Sidapvia Special Precautions

SIDAPVIA should not be used in patients with type 1 diabetes (see Indications/Uses) or for the treatment of diabetic ketoacidosis (see Ketoacidosis as follows).
Use in renal impairment: SIDAPVIA should not be used in patients with an eGFR <45 mL/min/1.73 m². Renal function should be evaluated prior to initiation of SIDAPVIA and periodically thereafter.
Dapagliflozin increases serum creatinine and decreases eGFR (see Adverse Reactions). Renal function abnormalities can occur after initiating dapagliflozin. Patients with hypovolaemia may be more susceptible to these changes.
Use in patients at risk for volume depletion and/or hypotension: The diuretic effect of dapagliflozin is a potential concern for volume depleted patients. Due to its mechanism of action, dapagliflozin induces osmotic diuresis which may lead to the modest decrease in blood pressure observed in clinical studies (see Pharmacology: Pharmacodynamics: Clinical trials under Actions).
When considering initiating dapagliflozin, there may be patients for whom the additional diuretic effect of dapagliflozin is a potential concern, either due to acute illness (such as gastrointestinal illness) or a history of hypotension or dehydration with diuretic therapy for patients who may become volume depleted. Initiation of therapy with dapagliflozin is therefore not recommended in these patients.
In case of intercurrent conditions that may lead to volume depletion, such as gastrointestinal illness, heat stress or severe infections, careful monitoring of volume status (e.g. physical examination, blood pressure measurements, laboratory tests including electrolytes) is recommended. Temporary interruption of dapagliflozin is recommended for patients who develop volume depletion until the depletion is corrected (see Adverse Reactions).
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 antihypertensive therapy with a history of hypotension or elderly patients.
Ketoacidosis: SIDAPVIA should not be used for the treatment of diabetic ketoacidosis (DKA).
There have been reports of ketoacidosis, including DKA, a serious life-threatening condition requiring urgent hospitalisation in patients taking dapagliflozin and other sodium-glucose cotransporter 2 (SGLT2) inhibitors. Fatal cases of ketoacidosis have been reported in patients taking dapagliflozin.
Patients treated with SIDAPVIA who present with signs and symptoms consistent with ketoacidosis, including nausea, vomiting, abdominal pain, malaise and shortness of breath, should be assessed for ketoacidosis, even if blood glucose levels are below 14 mmol/L (250 mg/dL). If ketoacidosis is suspected, SIDAPVIA should be suspended, the patient should be evaluated and prompt treatment initiated.
Treatment of ketoacidosis generally requires insulin, fluid, potassium and carbohydrate replacement.
Restarting SGLT2 inhibitor treatment in patients with previous DKA while on SGLT2 inhibitor treatment is not recommended unless another clear precipitating factor is identified and resolved.
Before initiating SIDAPVIA, consider factors in the patient history that may predispose to ketoacidosis.
Predisposing factors to ketoacidosis include insulin deficiency from any cause (including insulin pump failure, history of pancreatitis or pancreatic surgery), insulin dose reduction, reduced caloric intake or increased insulin requirements due to infections, low carbohydrate diet, acute illness, surgery, a previous ketoacidosis, dehydration and alcohol abuse. SIDAPVIA should be used with caution in these patients. Consider monitoring patients for ketoacidosis and temporarily discontinuing SIDAPVIA in clinical situations known to predispose to ketoacidosis.
Surgery: Treatment with SIDAPVIA should be ceased prior to major surgery. An increase in other glucose lowering agents may be required during this time. Patients scheduled for non-urgent surgery who have not ceased SIDAPVIA should be assessed and consideration should be given to postponing the procedure.
Treatment with SIDAPVIA may be restarted once the patient's condition has stabilised and oral intake is normal.
Urinary tract infections: There have been post-marketing reports of serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalisation in patients receiving SGLT2 inhibitors, including dapagliflozin. Urinary tract infections were more frequently reported for dapagliflozin 10 mg compared to control in a placebo-pooled analysis up to 24 weeks (4.7% vs. 3.5%, respectively). Urinary glucose excretion may be associated with an increased risk of urinary tract infection. Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated (see Adverse Reactions). Temporary interruption of SIDAPVIA should be considered when treating pyelonephritis or urosepsis. Discontinuation of SIDAPVIA may be considered in cases of recurrent urinary tract infections; see Adverse Reactions.
Necrotising fasciitis of the perineum (Fournier's gangrene): Post-marketing cases of necrotising fasciitis of the perineum (also known as Fournier's gangrene), a rare, but serious and potentially life-threatening necrotising infection, have been reported in female and male patients with diabetes mellitus treated with SGLT2 inhibitors, including dapagliflozin (see Adverse Reactions). Serious outcomes have included hospitalisation, multiple surgeries, and death.
Patients treated with SIDAPVIA who present with pain or tenderness, erythema, swelling in the genital or perineal area, fever, malaise should be evaluated for necrotising fasciitis. If suspected, SIDAPVIA should be discontinued and prompt treatment should be instituted (including broad-spectrum antibiotics and surgical debridement if necessary).
Lower limb amputations: In one long-term clinical study with another SGLT2 inhibitor, an increase in cases of lower limb amputation (primarily of the toe) has been observed. The medicine in that study is not dapagliflozin. However, it is unknown whether this constitutes a class effect. It is important to regularly examine the feet and counsel all patients with diabetes on routine preventative footcare.
Use with medications known to cause hypoglycaemia: Insulin and insulin secretagogues, such as sulfonylureas, cause hypoglycaemia. Hypoglycaemia has been observed when dapagliflozin or sitagliptin was used in combination with insulin or an insulin secretagogue. Therefore, a lower dose of insulin or the insulin secretagogue may be required to reduce the risk of hypoglycaemia when used in combination with SIDAPVIA.
Cardiac failure: There is limited clinical experience in patients with NYHA class IV.
Hypersensitivity reactions: Post-marketing reports of serious hypersensitivity reactions in patients treated with sitagliptin have been reported. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Onset of these reactions occurred within the first 3 months after initiation of treatment, with some reports occurring after the first dose. If a hypersensitivity reaction is suspected, SIDAPVIA should be discontinued. Other potential causes for the event should be assessed, and alternative treatment for diabetes initiated (see Contraindications and Adverse Reactions).
Pancreatitis: There have been reports of acute pancreatitis, including fatal and non-fatal haemorrhagic or necrotising pancreatitis (see Adverse Reactions). Patients should be informed of the characteristic symptom of acute pancreatitis: persistent, severe abdominal pain. Resolution of pancreatitis has been observed after discontinuation of sitagliptin. If pancreatitis is suspected, SIDAPVIA should be discontinued.
Arthralgia: Joint pain, which may be severe, has been reported in post-marketing reports for DPP4 inhibitors. Onset of symptoms following initiation of drug therapy may be rapid or may occur after longer periods of treatment. Discontinuation of therapy should be considered in patients who present with or experience an exacerbation of joint symptoms during treatment with DPP4 inhibitors (see Adverse Reactions).
Bullous pemphigoid: Post-marketing cases of bullous pemphigoid requiring hospitalisation have been reported with DPP4 inhibitor use, including sitagliptin. In reported cases, patients typically responded to topical or systemic immunosuppressive treatment and discontinuation of the DPP4 inhibitor. If a patient develops blisters or erosions while receiving SIDAPVIA and bullous pemphigoid is suspected, SIDAPVIA should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment (see Adverse Reactions).
Use in hepatic impairment: There is limited experience in clinical trials in patients with hepatic impairment. Dapagliflozin exposure is increased in patients with severe hepatic impairment. SIDAPVIA should not be used in patients with severe hepatic impairment (see Special populations under Dosage & Administration and Pharmacology: Pharmacokinetics: Special populations under Actions).
Effects on laboratory tests: Dapagliflozin: Interference with 1,5-anhydroglucitol (1,5-AG) Assay: Monitoring glycaemic control with 1,5-AG assay is not recommended as measurements of 1,5-AG are unreliable in assessing glycaemic control in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycaemic control.
Haematocrit: In the pool of 13 short-term placebo-controlled studies (see Adverse Reactions), increases from baseline in mean haematocrit values were observed in dapagliflozin-treated patients starting at Week 1. At Week 24, the mean changes from baseline in haematocrit were -0.33% in the placebo group and 2.30% in the dapagliflozin 10 mg group. By Week 24, haematocrit values >55% were reported in 0.4% of placebo-treated patients and 1.3% of dapagliflozin 10 mg-treated patients.
In the pool of 9 placebo-controlled studies with short-term and long-term data, at Week 102, the mean changes in haematocrit values were 2.68% versus -0.46%, respectively. Results for haematocrit values >55% during the short-term plus long-term phase (the majority of patients were exposed to treatment for more than one year) were similar to week 24.
Most patients with marked abnormalities of elevated haematocrit or haemoglobin had elevations measured a single time that resolved at subsequent visits.
Serum inorganic phosphorus: In the pool of 13 short-term placebo-controlled studies, increases from baseline in mean serum phosphorus levels were reported at Week 24 in dapagliflozin 10 mg-treated patients compared with placebo-treated patients (mean increases of 0.042 mmol/L versus -0.0013 mmol/L, respectively). Higher proportions of patients with marked laboratory abnormalities of hyperphosphatemia (≥1.81 mmol/L for age 17-65 or ≥1.65 mmol/L for age ≥66) were reported in dapagliflozin 10 mg group versus placebo at Week 24 (1.7% versus 0.9%, respectively).
In the pool of 9 placebo-controlled studies with short-term and long-term data, at Week 102, reported increases in mean serum phosphorus were similar to week 24 results. During the short-term plus long-term phase, laboratory abnormalities of hyperphosphataemia were reported in a higher proportion of patients in the dapagliflozin 10 mg group compared to placebo (3.0% versus 1.6%, respectively). The clinical relevance of these findings is unknown.
Lipids: In the pool of 13 short-term placebo-controlled studies, small changes from baseline in mean lipid values were reported at Week 24 in dapagliflozin 10 mg-treated patients compared with placebo-treated patients (see Adverse Reactions). Mean percent change from baseline at Week 24 for dapagliflozin 10 mg versus placebo, respectively, was as follows: total cholesterol, 2.5% versus 0.0%; high-density lipoprotein (HDL) cholesterol, 6.0% versus 2.7%; low-density lipoprotein (LDL) cholesterol, 2.9% versus -1.0%; triglycerides, -2.7% versus -0.7%. The ratio between LDL cholesterol and HDL cholesterol decreased for both treatment groups at Week 24.
In the pool of 9 placebo-controlled studies with short-term and long-term data, the mean percent change from baseline at Week 102 for dapagliflozin 10 mg versus placebo, respectively, was as follows: total cholesterol, 2.1% versus -1.5%; HDL cholesterol, 6.6% versus 2.1%; LDL cholesterol, 2.9% versus -2.2%; triglycerides, -1.8% versus -1.8%.
In the cardiovascular outcome study, no clinical important differences in total cholesterol, HDL cholesterol, LDL cholesterol or triglycerides were seen.
Liver function tests: In the 21-study active and placebo-controlled pool (see Adverse Reactions), there was no imbalance across treatment groups in the incidence of elevations of ALT or AST. ALT >3 x ULN was reported in 1.2% of patients treated with dapagliflozin 10 mg and 1.6% treated with comparator. ALT or AST >3 x ULN and bilirubin >2 x ULN was reported in 0.1% of patients on any dose of dapagliflozin, 0.2% of patients on dapagliflozin, and 0.1% of patients on comparator.
Sitagliptin: The incidence of laboratory adverse experiences was similar in patients treated with sitagliptin compared to patients treated with placebo. Across clinical studies, a small increase in white blood cell count (approximately 200 cells/microL difference in WBC vs placebo; mean baseline WBC approximately 6,600 cells/microL) was observed due to an increase in neutrophils. This observation was seen in most but not all studies. This change in laboratory parameters is not considered to be clinically relevant.
Effects on ability to drive and use machines: No studies on the effects on the ability to drive and use machines have been performed. SIDAPVIA has no anticipated or negligible influence on the ability to drive and use machines. However, when driving or operating machines, it should be taken into account that dizziness has been reported with sitagliptin. In addition, patients should be alerted to the risk of hypoglycaemia when SIDAPVIA is used in combination with insulin or an insulin secretagogue, such as a sulfonylurea.
Use in Children: Safety and effectiveness of SIDAPVIA in paediatric patients under 18 years have not been established.
Delayed growth and metabolic acidosis in rats were observed in both sexes at higher doses of dapagliflozin (greater than or equal to 15 mg/kg/day). The developmental age of animals in this study approximately correlates to 2 to 16 years in humans.
Sitagliptin should not be used in children and adolescents 10 to 17 years of age because of insufficient efficacy.
Use in the Elderly: SIDAPVIA may be used in elderly patients. However, older patients may be at greater risk of volume depletion and are more likely to have impaired renal function (see Special populations under Dosage & Administration and Pharmacology: Pharmacokinetics: Special populations under Actions).