LUSEFI Film-coated tablet Ref.[50975] Active ingredients: Luseogliflozin

1. Special Precautions for Use (This drug should be administered with care in the following patients)

(1) The following patients or conditions [Hypoglycemia may occur]

1) Pituitary dysfunction or adrenal insufficiency

2) Poor nutritional status, starvation, irregular diet, insufficient dietary intake or debility

3) Strenuous muscular exercise

4) Patients who consume alcohol excessively

(2) Patients using other antidiabetic drugs (in particular, sulfonylureas or, insulin preparations or GLP-1 receptor agonists) [Hypoglycemia may occur in combined use (See “Important Precautions”, “DRUG INTERACTIONS”, “ADVERSE REACTIONS” and “CLINICAL STUDIES”)]

(3) Patients with urinary tract infection or genital infection [Appropriate treatment should be provided before the administration of Lusefi because it may exacerbate the symptoms (See “Important Precautions”)]

(4) Patients who are likely to develop dehydration (patients whose plasma glucose is controlled extremely poorly, elderly patients, patients concomitantly using diuretics, etc.) [Diuretic effect of Lusefi may lead to dehydration (See “Important Precautions”, “DRUG INTERACTIONS”, “ADVERSE REACTIONS” and “DOSAGE AND ADMINISTRATION”)]

2. Important Precautions

(1) Before using Lusefi, hypoglycemic symptoms and the way to cope with them should be sufficiently explained to patients. In particular, when used with sulfonylureas or, insulin preparations or GLP-1 receptor agonists, risk of hypoglycemia may be increased. In combined use with sulfonylureas or, insulin preparations or GLP-1 receptor agonists, dose reduction of these drugs should be considered in order to decrease the risk of hypoglycemia associated with them. (See “Special Precautions for Use”, “DRUG INTERACTIONS”, “ADVERSE REACTIONS” and “CLINICAL STUDIES”)

(2) Use of Lusefi should be considered only for patients with established diagnosis of diabetes mellitus. It should be noted that there are diseases with diabetes-like symptoms such as impaired glucose tolerance and positive urinary glucose (renal glycosuria, thyroid dysfunction, etc.) other than diabetes mellitus.

(3) Use of Lusefi should be considered only when diet and exercise therapies, which are the basis of treatment of diabetes mellitus, were thoroughly used, but were not sufficiently effective.

(4) During the administration of Lusefi, plasma glucose and other parameters should be checked periodically to confirm its effect. When 3 months of the treatment is not sufficiently effective, a switch to a more appropriate treatment should be considered.

(5) The administration may become unnecessary or dose reduction may become necessary during the administration. The effect of administration may also be lost or become insufficient due to patients' lack of attention to their health or accompanying infections. Therefore, attention should be paid to dietary intake, plasma glucose, or presence or absence of infections and it should be constantly considered whether or not the administration can be continued as well as whether the dose and selection of drugs are appropriate.

(6) An increase in serum creatinine or a decrease in eGFR may be observed in the administration of Lusefi. Renal function should be checked periodically and in the treatment of patients with renal impairment, the course should be sufficiently monitored. (See “Special Precautions for Indications”)

(7) Urinary tract infection and genital infection may occur and result in serious infections, such as pyelonephritis, necrotising fasciitis of the perineum (Fournier’s gangrene) and sepsis. Genital infection, such as vaginal candidiasis, may occur. Onset of urinary tract infection and genital infection should be checked by sufficient observation and other methods. When they occur, appropriate treatment should be provided and interruption of administration or other measures should be considered depending on the conditions. The symptoms of urinary tract infection and genital infection and the way to cope with them should be explained to patients. (See “ADVERSE REACTIONS”)

(8) Polyuria or pollakiuria may occur due to the diuretic action of Lusefi. Reduction of body fluid volume may occur. Patients should be instructed to drink fluid appropriately and be monitored sufficiently. When abnormalities including dehydration and decrease in blood pressure occur, appropriate measures including interruption of administration and fluid replacement should be taken. Especially in patients who are likely to have hypovolemia (including elderly patients and patients with combined use of diuretics), attention should be paid to the onset of events including dehydration, diabetic ketoacidosis, hyperosmolar hyperglycemic syndrome, and thromboembolism such as cerebral infarction. (See “Special Precautions for Use”, “DRUG INTERACTIONS”, “ADVERSE REACTIONS” and “DOSAGE AND ADMINISTRATION”)

(9) Due to the mechanism of action of Lusefi, i.e., enhancement of urinary glucose excretion, fatty acid metabolism may be enhanced, which may lead to ketosis and ultimately ketoacidosis, even when plasma glucose is well controlled. Since marked increase in blood glucose levels may not be observed in this course, patients should be carefully monitored for the following conditions. (See “ADVERSE REACTIONS”)

1) When nausea/vomiting, decreased appetite, abdominal pain, severe thirst, malaise, dyspnea or disturbance of consciousness is present, tests, including blood or urine ketone tests, should be performed. If any abnormality is noted, administration should be discontinued and appropriate treatment should be provided. It should be known to patients that ketoacidosis can develop even if blood sugar levels increased are not found.

2) In particular, when impaired insulin secretion, dose reduction or discontinuation of insulin therapy, excessive carbohydrate intake restriction, poor food intake, infection, or dehydration is present, patients should be closely monitored because ketoacidosis is likely to occur.

3) The symptoms of ketoacidosis (e.g., nausea/vomiting, decreased appetite, abdominal pain, severe thirst, malaise, dyspnea, disturbance of consciousness) should be explained to patients. Patients should be instructed to visit the medical institution immediately when any of these symptoms occur.

(10) Because weight decreased has been reported in association with the administration of Lusefi, attention should be paid to excessive weight loss.

(11) In patients with symptoms of dysuria, anuria, oliguria, or urinary retention, treatment of these symptoms should be prioritized and treatment with other drugs should be considered.

(12) There is no experience in the use for patients with severe liver dysfunction and safety in these patients has not been established.

(13) Because hypoglycemic symptoms may occur, caution should be exercised in the administration to patients who work in high places or drive.

3. Precautions Concerning Use

When the drug is dispensed: In cases of drugs in PTP package, patients are instructed to remove the package and take the drug. (It has been reported that, when a sheet of PTP is mistakingly swallowed, sharp corners may pierce the esophageal mucosa, causing perforation and leading to a serious complications including mediastinitis)

4. Other Precautions

In the carcinogenicity study conducted by 104-week repeat oral administration of luseogliflozin at a dose of 4, 20, or 100 mg/kg/day in male and female rats, the incidence of pheochromocytoma in the adrenals, Leydig cell tumor in the testes and vascular tumors in the mesenteric lymph nodes was found to be increased in male animals treated at a dose of 100 mg/kg/day (equivalent to approximately 18 times the exposure [AUC] at the maximum recommended clinical dose (once daily administration of 5 mg)).

Luseogliflozin is mainly metabolized by CYP3A4/5, 4A11, 4F2, 4F3B and UGT1A1. (See “PHARMACOKINETICS”)

Precautions for co-administration (Caution should be exercised when considering the concomitant use of Lusefi with following drugs):

Effects on laboratory tests

Due to the mechanism of action of Lusefi, urinary glucose becomes positive and serum 1,5-AG (1,5-anhydroglucitol) is decreased during its administration. It should be noted that the test results of urinary glucose and serum 1,5-AG do not reflect plasma glucose control.

(1) In pregnant women or women who may possibly be pregnant, Lusefi should not be administered and other drugs including insulin preparations should be used. [Safety for use during pregnancy has not been established. In animal studies (rats) of luseogliflozin, skeletal variations, delayed ossification, or membranous ventricular septum defect which were considered to be caused by a decrease in body weight of dams were observed in the oral administration at a dose of 150 mg/kg/day (equivalent to approximately 47 times the exposure [AUC] at the maximum recommended clinical dose (once daily administration of 5 mg)) or higher doses to pregnant animals. In animal studies (rats) of similar drugs, exposure of juvenile animals in the period corresponding to the mid to late pregnancy in humans was reported to cause dilatation of renal pelvis and renal tubule. In addition, transfer to fetuses was reported in animal studies (rats) of luseogliflozin]

(2) Nursing women should be recommended to avoid breastfeeding during the administration of this drug. [In animal studies (rats), secretion into breast milk was observed]

Because hypoglycemic symptoms may occur, caution should be exercised in the administration to patients who work in high places or drive.

Adverse drug reactions including abnormal investigation findings were observed in 236 out of 1,262 subjects (18.7%) in clinical studies administered at 2.5 mg dose (including at increased dose of 5 mg) of luseogliflozin, at the time of approval in Japan. Major adverse drug reactions (adverse drug reactions observed in more than 2% of subjects) were pollakiuria in 35 subjects (2.8%), hypoglycemia in 30 subjects (2.4%), and β2-microglobulin urine increased in 26 subjects (2.1%).

1. Clinically Significant Adverse Reactions

(1) Hypoglycemia (1.0%*): Hypoglycemia may occur in combined use with other antidiabetic drugs (in particular, sulfonylureas, insulin preparations or GLP-1 receptor agonists). In addition, hypoglycemia was reported without combined use of other antidiabetic drugs. When hypoglycemic symptoms are observed, appropriate measures such as eating food containing carbohydrates should be taken. However, when hypoglycemic symptoms are observed in combined use with α-glucosidase inhibitors, glucose should be administered. (See “Special Precautions for Use”, “Important Precautions”, “DRUG INTERACTIONS” and “CLINICAL STUDIES”)

^*: The incidence calculated from the results of clinical studies (monotherapy), at the time of approval in Japan

(2) Pyelonephritis (0.1%), sepsis (incidence unknown): Since pyelonephritis may occur and result in sepsis (including septic shock), patients should be closely monitored. If any abnormality is noted, administration should be discontinued and appropriate treatment should be provided. (See “Important Precautions”)

(3) Necrotising fasciitis of the perineum (Fournier’s gangrene) (incidence unknown): Post-marketing cases of necrotising fasciitis of the perineum, (also known as Fournier’s gangrene), have been reported in female and male patients taking SGLT2 inhibitors. This is a rare but serious and potentially life-threatening event that requires urgent surgical intervention and antibiotic treatment. Patients should be advised to seek medical attention if they experience a combination of symptoms of pain, tenderness, erythema, or swelling in the genital or perineal area, with fever or malaise. Be aware that either uro-genital infection or perineal abscess may precede necrotizing fasciitis. If Fournier’s gangrene is suspected, Lusefi should be discontinued and prompt treatment (including antibiotics and surgical debridement) should be instituted. (See “Important Precautions”)

(4) Dehydration (0.1%): Dehydration may occur. Patients should be instructed to drink fluid appropriately and be monitored sufficiently. When symptoms including thirst, polyuria, pollakiuria and blood pressure decreased appear and dehydration is suspected, appropriate measures including interruption of administration and fluid replacement should be taken. Since onset of thromboembolism such as cerebral infarction following dehydration has been reported, sufficient attention should be paid. (See “Special Precautions for Use” and “Important Precautions”)

(5) Ketoacidosis (incidence unknown): Since ketoacidosis (including diabetic ketoacidosis) may occur, patients should be closely monitored. If any abnormality is noted, administration should be discontinued and appropriate treatment should be provided. (See “Important Precautions”)

2. Other Adverse Reactions

The following adverse reactions have been reported in all the clinical trials and from post-marketing experience with luseogliflozin. Adverse reactions listed below are classified according to frequency and system organ class (SOC). Frequency categories are defined according to the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data).