Zemidapa Special Precautions

Hepatic impairment: Gemigliptin/Dapagliflozin should be used with caution as there is no experience in clinical studies in patients with severe hepatic impairment in the case of gemigliptin. There is limited experience in clinical studies in patients with hepatic impairment in the case of dapagliflozin. Dapagliflozin exposure is increased in patients with severe hepatic impairment (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Cardiac impairment: There is limited clinical experience in patients with NYHA Class I, II cardiac status in the case of gemigliptin. Therefore, Gemigliptin/Dapagliflozin should be used with caution in this population. Gemigliptin/Dapagliflozin should be avoided in patients with NYHA Class III, IV cardiac status (see Dosage & Administration).
Acute pancreatitis: Pancreatitis has been reported in patients taking DPP-4 inhibitors including gemigliptin. Therefore, patients should be informed of the characteristic symptoms of acute pancreatitis: persistent, severe abdominal pain. If pancreatitis is suspected, Gemigliptin/Dapagliflozin should be discontinued and should not be restarted. Caution should be exercised in patients with a history of pancreatitis.
Use with medicinal products known to cause hypoglycemia: Patients receiving Gemigliptin/Dapagliflozin in combination with a sulfonylurea or with insulin may be at risk for hypoglycemia. Therefore, a reduction in the dose of the sulfonylurea or insulin maybe necessary.
Severe and disabling arthralgia: There have been post-marketing reports of severe and disabling arthralgia in patients taking other DPP-4 inhibitors. The time to onset of symptoms following initiation of drug therapy varied from one day to years. Patients experienced relief of symptoms upon discontinuation of the medication. A subset of patients experienced a recurrence of symptoms when restarting the same drug or a different DPP-4 inhibitor. Consider DPP-4 inhibitors as a possible cause for severe joint pain and discontinue drug if appropriate.
Bullous pemphigoid: There have been post-marketing reports of bullous pemphigoid requiring hospitalization in patients taking other DPP-4 inhibitors. In reported cases, patients typically recovered with topical or systemic immunosuppressive treatment and discontinuation of the DPP-4 inhibitor. Patient should be instructed to report development of blisters or erosions to their doctors while receiving Gemigliptin/Dapagliflozin. If bullous pemphigoid is suspected, Gemigliptin/Dapagliflozin should be discontinued and a dermatologist should be consulted for diagnosis and proper treatment.
Hypersensitive reactions: This medicinal product must not be used in patients who have had any serious hypersensitivity reaction to a DPP-4 inhibitor or a SGLT2 inhibitor (see Contraindications).
Severe hypersensitivity reactions have been reported in patients treated with gemigliptin post marketing, including Stevens-Johnson syndrome. If serious hypersensitivity reaction is suspected, this drug should be discontinued, other potential causes of the reaction should be identified, and administer other diabetes therapies.
Use in patients at risk for volume depletion and/or hypotension: Due to dapagliflozin's mechanism of action, this medicinal product increases diuresis which may lead to the modest decrease in blood pressure observed in clinical studies (see Pharmacology: Pharmacodynamics under Actions). It may be more pronounced in patients with very high blood glucose concentrations.
Caution should be exercised in patients for whom a dapagliflozin-induced drop in blood pressure could pose a risk, such as patients on anti-hypertensive therapy with a history of hypotension or elderly patients.
In case of intercurrent conditions that may lead to volume depletion (e.g. gastrointestinal illness), careful monitoring of volume status (e.g. physical examination, blood pressure measurements, laboratory tests including haematocrit and electrolytes) is recommended. Temporary interruption of treatment with this medicinal product is recommended for patients who develop volume depletion until the depletion is corrected (see Adverse Reactions).
Diabetic ketoacidosis: Rare cases of diabetic ketoacidosis (DKA), including life-threatening and fatal cases, have been reported in patients treated with SGLT2 inhibitors, including dapagliflozin. In a number of cases, the presentation of the condition was atypical with only moderately increased blood glucose values, below 14 mmol/litres (250 mg/dL). It is not known if DKA is more likely to occur with higher doses of dapagliflozin.
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 this medicinal product should be discontinued immediately.
Treatment should be interrupted in patients who are hospitalised for major surgical procedures or acute serious medical illnesses. Monitoring of ketones is recommended in these patients. Measurement of blood ketone levels is preferred to urine. Treatment with dapagliflozin may be restarted when the ketone values are normal and the patient's condition has stabilised.
Before initiating treatment with this medicinal product, factors in the patient history that may predispose to ketoacidosis should be considered.
Patients who may be at higher risk of DKA include patients with a low beta-cell function reserve (e.g. type 2 diabetes patients with low C-peptide or latent autoimmune diabetes in adults (LADA) or patients with a history of pancreatitis), patients with conditions that lead to restricted food intake or severe dehydration, patients for whom insulin doses are reduced and patients with increased insulin requirements due to acute medical illness, surgery or alcohol abuse. SGLT2 inhibitors should be used with caution in these patients.
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.
The safety and efficacy of the Gemigliptin/Dapagliflozin in patients with type 1 diabetes have not been established and it should not be used for treatment of patients with type 1 diabetes. In type 1 diabetes mellitus studies with dapagliflozin, DKA was reported with common frequency.
Genital mycotic infections: Dapagliflozin increases the risk of genital mycotic infections. Patients with a history of genital mycotic infections were more likely to develop genital mycotic infections. Monitor and treat appropriately.
Urinary laboratory assessments: Due to its mechanism of action, patients taking dapagliflozin will test positive for glucose in their urine.
Body weight loss: In placebo-controlled study of 24-week duration in subjects with inadequately controlled type 2 diabetes mellitus, dapagliflozin resulted in greater body weight reduction from baseline compared with placebo (-3.16 kg and -2.19 kg, respectively).
Lower limb amputations: An increase in cases of lower limb amputation (primarily of the toe) has been observed in long-term, clinical studies in type 2 diabetes mellitus with SGLT2 inhibitors. It is unknown whether this constitutes a class effect. It is important to counsel patients with diabetes on routine preventative foot care.
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 (see Adverse Reactions). 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 necrotising fasciitis. If Fournier's gangrene is suspected, Gemigliptin/Dapagliflozin should be discontinued and prompt treatment (including antibiotics and surgical debridement) should be instituted.
Effects on ability to drive and use machines: No studies on the effects on the ability to drive and use machines have been performed with Gemigliptin/Dapagliflozin. However, patients should be alerted to the risk of hypoglycemia when Gemigliptin/Dapagliflozin is used in combination with other anti-diabetic medicinal products known to cause hypoglycemia (e.g. sulfonylureas).
Use in the Elderly: 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.
Elderly patients may be at a greater risk for volume depletion and are more likely to be treated with diuretics.
There are insufficient data to draw conclusions regarding exposure in patients ≥70 years old.