forxiga

Dapagliflozin (Dapagliflozin) Instructions
Common name: Dapagliflozin
Trade name: Forxiga
All names: Dapagliflozin, Dapagliflozin, Forxiga, Dapagliflozin, Farxiga

Indications:
On the basis of diet and exercise, this product can be used as a monotherapy to improve blood sugar control in adults with type 2 diabetes.

Usage and dosage:
The recommended starting dose is 5mg, once a day, taken in the morning, without food restrictions.
For patients who require enhanced glycemic control and tolerate 5 mg once daily, the dose may be increased to 10 mg once daily.

Adverse reactions:
Important adverse reactions
Hypotension, ketoacidosis, acute kidney injury and renal function damage, urosepsis and pyelonephritis, hypoglycemia caused by combination with insulin and islet secretagogues, genital fungal infection, elevated low-density lipoprotein cholesterol (LDL-C), bladder cancer
≥2%
Female genital fungal infection, nasal Pharyngitis, urinary tract infection, back pain, increased urination, male genital fungal infection, nausea, influenza, dyslipidemia, constipation, urinary discomfort, limb pain
Female genital fungal infection: vulvovaginal fungal infection, vaginal infection, vulvovaginal candidiasis, vulvovaginitis, genital infection, genital candidiasis, fungal genital infection, vulvitis, genitourinary tract infection, vulvar abscess and bacterial vaginosis.
Urinary tract infection: urinary tract infection, cystitis, Escherichia urinary tract infection, genitourinary tract infection, pyelonephritis, trigone cystitis, urethritis, kidney infection, prostatitis.
Increased urination: Frequent urination, polyuria, and increased urine output.
Male genital fungal infection: balanitis, fungal genital infection, candidal balanitis, genital candidiasis, male genital infection, penile infection, balanoposthitis, infectious balanoposthitis, genital infection, posthitis.
Hypovolemia
Reports of dehydration, hypovolemia, orthostatic hypotension, or hypotension.
Kidney Impairment
Increased serum creatinine and decreased eGFR (glomerular filtration rate).
Kidney
Kidney failure and elevated serum creatinine
Hypoglycemia
Severe hypoglycemia, mild hypoglycemia
Genital fungal infection
Vulvovaginal fungal infection in women and balanitis in men.
Hypersensitivity reactions
Angioedema, urticaria, hypersensitivity
Laboratory tests
Increased hematocrit, elevated serum inorganic phosphorus, elevated low-density lipoprotein cholesterol
Post-marketing experience
Ketoacidosis, acute kidney injury and renal dysfunction, urosepsis and pyelonephritis

Contraindications:
Contraindicated in those with a history of severe hypersensitivity reactions to this product.
Contraindicated for patients with severe renal impairment (eGFR less than 30mL/min/1.73㎡), end-stage renal disease (ESRD), or patients requiring dialysis.

Precautions:
Hypotension: Dapagliflozin can cause intravascular volume contraction. Symptomatic hypotension may occur after starting treatment with this product, especially in patients with renal insufficiency (eGFR less than 60mL/min/1.73m2), elderly patients, or patients taking loop diuretics. Patients with one or more of the above characteristics should have their blood volume status evaluated and corrected before initiating treatment with this product. Monitor for signs and symptoms of hypotension during treatment.
Ketoacidosis: Reports of ketoacidosis, a serious life-threatening condition requiring urgent hospitalization, have been identified during postmarketing surveillance in patients with type 1 and type 2 diabetes mellitus receiving sodium-glucose cotransporter 2 (SGLT2) inhibitors, including dapagliflozin. Dapagliflozin is not intended to treat patients with type 1 diabetes. Patients receiving dapagliflozin who develop signs and symptoms of severe metabolic acidosis should be evaluated for ketoacidosis regardless of their blood glucose levels, as dapagliflozin-related ketoacidosis may occur even at blood glucose levels below 250 mg/dL. If ketoacidosis is suspected, dapagliflozin should be discontinued and the patient should be evaluated and treatment promptly initiated. Treatment of ketoacidosis may require insulin, fluids, and carbohydrate replacement. In many postmarketing reports, particularly in patients with type 1 diabetes, ketoacidosis was not immediately recognized and treatment was delayed because blood glucose levels were lower than typical for patients with diabetic ketoacidosis (usually less than 250 mg/dL). Signs and symptoms developed were consistent with dehydration and severe metabolic acidosis, including nausea, vomiting, abdominal pain, general malaise, and shortness of breath. Predisposing factors for ketoacidosis have been identified in some but not all cases: reduced insulin dose, acute febrile illness, reduced caloric intake due to illness or surgery, pancreatic disease suggestive of insulin deficiency (eg, type 1 diabetes, pancreatitis, or history of pancreatic surgery), and alcohol abuse.
Before initiating dapagliflozin treatment, factors in the patient's medical history that may lead to ketoacidosis need to be considered, including insufficient pancreatic insulin secretion from any cause, caloric restriction, and alcohol abuse. In patients already treated with dapagliflozin, monitoring for ketoacidosis and temporary discontinuation of dapagliflozin should be considered during clinical situations known to result in ketoacidosis (e.g., prolonged fasting due to emergencies or surgery).
Acute kidney injury and renal impairment: Dapagliflozin can cause a decrease in blood volume and lead to renal damage. There have been postmarketing reports of acute kidney injury in patients treated with dapagliflozin, some of which required hospitalization and dialysis, and some reports involved patients younger than 65 years of age. Before starting dapagliflozin treatment, it is necessary to consider whether there are factors that may cause acute kidney injury in patients, including hypovolemia, chronic renal insufficiency, congestive heart failure, and concomitant medications (diuretics, ACE inhibitors, ARBs, NSAIDs). Consider suspending dapagliflozin therapy in the event of any decrease in food intake (e.g., acute illness or fasting) or fluid loss (gastrointestinal illness or exposure to elevated temperatures); monitor patients for signs and symptoms of acute kidney injury. If acute kidney injury occurs, immediately discontinue dapagliflozin therapy and initiate treatment. Dapagliflozin may increase serum creatinine and decrease eGFR (glomerular filtration rate). Elderly patients and patients with renal insufficiency are more susceptible to the above changes. Adverse reactions related to kidney function may occur after treatment with this product. Renal function should be assessed before initiating treatment with this product and monitored periodically thereafter. Dapagliflozin is not recommended for patients whose eGFR ranges consistently from 30 to less than 60 mL/min/1.73㎡, and its use is contraindicated for patients whose eGFR is less than 30 mL/min/1.73㎡. The safety and efficacy of this product were evaluated in a study involving patients with moderate renal insufficiency (eGFR range from 30 to less than 60mL/min/1.73㎡). Patients with moderate renal insufficiency did not experience improved glycemic control and were more likely to experience renal-related adverse reactions and fractures than those treated with placebo; therefore, treatment with this drug is not recommended in this population. Based on the mechanism of action of this product, it is expected to be ineffective in patients with severe renal insufficiency (eGFR less than 30mL/min/1.73㎡) or ESRD (end-stage renal failure).
Urosepsis and Pyelonephritis: There have been postmarketing reports of serious urinary tract infections, including urosepsis and pyelonephritis requiring hospitalization, in patients treated with SGLT2 inhibitors, including dapagliflozin. SGLT2 inhibitor treatment increases the risk of urinary tract infections. If indicated, patients should be evaluated for signs and symptoms of UTI and managed promptly.
Hypoglycemia caused by combined use with insulin and insulin secretagogues: Insulin and insulin secretagogues are known to cause hypoglycemia. Coadministration of dapagliflozin with insulin or insulin secretagogues may increase the risk of hypoglycemia. Therefore, lower doses of insulin or an insulin secretagogue should be used when coadministered with dapagliflozin to reduce the risk of hypoglycemia.
Genital fungal infection: Dapagliflozin increases the risk of genital fungal infection. Patients with a history of genital fungal infection are more susceptible to genital fungal infection, so they should be monitored and treated accordingly.
Elevated low-density lipoprotein cholesterol (LDL-C): Dapagliflozin can cause an increase in LDL-C (low-density lipoprotein-cholesterol). After starting treatment with this product, monitor LDL-C and treat according to standard therapy.
Bladder cancer: Dapagliflozin can cause a decrease in blood volume and lead to kidney damage. There have been postmarketing reports of acute kidney injury in patients treated with dapagliflozin, some of which required hospitalization and dialysis, and some reports involved patients younger than 65 years of age. Before starting dapagliflozin treatment, it is necessary to consider whether there are factors that may cause acute kidney injury in patients, including hypovolemia, chronic renal insufficiency, congestive heart failure, and concomitant medications (diuretics, ACE inhibitors, ARBs, NSAIDs). Consider suspending dapagliflozin therapy in the event of any decrease in food intake (e.g., acute illness or fasting) or fluid loss (gastrointestinal illness or exposure to elevated temperatures); monitor patients for signs and symptoms of acute kidney injury. If acute kidney injury occurs, immediately discontinue dapagliflozin therapy and initiate treatment. Dapagliflozin may increase serum creatinine and decrease eGFR (glomerular filtration rate). Elderly patients and patients with renal insufficiency are more susceptible to the above changes. Adverse reactions related to kidney function may occur after treatment with this product. Renal function should be assessed before initiating treatment with this product and monitored periodically thereafter. Dapagliflozin is not recommended for patients whose eGFR ranges consistently from 30 to less than 60 mL/min/1.73㎡, and its use is prohibited for patients whose eGFR is less than 30 mL/min/1.73㎡. The safety and efficacy of this product were evaluated in a study involving patients with moderate renal insufficiency (eGFR range from 30 to less than 60mL/min/1.73㎡). Patients with moderate renal insufficiency did not experience improved glycemic control and were more likely to experience renal-related adverse reactions and fractures than those treated with placebo; therefore, treatment with this drug is not recommended in this population. Based on the mechanism of action of this product, it is expected to be ineffective in patients with severe renal insufficiency (eGFR less than 30mL/min/1.73㎡) or ESRD (end-stage renal failure). There are insufficient data to determine whether dapagliflozin has an effect on existing bladder cancer. Therefore, this product is contraindicated in patients with active bladder cancer. In patients with a history of bladder cancer, the benefits of glycemic control should be weighed against the unknown risk of cancer recurrence with dapagliflozin.
Macrovascular disease results: There are no clinical studies with conclusive evidence that this product or any other antidiabetic agent reduces macrovascular risk.

Storage:
Tightly sealed and stored at no more than 30℃.

Mechanism of action:
Sodium-glucose cotransporter 2 (SGLT2) is expressed in the proximal renal tubule and is the main transporter responsible for glucose reabsorption in renal tubular filtration. Dapagliflozin is an SGLT2 inhibitor. By inhibiting SGLT2, it reduces the reabsorption of filtered glucose and lowers the renal threshold of glucose, thereby increasing urinary glucose excretion.

Safety and Efficacy:
DECLARE-TIMI 58 is a randomized, double-blind, placebo-controlled, multicenter study sponsored by AstraZeneca that evaluated the effect of Farxiga compared to placebo on CV outcomes in adults with T2D at risk for cardiovascular (CV) events, including those with multiple CV risk factors and those with existing CV disease. The study involved more than 17,000 patients in 33 countries. The results showed that compared with placebo, Farxiga significantly reduced the composite risk of hospitalization for heart failure (hHF) or CV death by 17% (4.9% vs 5.8%, HR=0.83 [95% CI: 0.73-0.95], p=0.005), reaching one of the two primary efficacy endpoints of the study. The reduction in hHF or CV risk was consistent across the study population, including those with existing CV risk factors and those with established CV disease.
In terms of other primary efficacy endpoints, Farxiga had fewer major adverse cardiovascular events (MACE) compared with placebo, but the difference did not reach statistical significance (Farxiga 8.8% vs. placebo 9.4%, HR=0.93 [95% CI: 0.84-1.03], p=0.17). In addition, the renal composite endpoint showed that Farxiga reduced the incidence of new or worsening kidney disease by 24% (4.2% vs 5.6%, HR=0.76 [95% CI: 0.67-0.87]) and all-cause mortality (6.2% vs 6.6%, HR=0.93 [95% CI: 0.82-1.04]) compared with placebo in the broad population studied.
The study also confirmed the established safety profile of Farxiga, which did not increase the composite risk of MACE (CV death, heart attack, stroke) compared with placebo, achieving the study's primary safety endpoint of non-inferiority. In addition, there was no imbalance between Farxiga and placebo on other safety measures, including amputations (1.4% vs 1.3%), fractures (5.3% vs 5.1%), bladder cancer (0.3% vs 0.5%), or Fournier's gangrene (1 vs 5 cases). Diabetic ketoacidosis (0.3% vs 0.1%) and genital infection (0.9% vs 1.0%) were rare.
In August 2019, the FDA also granted fast track designation (FTD) to dapagliflozin for use in adult patients with heart failure with reduced ejection fraction (HFrEF) or heart failure with preserved ejection fraction (HFpEF) to reduce the risk of cardiovascular (CV) death or worsening of heart failure. At the end of July this year, the FDA also granted another FTD to dapagliflozin (Farxiga) for delaying the progression of renal failure and preventing cardiovascular (CV) and renal death in patients with chronic kidney disease (CKD), including those with CKD (chronic kidney disease) with or without type 2 diabetes (T2D).