Empagliflozin
Medicine Type :
Allopathy
Allopathy
Prescription Type:
Prescription Required
Prescription Required
Approval :
DCGI (Drugs Controller General of India)
DCGI (Drugs Controller General of India)
Schedule
Schedule H
Schedule H
Pharmacological Class:
Sodium-glucose cotransporter-2 (SGLT2) inhibitors, Therapy Class:
Antidiabetic Agent, Approved Countries
India, the United States, Canada, the United Kingdom, France, Japan, Germany and Australia.
Empagliflozin is an anti-diabetic Agent belonging to the pharmacological class of Sodium-glucose cotransporter-2 (SGLT2) Inhibitors.
Empagliflozin is approved to treat type 2 diabetes by helping to lower blood sugar levels through the inhibition of glucose reabsorption in the kidneys, leading to increased glucose excretion in urine.
Following oral administration, empagliflozin is rapidly absorbed and mostly dispersed in the systemic circulation. The liver breaks it down into active and inactive metabolites. Renal excretion is the primary process for elimination.
Empagliflozin's most common side effects are nausea, frequent urge to urinate, increased thirst, urinary tract infections, vaginal yeast infection, joint pain, and hypoglycemia (low blood sugar levels).
Empagliflozin is available in the form of oral tablets.
The molecule is available in India, the United States, Canada, the United Kingdom, France, Japan, Germany and Australia.
Empagliflozin is an anti-diabetic agent belonging to the pharmacological class of Sodium-glucose cotransporter-2 (SGLT2) Inhibitors.
Around 90% of the total glucose reabsorption in the kidneys occurs in the proximal tubule and is primarily carried through SGLT2 (sodium-glucose linked co-transporter-2). Therefore, the majority of glucose that is filtered through the glomerulus is reabsorbed in the tubule. To generate a Na+ gradient inside the tubular cell, Na+/K+-ATPase on the basolateral membrane of proximal tubular cells actively pumps Na+ ions into the interstitium surrounding the tubule using ATP. By blocking this co-transport, SGLT2 on the apical membrane of these cells can increase glucosuria and decrease blood glucose levels significantly. SGLT2 uses this gradient to facilitate secondary active co-transport of both Na+ and glucose out of the filtrate, reabsorbing glucose back into the blood. By increasing glucosuria, empagliflozin, a strong inhibitor of renal SGLT2 transporters found in the kidney's proximal tubules, lowers blood sugar levels.
Although the precise mechanism underlying this benefit remains unknown, empagliflozin also has cardiovascular benefits, particularly in preventing heart failure, independent of its effects on blood glucose levels. Several hypotheses have been proposed, such as the potential inhibition of the Na+/H+ exchangers (NHE) 1 in the heart and NHE3 in the proximal tubule, the reduction of pro-inflammatory adipokines and diuretic/natriuretic effects to lower blood pressure and pre-load, and the prevention of cardiac fibrosis through the suppression of pro-fibrotic markers.
Data duration of empagliflozin action typically lasts up to 24 hours after administration.
The Data of Tmax of empagliflozin is approximately 1.5 hours after oral administration.
The Data of Cmax of empagliflozin approximately 2 hours following oral administration.
Empagliflozin is available in the form of Oral Tablets.
Tablets: To be swallowed whole with water/liquid. Do not chew, crush or break it.
As the physician recommends, take the medication orally once daily, generally with or without a meal.
Management of type 2 diabetes mellitus is primarily done through the use of empagliflozin. To promote the elimination of extra glucose in the urine, it reduces the kidneys' ability to reabsorb glucose. This is commonly used with a nutritious diet and regular exercise to help treat diabetes mellitus type 2 since it lowers blood sugar levels.
In Treatment of Type 2 diabetes mellitus
For people with type 2 diabetes, sodium-glucose cotransporter-2 (SGLT-2) inhibitors like empagliflozin promote the excretion of extra glucose through the urine, which might improve blood sugar regulation and perhaps result in weight loss.
To effectively manage diabetes, the blood glucose levels must be reduced. Controlling blood sugar levels will lower the likelihood of any of the severe complications of diabetes, including kidney damage, eye damage, nerve problems, and amputation of limbs. The risk of cardiac disease and stroke can be decreased with proper diabetes management. Individuals can live longer if they take this medication consistently and follow a healthy diet and exercise routine.
Empagliflozin is indicated:
- To lower the risk of heart failure hospitalization and cardiovascular death in adult heart failure patients.
- To lessen the likelihood that persons with chronic renal disease at risk of progression may experience hospitalization, end-stage kidney disease, cardiovascular mortality, and a prolonged fall in eGFR.
- To lower the risk of cardiovascular death in individuals with existing cardiovascular disease and type 2 diabetes mellitus.
- As an addition to diet and exercise in those individuals with type 2 diabetes mellitus who are adults or pediatric patients ten years of age and older to enhance glycemic control.
Limitations of Use:
- It is not recommended for people with type 1 diabetes mellitus to utilize empagliflozin to achieve better glycemic control. It might put these individuals at higher risk for developing diabetic ketoacidosis.
- It is not recommended for people with type 1 diabetes mellitus to utilize empagliflozin to achieve better glycemic control. It might put these individuals at higher risk for developing diabetic ketoacidosis.
- For the treatment of chronic kidney disease (CKD) in patients with polycystic kidney disease, those requiring or having recently undergone intravenous immunosuppressive medication, or those taking more than 45 mg of prednisone or its equivalent for renal disease, empagliflozin is not recommended.
Orally: Empagliflozin can be taken with or without food. Patients should ensure they maintain proper fluid intake to reduce the risk of hypotension. If a dose is missed, it should be taken as soon as possible, but patients should not double the following amount.
The dosage and duration of treatment should be as per the treating physician's clinical judgment.
Tablets: 10mg, 25 mg.
Empagliflozin is available in the form of oral tablets.
Dose Adjustment in Adult Patients:
Diabetes Mellitus Type 2
10 mg per day PO
May increase to 25 mg per day if necessary and well tolerated.
Heart Failure
It is recommended to lower the risk of hospitalization and cardiovascular death in those adult patients with heart failure (HF)
10 mg per day PO
Chronic Kidney Disease
recommended to lessen the likelihood that persons with chronic renal disease at risk of progression may experience a prolonged fall in eGFR, end-stage kidney disease, cardiovascular death, and hospitalization.
10 mg per day PO
Dosage Adjustments
Surgery
If at all feasible, wait three days before undergoing major surgery or other operations involving extended fasting.
Resume as soon as the patient achieves oral intake and is clinically stable.
Empagliflozin should be used in treating Type 2 Diabetes Mellitus, along with appropriate nutritional limits.
While taking Empagliflozin, avoid large meals and maintain regular meals with balanced macronutrient content to help stabilize blood sugar levels.
Limit alcohol consumption while taking empagliflozin, as Alcohol can higher the risk of dehydration and hypotension.
Avoid high-calorie, high-fat meals as they may increase the risk of gastrointestinal side effects.
It is advised to stay hydrated, maintain a rich, balanced diet with appropriate carbohydrate intake, and consume plenty of vegetables, whole grains, fruits, and lean proteins to help manage your overall health and blood sugar levels effectively.
The dietary restriction should be individualized as per patient requirements.
Empagliflozin may be contraindicated in the following conditions: -
- Severe hypersensitivity to empagliflozin, such as angioedema or anaphylaxis.
- Patients undergoing dialysis.
- Hypotension: Evaluate and adjust the state of patients with renal impairment, the elderly, those with low systolic blood pressure, and those using diuretics before starting empagliflozin. Monitor for symptoms while receiving therapy.
Ketoacidosis: Regardless of blood glucose level, patients with metabolic acidosis signs and symptoms should be evaluated for ketoacidosis.
- Eliminate empagliflozin if suspected, assess the situation, and start treatment immediately. Consider the risks associated with ketoacidosis before starting Empagliflozin. In clinical settings where ketoacidosis is known to be predisposed, patients taking empagliflozin may need to be closely monitored and have their medication temporarily stopped. Patients with impaired renal function, the elderly, or those on loop diuretics should have their volume status and renal function evaluated, according to empagliflozin. While receiving therapy, monitor for any indications or symptoms.
- Pyelonephritis and Urosepsis: Assess for urinary tract infection symptoms and signs in patients and treat promptly if necessary.
- Necrotizing Fasciitis of the Perineum (Fournier's Gangrene): Both men and women have experienced severe, potentially fatal episodes of necrotizing fasciitis of the perineum, sometimes known as Fournier's gangrene. Assess those who exhibit fever or malaise associated with vaginal or perineal pain, soreness, or erythema. Give immediate therapy if suspected.
- Infections with Genital Mycotics: Close attention and appropriate action is required.
Alcohol Warning
It is unsafe to consume Empagliflozin with Alcohol.
Breast Feeding Warning
There is no sufficient scientific evidence traceable regarding the use and safety of Empagliflozin in breastfeeding.
Pregnancy Warning
Safe to use during pregnancy only if the possible benefit outweighs the potential risk to the foetus. Use caution.
Food Warning
Limit Alcohol and avoid fatty or high-calorie meals.
The adverse reactions related to Empagliflozin can be categorized as:
- Common Adverse Effects: Genital and urinary tract infections, Increased thirst, Hypoglycemia
- Less Common Adverse Effects: Upper respiratory tract infections, arthralgia, nausea, polydipsia, dyslipidemia, female genital mycotic infections, urinary tract infections, and increased urination.
- Rare Adverse Effects: Adverse effects of volume depletion, such as syncope, hypotension, hypovolemia, orthostatic hypotension, lowered blood pressure, and decreased blood pressure during ambulatory. Increased urination (such as nocturia)
Reports on Post-marketing
The ketoacidosis
Pyelonephritis and urosepsis
Necrotizing fasciitis of the lower leg (Fournier's gangrene)
Angiopathic swelling.
Skin responses
Acute kidney damage
Abdominal pain
Constipation
Patients with type 1 diabetes and other ketoacidosis may experience diabetic ketoacidosis.
The clinically relevant drug interactions of Empagliflozin are briefly summarized here.
- Diuretics: Concomitant use of diuretics may increase the risk of dehydration and hypotension. Close monitoring of blood pressure and renal function is recommended.
- Antihypertensive Medications: Combining empagliflozin with antihypertensive drugs may lead to additive blood pressure-lowering effects. Adjustments in antihypertensive medications may be required.
- Medications that Affect Renal Function: Medications that influence renal function, such as non-steroidal anti-inflammatory drugs (NSAIDs) and angiotensin-converting enzyme (ACE) inhibitors, may interact with empagliflozin. These interactions can affect kidney function, so caution and monitoring are essential.
- Insulin and Insulin-Secreting Medications: When empagliflozin is combined with insulin or insulin-secreting medications, the risk of Hypoglycemia (low blood sugar) increases. Dose adjustments of insulin or diabetes medication may be necessary.
- CYP2C8 Inhibitors and Inducers: Medications that inhibit or induce the CYP2C8 enzyme may alter the pharmacokinetics of empagliflozin. Dose adjustments may be required.
- High-Dose Salicylates: High-dose salicylates like aspirin may affect blood glucose control and require dose adjustments.
- P-gp Inhibitors: Co-administration of empagliflozin with P-glycoprotein (P-gp) inhibitors may impact empagliflozin's renal secretion. Adjustments in empagliflozin dosage might be needed.
The most common side effects of Empagliflozin include:
- Vomiting
- Urge to urinate frequently
- An increase in thirst
- Urinary tract infection
- Low blood sugar, or Hypoglycemia, combined with sulphonylurea or insulin
- Yeast infection in vagina
- Pain in the joints
- Pregnancy:
Pregnancy Category C. Use with caution if the benefits outweigh the risks.
Use is not advised during the second and third trimesters of pregnancy due to animal research demonstrating detrimental effects on the kidneys.
There is not enough information on pregnant women's use of drugs to establish a link between those drugs and severe birth abnormalities and miscarriages.
Inadequately managed diabetes during pregnancy poses risks for both the mother and the fetus.
Animal data
In experiments on animals, rats given empagliflozin at the time of renal development that corresponds to the late second and third trimesters of human pregnancy saw negative changes in their kidneys.
Renal pelvic and tubule dilatations were reversible when doses less than 13 times the maximum clinical dose were administered.
Not teratogenic in the rats and rabbits up to 300 mg/kg/day, or around 48 and 128 times, respectively, the maximum clinical dose of 25 mg when given during organogenesis.
Clinical Considerations
Uncontrolled diabetes during pregnancy raises the risk of diabetic ketoacidosis, pre-eclampsia, spontaneous miscarriages, preterm birth, stillbirth, and delivery complications for the mother; it also increases the risk of significant congenital disabilities, stillbirth, and morbidity related to macrosomia in the fetus.
- Nursing mothers:
There are no data on the presence of Empagliflozin in human milk, the effects on breastfed infants, or the impact on milk production. Empagliflozin was found in the milk of nursing rats.
In addition to the mother's clinical requirement for Empagliflozin and any possible adverse effects on the breastfed newborn from Empagliflozin or the underlying maternal disease, it is essential to consider the developmental and health advantages of breastfeeding.
Data
In lactating rats, Empagliflozin was present unchanged in milk at approximately 50% of maternal plasma concentrations.
- Pediatric Use:
In pediatric patients of 10 years of age and older, the safety and efficacy of empagliflozin as an addition to diet and exercise to improve glycemic control in type 2 diabetes mellitus have been proven. Evidence from a 26-week double-blind, placebo-controlled clinical trial, a pediatric pharmacokinetic study, and a double-blind active treatment safety extension period of up to 52 weeks in 157 pediatric patients with type 2 diabetes mellitus aged 10 to 17 years support the use of empagliflozin for this indication.
Dose Adjustment in Pediatric Patients:
Diabetes Mellitus Type 2
Less than ten years: effectiveness and safety are unknown.
>10 years
10 mg PO qAM
May increase to 25 mg per day if necessary and well tolerated.
Dosing Considerations
Restrictions on Use
Not recommended for the management of diabetic ketoacidosis or type 1 diabetes
When used to enhance glycemic control in patients with type 2 diabetes mellitus and an eGFR of <30 mL/min/1.73 m2, it is not advised.
Prior to starting treatment
Evaluate renal function both prior to and after each visit.
Accurate state in individuals experiencing volume depletion.
- Geriatric Use:
Empagliflozin is generally safe and effective in geriatric patients when used with proper monitoring. Adjustments in dosage might be necessary due to age-related changes. Potential side effects should be closely observed in this population.
Dosage adjustment in geriatric patients
Age-related dose changes are not advised; see Adult Dosing.
Patients over 75 years of age who had a higher risk of volume depletion-related adverse reactions: 2.1%, 2.3%, and 4.4% for placebo, 10 mg, and 25 mg, respectively.
Patients over the age of 75 had a higher risk of urinary tract infections: 10.5%, 15.7%, and 15.1%, respectively, for those randomly assigned to receive a placebo, 10 mg, and 25 mg.
Dose Adjustment in Kidney Impairment Patients:
Type 2 diabetes mellitus
30-90 mL/min/1.73 m2 eGFR: No dosage modification is necessary.
In the absence of cardiovascular risk factors, eGFR <30 mL/min/1.73 m2: Not suggested
Individuals with existing cardiovascular disease or cardiovascular risk factors who have end-stage renal disease or an eGFR >30 mL/min/1.73 m2: There is not enough data; There are no dosage guidelines provided.
Dialysis patients: Not recommended.
The benefit of 25 mg/day of glucose reduction was lessened in patients whose renal function was worsening.
As renal function declined, accompanied by the risks of volume depletion, adverse reactions, renal impairment, and adverse reactions due to urinary tract infections.
HF
eGFR ≥20 mL/min/1.73 m2: There is no need to change the dosage.
Lower than 20 mL/min/1.73 m2: There are no dose guidelines and insufficient data.
When a patient's eGFR is less than 30 mL/min/1.73 m2, and they have no history of cardiovascular disease (CVD) or cardiovascular risk factors, it is not advised.
Dialysis patients: Not recommended.
Dose Adjustment in Hepatic Impairment Patients:
Hepatic impairment: No dosage adjustment is required
Signs and Symptoms
The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of Empagliflozin.
Overconsumption of Empagliflozin may include hypotension (low blood pressure), dehydration, electrolyte imbalances, and possible symptoms of ketoacidosis in individuals with diabetes.
Management
There is no specific antidote or treatment for excessive intake of Empagliflozin. However, immediate medical attention is essential. Empagliflozin should be terminated immediately when an overdose is suspected or if any unusual symptoms occur after intake.
Activated charcoal may also be administered to reduce further absorption of the drug, especially if ingestion occurred recently.
Intravenous fluid administration is required to correct dehydration and maintain electrolyte balance. Patients may experience increased urine output due to the diuretic effect of empagliflozin, potentially leading to dehydration.
Management typically involves supportive measures like intravenous fluids, fluid replacement to prevent dehydration, and symptomatic treatment such as antiemetic medications for nausea and vomiting.
Maintain a healthy lifestyle through proper nutritional diet, regular physical activity, and stress management. These factors can help improve blood sugar control and reduce the risk of Hypoglycemia.
Pharmacodynamics:
By stopping the kidneys from reabsorbing glucose, empagliflozin decreases blood glucose levels by increasing the quantity of glucose expelled in urine. Its comparatively extended duration of effect necessitates only one dosage per day. Regardless of blood glucose level, patients should be constantly watched for ketoacidosis signs and symptoms since empagliflozin can cause diabetic ketoacidosis even when there is no hyperglycemia. Empagliflozin may be withheld in situations of acute kidney injury or stopped in patients who develop chronic renal illness because its mechanism of action depends on the renal excretion of glucose.
A sugar-rich urogenital environment produced by excessive glucose excretion raises the risk of urogenital infections in patients, both male and female. Continuously monitor for any indications of a disease.
Pharmacokinetics:
Absorption
Peak plasma concentrations of empagliflozin were determined 1.5 hours after oral administration. When 25 mg of empagliflozin was administered following the consumption of a high-fat, high-calorie meal, exposure was marginally reduced; compared to the fasting state, AUC decreased by about 16% and Cmax by 37%. Empagliflozin can be taken with or without meals, and the observed impact of food on its pharmacokinetics was determined to be clinically insignificant.
Peak plasma time: 1.5 hr
Peak plasma concentration: 259 nmol/L (10 mg/day); 687 nmol/L (25 mg/day)
AUC: 1870 nmol•hr/L (10 mg/day); 4740 nmol hr/L (25 mg/day)
Distribution
A population pharmacokinetic study reported an apparent steady-state volume of distribution estimate of 73.8 L. Red blood cell partitioning was roughly 36.8%, and plasma protein binding was 86.2% in healthy participants after oral [14C]-empagliflozin solution was administered.
Protein-bound: 86.2%
Red blood cell partitioning: 36.8%
Vd: 73.8 L
Metabolism
The study found no significant metabolites of empagliflozin in human plasma. The most prevalent metabolites were three glucuronide conjugates, specifically 2-O-, 3-O-, and 6-O-glucuronide. Each metabolite's systemic exposure accounted for less than 10% of the drug-related material. Research conducted in vitro revealed that the main pathway for empagliflozin metabolism in humans involves glucuronidation through the action of uridine 5'-diphosphate-glucuronosyltransferases UGT2B7, UGT1A3, UGT1A8, and UGT1A9.
The primary route of metabolism is glucuronidation by the uridine 5'-diphosphate-glucuronosyltransferases UGT2B7, UGT1A3, UGT1A8, and UGT1A9.
No significant metabolites were detected, and the most abundant metabolites were three glucuronide conjugates (2-O-, 3-O-, and 6-O-glucuronide)
Systemic exposure of each metabolite was <10%
Elimination
After administering healthy participants an oral [14C]-empagliflozin solution, stools (41.2%) and urine (54.4%) eliminated about 95.6% of the drug-related radioactivity. Almost half of the drug-related radioactivity discharged in urine and most drug-related radioactivity recovered in faeces were both unmodified parent drugs.
Half-life: 12.4 hr
Clearance: 10.6 L/hr
Excretion: 54.4% urine; 41.2% feces
- Ndefo UA, Anidiobi NO, Basheer E, Eaton AT. Empagliflozin (Jardiance): A Novel SGLT2 Inhibitor for the Treatment of Type-2 Diabetes. P T. 2015 Jun;40(6):364-8. PMID: 26045645; PMCID: PMC4450666.
- Frampton JE. Empagliflozin: A Review in Symptomatic Chronic Heart Failure. Drugs. 2022 Nov;82(16):1591-1602. Doi: 10.1007/s40265-022-01778-0. Epub 2022 Nov 14. PMID: 36374374.
- Packer M, et al; EMPEROR-Reduced Trial Investigators. Cardiovascular and Renal Outcomes with Empagliflozin in the Heart Failure. N Engl J Med. 2020 Oct 8;383(15):1413-1424. doi: 10.1056/NEJMoa2022190. Epub 2020 Aug 28. PMID: 32865377.
- Anker SD,et al. Effect of Empagliflozin on the Cardiovascular and Renal Outcomes in Patients With Heart Failure by the Baseline Diabetes Status: Results From the EMPEROR-Reduced Trial. Circulation. 2021 Jan 26;143(4):337-349. doi: 10.1161/CIRCULATIONAHA.120.051824. Epub 2020 Nov 11. PMID: 33175585; PMCID: PMC7834911.
- https://www.ncbi.nlm.nih.gov/books/NBK532925/
- https://pubmed.ncbi.nlm.nih.gov/30422520/
- https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm
- https://www.medicines.org.uk/emc/product/5441/smpc
- https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/204629s008lbl.pdf
Published on: 30 Oct 2023 5:01 AM GMT
