Qtern 5 mg/10 mg film-coated tablets

Each tablet contains saxagliptin hydrochloride equivalent to 5 mg saxagliptin and dapagliflozin propanediol monohydrate equivalent to 10 mg dapagliflozin.

Excipient with known effect

Each tablet contains 40 mg of lactose (as anhydrous).

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Light brown to brown, biconvex, 0.8 cm round, film-coated tablet, with “5/10” printed on one side, and “1122” printed on the other side, in blue ink.

 

Qtern, fixed dose combination of saxagliptin and dapagliflozin, is indicated in adults aged 18 years and older with type 2 diabetes mellitus:

• to improve glycaemic control when metformin and/or sulphonylurea (SU) and one of the monocomponents of Qtern do not provide adequate glycaemic control,

• when already being treated with the free combination of dapagliflozin and saxagliptin.

(See sections 4.2, 4.4, 4.5 and 5.1 for available data on combinations studied).

Posology

The recommended dose is one 5 mg saxagliptin/10 mg dapagliflozin tablet once daily (see sections 4.5 and 4.8).

Special populations

Renal impairment

Qtern can be used in patients with mild renal impairment.

This medicinal product should not be used in patients with moderate to severe renal impairment (patients with creatinine clearance [CrCl] < 60 ml/min or estimated glomerular filtration rate [eGFR] < 60 ml/min/1.73 m², see sections 4.4, 4.8, 5.1 and 5.2). It should also not be used in patients with end-stage renal disease (ESRD) (see section 4.4, 4.8, and 5.2).

Hepatic impairment

This medicinal product can be used in patients with mild or moderate hepatic impairment. Patients with moderate hepatic impairment should be eva luated prior to initiation and during treatment.

It is not recommended for use in patients with severe hepatic impairment (see section 4.4).

Elderly

There is no restriction based solely on age. However, renal function and risk of volume depletion should be taken into account in elderly patients (≥ 65 years). Based on very limited experience in patients 75 years and older, initiation of Qtern therapy is not recommended in this population (see sections 4.4 and 5.2).

Paediatric population

The safety and efficacy of this medicinal product in children and adolescents aged 0 to < 18 years have not yet been established. No data are available.

Method of administration

Qtern is taken orally once daily. It may be taken at any time of day with or without food. Tablet is to be swallowed whole.

If a dose is missed and it is ≥ 12 hours until the next dose, the dose should be taken. If a dose is missed and it is < 12 hours until the next dose, the missed dose should be skipped and the next dose taken at the usual time.

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 (DPP-4) inhibitor or to any sodium-glucose co-transporter 2 (SGLT2) inhibitor (see sections 4.4, 4.8 and 6.1).

General

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

Acute pancreatitis

Use of DPP-4 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, it 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.

Monitoring of renal function

The efficacy of dapagliflozin is dependent on renal function, and efficacy is reduced in patients who have moderate renal impairment and likely absent in patients with severe renal impairment (see section 4.2). In subjects with moderate renal impairment (patients with CrCl < 60 ml/min or eGFR < 60 ml/min/1.73 m²), a higher proportion of subjects treated with dapagliflozin had adverse reactions of increase in creatinine, phosphorus, parathyroid hormone (PTH) and hypotension, compared with placebo. Qtern should not be used in patients with moderate to severe renal impairment (patients with CrCl < 60 ml/min or eGFR < 60 ml/min/1.73 m²). This medicinal product has not been studied in severe renal impairment (CrCl < 30 ml/min or eGFR < 30 ml/min/1.73 m²) or end-stage renal disease (ESRD).

Monitoring of renal function is recommended as follows:

• Prior to initiation of this medicinal product and at least yearly, thereafter (see sections 4.2, 4.8, 5.1 and 5.2).

• Prior to initiation of concomitant medicinal products that may reduce renal function and periodically thereafter.

• For renal function approaching moderate renal impairment, at least 2 to 4 times per year. If renal function falls below CrCl < 60 ml/min or eGFR < 60 ml/min/1.73 m², Qtern treatment should be discontinued.

Use in patients at risk for volume depletion, hypotension and/or electrolyte imbalances

Due to dapagliflozin's mechanism of action, Qtern increases diuresis associated with a modest decrease in blood pressure (see section 5.1), which may be more pronounced in patients with very high blood glucose concentrations.

This medicinal product is not recommended for use in patients at risk of volume depletion (e.g. receiving loop diuretics) (see section 4.5) or who are volume depleted, e.g. due to acute illness (such as acute gastrointestinal illness with nausea, vomiting or diarrhoea).

Caution should be exercised in patients for whom a dapagliflozin-induced drop in blood pressure could pose a risk, such as patients with known cardiovascular disease, patients on anti-hypertensive therapy with a history of hypotension or elderly patients.

 

For patients receiving Qtern, in case of intercurrent conditions that may lead to volume depletion, careful monitoring of volume status (e.g. physical examination, blood pressure measurements, laboratory tests including haematocrit) and electrolytes is recommended. Temporary interruption of treatment with this medicinal product is recommended for patients who develop volume depletion until the depletion is corrected (see section 4.8).

Use in patients with hepatic impairment

There is limited experience in clinical trials in patients with hepatic impairment. Dapagliflozin and saxagliptin exposure is increased in patients with severe hepatic impairment (see sections 4.2 and 5.2).

Qtern can be used in patients with mild or moderate hepatic impairment. Patients with moderate hepatic impairment should be eva luated prior to initiation and during treatment. This medicinal product is not recommended for use in patients with severe hepatic impairment (see section 4.2).

Diabetic ketoacidosis

Rare cases of diabetic ketoacidosis (DKA), including life-threatening cases, have been reported in clinical trials and post-marketing in patients treated with SGLT2 inhibitors, including dapagliflozin. In a number of cases, the presentation of the condition was atypical with only moderately increased blood glucose values, below 14 mmol/litres (250 mg/dl). It is not known if DKA is more likely to occur with higher doses of dapagliflozin.

The risk of diabetic ketoacidosis must be considered in the event of non-specific symptoms such as nausea, vomiting, anorexia, abdominal pain, excessive thirst, difficulty breathing, confusion, unusual fatigue or sleepiness. Patients should be assessed for ketoacidosis immediately if these symptoms occur, regardless of blood glucose level.

In patients where DKA is suspected or diagnosed, treatment with Qtern should be discontinued immediately.

Treatment should be interrupted in patients who are hospitalised for major surgical procedures or acute serious medical illnesses. In both cases, treatment with dapagliflozin may be restarted once the patient's condition has stabilised.

Before initiating Qtern, factors in the patient history that may predispose to ketoacidosis should be considered.

Patients who may be at higher risk of DKA include patients with a low beta-cell function reserve (e.g. type 2 diabetes patients with low C-peptide or latent autoimmune diabetes in adults (LADA) or patients with a history of pancreatitis), patients with conditions that lead to restricted food intake or severe dehydration, patients for whom insulin doses are reduced and patients with increased insulin requirements due to acute medical illness, surgery or alcohol abuse. SGLT2 inhibitors should be used with caution in these patients.

Restarting SGLT2 inhibitor treatment in patients with previous DKA while on SGLT2 inhibitor treatment is not recommended, unless another clear precipitating factor is identified and resolved.

The safety and efficacy of dapagliflozin in patients with type 1 diabetes have not been established and Qtern should not be used for treatment of patients with type 1 diabetes. Limited data from clinical trials with dapagliflozin suggest that DKA occurs with common frequency when patients with type 1 diabetes are treated with SGLT2 inhibitors.

Hypersensitivity reactions

Qtern must not be used in patients who have had any serious hypersensitivity reaction to a DPP-4 inhibitor or a SGLT2 inhibitor (see section 4.3).

During post-marketing experience with saxagliptin, 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.

Qtern should be discontinued if a serious hypersensitivity reaction is suspected. The event should be assessed and alternative treatment for diabetes should be instituted (see section 4.8).

Urinary tract infections

In the pooled safety data, urinary tract infections were frequently reported across the 3 treatment groups: 5.7% in the saxagliptin plus dapagliflozin plus metformin group 7.4% in the saxagliptin plus metformin group and 5.6% in the dapagliflozin plus metformin group at 52 weeks (see section 4.8).

Additionally, urinary tract infections were frequently reported in saxagliptin and dapagliflozin clinical programmes.

Urosepsis and pyelonephritis

There have been post-marketing reports of serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization in patients receiving dapagliflozin and other SGLT2 inhibitors.

Treatment with SGLT2 inhibitors increases the risk for urinary tract infections. Patients with signs and symptoms of urinary tract infections should be eva luated and promptly treated, if indicated (see section 4.8).

Elderly

Elderly patients are more likely to have impaired renal function, and may be at a greater risk for volume depletion. In addition, elderly patients are more likely to be treated with anti-hypertensive medicinal products that may cause volume depletion and/or changes in renal function [e.g. angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin II type 1 receptor blockers (ARB)].

Therefore, renal function and risk of volume depletion should be taken into account prior to starting treatment with Qtern. The same recommendations for monitoring of renal function apply to elderly patients as to all patients (see sections 4.2, 4.4, 4.8, and 5.1).

In subjects ≥ 65 years of age, a higher proportion of subjects treated with dapagliflozin had adverse reactions related to volume depletion and renal impairment or failure compared with placebo (see section 4.8). The most commonly reported adverse reaction related to renal function was serum creatinine increases, the majority of which were transient and reversible (see section 4.8).

Therapeutic experience with Qtern in patients 65 years and older is limited, and very limited in patients 75 years and older. Initiation of this medicinal product's therapy in this population (> 75 years) is not recommended (see sections 4.2, 4.8, and 5.2).

Skin disorders

Ulcerative and necrotic skin lesions have been reported in extremities of monkeys in non clinical toxicology studies with saxagliptin (see section 5.3). Skin lesions were not observed at an increased incidence in saxagliptin clinical trials. Post-marketing reports of rash have been described in the DPP-4 inhibitor class. Rash is also noted as an adverse reaction for this medicinal product (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.

Cardiac failure

Experience in NYHA class I-II is limited in dapagliflozin. There is no experience in clinical trials with dapagliflozin in NYHA class III-IV. Experience in NYHA class III-IV is limited with saxagliptin.

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). Additional analysis did not indicate a differential effect among NYHA classes.

Caution is warranted if Qtern is used in patients who have known risk factors for hospitalization 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 post-marketing reports for DPP-4 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 DPP-4 inhibitor. Onset of symptoms following initiation of therapy may be rapid or may occur after longer periods of treatment. If a patient presents with severe joint pain, continuation of therapy should be individually assessed.

Use in patients treated with pioglitazone

While a causal relationship between dapagliflozin and bladder cancer is unlikely (see sections 4.8 and 5.3), as a precautionary measure, Qtern is not recommended for use in patients concomitantly treated with pioglitazone. Available epidemiological data for pioglitazone suggest a small increased risk of bladder cancer in diabetic patients treated with pioglitazone.

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 programme. The efficacy and safety profile of Qtern in these patients has not been established.

Elevated haematocrit

Haematocrit increase was observed with dapagliflozin treatment, (see section 4.8); therefore, caution in patients with already elevated haematocrit is warranted.

Use with medicinal products known to cause hypoglycaemia

Both saxagliptin and dapagliflozin can individually increase the risk of hypoglycaemia when combined with an insulin secretagogue. If Qtern is used in combination with insulin secretagogue (sulphonylurea), a reduction in the dose of sulphonylurea may be required to minimize the risk of hypoglycaemia (see section 4.8).

Urine laboratory assessments

Due to its mechanism of action, patients taking Qtern will test positive for glucose in their urine.

Use with potent CYP3A4 inducers

Using CYP3A4 inducers like carbamazepine, dexamethasone, phenobarbital, phenytoin, and rifampicin may reduce the glycaemic lowering effect of Qtern. Glycaemic control should be assessed when it is used concomitantly with a potent CYP3A4/5 inducer (see section 4.5).

Lactose

The tablets contain lactose anhydrous. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Pharmacodynamic interactions

Diuretics

Dapagliflozin may add to the diuretic effect of thiazide and loop diuretics and may increase the risk of dehydration and hypotension (see section 4.4).

Use with medicinal products known to cause hypoglycaemia

If Qtern is used in combination with insulin secretagogue (sulphonylurea), a reduction in the dose of sulphonylurea may be required to minimize the risk of hypoglycaemia (see section 4.4).

Pharmacokinetic interactions

Saxagliptin: The metabolism of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5).

Dapagliflozin: The metabolism of dapagliflozin is primarily via glucuronide conjugation mediated by UDP glucuronosyltransferase 1A9 (UGT1A9).

Interactions with other oral anti-diabetic or cardiovascular medicinal products

Saxagliptin: Saxagliptin did not meaningfully alter the pharmacokinetics of dapagliflozin, metformin, glibenclamide, pioglitazone, digoxin, diltiazem or simvastatin. These medicinal products did not alter the pharmacokinetics of saxagliptin or its major active metabolite.

Dapagliflozin: Dapagliflozin did not meaningfully alter the pharmacokinetics of saxagliptin, metformin, pioglitazone, sitagliptin, glimepiride, voglibose, hydrochlorothiazide, bumetanide, valsartan, or simvastatin. These medications did not alter the pharmacokinetics of dapagliflozin.

Effect of other medicinal products on saxagliptin or dapagliflozin

Saxagliptin: Concomitant administration of saxagliptin with the moderate inhibitor of CYP3A4/5 diltiazem, increased the C_max 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. These pharmacokinetic effects are not clinically meaningful and do not require dose adjustment.

Concomitant administration of saxagliptin with the potent inhibitor of CYP3A4/5 ketoconazole, increased the C_max 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. These pharmacokinetic effects are not clinically meaningful and do not require dose adjustment.

Concomitant administration of saxagliptin with the potent CYP3A4/5 inducer rifampicin reduced C_max and AUC of saxagliptin by 53% and 76%, respectively. The exposure of the active metabolite and the plasma DPP-4 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) has 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 CYP3A4/5 inducer.

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.

Dapagliflozin: Following coadministration of dapagliflozin with rifampicin (an inducer of various active transporters and drug-metabolising enzymes) a 22% decrease in dapagliflozin systemic exposure (AUC) was observed, but with no clinically meaningful effect on 24-hour urinary glucose excretion. No dose adjustment is recommended. A clinically relevant effect with other inducers (e.g. carbamazepine, phenytoin, phenobarbital) is not expected.

Following coadministration of dapagliflozin with mefenamic acid (an inhibitor of UGT1A9), a 55% increase in dapagliflozin systemic exposure was seen, but with no clinically meaningful effect on 24-hour urinary glucose excretion.

Effect of saxagliptin or dapagliflozin on other medicinal products

Saxagliptin: Saxagliptin did not meaningfully alter the pharmacokinetics of metformin, glibenclamide (a CYP2C9 substrate), pioglitazone [a CYP2C8 (major) and CYP3A4 (minor) substrate], digoxin (a P-gp substrate), simvastatin (a CYP3A4 substrate), the active components of a combined oral contraceptive (ethinylestradiol and norgestimate), diltiazem or ketoconazole.

Dapagliflozin: In interaction studies conducted in healthy subjects, using mainly a single-dose design, dapagliflozin did not alter the pharmacokinetics of metformin, pioglitazone [a CYP2C8 (major) and CYP3A4 (minor) substrate], sitagliptin, glimepiride (a CYP2C9 substrate), hydrochlorothiazide, bumetanide, valsartan, digoxin (a P-gp substrate) or warfarin (S-warfarin, a CYP2C9 substrate), or the anticoagulatory effects of warfarin as measured by INR. Combination of a single dose of dapagliflozin 20 mg and simvastatin (a CYP3A4 substrate) resulted in a 19% increase in AUC of simvastatin and 31% increase in AUC of simvastatin acid. The increase in simvastatin and simvastatin acid exposures are not considered clinically relevant.

Other interactions

The effects of smoking, diet, herbal products and alcohol use on the pharmacokinetics of saxagliptin, dapagliflozin or fixed dose combination tablet have not been studied.

Interference with 1,5-anhydroglucitol (1,5-AG) assay

Monitoring glycaemic control with 1,5-AG assay is not recommended as measurements of 1,5-AG are unreliable in assessing glycaemic control in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycaemic control.

Pregnancy

There are no data from the use of saxagliptin and dapagliflozin in pregnant women. Studies in animals with saxagliptin have shown reproductive toxicity at high doses (see section 5.3). Studies with dapagliflozin in rats have shown toxicity to the developing kidney in the time period corresponding to the second and third trimesters of human pregnancy (see section 5.3). Therefore, Qtern should not be used during pregnancy. If pregnancy is detected, treatment with Qtern should be discontinued.

Breast-feeding

It is unknown whether saxagliptin and dapagliflozin and/or its metabolites are excreted in human milk.

Animal studies have shown excretion of saxagliptin and/or metabolite in milk. Available pharmacodynamic/toxicological data in animals have shown excretion of dapagliflozin/metabolites in milk, as well as pharmacologically-mediated effects in breast-feeding offspring (see section 5.3). A risk to the newborns/infants cannot be excluded. Qtern should not be used while breast-feeding.

Fertility

The effect of saxagliptin and dapagliflozin on fertility in humans has not been studied. In male and female rats, dapagliflozin showed no effects on fertility at any dose tested. Effects on fertility were observed using saxagliptin in male and female rats at high doses producing overt signs of toxicity (see section 5.3).

Qtern has no or 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 combined use of saxagliptin and dapagliflozin. In addition, patients should be alerted to the risk of hypoglycaemia if used in combination with other antidiabetic medicinal products known to cause hypoglycaemia (e.g. sulphonylureas).