GLYXAMBI Empagliflozin / Linagliptin 25mg / 5mg Film-Coated Tablet 1's

During controlled clinical trials in healthy subjects, single doses of up to 800 mg empagliflozin, equivalent to 32 times the daily recommended dose, were well tolerated. During controlled clinical trials in healthy subjects, single doses of up to 600 mg linagliptin (equivalent to 120 times the recommended dose) were well tolerated. There is no experience with doses above 600 mg in humans.
Therapy: In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring and institute clinical measures as required.

Pregnancy: There is a limited amount of data from the use of empagliflozin and linagliptin in pregnant women. Nonclinical studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. As a precautionary measure it is recommended to avoid the use of Empagliflozin + Linagliptin (GLYXAMBI) during pregnancy unless clearly needed.
Lactation: No data in humans are available on excretion of empagliflozin and linagliptin into milk.
Available nonclinical data in animals have shown excretion of empagliflozin and linagliptin in milk. A risk to human newborns/infants cannot be excluded. It is recommended to discontinue breast feeding during treatment with Empagliflozin + Linagliptin (GLYXAMBI).
Fertility: No studies on the effect on human fertility have been conducted for Empagliflozin + Linagliptin (GLYXAMBI) or with the individual components.
Nonclinical studies of empagliflozin alone and of linagliptin alone do not indicate direct or indirect harmful effects with respect to fertility.

Store at temperatures not exceeding 30°C.

Pharmacotherapeutic group: Combinations of oral blood glucose lowering drugs. ATC code: A10BD19.
Pharmacology: Pharmacodynamics: Mode of Action: Combination empagliflozin/linagliptin: The mechanism of action of empagliflozin, which is independent of the insulin pathway and β-cell function, is different from and complementary to the mechanisms of currently available medications to treat Type 2 diabetes mellitus (T2DM). Therefore the efficacy of empagliflozin was found to be additive to all drugs with other mechanisms of action, such as dipeptidyl peptidase-4 (DPP-4) inhibitors.
The combination of empagliflozin and linagliptin, after single oral dosing, showed a superior effect on glycemic control (OGTT) as compared to the respective monotherapies tested in diabetic ZDF rats. Chronic treatment of empagliflozin in combination with linagliptin significantly improved insulin sensitivity (tested by euglycemic-hyperinsulinemic clamp studies) in diabetic db/db mice. The improved insulin sensitivity was significantly superior with the combination in comparison to the monotherapies.
Empagliflozin: Empagliflozin is a reversible, highly potent and selective competitive inhibitor of SGLT2 with an IC₅₀ of 1.3 nM. It has a 5000-fold selectivity over human SGLT1 (IC₅₀ of 6278 nM), responsible for glucose absorption in the gut. In the kidney, the glucose filtered is almost completely reabsorbed by SGLT2 (up to 90%) and to a lesser extent by SGLT1 located in the S1 and S3 segments of the proximal tubule of the nephron respectively. Empagliflozin, by inhibiting the reabsorption of glucose by the kidney, leads to increased urinary glucose excretion that triggers the lowering of blood glucose after single oral dosing, as well as after chronic treatment. In addition, the glucosuric effect of empagliflozin, leading to calorie loss, translated into body weight reduction.
Empagliflozin improves glycaemic control in patients with T2DM by reducing renal glucose reabsorption. The amount of glucose removed by the kidney through this glucuretic mechanism is dependent upon the blood glucose concentration and GFR. Through inhibition of SGLT-2 in patients with T2DM and hyperglycemia, excess glucose is excreted in the urine.
The insulin independent mechanism of action of empagliflozin contributes to a low risk of hypoglycaemia.
The glucosuria observed with empagliflozin is accompanied by mild diuresis which may contribute to sustained and moderate reduction of blood pressure.
Linagliptin: Linagliptin is an inhibitor of the enzyme DPP-4 an enzyme which is involved in the inactivation of the incretin hormones GLP-1 and GIP (glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide). Linagliptin binds very effectively to DPP-4 in a reversible manner and thus leads to a sustained increase and a prolongation of active incretin levels. Linagliptin binds selectively to DPP-4 and exhibits a >10000-fold selectivity versus DPP-8 or DPP-9 activity in vitro. GLP-1 and GIP increase insulin biosynthesis and secretion from pancreatic beta cells in the presence of normal and elevated blood glucose levels. Furthermore GLP-1 also reduces glucagon secretion from pancreatic alpha cells, resulting in a reduction in hepatic glucose output. Linagliptin glucose-dependently increases insulin secretion and lowers glucagon secretion thus resulting in an overall improvement in the glucose homoeostasis.
Clinical Trials: A total of 2173 patients with T2DM and inadequate glycaemic control were treated in clinical studies to evaluate the safety and efficacy of Empagliflozin + Linagliptin (GLYXAMBI); 1005 patients were treated with Empagliflozin + Linagliptin (GLYXAMBI) 10 or 25 mg, and linagliptin 5 mg. In clinical trials, patients were treated for up to 24 or 52 weeks.
Empagliflozin + Linagliptin (GLYXAMBI) added to metformin: In a factorial design study, patients inadequately controlled on metformin, 24-weeks treatment with Empagliflozin + Linagliptin (GLYXAMBI) 10 mg/5 mg and Empagliflozin + Linagliptin (GLYXAMBI) 25 mg/5 mg provided statistically significant improvements in HbA_1c and fasting plasma glucose (FPG) compared to linagliptin 5 mg and also compared to empagliflozin 10 or 25 mg. Compared to linagliptin 5 mg Empagliflozin + Linagliptin (GLYXAMBI) provided statistically significant improvements in body weight.
A greater proportion of patients with a baseline HbA_1c ≥7.0% and treated with Empagliflozin + Linagliptin (GLYXAMBI) achieved a target HbA_1c of <7% compared to the individual components (Table 1). After 24 weeks' treatment with empagliflozin/linagliptin, both systolic and diastolic blood pressures were reduced, -5.6/-3.6 mmHg (p<0.001 versus linagliptin 5 mg for SBP and DBP) for Empagliflozin + Linagliptin (GLYXAMBI) 25 mg/5 mg and -4.1/-2.6 mmHg (p<0.05 versus linagliptin 5 mg for SBP, n.s. for DBP) for Empagliflozin + Linagliptin (GLYXAMBI) 10 mg/5 mg.
Clinically meaningful reductions in HbA_1c (Table 1) and both systolic and diastolic blood pressures were observed at week 52, -3.8/-1.6 mmHg (p<0.05 versus linagliptin 5 mg for SBP and DBP) for Empagliflozin + Linagliptin (GLYXAMBI) 25 mg/5 mg and -3.1/-1.6 mmHg (p<0.05 versus linagliptin 5 mg for SBP, n.s. for DBP) for Empagliflozin + Linagliptin (GLYXAMBI) 10 mg/5 mg.
After 24 weeks, rescue therapy was used in 1 (0.7%) patient treated with Empagliflozin + Linagliptin (GLYXAMBI) 25 mg/5 mg and in 3 (2.2%) patients treated with Empagliflozin + Linagliptin (GLYXAMBI) 10 mg/5 mg, compared to 4 (3.1%) patients treated with linagliptin 5 mg and 6 (4.3%) patients treated with empagliflozin 25 mg and 1 (0.7%) patient treated with empagliflozin 10 mg. (See Table 1.)


In a prespecified subgroup of patients with baseline HbA_1c greater or equal to 8.5% the reduction from baseline in HbA_1c with Empagliflozin + Linagliptin (GLYXAMBI) 25 mg/5 mg was -1.8% at 24 weeks (p<0.0001 versus linagliptin 5 mg, p<0.001 versus empagliflozin 25 mg) and -1.8% at 52 weeks (p<0.0001 versus linagliptin 5 mg, p<0.05 versus empagliflozin 25 mg) and with Empagliflozin + Linagliptin (GLYXAMBI) 10 mg/5 mg -1.6% at 24 weeks (p<0.01 versus linagliptin 5 mg, n.s. versus empagliflozin 10 mg) and -1.5% at 52 weeks (p<0.01 versus linagliptin 5 mg, n.s. versus empagliflozin 10 mg).
Empagliflozin + Linagliptin (GLYXAMBI) in treatment-naïve patients: In a factorial design study, after 24-weeks treatment, Empagliflozin + Linagliptin (GLYXAMBI) 25 mg/5 mg in treatment-naïve patients provided statistically significant improvement in HbA_1c compared to linagliptin 5 mg, but there was no statistically significant difference between Empagliflozin + Linagliptin (GLYXAMBI) 25 mg/5 mg and empagliflozin 25 mg (Table 2). Empagliflozin + Linagliptin (GLYXAMBI) 10 mg/5 mg had a 0.4% decrease in HbA_1c as compared to empagliflozin 10 mg. Compared to linagliptin 5 mg both doses of Empagliflozin + Linagliptin (GLYXAMBI) provided statistically relevant improvements in body weight. After 24 weeks' treatment with Empagliflozin + Linagliptin (GLYXAMBI), both systolic and diastolic blood pressures were reduced, -2.9/-1.1 mmHg (n.s. versus linagliptin 5 mg for SBP and DBP) for Empagliflozin + Linagliptin (GLYXAMBI) 25 mg/5 mg and -3.6/-0.7 mmHg (p<0.05 versus linagliptin 5 mg for SBP, n.s. for DBP) for Empagliflozin + Linagliptin (GLYXAMBI) 10 mg/5 mg. Rescue therapy was used in 2 (1.5%) patients treated with Empagliflozin + Linagliptin (GLYXAMBI) 25 mg/5 mg and in 1 (0.7%) patient treated with Empagliflozin + Linagliptin (GLYXAMBI) 10 mg/5 mg compared to 11 (8.3%) patients treated with linagliptin 5 mg, 1 (0.8%) patient treated with empagliflozin 25 mg and 4 (3.0%) patients treated with empagliflozin 10 mg. (See Table 2.)

In a prespecified subgroup of patients with baseline HbA_1c greater or equal to 8.5%, the reduction from baseline in HbA_1c with Empagliflozin + Linagliptin (GLYXAMBI) 25 mg/5 mg was -1.9% at 24 weeks (p<0.0001 versus linagliptin 5 mg, n.s. versus empagliflozin 25 mg) and -2.0% at 52 weeks (p<0.0001 versus linagliptin 5 mg, p<0.05 versus empagliflozin 25 mg) and with Empagliflozin + Linagliptin (GLYXAMBI) 10 mg/5 mg -1.9% at 24 weeks (p<0.0001 versus linagliptin 5 mg, p<0.05 versus empagliflozin 10 mg) and -2.0% at 52 weeks (p<0.0001 versus linagliptin 5 mg, p<0.05 versus empagliflozin 10 mg).
Empagliflozin in patients inadequately controlled on metformin and linagliptin: In patients inadequately controlled on metformin and linagliptin 5 mg, 24-weeks treatment with both empagliflozin 10 mg/linagliptin 5 mg and empagliflozin 25 mg/linagliptin 5 mg provided statistically significant improvements in HbA_1c, FPG and body weight compared to placebo/linagliptin 5 mg. A statistically significant difference in the number of patients with a baseline HbA_1c ≥7.0% and treated with both doses of empagliflozin/linagliptin achieved a target HbA_1c of <7% compared to placebo/linagliptin 5 mg (Table 3). After 24 weeks' treatment with empagliflozin/linagliptin, both systolic and diastolic blood pressures were reduced, -2.6/-1.1 mmHg (n.s. versus placebo for SBP and DBP) for empagliflozin 25 mg/linagliptin 5 mg and -1.3/-0.1 mmHg (n.s. versus placebo for SBP and DBP) for empagliflozin 10 mg/linagliptin 5 mg.
After 24 weeks, rescue therapy was used in 4 (3.6%) patients treated with empagliflozin 25 mg/linagliptin 5 mg and in 2 (1.8%) patients treated with empagliflozin 10 mg/linagliptin 5 mg, compared to 13 (12.0%) patients treated with placebo/linagliptin 5 mg. (See Table 3.)

In a prespecified subgroup of patients with baseline HbA_1c greater or equal to 8.5% the reduction from baseline in HbA_1c with empagliflozin 25 mg/linagliptin 5 mg was -1.3% at 24 weeks (p<0.0001 versus placebo+linagliptin 5 mg) and with empagliflozin 10 mg/linagliptin 5 mg -1.3% at 24 weeks (p<0.0001 versus placebo+linagliptin 5 mg).
Linagliptin 5 mg in patients inadequately controlled on empagliflozin 10 mg and Metformin: In patients inadequately controlled on empagliflozin 10 mg and metformin, 24-weeks treatment with empagliflozin 10 mg/linagliptin 5 mg provided statistically significant improvements in HbA_1c and FPG compared to placebo/empagliflozin 10 mg. Compared to placebo/empagliflozin 10 mg, empagliflozin 10 mg/linagliptin 5 mg provided similar results on body weight. A statistically significantly greater proportion of patients with a baseline HbA_1c ≥7.0% and treated with the empagliflozin 10 mg/linagliptin 5 mg achieved a target HbA_1c of <7% compared to placebo/empagliflozin 10 mg (Table 4). After 24 weeks' treatment with empagliflozin 10 mg/linagliptin 5 mg, both systolic and diastolic blood pressures were similar to placebo/empagliflozin 10 mg (n.s. for SBP and DBP).
After 24 weeks, rescue therapy was used in 2 (1.6%) patients treated with empagliflozin 10 mg/linagliptin 5 mg and in 5 (4.0%) patients treated with placebo/empagliflozin 10 mg.
In a prespecified subgroup of patients (n=66) with baseline HbA_1c greater or equal to 8.5%, the reduction from baseline in HbA_1c empagliflozin 10 mg/linagliptin 5 mg (n=31) was -0.97% at 24 weeks (p=0.0875 versus placebo/empagliflozin 10 mg).
Linagliptin 5 mg in patients inadequately controlled on empagliflozin 25 mg and metformin: In patients inadequately controlled on empagliflozin 25 mg and metformin, 24-weeks treatment with empagliflozin 25 mg/linagliptin 5 mg provided statistically significant improvements in HbA_1c and FPG compared to placebo/empagliflozin 25 mg. Compared to placebo/empagliflozin 25 mg, empagliflozin 25 mg/linagliptin 5 mg provided similar results on body weight. A statistically significantly greater proportion of patients with a baseline HbA_1c ≥7.0% and treated with the empagliflozin 25 mg/linagliptin 5 mg achieved a target HbA_1c of <7% compared to placebo/empagliflozin 25 mg (Table 4). After 24 weeks' treatment with empagliflozin 25 mg/linagliptin 5 mg, both systolic and diastolic blood pressures were similar to placebo/empagliflozin 25 mg (n.s. for SBP and DBP).
After 24 weeks, rescue therapy was used in 0 (0.0%) patients treated with empagliflozin 25 mg/linagliptin 5 mg and in 3 (2.7%) patients treated with placebo/empagliflozin 25 mg.
In a prespecified subgroup of patients (n=42) with baseline HbA_1c greater or equal to 8.5%, the reduction from baseline in HbA_1c with empagliflozin 25 mg/linagliptin 5 mg (n=20) was -1.16% at 24 weeks (p=0.0046 versus placebo+empagliflozin 25 mg). (See Table 4.)

Laboratory parameters: Hematocrit increased: In a placebo controlled trial, mean changes from baseline in haematocrit were 3.3% and 4.2% for Empagliflozin + Linagliptin (GLYXAMBI) 10 mg/5 mg and 25 mg/5 mg, respectively, compared to 0.2% for placebo. In the EMPA-REG OUTCOME trial, haematocrit values returned towards baseline values after a follow-up period of 30 days after treatment stop.
Serum lipids increased: In a placebo controlled trial, mean percent increases from baseline for Empagliflozin + Linagliptin (GLYXAMBI) 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 %.
Cardiovascular safety: In the EMPA-REG OUTCOME trial, empagliflozin significantly reduced the risk of the combined endpoint of CV death, non-fatal myocardial infarction or non-fatal stroke (MACE-3) by 14% when added to standard of care in adults with T2DM and established CV disease. This result was driven by a 38% reduction in CV death, with no significant difference in the risk of non-fatal myocardial infarction or non-fatal stroke.
In the CARMELINA study, linagliptin did not increase the risk of the combined endpoint of CV death, non-fatal myocardial infarction or non-fatal stroke (MACE-3) [Hazard Ratio (HR)=1.02; (95% CI 0.89, 1.17); p=0.0002 for non-inferiority], or the risk of combined endpoint of renal death, ESRD, 40% or more sustained decrease in eGFR [HR=1.04; (95% CI 0.89, 1.22)], when added to standard of care in adult patients with T2DM with increased CV risk evidenced by a history of established macrovascular or renal disease. In addition, linagliptin did not increase the risk of hospitalization for heart failure [HR=0.90; (95% CI 0.74, 1.08)]. No increased risk of CV death or all-cause mortality was observed. Safety data from this study was in line with previous known safety profile of linagliptin.
In the CAROLINA study, linagliptin did not increase the risk of the combined endpoint of CV death, non-fatal myocardial infarction or non-fatal stroke (MACE-3) [Hazard Ratio (HR)=0.98; (95% CI 0.84, 1.14); p<0.0001 for noninferiority], when added to standard of care in adult patients with T2DM with increased CV risk compared to glimepiride. For the entire treatment period the rate of patients with moderate or severe hypoglycaemia was 6.5% on linagliptin versus 30.9% on glimepiride, severe hypoglycaemia (requiring assistance) occurred in 0.3% of patients on linagliptin versus 2.2% on glimepiride.
There have been no clinical studies establishing conclusive evidence of Empagliflozin + Linagliptin (GLYXAMBI)'s effect on cardiovascular morbidity and mortality.
Pharmacokinetics: Pharmacokinetics of the Fixed Dose Combination: The rate and extent of absorption of empagliflozin and linagliptin in empagliflozin/linagliptin are equivalent to the bioavailability of empagliflozin and linagliptin when administered as individual tablets.
The pharmacokinetics of empagliflozin and linagliptin have been extensively characterized in healthy volunteers and patients with T2DM. No clinically relevant differences in pharmacokinetics were seen between healthy volunteers and T2DM patients.
Pharmacokinetics of the single components: Empagliflozin: Absorption: After oral administration, empagliflozin was rapidly absorbed with peak plasma concentrations occurring at a median t_max 1.5 h post-dose. Plasma concentrations declined in a biphasic manner with a rapid distribution phase and a relatively slow terminal phase. With once-daily dosing, steady-state plasma concentrations of empagliflozin were reached by the fifth dose. Systemic exposure increased in a dose-proportional manner for single-dose and steady-state suggesting linear pharmacokinetics with respect to time.
A high-fat, high calorie meal prior to intake of 25 mg empagliflozin resulted in slightly lower exposure compared to fasted condition. The effect was not considered clinically relevant and empagliflozin may be administered with or without food.
Distribution: The apparent steady-state volume of distribution was estimated to be 73.8 L, based on a population pharmacokinetic analysis. Following administration of an oral [¹⁴C]-empagliflozin solution to healthy subjects, the red blood cell partitioning was approximately 36.8% and plasma protein binding was 86.2%.
Biotransformation: No major metabolites of empagliflozin were detected in human plasma and the most abundant metabolites were three glucuronide conjugates (2-O-, 3-O-, and 6-O-glucuronide). Systemic exposure of each metabolite was less than 10% of total drug-related material. In vitro studies suggested that the primary route of metabolism of empagliflozin in humans is glucuronidation by the uridine 5'-diphospho-glucuronosyltransferases UGT2B7, UGT1A3, UGT1A8, and UGT1A9.
Elimination: The apparent terminal elimination half-life of empagliflozin was estimated to be 12.4 h and apparent oral clearance was 10.6 L/h based on the population pharmacokinetic analysis. The inter-subject and residual variabilities for empagliflozin oral clearance were 39.1% and 35.8%, respectively. Consistent with half-life, up to 22% accumulation, with respect to plasma AUC, was observed at steady-state. Following administration of an oral [¹⁴C]-empagliflozin solution to healthy subjects, approximately 95.6% of the drug related radioactivity was eliminated in faeces (41.2%) or urine (54.4%). The majority of drug related radioactivity recovered in faeces was unchanged parent drug and approximately half of drug-related radioactivity excreted in urine was unchanged parent drug.
Linagliptin: Absorption: After oral administration, linagliptin was rapidly absorbed with peak plasma concentrations occurring at a median t_max 1.5 hours post-dose.
After once-daily dosing, steady-state plasma concentrations are reached by the third dose. Plasma AUC increased approximately 33% following 5 mg doses at steady-state compared to the first dose. The intra-subject and inter-subject coefficients of variation for AUC were small (12.6% and 28.5%, respectively). Plasma AUC increased in a less than dose-proportional manner.
The absolute bioavailability of linagliptin is approximately 30%. As coadministration of a high-fat, high calorie meal with linagliptin had no clinically relevant effect on the pharmacokinetics, linagliptin may be administered with or without food.
Distribution: As a result of tissue binding, the mean apparent volume of distribution at steady state following a single 5 mg intravenous dose of linagliptin to healthy subjects is approximately 1110 litres, indicating that linagliptin extensively distributes to the tissues. Plasma protein binding of linagliptin is concentration-dependent, decreasing from about 99% at 1 nmol/L to 75-89% at ≥30 nmol/L, reflecting saturation of binding to DPP-4 with increasing concentration of linagliptin. At high concentrations, where DPP-4 is fully saturated, 70-80% of linagliptin was bound to other plasma proteins than DPP-4, hence 20-30% were unbound in plasma.
Biotransformation: Metabolism plays a subordinate role in the elimination of linagliptin. Following a [¹⁴C] linagliptin oral 10 mg dose, only 5% of the radioactivity was excreted in urine. The main metabolite with a relative exposure of 13.3% of linagliptin at steady state was pharmacologically inactive and thus does not contribute to the plasma DPP-4 inhibitory activity of linagliptin.
Elimination: Plasma concentrations declined in an at least biphasic manner with a long terminal half-life (more than 100 hours), that is mostly related to the saturable, tight binding of linagliptin to DPP-4 and does not contribute to the accumulation of the drug. The effective half-life for accumulation, as determined from oral administration of multiple doses of 5 mg linagliptin, is approximately 12 hours.
Following administration of an oral [¹⁴C] linagliptin dose to healthy subjects, approximately 85% of the administered radioactivity was eliminated in faeces (80%) or urine (5%) within 4 days of dosing. Renal clearance at steady state was approximately 70 mL/min.
Specific Populations: Renal Impairment: Based on pharmacokinetics, no dosage adjustment is recommended for Empagliflozin + Linagliptin (GLYXAMBI) in patients with renal impairment.
Empagliflozin: In patients with mild (eGFR: 60-<90 mL/min/1.73 m²), moderate (eGFR: 30-<60 mL/min/1.73 m²), severe (eGFR: <30 mL/min/1.73 m²) renal impairment (RI) and patients with ESRD, AUC of empagliflozin increased by approximately 18%, 20%, 66%, and 48%, respectively, compared to healthy subjects. Peak plasma levels were similar in patients with moderate RI and ESRD compared to healthy subjects. Peak plasma levels were roughly 20% higher in patients with mild and severe RI compared to healthy subjects. Population pharmacokinetic analysis showed that the apparent oral clearance of empagliflozin decreased with a decrease in eGFR leading to an increase in drug exposure. Based on pharmacokinetics, no dosage adjustment is recommended in patients with RI.
Linagliptin: A study was conducted to compare pharmacokinetics in patients with mild (50 to <80 mL/min), moderate (30 to <50 mL/min), and severe (<30 mL/min) RI and patients with ESRD on hemodialysis. In addition patients with T2DM and severe RI (<30 mL/min) were compared to T2DM patients with normal renal function.
Under steady-state conditions, linagliptin exposure in patients with mild RI was comparable to healthy subjects. In patients with moderate RI, a moderate increase in exposure of about 1.7-fold was observed compared with control. Exposure in patients with T2DM and severe RI was increased by about 1.4-fold compared to patients with T2DM and normal renal function. Steady-state predictions for AUC of linagliptin in patients with ESRD indicated comparable exposure to that of patients with moderate or severe RI. In addition, linagliptin is not expected to be eliminated to a therapeutically significant degree by hemodialysis or peritoneal dialysis. In addition, mild renal insufficiency had no effect on linagliptin pharmacokinetics in patients with T2DM as assessed by population pharmacokinetic analyses.
Hepatic Impairment: Based on pharmacokinetics of the two individual components, no dosage adjustment of Empagliflozin + Linagliptin (GLYXAMBI) is recommended in patients with hepatic impairment.
Body Mass Index (BMI): No dosage adjustment is necessary for Empagliflozin + Linagliptin (GLYXAMBI) based on BMI. Body mass index had no clinically relevant effect on the pharmacokinetics of empagliflozin or linagliptin based on population pharmacokinetic analysis.
Gender: No dosage adjustment is necessary for Empagliflozin + Linagliptin (GLYXAMBI). Gender had no clinically relevant effect on the pharmacokinetics of empagliflozin or linagliptin based on population pharmacokinetic analysis.
Race: No dosage adjustment is necessary for Empagliflozin + Linagliptin (GLYXAMBI) based on population pharmacokinetic analysis and on dedicated phase I studies.
Geriatric: Age did not have a clinically meaningful impact on the pharmacokinetics of empagliflozin or linagliptin based on population pharmacokinetic analysis. Elderly subjects (65 to 80 years) had comparable plasma concentrations of linagliptin compared to younger subjects.
Paediatric: Studies characterizing the pharmacokinetics of empagliflozin or linagliptin in paediatric patients have not been performed.
Drug Interactions: In vitro assessment of drug interactions: For empagliflozin: Empagliflozin does not inhibit, inactivate, or induce CYP450 isoforms. In vitro data suggest that the primary route of metabolism of empagliflozin in humans is glucuronidation by the uridine 5'-diphospho-glucuronosyltransferases UGT2B7, UGT1A3, UGT1A8, and UGT1A9. Empagliflozin does not inhibit UGT1A1. At therapeutic doses, the potential for empagliflozin to reversibly inhibit or inactivate the major CYP450 isoforms or UGT1A1 is remote. Drug-drug interactions involving the major CYP450 isoforms or UGT1A1 with empagliflozin and concomitantly administered substrates of these enzymes are therefore considered unlikely.
Empagliflozin is a substrate for P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), but it does not inhibit these efflux transporters at therapeutic doses. Based on in vitro studies, empagliflozin is considered unlikely to cause interactions with drugs that are P-gp substrates. Empagliflozin is a substrate of the human uptake transporters OAT3, OATP1B1, and OATP1B3, but not OAT1 and OCT2. Empagliflozin does not inhibit any of these human uptake transporters at clinically relevant plasma concentrations and, as such, drug-drug interactions with substrates of these uptake transporters are considered unlikely.
For linagliptin: Linagliptin is a weak competitive and a weak to moderate mechanism-based inhibitor of CYP3A4, but does not inhibit other CYP isozymes. It is not an inducer of CYP isozymes. Linagliptin is a P-glycoprotein substrate, and inhibits P-glycoprotein mediated transport of digoxin with low potency. Based on these results and in vivo drug interaction studies, linagliptin is considered unlikely to cause interactions with other P-gp substrates. Linagliptin was a substrate for OATP8-, OCT2-, OAT4-, OCTN1- and OCTN2, suggesting a possible OATP8-mediated hepatic uptake, OCT2-mediated renal uptake and OAT4-, OCTN1- and OCTN2-mediated renal secretion and reabsorption of linagliptin in vivo. OATP2, OATP8, OCTN1, OCT1 and OATP2 activities were slightly to weakly inhibited by linagliptin.
In vivo assessment of drug interactions: No clinically meaningful interactions were observed when empagliflozin or linagliptin were coadministered with other commonly used medicinal products. Based on results of pharmacokinetic studies no dose adjustment of Empagliflozin + Linagliptin (GLYXAMBI) is recommended when co-administered with commonly prescribed medicinal products.
Empagliflozin: Empagliflozin had no clinically relevant effect on the pharmacokinetics of linagliptin, metformin, glimepiride, pioglitazone, sitagliptin, warfarin, digoxin, verapamil, ramipril, simvastatin, torasemide, hydrochlorothiazide and oral contraceptives when coadministered in healthy volunteers. Increases in overall exposure (AUC) of empagliflozin were seen following co-administration with gemfibrozil (59%), rifampicin (35%), or probenecid (53%). These changes were not considered to be clinically meaningful.
Empagliflozin may add to the diuretic effect of thiazide and loop diuretics and may increase the risk of dehydration and hypotension.
Linagliptin: Linagliptin had no clinically relevant effect on the pharmacokinetics of metformin, glibenclamide, simvastatin, pioglitazone, warfarin, digoxin, empagliflozin, or oral contraceptives providing in vivo evidence of a low propensity for causing drug interactions with substrates of CYP3A4, CYP2C9, CYP2C8, P-glycoprotein, and organic cationic transporter (OCT).
Changes in overall exposure (AUC) of linagliptin were seen following co-administration with ritonavir (approx. 2-fold increase) and rifampicin (40% decrease). These changes were not considered to be clinically meaningful.
Toxicology: General toxicity studies in rats up to 13 weeks were performed with the combination of empagliflozin and linagliptin. Signs of toxicity were observed at exposures greater than 13 times the clinical AUC exposure. These studies indicated that no additive toxicity was caused by the combination of empagliflozin and linagliptin.
Carcinogenicity: No carcinogenicity studies with the combination of empagliflozin and linagliptin have been performed.
Empagliflozin did not increase the incidence of tumors in female rats at doses up to the highest dose of 700 mg/kg/day, which is approximately 72 times the clinical AUC exposure of 25 mg. In male rats, treatment-related benign vascular proliferative lesions (hemangiomas) of the mesenteric lymph node, were observed at 700 mg/kg/day, but not at 300 mg/kg/day, which is approximately 26 times the clinical exposure of 25 mg. These tumors are common in rats and are unlikely to be relevant to humans. Empagliflozin did not increase the incidence of tumors in female mice at doses up to 1000 mg/kg/day, which is approximately 62 times the clinical exposure of 25 mg. Renal tumors were not observed in male mice at 300 mg/kg/day, which is approximately 11 times the clinical exposure of 25 mg. There was an increase in renal adenomas and carcinomas in male mice given empagliflozin at 700 mg/kg/day, which is approximately 45 times the clinical exposure of 25 mg. The mode of action for these tumors is dependent on the natural predisposition of the male mouse to renal pathology and a metabolic pathway not reflective of humans. The male mouse renal tumors are considered not relevant to humans.
A two-year carcinogenicity study was conducted in male and female rats given oral doses of linagliptin of 6, 18, and 60 mg/kg/day. There was no increase in the incidence of tumors in any organ up to 60 mg/kg/day. This dose results in exposures approximately 418 times the human exposure at the maximum recommended daily adult human dose (MRHD) of 5 mg/day based on AUC comparisons. A two-year carcinogenicity study was conducted in male and female mice given oral doses of 8, 25 and 80 mg/kg/day. There was no evidence of a carcinogenic potential up to 80 mg/kg/day, approximately 242 times human exposure at the MRHD.
Genotoxicity: No genotoxicity studies with the combination of empagliflozin and linagliptin have been performed.
Empagliflozin and linagliptin are not genotoxic.
Reproduction Toxicity: The combined products administered during the period of organogenesis were not teratogenic in rats up to and including a combined dose of 700 mg/kg/day empagliflozin and 140 mg/kg/day linagliptin, which is 253- and 353-times the clinical AUC exposure. No maternal toxicity was seen in a combination of 300 mg/kg/day empagliflozin and 60 mg/kg/day linagliptin which is 99- and 227-times the clinical AUC exposure. Adverse effects on renal development were not observed after administration of empagliflozin alone, linagliptin alone or after administration of the combined products.
Nonclinical studies show that empagliflozin crosses the placenta during late gestation to a very limited extent but do not indicate direct or indirect harmful effects with respect to early embryonic development. Empagliflozin administered during the period of organogenesis was not teratogenic at doses up to 300 mg/kg in the rat or rabbit, which corresponds to approximately 48- and 122-times or 128- and 325-times the clinical dose of empagliflozin based on AUC exposure associated with the 25 mg and 10 mg doses, respectively. Doses of empagliflozin causing maternal toxicity in the rat also caused the malformation of bent limb bones at exposures approximately 155- and 393-times the clinical dose associated with the 25 mg and 10 mg doses, respectively. Maternally toxic doses in the rabbit also caused increased embryofetal loss at doses approximately 139- and 353-times the clinical dose associated with the 25 mg and 10 mg doses, respectively.
In pre- and postnatal toxicity studies in rats, reduced weight gain in offspring was observed at maternal exposures approximately 4- and 11-times the clinical dose associated with the 25 mg and 10 mg doses, respectively.
In rat fertility studies of linagliptin with oral gavage doses of 10, 30 and 240 mg/kg/day, males were treated for 4 weeks prior to mating and during mating; females were treated 2 weeks prior to mating through gestation day 6. No adverse effect on early embryonic development, mating, fertility, and bearing live young were observed up to the highest dose of 240 mg/kg/day (approximately 943 times human exposure at the MRHD of 5 mg/day based on AUC comparisons).
In the studies on embryo-fetal development in rats and rabbits, linagliptin was shown to be not teratogenic at dosages up to and including 240 mg/kg/day (943x MRHD) in the rat and 150 mg/kg/day (1943x MRHD) in the rabbit.
A NOAEL of 30 mg/kg/day (49x MRHD) and 25 mg/kg (78x MRHD) was derived for embryo-fetal toxicity in the rat and the rabbit, respectively.
In a juvenile toxicity study in the rat, when empagliflozin was administered from postnatal day 21 until postnatal day 90, non-adverse, minimal to mild renal tubular and pelvic dilation in juvenile rats was seen only at 100 mg/kg/day, which approximates 11-times the maximum clinical dose of 25 mg. These findings were absent after a 13-week, drug-free recovery period.