|Composition||:||Diacolin 10/5: Each F.C.Tablet contains: Empagliflozin 10 mg + Linagliptin 5 mg.|
|Excipients||:||Mannitol, Pre-gelatinised starch, Maize starch, Copovidone, Crospovidone, Talc, Magnesium stearate, Hypromellose, Titanium dioxide, Macrogol 6000, Red Iron Oxide, and Yellow Iron Oxide.|
|Mechanism Of Action||:||This product combines 2 antihyperglycemic agents with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes: empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, and linagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor.
Sodium-glucose co-transporter 2 (SGLT2) is the predominant transporter responsible for reabsorption of glucose from the glomerular filtrate back into the circulation. Empagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, empagliflozin reduces renal reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion.
Linagliptin is an inhibitor of DPP-4, an enzyme that degrades the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Thus, linagliptin increases the concentrations of active incretin hormones, stimulating the release of insulin in a glucose-dependent manner and decreasing the levels of glucagon in the circulation.
After oral administration, peak plasma concentrations of empagliflozin were reached at 1.5 hours post-dose.
Administration of 25 mg empagliflozin after intake of a high-fat and high-calorie meal resulted in slightly lower exposure; AUC decreased by approximately 16% and Cmax decreased by approximately 37%, compared to fasted condition.
The absolute bioavailability of linagliptin is approximately 30%. High-fat meal reduced Cmax by 15% and increased AUC by 4%; this effect is not clinically relevant. Linagliptin may be administered with or without food.
The apparent steady-state volume of distribution was estimated to be 73.8 L based on a population pharmacokinetic analysis. Following administration of an oral [14C]-empagliflozin solution to healthy subjects, the red blood cell partitioning was approximately 36.8% and plasma protein binding was 86.2%.
protein binding of linagliptin is concentration-dependent, decreasing from about 99% at 1 nmol/L to 75% to 89% at ≥30 nmol/L, reflecting saturation of binding to DPP-4 with increasing concentration of linagliptin. At high concentrations, where DPP-4 is fully saturated, 70% to 80% of linagliptin remains bound to plasma proteins and 20% to 30% is unbound in plasma. Plasma binding is not altered in patients with renal or hepatic impairment.
Empagliflozin: No major metabolites of empagliflozin were detected in human plasma and the most abundant metabolites were three glucuronide conjugates .
Following oral administration, the majority (about 90%) of linagliptin is excreted unchanged.
The apparent terminal elimination half-life of empagliflozin was estimated to be 12.4 h and apparent oral clearance was 10.6 L/h based on the population pharmacokinetic analysis.
Following administration of an oral [14C]-empagliflozin solution to healthy subjects, approximately 95.6% of the drug-related radioactivity was eliminated in feces (41.2%) or urine (54.4%). The majority of drug-related radioactivity recovered in feces was unchanged parent drug and approximately half of drug-related radioactivity excreted in urine was unchanged parent drug.
Following administration of an oral [14C]-linagliptin dose to healthy subjects, approximately 85% of the administered radioactivity was eliminated via the enterohepatic system (80%) or urine (5%) within 4 days of dosing. Renal clearance at steady state was approximately 70 mL/min.
|INDICATIONS||:||Diacolin is a combination of empagliflozin and linagliptin indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both empagliflozin and linagliptin is appropriate.
Empagliflozin is indicated to reduce the risk of cardiovascular death in adults with type 2 diabetes mellitus and established cardiovascular disease . However, the effectiveness of This product on reducing the risk of cardiovascular death in adults with type 2 diabetes mellitus and cardiovascular disease has not been established.
|CONTRAINDICATIONS||:||This product is contraindicated in patients with:
• Severe renal impairment, end-stage renal disease, or dialysis .
• A history of serious hypersensitivity reaction to empagliflozin, linagliptin, or any of the excipients in This product such as anaphylaxis, angioedema, exfoliative skin conditions, urticaria, or bronchial hyperreactivity .
|Limitations Of Use||:||This product is not recommended for patients with type 1 diabetes or for the treatment of diabetic ketoacidosis .
This product has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at an increased risk for the development of pancreatitis while using This product.
|Dosage & Administration||:||The recommended dose of Diacolin 10/5 once daily in the morning, taken with or without food. In patients tolerating This product, the dose may be increased to Diacolin 25/5 once daily.
In patients with volume depletion, correcting this condition prior to initiation of This product is recommended.
Patients With Renal Impairment:
Assessment of renal function is recommended prior to initiation of This Product and periodically thereafter.
This product should not be initiated in patients with an eGFR less than 45 mL/min/1.73 m².
No dose adjustment is needed in patients with an eGFR greater than or equal to 45 mL/min/1.73 m².
|SIDE EFFECTS||:||Pancreatitis ,Heart Failure ,Hypotension ,Ketoacidosis ,Acute Kidney Injury and Impairment in Renal Function ,Urosepsis and Pyelonephritis ,Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues ,Necrotizing Fasciitis of the Perineum (Fournier's Gangrene) ,Genital Mycotic Infections Hypersensitivity Reactions ,Increased Low-Density Lipoprotein Cholesterol (LDL-C) ,Severe and Disabling Arthralgia ,Bullous Pemphigoid ,Urinary tract infection ,Nasopharyngitis ,Upper respiratory tract infection, diarrhea ,cough ,urticaria, angioedema, localized skin exfoliation, or bronchial hyperreactivity) and myalgia, ,dyslipidemia , arthralgia , Hypoglycemia , Increase in Hematocrit, Increase in Uric Acid.|
|DRUG INTERACTIONS||:||Drug Interactions With Empagliflozin:
Coadministration of empagliflozin with diuretics resulted in increased urine volume and frequency of voids, which might enhance the potential for volume depletion .
Insulin Or Insulin Secretagogues
Coadministration of empagliflozin with insulin or insulin secretagogues increases the risk for hypoglycemia .
Positive Urine Glucose Test
Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors as SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests. Use alternative methods to monitor glycemic control.
Interference With 1,5-anhydroglucitol (1,5-AG) Assay:
Monitoring glycemic control with 1,5-AG assay is not recommended as measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control.
Drug Interactions With Linagliptin:
Inducers Of P-glycoprotein Or CYP3A4 Enzymes:
Rifampin decreased linagliptin exposure, suggesting that the efficacy of linagliptin may be reduced when administered in combination with a strong P-gp or CYP3A4 inducer. Therefore, use of alternative treatments is strongly recommended when linagliptin is to be administered with a strong P-gp or CYP3A4 inducer.
There have been postmarketing reports of acute pancreatitis, including fatal pancreatitis, in patients taking linagliptin. Take careful notice of potential signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly discontinue this product and initiate appropriate management. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using this product.
An association between DPP-4 inhibitor treatment and heart failure has been observed in cardiovascular outcomes trials for two other members of the DPP-4 inhibitor class. These trials evaluated patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease.
Consider the risks and benefits of this product prior to initiating treatment in patients at risk for heart failure,
Empagliflozin causes intravascular volume contraction. Symptomatic hypotension may occur after initiating empagliflozin particularly in patients with renal impairment, the elderly, in patients with low systolic blood pressure, and in patients on diuretics. Before initiating this product, assess for volume contraction and correct volume status if indicated.
Reports of ketoacidosis, a serious life-threatening condition requiring urgent hospitalization have been identified in postmarketing surveillance in patients with type 1 and type 2 diabetes mellitus receiving sodium glucose co-transporter-2 (SGLT2) inhibitors, including empagliflozin. Fatal cases of ketoacidosis have been reported in patients taking empagliflozin. This product is not indicated for the treatment of patients with type 1 diabetes mellitus.
Before initiating this product, consider factors in the patient history that may predispose to ketoacidosis including pancreatic insulin deficiency from any cause, caloric restriction, and alcohol abuse. In patients treated with this product consider monitoring for ketoacidosis and temporarily discontinuing this product in clinical situations known to predispose to ketoacidosis (e.g., prolonged fasting due to acute illness or surgery).
Acute Kidney Injury And Impairment In Renal Function:
Empagliflozin causes intravascular volume contraction [see Hypotension] and can cause renal impairment . There have been postmarketing reports of acute kidney injury, some requiring hospitalization and dialysis, in patients receiving SGLT2 inhibitors, including empagliflozin; some reports involved patients younger than 65 years of age.
Before initiating this product, consider factors that may predispose patients to acute kidney injury including hypovolemia, chronic renal insufficiency, congestive heart failure and concomitant medications (diuretics, ACE inhibitors, ARBs, NSAIDs). Consider temporarily discontinuing this product in any setting of reduced oral intake (such as acute illness or fasting) or fluid losses (such as gastrointestinal illness or excessive heat exposure); monitor patients for signs and symptoms of acute kidney injury. If acute kidney injury occurs, discontinue this product promptly and institute treatment.
Empagliflozin increases serum creatinine and decreases eGFR. Patients with hypovolemia may be more susceptible to these changes. Renal function abnormalities can occur after initiating This product
More frequent renal function monitoring is recommended in patients with an eGFR below 60 mL/min/1.73 m². Use of this product is not recommended when eGFR is persistently less than 45 mL/min/1.73 m² and is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m².
Urosepsis And Pyelonephritis:
There have been postmarketing reports of serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization in patients receiving SGLT2 inhibitors, including empagliflozin. Treatment with SGLT2 inhibitors increases the risk for urinary tract infections. Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated .
Hypoglycemia With Concomitant Use With Insulin And Insulin Secretagogues: Insulin and insulin secretagogues are known to cause hypoglycemia. The use of empagliflozin or linagliptin in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin was associated with a higher rate of hypoglycemia compared with placebo in a clinical trial. Therefore, a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia when used in combination with This product.
Necrotizing Fasciitis Of The Perineum (Fournier’s Gangrene):
Reports of necrotizing fasciitis of the perineum (Fournier's gangrene), a rare but serious and life-threatening necrotizing infection requiring urgent surgical intervention, have been identified in postmarketing surveillance in patients with diabetes mellitus receiving SGLT2 inhibitors, including empagliflozin. Cases have been reported in both females and males. Serious outcomes have included hospitalization, multiple surgeries, and death.
Patients treated with this product presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise, should be assessed for necrotizing fasciitis. If suspected, start treatment immediately with broad-spectrum antibiotics and, if necessary, surgical debridement. Discontinue this product, closely monitor blood glucose levels, and provide appropriate alternative therapy for glycemic control.
Genital Mycotic Infections:
Empagliflozin increases the risk for genital mycotic infections. Patients with a history of chronic or recurrent genital mycotic infections were more likely to develop genital mycotic infections. Monitor and treat as appropriate.
There have been postmarketing reports of serious hypersensitivity reactions in patients treated with linagliptin (one of the components of this product). These reactions include anaphylaxis, angioedema, and exfoliative skin conditions. Onset of these reactions occurred within the first 3 months after initiation of treatment with linagliptin, with some reports occurring after the first dose.
Angioedema has also been reported with other dipeptidyl peptidase-4 (DPP-4) inhibitors. Use caution in a patient with a history of angioedema to another DPP-4 inhibitor because it is unknown whether such patients will be predisposed to angioedema with this product.
There have been postmarketing reports of serious hypersensitivity reactions, (e.g., angioedema) in patients treated with empaglifozin (one of the components of this product).
If a hypersensitivity reaction occurs, discontinue this product, treat promptly per standard of care, and monitor until signs and symptoms resolve. This product is contraindicated in patients with a previous serious hypersensitivity reaction to linagliptin or empagliflozin .
Increased Low-Density Lipoprotein Cholesterol (LDL-C):
Increases in LDL-C can occur with empagliflozin .Monitor and treat as appropriate.
Severe And Disabling Arthralgia:
There have been postmarketing reports of severe and disabling arthralgia in patients taking 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 as a possible cause for severe joint pain and discontinue drug if appropriate.
Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP-4 inhibitor use. In reported cases, patients typically recovered with topical or systemic immunosuppressive treatment and discontinuation of the DPP-4 inhibitor. Tell patients to report development of blisters or erosions while receiving this product. If bullous pemphigoid is suspected, this product should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with this product.
Inform patients that acute pancreatitis has been reported during postmarketing use of linagliptin. Inform patients that persistent severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting, is the hallmark symptom of acute pancreatitis. Instruct patients to discontinue this product promptly and contact their physician if persistent severe abdominal pain occurs .
Inform patients of the signs and symptoms of heart failure. Before initiating this product, patients should be asked about a history of heart failure or other risk factors for heart failure including moderate to severe renal impairment. Instruct patients to contact their healthcare provider as soon as possible if they experience symptoms of heart failure, including increasing shortness of breath, rapid increase in weight or swelling of the feet .
Inform patients that the incidence of hypoglycemia is increased when empagliflozin, linagliptin, or this product is added to a sulfonylurea or insulin and that a lower dose of the sulfonylurea or insulin may be required to reduce the risk of hypoglycemia.
Inform patients that hypotension may occur with this product and advise them to contact their healthcare provider if they experience such symptoms .Inform patients that dehydration may increase the risk for hypotension, and to have adequate fluid intake.
Inform patients that ketoacidosis is a serious life-threatening condition. Cases of ketoacidosis have been reported during use of empagliflozin. Instruct patients to check ketones (when possible) if symptoms consistent with ketoacidosis occur even if blood glucose is not elevated. If symptoms of ketoacidosis (including nausea, vomiting, abdominal pain, tiredness, and labored breathing) occur, instruct patients to discontinue this product and seek medical advice immediately .
Acute Kidney Injury
Inform patients that acute kidney injury has been reported during use of empagliflozin. Advise patients to seek medical advice immediately if they have reduced oral intake (such as due to acute illness or fasting) or increased fluid losses (such as due to vomiting, diarrhea, or excessive heat exposure), as it may be appropriate to temporarily discontinue this product use in those settings .
Serious Urinary Tract Infections
Inform patients of the potential for urinary tract infections, which may be serious. Provide them with information on the symptoms of urinary tract infections. Advise them to seek medical advice if such symptoms occur .
Necrotizing Fasciitis Of The Perineum (Fournier’s Gangrene):
Inform patients that necrotizing infections of the perineum (Fournier's gangrene) have occurred with empagliflozin, a component of THIS PRODUCT. Counsel patients to promptly seek medical attention if they develop pain or tenderness, redness, or swelling of the genitals or the area from the genitals back to the rectum, along with a fever above 100.4°F or malaise.
Genital Mycotic Infections In Females (e.g., Vulvovaginitis):
Inform female patients that vaginal yeast infections may occur and provide them with information on the signs and symptoms of vaginal yeast infections. Advise them of treatment options and when to seek medical advice .
Genital Mycotic Infections In Males (e.g., Balanitis or Balanoposthitis)
Inform male patients that yeast infection of penis (e.g., balanitis or balanoposthitis) may occur, especially in uncircumcised males and patients with chronic and recurrent infections. Provide them with information on the signs and symptoms of balanitis and balanoposthitis (rash or redness of the glans or foreskin of the penis). Advise them of treatment options and when to seek medical advice .
Inform patients that serious allergic reactions, such as anaphylaxis, angioedema, and exfoliative skin conditions, have been reported during postmarketing use of linagliptin or empagliflozin, components of this product. If symptoms of allergic reactions (such as rash, skin flaking or peeling, urticaria, swelling of the skin, or swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing) occur, patients must stop taking this product and seek medical advice promptly .
Severe And Disabling Arthralgia
Inform patients that severe and disabling joint pain may occur with this class of drugs. The time to onset of symptoms can range from one day to years. Instruct patients to seek medical advice if severe joint pain occurs .
Inform patients that bullous pemphigoid may occur with this class of drugs. Instruct patients to seek medical advice if blisters or erosions occur .
Inform patients that renal function should be assessed prior to initiation of this product and monitored periodically thereafter.
Inform patients that elevated glucose in urinalysis is expected when taking this product.
Inform patients that response to all diabetic therapies should be monitored by periodic measurements of blood glucose and HbA1c levels, with a goal of decreasing these levels toward the normal range. Hemoglobin A1c is especially useful for evaluating long-term glycemic control.
|Pregnancy & lactations||:||Pregnancy:
The limited available data with THIS PRODUCT, linagliptin, or empagliflozin in pregnant women are not sufficient to determine a drug-associated risk for major birth defects and miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy.
Based on animal data showing adverse renal effects, from empagliflozin, this product is not recommended during the second and third trimesters of pregnancy.
There is no information regarding the presence of THIS PRODUCT, or its individual components in human milk, the effects on the breastfed infant, or the effects on milk production. Empagliflozin and linagliptin are present in rat milk . Because of the potential for serious adverse reactions in a breastfed infant, including the potential for empagliflozin to affect postnatal renal development, advise patients that use of THIS PRODUCT is not recommended while breastfeeding.
|Hepatic & Renal Impairment||:||Renal Impairment:
The glucose lowering benefit of empagliflozin 25 mg decreased in patients with worsening renal function.
This product may be used in patients with hepatic impairment.
|OVERDOSE||:||In the event of an overdose with this product, contact the Poison Control Center. Employ the usual supportive measures (e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment) as dictated by the patient's clinical status. Removal of empagliflozin by hemodialysis has not been studied, and removal of linagliptin by hemodialysis or peritoneal dialysis is unlikely.|
|STORAGE||:||Store below 25⁰C.|
|PACKAGING||:||Diacolin 10/5: Carton box of 20 Film Coated Tablets packed inside blisters with a leaflet.|