Linagliptin and Empagliflozin

Co-administration of rifampicin decreased linagliptin exposure by 40%, suggesting that the efficacy of linagliptin may be reduced when administered in combination with a strong P-glycoprotein (P-gp) or cytochrome P450 (CYP) isozyme CYP3A4 inducer, particularly if these are administed long-term. Co-administration with other potent inducers of P-gp and CYP3A4, such as carbamazepine, phenobarbital and phenytoin, has not been studied.

Empagliflozin and linagliptin as single agents showed an incidence of hypoglycaemia comparable to placebo when used alone or in combination with other antidiabetics not known to cause hypoglycaemia (e.g. metformin, thiazolidinediones). When used in combination with antidiabetics known to cause hypoglycaemia (e.g. sulphonylureas and/or insulin), the incidence of hypoglycaemia of both agents was increased.

There are no data about the hypoglycaemic risk of empagliflozin/linagliptin when used with insulin and/or sulphonylurea. However, caution is advised when empagliflozin/linagliptin is used in combination with antidiabetics. A dose reduction of the sulphonylurea or insulin may be considered.

Linagliptin is a P-glycoprotein substrate, and inhibits P-glycoprotein mediated transport of digoxin with low potency.

Use of dipeptidyl peptidase-4 (DPP-4) inhibitors has been associated with a risk of developing acute pancreatitis. Caution should be exercised in patients with a history of pancreatitis.

There are no data from the use of empagliflozin and linagliptin in pregnant women. Animal studies have shown that empagliflozin and linagliptin cross the placenta during late gestation, but do not indicate direct or indirect harmful effects with respect to early embryonic development with either empagliflozin or linagliptin. Animal studies with empagliflozin have shown adverse effects on postnatal development. As a precautionary measure it is preferable to avoid the use of empagliflozin/linagliptin during pregnancy.

No data in humans are available on excretion of empagliflozin and linagliptin into milk. Available non-clinical data in animals have shown excretion of empagliflozin and linagliptin in milk. A risk to newborns or infants cannot be excluded. Empagliflozin/linagliptin should not be used during breast-feeding.

Fertility

No trials on the effect on human fertility have been conducted with empagliflozin/linagliptin or with the individual active substances. Non-clinical studies with empagliflozin and linagliptin as single agents do not indicate direct or indirect harmful effects with respect to fertility.

Empagliflozin/linagliptin combination has minor influence on the ability to drive and use machines. Patients should be advised to take precautions to avoid hypoglycaemia while driving and using machines, in particular when empagliflozin/linagliptin is used in combination with other antidiabetic medicinal products known to cause hypoglycaemia (e.g. insulin and analogues, sulphonylureas).

Summary of the safety profile

The most frequent adverse reaction was urinary tract infection (7.5% with 10 mg empagliflozin/5 mg linagliptin and 8.5% with 25 mg empagliflozin/5 mg linagliptin) (see Description of selected adverse reactions). The most serious adverse reactions were ketoacidosis (<0.1%), pancreatitis (0.2%), hypersensitivity (0.6%), and hypoglycaemia (2.4%).

Overall, the safety profile of empagliflozin/linagliptin combination was in line with the safety profiles of the individual active substances (empagliflozin and linagliptin). No additional adverse reactions were identified with empagliflozin/linagliptin.

Tabulated list of adverse reactions

The adverse reactions shown in the table below (see table) are listed by system organ class and are based on the safety profiles of empagliflozin and linagliptin monotherapy. Frequency categories are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1 000 to <1/100), rare (≥1/10 000 to <1/1000), very rare (<1/10000) and not known (cannot be estimated from the available data).

Tabulated list of adverse reactions (MedDRA) from reported placebo-controlled trials and from post-marketing experience:

¹ derived from empagliflozin experiences
² derived from linagliptin experiences
³ derived from linagliptin postmarketing experience
⁴ derived from empagliflozin postmarketing experience
⁵ Mean changes from baseline in haematocrit were 3.3% and 4.2% for empagliflozin/linagliptin 10 mg/5 mg and 25 mg/5 mg, respectively, compared to 0.2% for placebo. In a clinical trial with empagliflozin, haematocrit values returned towards baseline values after a follow-up period of 30 days after treatment stop.
⁶ Mean percent increases from baseline for empagliflozin/linagliptin 10 mg/5 mg and 25 mg/5 mg versus placebo, respectively, were total cholesterol 3.2% and 4.6% versus 0.5%; HDL-cholesterol 8.5% and 6.2% versus 0.4%; LDL-cholesterol 5.8% and 11.0% versus 3.3%; triglycerides -0.5% and 3.3% versus 6.4%.
^a In the CARMELINA trial, bullous pemphigoid was reported in 0.2% patients treated with linagliptin and in no patients treated with placebo.
^b Pooled data of empagliflozin trials in patients with heart failure (where half of the patients had type 2 diabetes mellitus) showed a higher frequency of volume depletion (“very common”: 11.4% for empagliflozin versus 9.7% for placebo).
^* see subsection below for additional information

Description of selected adverse reactions

Hypoglycaemia

In pooled clinical trials of empagliflozin/linagliptin in patients with type 2 diabetes and inadequate glycaemic control on background metformin, the frequency of the reported hypoglycaemic events was 2.4%. The incidence of confirmed hypoglycaemic events was low (<1.5%). There was no notable difference of the incidence in patients treated with different dose strengths of empagliflozin/linagliptin compared to the treatment with empagliflozin or linagliptin.

One patient administered empagliflozin/linagliptin experienced a confirmed (investigator-defined), major hypoglycaemic event (defined as an event requiring assistance) in the active- or placebo-controlled trials (overall frequency 0.1%).

Based on the experience with empagliflozin and linagliptin, an increase of the risk of hypoglycaemia is expected with the concomitant treatment of insulin and/or sulphonylurea.

Hypoglycaemia with empagliflozin

The frequency of hypoglycaemia depended on the background therapy in the respective trials and was similar for empagliflozin and placebo as monotherapy, as add-on to metformin, and as add-on to pioglitazone +/- metformin. The frequency of patients with hypoglycaemia was increased in patients treated with empagliflozin compared to placebo when given as add-on to metformin plus sulphonylurea (empagliflozin 10 mg: 16.1%, empagliflozin 25 mg: 11.5%, placebo: 8.4%), add-on to basal insulin +/- metformin and +/-sulphonylurea (empagliflozin 10 mg: 19.5%, empagliflozin 25 mg: 28.4%, placebo: 20.6% during initial 18 weeks treatment when insulin could not be adjusted; empagliflozin 10 mg and 25 mg: 36.1%, placebo 35.3% over the 78 week trial), and add-on to MDI insulin with or without metformin (empagliflozin 10 mg: 39.8%, empagliflozin 25 mg: 41.3%, placebo: 37.2% during initial 18 weeks treatment when insulin could not be adjusted; empagliflozin 10 mg: 51.1%, empagliflozin 25 mg: 57.7%, placebo: 58% over the 52-week trial).

Major hypoglycaemia with empagliflozin (events requiring assistance)

The frequency of patients with major hypoglycaemic events was low (<1%) and similar for empagliflozin and placebo as monotherapy, as add-on to metformin +/- sulfonylurea, and as add-on to pioglitazone +/- metformin.

The frequency of patients with major hypoglycaemic events was increased in patients treated with empagliflozin compared to placebo when given as add-on to basal insulin +/- metformin and +/- sulphonylurea (empagliflozin 10 mg: 0%, empagliflozin 25 mg: 1.3%, placebo: 0% during initial 18 weeks treatment when insulin could not be adjusted; empagliflozin 10 mg: 0%, empagliflozin 25 mg: 1.3%, placebo 0% over the 78-week trial), and add-on to MDI insulin with or without metformin (empagliflozin 10 mg: 1.6%, empagliflozin 25 mg: 0.5%, placebo: 1.6% during initial 18 weeks treatment when insulin could not be adjusted and over the 52-week trial).

Hypoglycaemia with linagliptin

The most frequently reported adverse event in clinical trials with linagliptin was hypoglycaemia observed under the triple combination, linagliptin plus metformin plus sulphonylurea (22.9% vs 14.8% in placebo).

Hypoglycaemias in the placebo-controlled trials (10.9%; N=471) were mild (80%; N=384), moderate (16.6%; N=78) or severe (1.9%; N=9) in intensity.

Urinary tract infection

In clinical trials with empagliflozin/linagliptin, there was no notable difference of the frequency of urinary tract infections in patients treated with empagliflozin/linagliptin (empagliflozin/linagliptin 25 mg/5 mg: 8.5%; empagliflozin/linagliptin 10 mg/5 mg: 7.5%) compared to the patients treated with empagliflozin and linagliptin. The frequencies have been comparable to those reported from the empagliflozin clinical trials.

In empagliflozin trials, the overall frequency of urinary tract infection was similar in patients treated with empagliflozin 25 mg and placebo (7.0% and 7.2%), and higher in patients treated with empagliflozin 10 mg (8.8%). Similar to placebo, urinary tract infection was reported more frequently for empagliflozin in patients with a history of chronic or recurrent urinary tract infections. The intensity of urinary tract infections was similar to placebo for mild, moderate and severe intensity reports. Urinary tract infection was reported more frequently in female patients treated with empagliflozin compared to placebo, but not in male patients.

Vaginal moniliasis, vulvovaginitis, balanitis and other genital infection

In clinical trials with empagliflozin/linagliptin, genital infections in patients treated with empagliflozin/linagliptin (empagliflozin/linagliptin 25 mg/5 mg: 3.0%; empagliflozin/linagliptin 10 mg/5 mg: 2.5%) were reported more frequently than for linagliptin but less freqeuntly than for empagliflozin. Overall, the frequencies for empagliflozin/linagliptin have been comparable to those reported from the empagliflozin clinical trials.

In empagliflozin trials, vaginal moniliasis, vulvovaginitis, balanitis and other genital infections were reported more frequently for empagliflozin 10 mg (4.0%) and empagliflozin 25 mg (3.9%) compared to placebo (1.0%). These infections were reported more frequently for empagliflozin compared to placebo in female patients, and the difference in frequency was less pronounced in male patients. The genital tract infections were mild and moderate in intensity, none was severe in intensity.

Increased urination

In clinical trials with empagliflozin/linagliptin, increased urination in patients treated with empagliflozin/linagliptin (empagliflozin/linagliptin 25 mg/5 mg: 2.6%; empagliflozin/linagliptin 10 mg/5 mg: 1.4%) was reported more frequently than for linagliptin and with similar frequency than for empagliflozin. Overall, the frequencies for empagliflozin/linagliptin have been comparable to those reported from the empagliflozin clinical trials.

In clinical trials with empagliflozin, increased urination (including the predefined terms pollakiuria, polyuria, nocturia) was observed at higher frequencies in patients treated with empagliflozin (empagliflozin 10 mg: 3.5%, empagliflozin 25 mg: 3.3%) compared to placebo (1.4%). Increased urination was mostly mild or moderate in intensity. The frequency of reported nocturia was comparable between placebo and empagliflozin (<1%).

Volume depletion

In clinical trials with empagliflozin/linagliptin, there was no notable difference in the frequency of volume depletion in patients treated with empagliflozin/linagliptin (empagliflozin/linagliptin 25 mg/5 mg: 0.4%; empagliflozin/linagliptin 10 mg/5 mg: 0.8%) compared to the patients treated with empagliflozin and linagliptin. The frequencies have been comparable to those reported from the empagliflozin clinical trials.

In clinical trials with empagliflozin, the overall frequency of volume depletion (including the predefined terms blood pressure (ambulatory) decreased, blood pressure systolic decreased, dehydration, hypotension, hypovolaemia, orthostatic hypotension, and syncope) was similar in patients treated with empagliflozin (empagliflozin 10 mg: 0.6%, empagliflozin 25 mg: 0.4%) and placebo (0.3%). The frequency of volume depletion events was increased in patients 75 years and older treated with empagliflozin 10 mg (2.3%) or empagliflozin 25 mg (4.3%) compared to placebo (2.1%).

Blood creatinine increased/Glomerular filtration rate decreased

In clinical trials with empagliflozin/linagliptin, the frequency of patients with increased blood creatinine (empagliflozin/linagliptin 25 mg/5 mg: 0.4%; empagliflozin/linagliptin 10 mg/5 mg: 0%) and decreased glomerular filtration rate (empagliflozin/linagliptin 25 mg/5 mg: 0.4%; empagliflozin/linagliptin 10 mg/5 mg: 0.6%) has been comparable to those reported from the empagliflozin clinical trials.

In clinical trials with empagliflozin, the overall frequency of patients with increased blood creatinine and decreased glomerular filtration rate were similar between empagliflozin and placebo (blood creatinine increased: empagliflozin 10 mg 0.6%, empagliflozin 25 mg 0.1%, placebo 0.5%; glomerular filtration rate decreased: empagliflozin 10 mg 0.1%, empagliflozin 25 mg 0%, placebo 0.3%).

Elderly

In clinical trials, nineteen patients 75 years or older were treated with empagliflozin/linagliptin. No patient was older than 85 years. The safety profile of empagliflozin/linagliptin did not differ in the elderly. Based on empagliflozin experiences, elderly patients may be at increased risk of volume depletion.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.