Adlina-EM

Approved Indications:

• Type 2 Diabetes Mellitus (T2DM):
  For adults with type 2 diabetes to improve glycemic control when diet and exercise alone are inadequate.
• Particularly beneficial in patients with inadequate response to metformin or other oral antidiabetic agents.
• Cardiovascular Risk Reduction:
  Empagliflozin (a component of the combination) has demonstrated cardiovascular risk reduction in patients with established atherosclerotic cardiovascular disease.

Off-label (Clinically Accepted) Uses:

• Early Intensification Therapy:
  Used in newly diagnosed T2DM where dual therapy is appropriate at diagnosis due to high HbA1c.
• Add-on Therapy:
  In cases where single-agent therapy with either empagliflozin or linagliptin is not sufficient.

Route of Administration: Oral

Adults (≥18 years):

• Initial Dose:
  Empagliflozin 10 mg + Linagliptin 5 mg once daily, preferably in the morning, with or without food.
• Titration:
  May be increased to Empagliflozin 25 mg + Linagliptin 5 mg once daily based on glycemic response and tolerability.

Elderly (≥65 years):

• No dose adjustment is required, but renal function must be assessed before and during treatment.

Renal Impairment:

• eGFR ≥30 mL/min/1.73 m²: Can be used.
• eGFR <30 mL/min/1.73 m²: Not recommended due to reduced efficacy of empagliflozin and increased risk of adverse events.

Hepatic Impairment:

• Mild to moderate impairment: No dose adjustment.
• Severe impairment: Use with caution due to limited data.

Pediatrics (<18 years):

• Not recommended. Safety and efficacy not established.

Missed Dose:

• Take as soon as remembered. Do not double dose.

Empagliflozin is a sodium-glucose co-transporter-2 (SGLT2) inhibitor that works by blocking glucose reabsorption in the proximal renal tubules, leading to increased urinary glucose excretion and reduced blood glucose levels.
Linagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor that prolongs the action of incretin hormones (GLP-1 and GIP), increasing insulin secretion and decreasing glucagon release in a glucose-dependent manner. Together, these mechanisms provide complementary glucose-lowering effects through both insulin-independent (empagliflozin) and insulin-dependent (linagliptin) pathways.

Empagliflozin:

• Absorption: Oral bioavailability ~78%.
• Peak Plasma Concentration: 1.5 hours post-dose.
• Distribution: High protein binding (~86%).
• Metabolism: Minimally metabolized; mainly via glucuronidation (UGT enzymes).
• Elimination: ~95% excreted in feces and urine (unchanged drug and metabolites).
• Half-life: ~12 hours.

Linagliptin:

• Absorption: Absolute bioavailability ~30%.
• Peak Plasma Concentration: 1.5 hours post-dose.
• Distribution: >99% protein bound.
• Metabolism: Minimal; excreted mostly unchanged.
• Elimination: Primarily via enterohepatic route (80% feces, 5% urine).
• Half-life: Terminal half-life >100 hours, but pharmacodynamic effect persists for ~24 hours.

Pregnancy:

• Empagliflozin:
  Avoid use during the second and third trimesters due to potential risk of fetal renal damage.
• Linagliptin:
  Limited human data; animal studies show no teratogenicity. Should be used during pregnancy only if the potential benefit justifies the risk.

Lactation:

• Empagliflozin and linagliptin are excreted in the milk of lactating animals.
• Human data is lacking. Use caution if administered to breastfeeding women.

Recommendation: Avoid during pregnancy and breastfeeding unless absolutely necessary.

• Primary Class: Antidiabetic Agent
• Subclasses:
• Empagliflozin: SGLT2 Inhibitor
• Linagliptin: DPP-4 Inhibitor
• Combination Type: Dual oral antidiabetic therapy

• Known hypersensitivity to empagliflozin, linagliptin, or any excipient in the formulation
• Patients with type 1 diabetes mellitus
• Diabetic ketoacidosis
• End-stage renal disease (eGFR <30 mL/min/1.73 m²) or on dialysis
• History of serious hypersensitivity reactions (e.g., angioedema) to linagliptin

• Genital Mycotic Infections: Increased risk due to glucosuria
• Hypoglycemia: Especially when combined with sulfonylureas or insulin
• Volume Depletion: Risk of hypotension; monitor in elderly or diuretic users
• Pancreatitis: Rare, but associated with DPP-4 inhibitors
• Ketoacidosis: Even with near-normal blood glucose; monitor for signs
• Renal Monitoring: Assess renal function before and during therapy
• Bullous Pemphigoid: Rare dermatological reaction reported with DPP-4 inhibitors

Common (≥1%):

• Genitourinary: Genital yeast infections, urinary tract infections
• Metabolic: Hypoglycemia (especially with insulin/sulfonylureas)
• Gastrointestinal: Nausea, diarrhea
• General: Increased urination, dehydration

Serious/Rare:

• Pancreatitis
• Ketoacidosis (euglycemic)
• Severe hypersensitivity reactions (angioedema, urticaria)
• Acute kidney injury
• Bullous pemphigoid

Timing & Severity:

• Most side effects are mild to moderate and occur within the first weeks of therapy.
• Serious events are rare but require immediate discontinuation.

Major Interactions:

• Diuretics: Increased risk of volume depletion and hypotension (additive effect with empagliflozin)
• Insulin/Sulfonylureas: Risk of hypoglycemia (linagliptin potentiates insulin effect)
• Rifampin: May reduce linagliptin levels (CYP3A4 inducer)
• ACE inhibitors/ARBs: Caution due to additive effect on kidney function
• Alcohol: May enhance the risk of hypoglycemia or ketoacidosis

Enzyme Systems:

• Linagliptin: Minor substrate of CYP3A4 (not a significant inducer/inhibitor)
• Empagliflozin: Not significantly metabolized via CYP450 enzymes

• ADA/EASD Guidelines (2024–2025):
  Reaffirmed empagliflozin + linagliptin combination as a preferred second-line therapy in patients with high HbA1c or cardiovascular risks.
• FDA Update:
  Emphasized monitoring for rare but serious side effects like euglycemic ketoacidosis and bullous pemphigoid.
• Renal Dosing Update:
  Use permitted down to eGFR 30 mL/min/1.73 m² for empagliflozin per updated product labeling.

• Temperature: Store below 30°C
• Humidity: Keep in original blister pack to protect from moisture
• Light: Store in a dry place, away from direct sunlight
• Handling:
• Do not crush or chew the tablet
• No refrigeration required
• Keep out of reach of children
• Discard if past expiration date