Empagliflozin/Linagliptin – Pharmacy Diabetes

Name of Medicine

Empagliflozin and linagliptin.

Presentation

Empagliflozin/Linagliptin 25 mg/5 mg contains 25 mg empagliflozin and 5 mg linagliptin.
Empagliflozin/Linagliptin 10 mg/5 mg contains 10 mg empagliflozin and 5 mg linagliptin.

Key Practice Points

Therapeutic Indications:

Empagliflozin/Linagliptin tablets are indicated as an adjunct to healthy eating and physical activity to improve glycaemic management in adults with type 2 diabetes when treatment with both empagliflozin and linagliptin is appropriate.

For the latest PBS indications for Empagliflozin/Linagliptin, please see

https://www.pbs.gov.au/medicine/item/11269D-11298P-11303X-11310G

Dose:

The recommended starting dose of mpagliflozin/Linagliptin is 10 mg/5 mg once daily.
In those tolerating empagliflozin/Linagliptin 10 mg/5 mg once daily and requiring additional glycaemic management, the dose can be increased to mpagliflozin/Linagliptin 25 mg/5 mg once daily.
In individuals already on empagliflozin, the dose of Empagliflozin/Linagliptin should provide the dose of empagliflozin similar to the dose already taken.
Empagliflozin/Linagliptin can be taken with or without food and at any time of day.
Combination therapy. When Empagliflozin/Linagliptin is used in combination with a sulfonylurea or with insulin, a lower dose of the sulfonylurea or insulin maybe considered to reduce the risk of hypoglycaemia.

Note: Diabetes MedsCheck with counselling on managing hypoglycaemia and referral to healthcare team and blood glucose monitoring.

Renal Impairment. Assess renal function prior to initiation of empagliflozin and periodically thereafter.

Glycaemic management is reduced in those with eGFR< 30 mL/min/1.73 m. Empagliflozin/Linagliptin is contraindicated in individuals with persistent eGFR< 30 mL/min/1.73 m.

Therapeutic experience with Empagliflozin/Linagliptin is limited in those with eGFR< 60 mL/min.

No dose adjustment is required for those with eGFR≥ 30 mL/min/1.73 m.

Monitoring of renal function. Due to its mechanism of action, the efficacy of empagliflozin is dependent on renal function. Therefore, assessment of renal function is recommended: prior to empagliflozin initiation and periodically during treatment, i.e., at least yearly; prior to initiation of concomitant medicines that may reduce renal function and periodically thereafter.

Empagliflozin/Linagliptin should be discontinued when the eGFR is persistently below 30 mL/min/1.73 m or CrCl < 30 mL/min.

Hepatic impairment. No dose adjustment is recommended for people with hepatic impairment.

Elderly:

No dosage adjustment is recommended based on age. Therapeutic experience in those aged 75 years and older is limited. Initiation of Empagliflozin/Linagliptin therapy in this population is not recommended.

Paediatric:

The safety and effectiveness of Empagliflozin/Linagliptin in children below 18 years of age have not been established. Empagliflozin/Linagliptin is not recommended for use in individuals under 18 years of age.

Contraindications:

Hypersensitivity to empagliflozin or linagliptin or any of the excipients.
Individuals with eGFR persistently < 30 mL/min/1.73 m or CrCl persistently < 30 mL/min.
Type 1 diabetes.

Precautions:

Ketoacidosis

Empagliflozin/Linagliptin should not be used for the treatment of ketoacidosis.

Ketoacidosis, a serious life-threatening condition requiring urgent hospitalisation, have been reported in post marketing surveillance in individuals treated with SGLT2 inhibitors, including empagliflozin. Fatal cases of ketoacidosis have been reported in people taking Those treated with Empagliflozin/Linagliptin who present with signs and symptoms consistent with severe metabolic acidosis should be assessed for ketoacidosis regardless of presenting blood glucose levels as ketoacidosis associated with Empagliflozin/Linagliptin maybe present even if blood glucose levels are less than 13.8 mmol/L.
Signs and symptoms of ketoacidosis may include excessive thirst, nausea, vomiting, abdominal pain, generalised malaise, and shortness of breath. If ketoacidosis is suspected Empagliflozin/Linagliptin should be discontinued, the person should be evaluated, and prompt treatment should be instituted.
Treatment of ketoacidosis generally requires insulin, fluid, potassium, and carbohydrate replacement.
Restarting SGLT2 inhibitor treatment in those with previous ketoacidosis while on SGLT2 inhibitor treatment is not recommended unless another clear precipitating factor is identified and resolved.
Before initiating Empagliflozin/Linagliptin, consider factors in the history that may predispose to ketoacidosis.
Factors that predispose individuals to ketoacidosis include a low carbohydrate diet, dehydration, acute illness, surgery, previous ketoacidosis, insulin deficiency from any cause (history of pancreatitis, or pancreatic surgerourishment/reduced caloric intake or increased insulin requirements due to infections, and alcohol abuse). Empagliflozin/Linagliptin should be used with caution in these individuals.

Note: Diabetes MedsCheck with referral to healthcare team for sick day management plan.

Surgery

Treatment with Empagliflozin/Linagliptin should be ceased prior to major surgery. An increase in other glucose lowering agents maybe required during this time. Those scheduled for non-urgent surgery who have not ceased empagliflozin should be assessed and consideration should be given to postponing the procedure.

Treatment with Empagliflozin/Linagliptin may be restarted once the person’s condition has stabilised and oral intake is normal.

Note: Diabetes MedsCheck with referral to healthcare team for sick day management plan.

Adverse Effects:

Empagliflozin.

Lower limb amputations.

An increase in cases of lower limb amputation (primarily of the toe) has been observed in a long-term clinical study with another SGLT2 inhibitor. The medicine in that study is not empagliflozin. However, it is unknown whether this constitutes a class effect. It is important to regularly examine the feet and counsel all individuals with diabetes on routine preventative foot care.

Note: Diabetes MedsCheck with referral to healthcare team for annual cycle of care – footcare.

Volume depletion.

Based on the mode of action of SGLT2 inhibitors, osmotic diuresis accompanying therapeutic glucosuria may lead to a modest decrease in BP. Therefore, caution should be exercised in those for whom an empagliflozin-induced drop in BP could pose a risk. This includes cardiovascular disease those on anti-hypertensive therapy, with a history of hypotension or those aged 75 years and older.

Note: Diabetes MedsCheck and counselling on side effect profile.

Urosepsis and pyelonephritis.

There have been post marketing reports of serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalisation in individuals receiving SGLT2 inhibitors, including empagliflozin. Treatment with SGLT2 inhibitors increases the risk for urinary tract infections. Evaluate for signs and symptoms of urinary tract infections and treat promptly, if indicated discontinuation of empagliflozin maybe considered in cases of recurrent urinary tract infections.

Note: Diabetes MedsCheck with counselling on side effect profile.

Genital infections including life threatening necrotising fasciitis. Post marketing cases of necrotising fasciitis of the perineum (also known as Fournier’s gangrene), are rare, but serious and life-threatening necrotising infection, have been reported in females and males with diabetes mellitus treated with SGLT2 inhibitors, including empagliflozin. Serious outcomes have included hospitalisation, multiple surgeries, and death. Those treated with v who present with pain or tenderness, erythema, swelling in the genital or perineal area, fever, malaise should be evaluated for necrotising. Note: Diabetes MedsCheck with counselling on side effect profile

Linagliptin

Bullous pemphigoid. Bullous pemphigoid has been observed in individuals taking linagliptin. If bullous pemphigoid is suspected, Empagliflozin/Linagliptin should be discontinued. Note: Diabetes MedsCheck with counselling on side effect profile.

Arthragia.

There have been post marketing reports of joint pain, which maybe severe, in those taking DPP-4 inhibitors. Onset of symptoms following initiation of treatment maybe rapid or may occur after longer periods. Discontinuation of therapy should be considered in those who present with or experience an exacerbation of joint symptoms during treatment with linagliptin.

Pencreatitis.

Acute pancreatitis has been observed in those taking linagliptin. If pancreatitis is suspected, Empagliflozin/Linagliptin should be discontinued.

Note: Diabetes MedsCheck with counselling on side effect profile.

Pharmacokinetic Properties Summary

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 characterised in people with and without type 2 diabetes. No clinically relevant differences in pharmacokinetics were seen between either group.
The following statements reflect the pharmacokinetic properties of the individual active substances of Empagliflozin/Linagliptin.

Absorption:

Empagliflozin

After oral administration, empagliflozin was rapidly absorbed with peak plasma concentrations with a median Cmax (t max) of 1.5 h post-dose. The observed effect of food on empagliflozin pharmacokinetics was not considered clinically relevant and empagliflozin maybe administered with or without food.

Linagliptin

The effective half-life for accumulation of linagliptin, as determined from oral administration of multiple doses of 5 mg linagliptin, is approximately12 hours. Linagliptin maybe administered with or without food

Distribution:

The apparent steady-state volume of distribution was estimated to be 73.8 L. The red blood cell partitioning was approximately 36.8% and plasma protein binding was 86.2%.

Linagliptin. Plasma protein binding of linagliptin is concentration-dependent, decreasing from about 99% at 1 nanomol/L to 75-89% at ≥ 30 nanomol/L, reflecting saturation of binding to DPP-4 with increasing concentration of linagliptin.

Metabolism:

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).

Linagliptin. Following a [ C]-linagliptin oral 10 mg dose, only 5%of the radioactivity was excreted in urine. Metabolism plays a subordinate role in the elimination of linagliptin.

Excretion:

The apparent terminal elimination half-life of empagliflozin was estimated to be 12.4 h.

Following administration of an oral [ C]-linagliptin dose to people without diabetesproximately 85% of the administered radio activity was eliminated in faeces (80%) or urine (5%) within 4 days of dosing. Renal clearance at steady state was approximately 70 mL/min.

More Information

For further information on Empagliflozin/Linagliptin, please see

https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/PICMI?OpenForm&t=&q=empagliflozin