being treated with the combination of saxagliptin and metformin as separate tablets.

Komboglyze is also indicated in combination with insulin (ie, triple combination therapy) as an adjunct to diet and exercise to improve glycaemic control in adult patients aged 18 years and older with type 2 diabetes mellitus when insulin and metformin alone do not provide adequate glycaemic control.

Komboglyze is also indicated in combination with a sulphonylurea (i.e., triple combination therapy) as an adjunct to diet and exercise to improve glycaemic control in adult patients aged 18 years and older with type 2 diabetes mellitus when the maximally tolerated dose of both metformin and the sulphonylurea does not provide adequate glycaemic control.

Posology

For patients inadequately controlled on maximal tolerated dose of metformin monotherapy

Patients not adequately controlled on metformin alone should receive a dose of Komboglyze 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.

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 Komboglyze 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 Komboglyze 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 Komboglyze 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 Komboglyze 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).

Special populations

Renal impairment

No dose adjustment is recommended for patients with mild renal impairment. Komboglyze should not be used in patients with moderate to severe renal impairment (see sections 4.3, 4.4 and 5.2).

Hepatic impairment

Komboglyze should not be used in patients with hepatic impairment (see sections 4.3 and 5.2).

Elderly (≥ 65 years)

As metformin and saxagliptin are excreted by the kidney, Komboglyze 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 Komboglyze in children 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.

Komboglyze is contraindicated in patients with:

 - hypersensitivity to the active substance(s) 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);
 
- diabetic ketoacidosis, diabetic pre-coma;
 
- moderate and severe renal impairment (creatinine clearance < 60 ml/min) (see section 4.4);
 
- 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 5.2);
 
- acute alcohol intoxication, alcoholism (see section 4.5);
 
- breastfeeding (see section 4.6).  

General

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

Komboglyze is not a substitute for insulin in insulin-requiring patients.

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, Komboglyze should be discontinued; if acute pancreatitis is confirmed, Komboglyze should not be restarted. Caution should be exercised in patients with a history of pancreatitis.

In post-marketing experience of saxagliptin, there have been spontaneously reported adverse reactions of acute pancreatitis.

Lactic acidosis

Lactic acidosis is a very rare, but serious (high mortality in the absence of prompt treatment), metabolic complication that can occur due to metformin, a component of Komboglyze, accumulation. Reported cases of lactic acidosis in patients on metformin have occurred primarily in diabetic patients with significant renal failure. The incidence of lactic acidosis can and should be reduced by also assessing other associated risk factors such as poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, hepatic insufficiency and any conditions associated with hypoxia.

Diagnosis

Lactic acidosis is characterised by acidotic dyspnoea, abdominal pain and hypothermia followed by coma. Diagnostic laboratory findings are decreased blood pH, plasma lactate levels above 5 mmol/l, and an increased anion gap and lactate/pyruvate ratio. If metabolic acidosis is suspected, treatment with the medicinal product should be discontinued and the patient hospitalised immediately (see section 4.9).

Renal function

As metformin is excreted by the kidney, serum creatinine concentrations should be determined regularly:

- at least once a year in patients with normal renal function

- at least two to four times a year in patients with serum creatinine levels at or above the upper limit of normal and in elderly patients.

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 nonsteroidal anti-inflammatory drug (NSAID).

Surgery

As Komboglyze contains metformin, the treatment should be discontinued 48 hours before elective surgery with general, spinal or epidural anaesthesia. Komboglyze should not usually be resumed earlier than 48 hours afterwards and only after renal function has been re-eva luated and found to be normal.

Administration of iodinated contrast agent

The intravascular administration of iodinated contrast agents in radiological studies can lead to renal failure which has been associated with lactic acidosis in patients receiving metformin. Therefore, Komboglyze must be discontinued prior to, or at the time of the test and not reinstituted until 48 hours afterwards, and only after renal function has been re-eva luated and found to be normal (see section 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.

Hypersensitivity reactions

As Komboglyze 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 Komboglyze, 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 Komboglyze 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 eva luated promptly for evidence of ketoacidosis or lactic acidosis. eva luation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate, and metformin levels. If acidosis of either form occurs, Komboglyze must be stopped immediately and other appropriate corrective measures initiated.

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 CYP 3A4 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.