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DAPZIN-10 (Dapagliflozin 10 mg Tablets)

DAPZIN-10

Pharmacotherapeutic group: Drugs used in diabetes, Sodium-glucose co-transporter 2 (SGLT2) inhibitors, ATC code: A10BK01

Dapagliflozin is a highly potent (Ki: 0.55 nM), selective and reversible inhibitor of SGLT2. The SGLT2 is selectively expressed in the kidney with no expression detected in more than 70 other tissues including liver, skeletal muscle, adipose tissue, breast, bladder and brain. SGLT2 is the predominant transporter responsible for reabsorption of glucose from the glomerular filtrate back into the circulation. Despite the presence of hyperglycemia in type 2 diabetes, reabsorption of filtered glucose continues.

Dapagliflozin improves both fasting and post-prandial plasma glucose levels by reducing renal glucose reabsorption leading to urinary glucose excretion. This glucose excretion (glucuronic effect) is observed after the first dose, is continuous over the 24- hour dosing interval and is sustained for the duration of treatment. The amount of glucose removed by the kidney through this mechanism is dependent upon the blood glucose concentration and GFR.

Dapagliflozin does not impair normal endogenous glucose production in response to hypoglycaemia. Dapagliflozin acts independently of insulin secretion and insulin action. Improvement in homeostasis model assessment for beta cell function (HOMA beta-cell) has been observed in clinical studies with Dapagliflozin.

Urinary glucose excretion (glucuresis) induced by dapagliflozin is associated with caloric loss and reduction in weight. Inhibition of glucose and sodium co-transport by dapagliflozin is also associated with mild diuresis and transient natriuresis.

Dapagliflozin does not inhibit other glucose transporters important for glucose transport into peripheral tissues and is > 1,400 times more selective for SGLT2 versus SGLT1, the major transporter in the gut responsible for glucose absorption.

DAPZIN-10 Therapeutic indications

Type 2 diabetes mellitus: Dapagliflozin is indicated in adults for the treatment of insufficiently controlled type 2 diabetes mellitus as an adjunct to diet and exercise

  • As monotherapy when metformin is considered inappropriate due to intolerance.
  • In addition to other medicinal products for the treatment of type 2 diabetes.

For study results with respect to combination of therapies, effects on glycaemic control and cardiovascular events, and the populations studied.

Type 1 diabetes mellitus: Dapagliflozin is indicated in adults for the treatment of insufficiently controlled type 1 diabetesmellitus as an adjunct to insulin in patients with BMI ≥ 27 kg/m2, when insulin alone does not provide adequate glycaemic control despite optimal insulin therapy.’

DAPZIN-10 Posology and method of administration

Type 2 diabetes mellitus: The recommended dose is 10 mg dapagliflozin once daily.When dapagliflozin is used in combination with insulin or an insulin secretagogue, such as asulphonylurea, a lower dose of insulin or insulin secretagogue may be considered to reduce therisk of hypoglycaemia.

Type 1 diabetes mellitus: Treatment with Dapagliflozin is to be initiated and supervised by specialists in type 1diabetes. The recommended dose is 5 mg once daily.

Dapagliflozin must only be administered as an adjunct to insulin.

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Before initiating treatment with dapagliflozin:

  • Risk factors for diabetic ketoacidosis (DKA) should be assessed
  • It should be ensured that ketone levels are normal. If ketones are elevated (blood betahydroxybutyrate reading greater than 0.6 mmol/L or urine ketones one plus (+)), treatment with dapagliflozin should not be started until the ketone levels are normal.
  • It should be ensured that the patient demonstrates the ability to monitor ketone levels.
  • It is recommended that patients obtain several baseline ketone levels over one to two weeks prior to initiation of dapagliflozin therapy, and patients should become familiar with how their behaviour and circumstances affect their ketone levels.
  • Patients should be informed, in a dedicated education session, on the risk of DKA, how to recognize DKA risk factors, signs or symptoms, how and when to monitor ketone levels and what actions to take at elevated ketone readings.
  • Correction of volume depletion prior to initiation of dapagliflozin is recommended in patients with this condition.

In order to avoid hypoglycaemia with the first dose of dapagliflozin, a 20% reduction in the first mealtime bolus insulin may be considered. Subsequent bolus doses should be adjusted individually based on blood glucose results. No reduction in basal insulin is recommended when initiating dapagliflozin. Subsequently, basal insulin should be adjusted based on blood glucose results. When needed, insulin dose reduction should be done cautiously to avoid ketosis and DKA.

Ketone monitoring during treatment: During the initial one to two weeks of treatment with dapagliflozin, ketones should bemonitored on a regular basis, then the frequency of ketone level testing should beindividualized, according to the patient’s lifestyle and/or risk factors.

Patients should be informed about what actions to take if ketone levels are elevated. The recommended actions are listed in Table 1. Measurement of blood ketone levels is preferred to urine.

Table 1

Clinical stageBlood Ketone (betahydroxybutyrate)Urine KetoneActions
Ketonemia0.6-1.5 mmol/LTrace or Small +The patient may need to take extra insulin and drink water. The patient should measure blood glucose and consider taking extra carbohydrates if the glucose levels are normal or low.   Ketone levels should be measured again after two hours. The patient should immediately seek medical advice and stop taking dapagliflozin if levels persist and symptoms present.
Impending DKA> 1.5-3.0 mmol/LModerate ++The patient should immediately seek medical advice and stop taking dapagliflozin.   The patient may need to take extra insulin and drink water. The patient should measure blood glucose and consider taking extra carbohydrates if the glucose levels are normal or low. Ketone levels should be measured again after two hours.
Probable DKA> 3.0 mmol/LLarge to very large +++ / ++++The patient should go to emergency department without delay and stop taking dapagliflozin.   The patient may need to take extra insulin and drink water. The patient should measure blood glucose and consider taking extra carbohydrates if the glucose levels are normal or low.

DAPZIN-10 Special populations

Renal impairment: Dapagliflozin should not be initiated in patients with a glomerular filtration rate [GFR] <60 mL/min and should be discontinued at GFR persistently below 45 mL/min.

No dose adjustment is required based on renal function.

Hepatic impairment: No dose adjustment is necessary for patients with mild or moderate hepatic impairment. Inpatients with severe hepatic impairment, a starting dose of 5 mg is recommended. Ifwell tolerated, the dose may be increased to 10 mg when indicated.

Elderly (≥ 65 years): In general, no dose adjustment is recommended based on age. Renal function and risk ofvolume depletion should be taken into account.

Paediatric population: The safety and efficacy of dapagliflozin in children aged 0 to < 18 years have not yet beenestablished. No data are available.

DAPZIN-10 Method of administration

Dapagliflozin can be taken orally once daily at any time of day with or without food. Tablets are to be swallowed whole.

DAPZIN-10 Contraindications

Hypersensitivity to the active substance or to any of the excipients

DAPZIN-10 Special warnings and precautions for use

Diabetic ketoacidosis: Rare cases of diabetic ketoacidosis (DKA), including life-threatening and fatal cases, have beenreported in patients treated with sodium-glucose co-transporter 2 (SGLT2) inhibitors, includingdapagliflozin. In a number of cases, the presentation of the condition was atypical with onlymoderately increased blood glucose values, below 14 mmol/l (250 mg/dl). It is not known ifDKA is more likely to occur with higher doses of dapagliflozin.

Type 1 diabetes mellitus: In type 1 diabetes mellitus studies with dapagliflozin, patients had a higher number of DKAevents compared with the placebo group.

Before starting treatment, patients should be evaluated with respect to DKA risk. Dapagliflozin should not be initiated when patients are at a higher risk of DKA, such as:

  • Patients with low insulin needs.
  • Patient not on optimal insulin dose or who have recent issues with noncompliance or recurrent errors with insulin dosing and who are unlikely to maintain adequate insulin dosing.
  • Patients with increased insulin requirements due to acute medical illness or surgery.
  • Patients who insist on maintaining caloric restriction, carbohydrate restriction or ketogenic diet or who chronically under-dose insulin (e.g. in order to remain in a lipolytic state).
  • Patients with recent or recurrent history of DKA.
  • Patients with elevated ketones levels (BHB reading is greater than 0.6 mmol/L or urine ketones one plus (+)). If ketones are elevated (blood beta-hydroxybutyrate reading 0.6 mmol/L or greater), treatment with dapagliflozin should not be started until the ketone levels are normal
  • Patients unable or unwilling to monitor ketones.
  • Patients with excessive alcohol consumption or who use illicit drugs.

Patients using an insulin infusion pump have a higher risk of DKA and should be experienced with pump use, common trouble-shooting strategies when interruptions of insulin delivery via pump occur (issues with insertion site, clogged tubing, empty reservoir, etc.) and use of supplemental insulin injections with pen or syringe as needed in case of pump failure.

Ketone monitoring: The patient should be advised to test their ketone level (urine or blood) if signs or symptoms ofketoacidosis occur. Measurement of blood ketone levels is preferred to urine. Ketones should bemonitored on a regular basis during the initial one to two weeks, then the frequency of ketonelevel testing should be individualized, according to the patient’s lifestyle and/or risk factors.Ketone levels should be also checked in situations that may predispose to or increase risk ofDKA.

Patients must be informed about what actions to take if ketone levels are elevated. Necrotising fasciitis of the perineum (Fournier’s gangrene) 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.

Urinary tract infections: Urinary glucose excretion may be associated with an increased risk of urinary tract infection;therefore, temporary interruption of dapagliflozin should be considered when treatingpyelonephritis or urosepsis.

Elderly (≥ 65 years): Elderly patients may be at a greater risk for volume depletion and are more likely to betreated with diuretics.

Elderly patients are more likely to have impaired renal function, and/or to be treated with anti- hypertensive medicinal products that may cause changes in renal function such as angiotensin converting enzyme inhibitors (ACE-I) and angiotensin II type 1 receptor blockers (ARB). The same recommendations for renal function apply to elderly patients as to all patients

Cardiac failure: There is no experience in clinical studies with dapagliflozin in NYHA class IV.

Lower limb amputations: An increase in cases of lower limb amputation (primarily of the toe) has been observed inongoing long-term, clinical studies with another SGLT2 inhibitor. It is unknown whether thisconstitutes a class effect. Like for all diabetic patients it is important to counsel patients onroutine preventative foot care.

Urine laboratory assessments: Due to its mechanism of action, patients taking Dapagliflozin will test positive for glucose intheir urine.

Lactose: The tablets contain lactose. Patients with rare hereditary problems of galactose intolerance,total lactase deficiency or glucose-galactose malabsorption should not take this medicinalproduct.

DAPZIN-10 Interaction with other medicinal products and other forms of interaction

Diuretics: Dapagliflozin may add to the diuretic effect of thiazide and loop diuretics and may increasethe risk of dehydration and hypotension.

Insulin and insulin secretagogue: Insulin and insulin secretagogue, such as sulphonylureas, cause hypoglycaemia. Therefore, alower dose of insulin or an insulin secretagogue may be required to reduce the risk ofhypoglycaemia when used in combination with dapagliflozin.

DAPZIN-10 Pregnancy and lactation
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Pregnancy: There are no data from the use of dapagliflozin in pregnant women. Studies in rats have showntoxicity to the developing kidney in the time period corresponding to the second and thirdtrimesters of human pregnancy. Therefore, the use of dapagliflozin is not recommended duringthe second and third trimesters of pregnancy.When pregnancy is detected, treatment with dapagliflozin should be discontinued.

Lactation: It is unknown whether dapagliflozin and/or its metabolites are excreted in human milk.Available Pharmacodynamic/toxicological data in animals have shown excretion ofdapagliflozin/metabolites in milk, as well as pharmacologically-mediated effects in nursingoffspring. A risk to the newborns/infants cannot be excluded. Dapagliflozin should not be usedwhile breast-feeding.

Fertility: The effect of dapagliflozin on fertility in humans has not been studied. In male and femalerats, dapagliflozin showed no effects on fertility at any dose tested.

DAPZIN-10 Effects on ability to drive and use machines

Dapagliflozin has no or negligible influence on the ability to drive and use machines. Patients should be alerted to the risk of hypoglycaemia when dapagliflozin is used in combination with a sulphonylurea or insulin.

DAPZIN-10 Overdose

Dapagliflozin did not show any toxicity in healthy subjects at single oral doses up to 500 mg (50 times the maximum recommended human dose). These subjects had detectable glucose in the urine for a dose-related period of time (at least 5 days for the 500 mg dose), with no reports of dehydration, hypotension or electrolyte imbalance, and with no clinically meaningful effect on QTc interval. The incidence of hypoglycaemia was similar to placebo. In clinical studies where once-daily doses of up to 100 mg (10 times the maximum recommended human dose) were administered for 2 weeks in healthy subjects and type 2 diabetes subjects, the incidence of hypoglycaemia was slightly higher than placebo and was not dose-related. Rates of adverse events including dehydration or hypotension were similar to placebo, and there were no clinically meaningful dose-related changes in laboratory parameters, including serum electrolytes and biomarkers of renal function.

In the event of an overdose, appropriate supportive treatment should be initiated as dictated by the patient’s clinical status. The removal of dapagliflozin by hemodialysis has not been studied.

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