DAPAGOOD S 100

Indications

• Type 2 diabetes mellitus as monotherapy or in combination with insulin or other antidiabetic drugs
• Chronic heart failure with reduced ejection fraction
• Chronic kidney disease

Dosage

Children: Refer to the BNF for Children for specific dosing information

Adults: 10 mg once daily, with caution advised in renal impairment (avoid initiation if eGFR less than 30 mL/min/1.73 m2).

Mechanism of action

Dapagliflozin inhibits the sodium-glucose cotransporter 2 (SGLT2) located in the proximal tubule of the nephron, leading to decreased glucose reabsorption and increased urinary glucose excretion. This mechanism contributes to better glycemic control in patients with type 2 diabetes mellitus.

Pharmacodynamics

Dapagliflozin reduces sodium reabsorption, increasing sodium delivery to the distal tubule, which may decrease both pre- and afterload on the heart. This results in downregulation of sympathetic activity and reduced intraglomerular pressure, mediated by increased tubuloglomerular feedback. Clinical studies have shown that doses of dapagliflozin lead to significant urinary glucose excretion, with near-maximum effects observed at higher doses.

Pharmacokinetics

Dapagliflozin is rapidly absorbed after oral administration, with peak plasma concentrations occurring within 1 to 2 hours. It has a half-life of approximately 12.9 hours. The drug undergoes extensive metabolism primarily via UGT1A9 and UGT2B7, with renal excretion of metabolites. The pharmacokinetics may be affected by renal function, with caution advised if the estimated glomerular filtration rate (eGFR) is less than 60 mL/min/1.73 m2.

Contra-indications

• Severe renal impairment (eGFR less than 30 mL/minute/1.73 m2)
• Hypersensitivity to dapagliflozin or any excipients

Adverse effects

• Genital mycotic infections
• Urinary tract infections
• Dehydration
• Hypotension
• Diabetic ketoacidosis
• Acute kidney injury

Interactions

• Concomitant use with insulin or other antidiabetic agents may require dose adjustments to avoid hypoglycaemia
• Diuretics may enhance the risk of dehydration and hypotension
• Other drugs affecting renal function may require monitoring

Precautions

• Monitor renal function before initiation and periodically thereafter
• Consider risk of diabetic ketoacidosis in patients
• Use with caution in patients with a history of urinary tract infections or genital infections

Pregnancy

Avoid-toxicity in animal studies.

Breast-feeding

Avoid-present in milk in animal studies.

Storage

Store at room temperature, away from moisture and heat.

Formulations

• Tablets: 5 mg, 10 mg

Indications

• Used as a solvent for injectable medications
• Utilized in topical formulations to enhance skin hydration
• Serves as a humectant in various food and cosmetic products

Dosage

Children: Refer to specific product guidelines for pediatric dosing as it is dependent on formulation and indication.

Adults: Refer to specific product guidelines for dosage as it varies based on formulation and indication.

Mechanism of action

Propanediol functions primarily as a solvent and excipient, enhancing the solubility of various drug compounds. It is also known to stabilize emulsions and improve the bioavailability of certain medications by facilitating their absorption in the gastrointestinal tract. Additionally, it may exert mild osmotic effects, influencing hydration and moisture retention in topical formulations.

Pharmacodynamics

Propanediol exhibits low toxicity and is well absorbed when administered. Its pharmacodynamic profile includes its ability to enhance drug solubility and stability, which is crucial in pharmaceutical formulations. The substance does not possess significant pharmacological activity on its own but rather acts to improve the pharmacological effects of co-administered drugs.

Pharmacokinetics

Propanediol is rapidly absorbed from the gastrointestinal tract when ingested, with peak plasma concentrations occurring within 1 to 4 hours. It is metabolized primarily in the liver to lactic acid and other minor metabolites, with a half-life that can vary depending on the dosage and route of administration. The majority of propanediol is excreted in urine as metabolites, indicating minimal accumulation in the body during normal use.

Pregnancy

There is insufficient data regarding the safety of propanediol during pregnancy, consult available guidelines before use.

Breast-feeding

Due to lack of data on excretion in breast milk, caution is advised when using propanediol during breastfeeding.

Storage

Store in a cool, dry place away from light.

Indications

• Type 2 diabetes mellitus as monotherapy (if metformin is inappropriate)
• Type 2 diabetes mellitus in combination with other antidiabetic drugs (including insulin) when metformin alone or in combination fails to achieve adequate glycemic control

Dosage

Adults: 100 mg once daily, or 50 mg twice daily when used in combination with a sulfonylurea or insulin. Dose adjustments may be required based on renal function.

Mechanism of action

Sitagliptin inhibits the enzyme dipeptidyl peptidase-4 (DPP-4), which is responsible for the degradation of incretin hormones. This inhibition results in prolonged active incretin levels, which enhances insulin secretion from pancreatic beta cells and decreases glucagon secretion from alpha cells in the pancreas, leading to lowered blood glucose levels.

Pharmacodynamics

Sitagliptin's pharmacodynamic effects include improved glycemic control, characterized by reduced fasting and postprandial blood glucose levels. The drug is effective in lowering HbA1c levels and is associated with a low risk of hypoglycemia. It has a beneficial effect on weight management, as it typically does not promote weight gain.

Pharmacokinetics

Sitagliptin is absorbed rapidly after oral administration, with peak plasma concentrations occurring within 1-4 hours. Its bioavailability is approximately 87%. The drug is predominantly eliminated via renal excretion, with about 80% of the dose excreted unchanged in the urine. The elimination half-life is approximately 12.4 hours. Renal impairment may necessitate dose adjustments, as clearance is significantly reduced in patients with decreased renal function.

Contra-indications

• History of pancreatitis
• Severe heart failure

Adverse effects

• Headache
• Constipation
• Dizziness
• Skin reactions
• Angioedema
• Back pain
• Cutaneous vasculitis
• Joint disorders
• Myalgia
• Acute pancreatitis
• Acute renal impairment
• Stevens-Johnson syndrome
• Vomiting

Interactions

• Concomitant use with sulfonylureas or insulin may require dose adjustments
• Moderate interaction with vemurafenib (increases exposure)

Precautions

• Monitor renal function before treatment and periodically thereafter
• Discontinue if symptoms of acute pancreatitis occur, such as persistent severe abdominal pain

Pregnancy

Avoid-toxicity observed in animal studies.

Breast-feeding

Avoid-present in milk in animal studies.

Storage

Store at room temperature, away from moisture and heat.

Formulations

• Tablets: 50 mg, 100 mg

Mechanism of action

Dapagliflozin inhibits the sodium-glucose cotransporter 2(SGLT2) which is primarily located in the proximal tubule of the nephron. SGLT2 facilitates 90% of glucose reabsorption in the kidneys and so its inhibition allows for glucose to be excreted in the urine. This excretion allows for better glycemic control and potentially weight loss in patients with type 2 diabetes mellitus.

Pharmacodynamics

Dapagliflozin also reduces sodium reabsorption and increases the delivery of sodium to the distal tubule. This may influence several physiological functions including, but not restricted to, lowering both pre- and afterload of the heart and downregulation of sympathetic activity, and decreased intraglomerular pressure which is believed to be mediated by increased tubuloglomerular feedback. Increases in the amount of glucose excreted in the urine were observed in healthy subjects and in patients with type 2 diabetes mellitus following the administration of dapagliflozin. Dapagliflozin doses of 5 or 10 mg per day in patients with type 2 diabetes mellitus for 12 weeks resulted in excretion of approximately 70 grams of glucose in the urine per day at Week 12. A near-maximum glucose excretion was observed at the dapagliflozin daily dose of 20 mg. This urinary glucose excretion with dapagliflozin also results in increases in urinary volume. After discontinuation of dapagliflozin, on average, the elevation in urinary glucose excretion approaches baseline by about 3 days for the 10 mg dose. Dapagliflozin was not associated with clinically meaningful prolongation of QTc interval at daily doses up to 150 mg (15 times the recommended maximum dose) in a study of healthy subjects. In addition, no clinically meaningful effect on QTc interval was observed following single doses of up to 500 mg (50 times the recommended maximum dose) of dapagliflozin in healthy subjects.

Mechanism of action

Inhibition of DPP-4 by sitagliptin slows DPP-4 mediated inactivation of incretins like GLP-1 and GIP. Incretins are released throughout the day and upregulated in response to meals as part of glucose homeostasis. Reduced inhibition of incretins increase insulin synthesis and decrease glucagon release in a manner dependant on glucose concentrations. These effects lead to an overall increase in blood glucose control which is demonstrated by reduced glycosylated hemoglobin (HbA1c). Januvia is a member of a class of oral anti-hyperglycemic agents called dipeptidyl peptidase 4 (DPP-4) inhibitors. The improvement in glycemic control observed with this medicinal product may be mediated by enhancing the levels of active incretin hormones. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. Treatment with GLP-1 or with DPP-4 inhibitors in animal models of type 2 diabetes has been demonstrated to improve beta cell responsiveness to glucose and stimulate insulin biosynthesis and release. With higher insulin levels, tissue glucose uptake is enhanced. In addition, GLP-1 lowers glucagon secretion from pancreatic alpha cells. Decreased glucagon concentrations, along with higher insulin levels, lead to reduced hepatic glucose production, resulting in a decrease in blood glucose levels. The effects of GLP-1 and GIP are glucose-dependent such that when blood glucose concentrations are low, stimulation of insulin release and suppression of glucagon secretion by GLP-1 are not observed. For both GLP-1 and GIP, stimulation of insulin release is enhanced as glucose rises above normal concentrations. Further, GLP-1 does not impair the normal glucagon response to hypoglycemia. The activity of GLP-1 and GIP is limited by the DPP-4 enzyme, which rapidly hydrolyzes the incretin hormones to produce inactive products. Sitagliptin prevents the hydrolysis of incretin hormones by DPP-4, thereby increasing plasma concentrations of the active forms of GLP-1 and GIP. By enhancing active incretin levels, sitagliptin increases insulin release and decreases glucagon levels in a glucose-dependent manner. In patients with type 2 diabetes with hyperglycemia, these changes in insulin and glucagon levels lead to lower hemoglobin A1c (HbA1c) and lower fasting and postprandial glucose concentrations. The glucose-dependent mechanism of sitagliptin is distinct from the mechanism of sulfonylureas, which increase insulin secretion even when glucose levels are low and can lead to hypoglycemia in patients with type 2 diabetes and in normal subjects. Sitagliptin is a potent and highly selective inhibitor of the enzyme DPP-4 and does not inhibit the closely-related enzymes DPP-8 or DPP-9 at therapeutic concentrations. Sitagliptin is a DPP-4 inhibitor, which is believed to exert its actions in patients with type 2 diabetes by slowing the inactivation of incretin hormones. Concentrations of the active intact hormones are increased by Januvia, thereby increasing and prolonging the action of these hormones. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. These hormones are rapidly inactivated by the enzyme, DPP-4. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by

Pharmacodynamics

Sitagliptin inhibits DPP-4 which leads to increased levels of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide(GIP), decreased levels of glucagon, and a stronger insulin response to glucose.