COMPOSITION AND ECIPIENTS
Active ingredient:
Each film coated tablet of Glozin 5 contains Dapagliflozin propanediol monohydrate equivalent to 5 mg dapagliflozin.
Each film coated tablet of Glozin 10 contains Dapagliflozin propanediol monohydrate equivalent to 10 mg dapagliflozin.
Excipients:
Microcrystalline cellulose, Anhydrous lactose, Crospovidone, Silicon dioxide, Magnesium stearate, Polyvinyl alcohol, Titanium dioxide, Macrogol. Talc, Yellow iron oxide (for 10 mg).
MECHANISM OF ACTION
Dapagliflozin is an inhibitor of Sodium-glucose cotransporter 2 (SGLT2) in the proximal renal tubules, it reduces reabsorption of filtered glucose from the tubular lumen and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion. improves both fasting and post-prandial plasmaglucose levels. Dapagliflozin does not impair normal endogenous glucose production in responseto hypoglycaemia. Dapagliflozin acts independently of insulin secretion and insulin action. Urinary glucose excretion (glucuresis) induced by dapagliflozin is associated with caloric loss and reduction in weight.
PHARMACOKINETICS
Absorption: Following oral administration of dapagliflozin, the maximum plasma concentration (C max ) is usually attained within 2 hours under fasting state. The absolute oral bioavailability of dapagliflozin following the administration of a 10 mg dose is 78%. Administration of dapagliflozin with a high-fat meal decreases its C max by up to 50% and prolongs T max by approximately 1 hour, but does not alter AUC as compared with the fasted state. These changes are not considered to be clinically meaningful and dapagliflozin can be administered with or without food.
Distribution: Dapagliflozin is approximately 91% protein bound. Protein binding is not altered in patients with renal or hepatic impairment.
Metabolism: The metabolism of dapagliflozin is primarily mediated by UGT1A9. Dapagliflozin is extensively metabolized, primarily to yield dapagliflozin 3-O-glucuronide, which is an
inactive metabolite.
Elimination: Dapagliflozin and related metabolites are primarily eliminated via the renal pathway. The mean plasma terminal half-life (t½) for dapagliflozin is approximately 12.9 hours following a single oral dose of Dapagliflozin 10 mg.
INDICATIONS
It is indicated in adults aged 18 years and older with type 2 diabetes mellitus to improve glycaemic control as:
Monotherapy: When diet and exercise alone do not provide adequate glycaemic control in patients for whom use of metformin is considered inappropriate due to intolerance.
Add-on combination therapy: In combination with other glucose-lowering medicinal products including insulin, when these, together with diet and exercise, do not provide adequate glycaemic control.
To reduce the risk of hospitalization for heart failure in adults with type 2 diabetes mellitus and established cardiovascular disease (CVD) or multiple cardiovascular (CV) risk factors.
CONTRAINDICATIONS
Hypersensitivity to the active substance or to any of the excipients.
Severe renal impairment, (eGFR less than 30 mL/min/1.73 m2 ) end-stage renal disease (ESRD), or patients on dialysis.
WARNING AND PRECAUTIONS
Dapagliflozin should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.
Renal impairment: The efficacy of dapagliflozin is dependent on renal function, and efficacy is reduced in patients who have moderate renal impairment and likely absent in patients with severe renal impairment. Dapagliflozinis not recommended for use in patients with moderate to severe renal impairment(patients with CrCl< 60 ml/min or eGFR< 60 ml/min/1.73 m2). Dapagliflozinhas not been studied in severe renal impairment(CrCl< 30 ml/min or eGFR< 30 ml/min/1.73 m2) or end-stage renal.
Hepatic impairment: Dapagliflozin exposure is increased in patients with severe hepatic impairment.
Use in patients at risk for volume depletion, hypotension and/or electrolyte imbalances.
Due to its mechanism of action, dapagliflozin increases diuresis associated with a modest decrease in blood pressure which may be more pronounced in patients with very high blood glucose concentrations.
Dapagliflozin is not recommended for use in patients receiving loop diuretics.
Caution should be exercised in patients for whom a dapagliflozin-induced drop in blood pressure could pose a risk, such as patients with known cardiovascular disease, patients on anti-hypertensive therapy with a history of hypotension or elderly patients.
For patients receiving dapagliflozin, in case of intercurrent conditions that may lead to volume depletion, careful monitoring of volume status and electrolytes is recommended.
Rare cases of diabetic ketoacidosis (DKA), including life-threatening and fatal cases.
The risk of diabetic ketoacidosis must be considered in the event of non-specific symptoms such as nausea, vomiting, anorexia, abdominal pain, excessive thirst, difficulty breathing, confusion, unusual fatigue or sleepiness. Patients should be assessed for ketoacidosis immediately if these symptoms occur, regardless of blood glucose level.
In patients where DKA is suspected or diagnosed, treatment with dapagliflozin should be discontinued immediately.
Urinary tract infections: Urinary tract infections were more frequently reported for dapagliflozin 10 mg compared to placebo.
Pyelonephritis was uncommon. Urinaryglucose excretion may be associated with an increased risk of urinary tract infection.
Elderly: The same recommendations for renal function apply to elderly patients as to all patient.
Elderly patients may be at a greater risk for volume depletion and are more likely to be treated with diuretics.
Therapeutic experience in patients 75 years and older is limited. Initiation of dapagliflozin therapy in this population is not recommended.
Dapagliflozin is not recommended for use in patients concomitantly treated with pioglitazone.
Haematocrit increase was observed with dapagliflozin treatment.
An increase in cases of lower limb amputation (primarily of the toe) has been observed.
Due to its mechanism of action, patients taking dapagliflozinwill test positive for glucose in their urine.
There are insufficient data to determine whether dapagliflozin has an effect on pre-existing bladder tumors. Consequently, dapagliflozin should not be used in patients with active bladder cancer.
The tablets contain lactose anhydrous. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.
Pregnancy (Category C):
there are no adequate and well-controlled studies of Dapagliflozin in pregnant women. Based on results of reproductive and developmental toxicity studies in animals, dapagliflozin may affect renal development and maturation. When pregnancy is detected, treatment with dapagliflozin should be discontinued.
Nursing mothers:
It is not known whether Dapagliflozin is excreted in human milk. a decision should be made whether to discontinue nursing or to discontinue Dapagliflozin, taking into account the importance of the drug to the mother.
Dapagliflozin should not be used while breast-feeding.
Pediatric use:
Safety and effectiveness of Dapagliflozin in pediatric patients under 18 years of age have not been established.
Geriatric Use:
No dosage adjustment is recommended based on age. efficacy was similar for patients under age 65 years and those 65 years and older. In patients ≥65 years of age, a higher proportion of patients treated with Dapagliflozin had adverse reactions related to volume depletion and renal impairment or failure compared to patients treated with placebo.
Renal Impairment:
The efficacy of dapagliflozin is dependent on renal function, and efficacy is reduced in patients who have moderate renal impairment and likely absent in patients with severe renal impairment.
A higher proportion of subjects treated with dapagliflozin had adverse reactions of increase in creatinine, phosphorus, parathyroid hormone (PTH) and hypotension ,compared with placebo. Dapagliflozin is not recommended for use in patients with moderate to severe renal impairment
(patients with CrCl< 60 ml/min or eGFR< 60 ml/min/1.73 m2).
Hepatic Impairment:
No dose adjustment is recommended for patients with mild or moderate hepatic impairment. Dapagliflozin exposure is increased in patients with severe hepatic impairment.
DRUG INTERACTIONS
Dapagliflozin may add to the diuretic effect of thiazide and loop diuretics and may increase the risk of dehydration and hypotension.
Insulin and insulin secretagogues, such as sulphonylureas, cause hypoglycaemia. Therefore, a lower dose of insulin or an insulin secretagogue may be required to reduce the risk of hypoglycaemia when used in combination with dapagliflozin.
coadministration of dapagliflozin with rifampicin decrease in dapagliflozin systemic exposure.
No dose adjustment is recommended.
Dapagliflozin with mefenamic acid (an inhibitor of UGT1A9), increase in dapagliflozin systemic exposure .No dose adjustment is recommended.
Combination of a single dose of dapagliflozin 20 mg and simvastatin (a CYP3A4 substrate) resulted in increase in AUC of simvastatin and 31% increase in AUC of simvastatin acid. The increase in simvastatin and simvastatin acid exposures are not considered clinically relevant.
ADVERSE REACTIONS
Hypotension, Ketoacidosis, Acute kidney injury and Impairment in renal function, Urosepsis and pyelonephritis, Hypoglycemia with concomitant use with insulin and insulin secretagogues, Genital mycotic infections, increase in low density lipoprotein cholesterol (LDL-C),Volume Depletion, Urinary tract infections, Increased urination, Nasopharyngitis, Back pain, Nausea, Influenza, Dyslipidemia, Constipation, Discomfort with urination, Pain in extremity, Increase in Hematocrit, Increase in Serum Inorganic Phosphorus, Cholesterol, Rash, Dry mouth, Vulvovaginal pruritus, Pruritus genital, Dizziness, Thirst.
DOSAGE AND ADMINISTRATION
Recommended Dosing:
The recommended starting dose of Dapagliflozin is 5 mg once daily, taken in the morning, with or without food. In patients tolerating Dapagliflozin 5 mg once daily who require additional glycemic control, the dose can be increased to 10 mg once daily. In patients with volume depletion, correcting this condition prior to initiation of Dapagliflozin is recommended.
To reduce the risk of hospitalization for heart failure, the recommended dose is 10 mg once daily.
Patients with Renal Impairment:
Assessment of renal function is recommended prior to initiation of Dapagliflozin therapy and periodically thereafter. No dose adjustment is needed in patients with an eGFR greater than or equal to 45 mL/min/1.73 m².
Use of Dapagliflozin is not recommended when the eGFR is less than 45 mL/min/1.73 m².
Dapagliflozin is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m².
OVERDOSAGE
There were no reports of overdose during the clinical development program for Dapagliflozin.
In the event of an overdose It is reasonable to employ supportive measures, as dictated by the patient’s clinical status. The removal of dapagliflozin by hemodialysis has not been studied.
STORAGE CONDITIONS
Store at temperature between 15° – 30 °.
PACKAGING
Glozin (5 – 10) mg is supplied as blister strips (Aluminum – White P.V.D.C),each strip contains 10 F.C. Tablets and each pack contains 1 or 3 strips with enclosed leaflet ( 10 or 30 F.C. Tablets per pack).