Zensita Trio 1000 Tablets

Dapagliflozin, Sitagliptin and Metformin Hydrochloride (as extended release) Tablets (10 mg + 100 mg + 500 mg)

Dapagliflozin, Sitagliptin and Metformin Hydrochloride (as extended release) Tablets (10 mg + 100 mg + 1000 mg)

Zensita-Trio 500

Each film coated tablet contains :

Dapagliflozin Propanediol Monohydrate

equivalent to Dapagliflozin 10 mg

Sitagliptin Phosphate Monohydrate IP

equivalent to Sitagliptin 100 mg

Metformin Hydrochloride IP 500 mg

(as extended release)

Excipients q.s.

Colours : Ferric Oxide Red USP-NF, Ferric

Oxide Yellow USP-NF & Titanium Dioxide IP

Zensita-Trio 1000

Each fllm coated tablet contains :

Dapagliflozin Propanediol Monohydrate

equivalent to Dapagliflozin 10 mg

Sitagliptin Phosphate Monohydrate IP

equivalent to Sitagliptin 100 mg

Metformin Hydrochloride IP 1000 mg

(as extended release)

Excipients q.s.

Colours : Indigo Carmine Aluminium Lake & Titanium Dioxide IP

Film coated tablet, Dapagliflozin 10 mg + Sitagliptin 100 mg + Metformin Hydrochloride Extended Release 500 mg/ 1000 mg tablets

4.1 Therapeutic indication

It is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

4.2 Posology & method of administration

Posology

The recommended dose is one tablet daily.

Elderly (≥ 65 years)

Because metformin is eliminated in part by the kidney, and because elderly patients are more likely to have decreased renal function, this medicinal product should be used with caution as age increases.

Paediatric population

The safety and efficacy of Dapagliflozin, Sitagliptin and Metformin Hydrochloride ER tablets have not yet been established. No data are available.

Method of administration

Dapagliflozin, Sitagliptin and Metformin Hydrochloride ER tablets should be given once daily with meals to reduce the gastrointestinal adverse reactions associated with metformin. It should be given orally once daily.

4.3 Contraindications

• Hypersensitivity to the active substances or to any sodium-glucose co-transporter 2 (SGLT2) inhibitor or to any dipeptidyl peptidase-4 (DPP-4) inhibitor or to any of the excipients listed in the formulation.

• Any type of acute metabolic acidosis (such as lactic acidosis, diabetic ketoacidosis).

• Diabetic pre-coma.

• Moderate 2 to severe renal impairment (eGFR less than 45 mL/min/1.73 m ), end-stage renal disease (ESRD), or patients on dialysis.

• Acute conditions with the potential to alter renal function such as: dehydration, severe infection, shock.

• Disease which may cause tissue hypoxia (especially acute disease, or worsening of chronic disease) such as : decompensated heart failure, respiratory failure, recent myocardial infarction, shock.

• Hepatic insufficiency, acute alcohol intoxication, alcoholism.

4.4 Warning & precautions

Renal impairment

Zensita-Trio is contraindicated in patients with moderate to severe renal impairment 2 (eGFR less than 45 mL/min/1.73 m ), ESRD, or on dialysis.

Use in patients at risk for volume depletion and/or hypotension Dapagliflozin increases diuresis which may lead to the modest decrease in blood pressure observed in clinical studies. 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 hematocrit and electrolytes) is recommended. Temporary interruption of treatment with Zensita-Trio is recommended for patients who develop volume depletion until the depletion is corrected.

Diabetic ketoacidosis

Rare cases of diabetic ketoacidosis (DKA), including life-threatening and fatal cases, have been reported in patients treated with sodium-glucose co-transporter 2 (SGLT2) inhibitors, including dapaglifozin. In a number of cases, the presentation of the condition was atypical with only moderately increased blood glucose values, below 14 mmol/L (250 mg/dL).

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, Zensita-Trio treatment should be stopped immediately.

Treatment should be interrupted in patients who are hospitalized 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 Zensita-Trio may be restarted when the ketone values are normal and the patient's condition has stabilized.

Before initiating Zensita-Trio, 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 experiencing a DKA while on SGLT2 inhibitor treatment is not recommended, unless another clear precipitating factor is identified and resolved.

In type 1 diabetes mellitus studies with dapagliflozin, DKA was reported with common frequency. Zensita-Trio should not be used for treatment of patients with type 1 diabetes

Type 2 diabetes mellitus Rare cases of DKA, including life-threatening and fatal cases, have been reported in patients treated with SGLT2 inhibitors, including dapaglifiozin. In a number of cases, the presentation of the condition was atypical with only moderately increased blood glucose values, below 14 mmol/L (250 mg/dL).

In patients where DKA is suspected or diagnosed, Zensita-Trio treatment should be stopped immediately.

Restarting SGLT2 inhibitor treatment in patients experiencing a DKA while on SGLT2 inhibitor treatment is not recommended, unless another clear precipitating factor is identified and resolved.

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. 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, Zensita-Trio should be discontinued and prompt treatment (including antibiotics and surgical debridement) should be instituted.

Urinary tract infections

Urinary glucose excretion may be associated with an increased risk of urinary tract infection; therefore, temporary interruption of Zensita-Trio should be considered when treating pyelonephritis or urosepsis.

Elderly (≥ 65 years)

Elderly patients may be at a greater risk for volume depletion and are more likely to be treated with diuretics. 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.

Lower limb amputations

It is important to counsel patients with diabetes on routine preventative foot care.

Acute pancreatitis

Use of DPP-4 inhibitors has been associated with a risk of developing acute pancreatitis. 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 (with or without supportive treatment), but very rare cases of necrotising or haemorrhagic pancreatitis and/or death have been reported. If pancreatitis is suspected, Zensita-Trio should be discontinued; if acute pancreatitis is confirmed, Zensita-Trio should not be restarted. Caution should be exercised in patients with a history of pancreatitis. Hypoglycaemia when used in combination with other anti-hyperglycaemic medicinal products Hypoglycaemia has been observed when sitagliptin was used in combination with insulin or a sulphonylurea. Therefore, to reduce the risk of hypoglycaemia, a lower dose of Zensita-Trio or insulin may be considered.

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. 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, Zensita-Trio should be discontinued. Other potential causes for the event should be assessed, and alternative treatment for diabetes initiated.

Bullous pemphigoid

There have been post-marketing reports of bullous pemphigoid in patients taking DPP-4 inhibitors including sitagliptin. If bullous pemphigoid is suspected, Zensita-Trio should be discontinued.

Severe and Disabling Arthralgia

There have been post marketing 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 Zensita-Trio as a possible cause for severe joint pain and discontinue drug if appropriate.

Cardiac function

Patients with heart failure are more at risk of hypoxia and renal insufficiency. In patients with stable chronic heart failure, metformin may be used with a regular monitoring of cardiac and renal function. For patients with acute and unstable heart failure, Zensita-Trio is contraindicated.

Surgery

Zensita-Trio must be discontinued at the time of surgery under general, spinal or epidural anesthesia. Therapy may be restarted no earlier than 48 hours following surgery or resumption of oral nutrition and provided that renal function has been reevaluated and found to be stable.

Other precautions

All patients should continue their diet with a regular distribution of carbohydrate intake during the day. Overweight patients should continue their energy-restricted diet. The usual laboratory tests for diabetes monitoring should be performed regularly. Metformin may reduce vitamin B12 serum levels. The risk of low vitamin B12 levels increases with increasing metformin dose, treatment duration, and/or in patients with risk factors known to cause vitamin B12 deficiency. In case of suspicion of vitamin B12 deficiency (such as anemia or neuropathy), vitamin B12 serum levels should be monitored. Periodic vitamin B12 monitoring could be necessary in patients with risk factors for vitamin B12 deficiency. Zensita-Trio therapy should be continued for as long as it is tolerated and not contra-indicated and appropriate corrective treatment for vitamin B12 deficiency provided in line with current clinical guidelines. Metformin alone does not cause hypoglycemia, but caution is advised when it is used in combination with insulin or other oral antidiabetics (e.g. sulfonylureas or meglitinides).

4.5 Drug interactions

Drug Interaction between Dapaglifiozin and Sitagliptin and Glimepiride was evaluated in an open-label, randomized, five-period, five-treatment, unbalanced crossover study. In this study 18 subjects first received 20 mg dapaglifiozin, 4 mg glimepiride or the combination, and afterward 100 mg sitagliptin or sitagliptin plus 20 mg dapaglifiozin. Co-administration of dapaglifiozin with pioglitazone, metformin, glimepiride or sitagliptin had no effect on dapaglifiozin maximum plasma concentration (Cmax) or area under the plasma concentration-time curve (AUC). Similarly, dapaglifiozin did not affect the Cmax or AUC for the co-administered drug, except for slight extensions of the 90% CI for the ratio of geometric means for glimepiride AUC (upper limit 1.29) and pioglitazone Cmax (lower limit 0.75). All monotherapies and combination therapies were well tolerated.

Co-administration of sitagliptin (50 mg twice daily) and metformin (1000 mg twice daily), co-administration of multiple doses of sitagliptin (50 mg twice daily) and metformin (1000 mg twice daily) did not meaningfully alter the pharmacokinetics of either sitagliptin or metformin in patients with type 2 diabetes.

4.6 Special populations

Pregnancy

When pregnancy is detected, treatment with FDC of dapagliflozin, sitagliptin and metformin should be discontinued.

Breastfeeding

FDC of dapaglifozin, sitagliptin and metformin should not be used during breastfeeding.

4.7 Effects on ability to drive and use machines

FDC of Dapagliflozin, sitagliptin, and metformin has no or negligible influence on the ability to drive and use machines. However, when driving or using machines, it should be taken into account that dizziness and somnolence have been reported with sitagliptin.

4.8 Undesirable effects

Metabolism and nutrition disorders

Very common : Hypoglycaemia

Common: Vitamin B12 decrease/deficiency

Uncommon: Volume depletion, thirst

Rare: Diabetic ketoacidosis (when used in type 2 diabetes mellitus)

Very rare: Lactic acidosis.

Nervous system disorders

Common: Taste disturbance, dizziness

Gastrointestinal disorders

Very common: Gastrointestinal disorders such as nausea, vomiting, diarrhoea, abdominal pain and loss of appetite. These undesirable effects occur most frequently during initiation of therapy and resolve spontaneously in most cases. Uncommon: Constipation, dry mouth

Hepatobiliary disorders

Very rare: Isolated reports of liver function tests abnormalities or hepatitis resolving upon metformin discontinuation.

Skin and subcutaneous tissue disorders

Common: Rash

Very rare: Skin reactions such as erythema, pruritus, urticaria, angioedema

Infections and infestations

Common: Vulvovaginitis, balanitis and related genital infections, urinary tract infection

Uncommon: Fungal infection

Very rare: Necrotising fasciitis of the perineum (Fournier's gangrene)

Musculoskeletal and connective tissue disorders

Common: Back pain

Renal and urinary disorders

Common: Dysuria, polyuria

Uncommon: Nocturia

Reproductive system and breast disorders

Uncommon: Vulvovaginal pruritus, pruritus of genital

Investigations

Common : Hematocrit increased, creatinine renal clearance decreased during initial treatment, dyslipidemia

Uncommon : Blood creatinine increased during initial treatment, Blood urea increased, weight decreased

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to : medico@zuventus.com

Website : https://www.zuventus.com/drug-safety-reporting By reporting side effects, you can help provide more information on the safety of this medicine

4.9 Overdose

In overdose, the stomach should be emptied by aspiration and gastric lavage. Vital parameters should be managed symptomatically and institute supportive measures as required.

5.1 Mechanism of action

Dapaglifiozin, Sitagliptin and Metformin Hydrochloride ER tablets combines three antihyperglycaemic medicinal products with different and complementary mechanisms of action to improve glycaemic control in patients with type 2 diabetes: (1) Dapaglifiozin, a SGLT2 inhibitor, (2) Sitagliptin, a dipeptidyl peptidase-4 (DPP4) inhibitor, and (3) metformin hydrochloride, a member of the biguanide class.

Sitagliptin

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 Sitagliptin, thereby increasing and prolonging the action of these hormones. Incretin hormones, including glucagon-like peptide-1 (GLP1) 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 intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. By increasing and prolonging active incretin levels, Sitagliptin increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.

Dapagliflozin

Sodium-glucose cotransporter 2 (SGLT2), expressed in the proximal renal tubules, is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen. Dapagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, dapagliflozin reduces reabsorption of filtered glucose and lowers the renal threshold for glucose and thereby increases urinary glucose excretion.

Metformin Hcl

Metformin is an ant hyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Its pharmacologic mechanisms of action are different from other classes of oral ant hyperglycemic agents. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not produce hypoglycemia in either patients with type 2 diabetes or normal subjects and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.

5.2 Pharmacodynamic properties

Sitagliptin

In patients with type 2 diabetes, administration of sitagliptin led to inhibition of DPP-4 enzyme activity for a 24-hour period. After an oral glucose load or a meal, this DPP-4 inhibition resulted in a 2-to 3-fold increase in circulating levels of active GLP-1 and GIP, decreased glucagon concentrations, and increased responsiveness of insulin release to glucose, resulting in higher C-peptide and insulin concentrations. The rise in insulin with the decrease in glucagon was associated with lower fasting glucose concentrations and reduced glucose excursion following an oral glucose load or a meal.

Dapagliflozin

Increases in the amount of glucose excreted in the urine were observed in healthy subjects and in subjects with type 2diabetes mellitus following the administration of dapagliflozin.

Metformin

In humans, independently of its action on glycaemia, metformin has favourable effects on lipid metabolism. This has been shown at therapeutic doses in controlled, mediumterm or long-term clinical studies: metformin reduces total cholesterol, LDL cholesterol and triglyceride levels.

5.3 Pharmacokinetic properties

6.1 Animal toxicology or pharmacology

Dapagliflozin

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and fertility. Dapagliflozin did not induce tumors in either mice or rats at any of the doses evaluated in two-year carcinogenicity studies.

Direct administration of dapagliflozin to weanling juvenile rats and indirect exposure during late pregnancy (time periods corresponding to the second and third trimesters of pregnancy with respect to human renal maturation) and lactation are each associated with increased incidence and/or severity of renal pelvic and tubular dilatations in progeny. Therefore, the use of dapagliflozin is not recommended during the second and third trimesters of pregnancy

In a juvenile toxicity study, when dapagliflozin was dosed directly to young rats from postnatal day 21 until postnatal day 90, renal pelvic and tubular dilatations were reported at all dose levels; pup exposures at the lowest dose tested were ≥15 times the maximum recommended human dose (MRHD). These findings were associated with dose-related increases in kidney weight and macroscopic kidney enlargement observed at all doses. The renal pelvic and tubular dilatations observed in juvenile animals did not fully reverse within the approximate 1-month recovery period. In a separate study of pre- and post-natal development, maternal rats were dosed from gestation Day 6 through postnatal Day 21, and pups were indirectly exposed in utero and throughout lactation. Increased incidence or severity of renal pelvic dilatation was observed in adult offspring of treated dams at 75 mg/kg/day, the highest dose tested (associated maternal and pup dapagliflozin exposures were 1,415 times and 137 times, respectively, the human exposure at the MRHD based on AUC comparisons). Additional developmental toxicity was limited to dose-related reductions in pup body weights, and observed only at doses ≥15 mg/kg/day (associated with pup exposures ≥29 times the human exposure at the MRHD based on AUC comparisons). Maternal toxicity was evident only at the highest dose tested, and limited to transient reductions in body weight and food consumption. The no observed adverse effect level (NOAEL) for developmental toxicity, was 1 mg/kg/day (~19 times the human exposure at the MRHD based on AUC comparisons).

In embryo-fetal development studies in rats and rabbits, dapagliflozin was administered throughout organogenesis, corresponding to the first trimester of human pregnancy. In rats, dapagliflozin was neither embryo lethal nor teratogenic at doses up to 75 mg/kg/day (~1441-times the human exposure at the MRHD, based on AUC comparisons). No maternal or developmental toxicities were observed in rabbits at doses up to 180 mg/kg/day (~1191 times the human exposure at the MRHD, based on AUC comparisons).

Sitagliptin

Renal and liver toxicity were observed in rodents at systemic exposure values 58 times the human exposure level, while the no-effect level was found at 19 times the human exposure level. Incisor teeth abnormalities were observed in rats at exposure levels 67 times the clinical exposure level; the no-effect level for this finding was 58-fold based on the 14-week rat study. The relevance of these findings for humans is unknown. Transient treatment-related physical signs, some of which suggest neural toxicity, such as openmouth breathing, salivation, white foamy emesis, ataxia, trembling, decreased activity, and/or hunched posture were observed in dogs at 50 mg/kg/day (~23 times the human exposure at the MRHD based on AUC comparisons). In addition, very slight to slight skeletal muscle degeneration was also observed histologically in the 3- and 6-month toxicity studies at the 50 mg/kg/day. However, no skeletal muscle degeneration was found in the 12-month toxicity study, indicating the lack of reproducibility or progression of this change with increased duration of treatment. A no-effect level for these findings was 10 mg/kg/day (~6 times the human exposure at the MRHD, based on AUC comparisons).

Sitagliptin has not been demonstrated to be genotoxic in preclinical studies. Sitagliptin was not carcinogenic in mice. In rats, there was an increased incidence of hepatic adenomas and carcinomas (~58 times the human exposure at the MRHD, based on AUC comparisons). Since hepatotoxicity has been shown to correlate with induction of hepatic neoplasia in rats, this increased incidence of hepatic tumors in rats was likely secondary to chronic hepatic toxicity at this high dose. Because of the high safety margin (~19-fold the human exposure at the MRHD, based on AUC comparisons), these neoplastic changes are not considered relevant for the situation in humans. No adverse effects upon fertility were observed in male and female rats given sitagliptin prior to and throughout mating. No adverse effect on fertility was observed at 125 mg/kg/day (~12 times human exposure at the MRHD based on AUC comparisons). In a pre-/postnatal development study performed in rats sitagliptin showed no adverse effects on functional or behavioral toxicity in offspring were noted at doses up to 1000 mg/kg/day

Reproductive toxicity studies showed a slight treatment-related increased incidence of fetal rib malformations (absent, hypoplastic and wavy ribs) in the offspring of rats at systemic exposure levels more than 29 times the human exposure levels. Maternal toxicity was seen in rabbits at more than 29 times the human exposure levels. Because of the high safety margins, these findings do not suggest a relevant risk for human reproduction. Sitagliptin is secreted in considerable amounts into the milk of lactating rats (milk/plasma ratio: 4:1).

Metformin

Preclinical data reveal no special hazard for humans based on conventional studies on safety, pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and reproductive toxicity.

Dapagliflozin

Dapagliflozin Propanediol monohydrate: D-glucitol, 1,5-anhydro-1-C-[4-chloro-3-[(4- ethoxyphenyl)methyl]phenyl]-, (1S)-, compounded with (2S)-1,2-propanediol, hydrate

(1:1:1); It has an empirical formula of C₂₁H₂₅ClO₆•C₃H₈O₂•H₂O and a molecular weight of 502.98 gm/mole. The Structural formula is :

Sitagliptin

Sitagliptin is an orally-active inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme. Sitagliptin is present in the form of sitagliptin phosphate monohydrate. Sitagliptin phosphate monohydrate is described chemically as 7-[(3R)-3-amino-1-oxo-4-(2,4,5- trifluorophenyl)butyl]-5,6,7,8¬tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3- a]pyrazine phosphate (1:1) monohydrate with an empirical formula of C₁₆H₁₅F₆N₅O•H₃PO₄•H₂O and a molecular weight of 523.32. The structural formula is :

Metformin Hcl

Metformin hydrochloride (N, N-dimethylimidodicarbonimidic diamide hydrochloride) is a white to off-white crystalline compound with a molecular formula of C4H11N5•HCl and a molecular weight of 165.63. Metformin hydrochloride is freely soluble in water, slightly soluble in alcohol, and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68.

The structural formula is:

8.1 Incompatibilities

Not applicable.

8.2 Shelf-life

Refer on the pack.

8.3 Packaging information

Zensita-Trio 500 : Alu-Alu Blister strip of 15 tablets.

Zensita-Trio 1000 : Alu-Alu Blister strip of 15 tablets.

8.4 Storage and handing instructions

Store below 30°C.

Keep out of reach of children.

Do not take Sitagliptin and Metformin Extended Release and Dapagliflozin Tablets : If you are allergic to Dapagliflozin, Sitagliptin and Metformin or any of the other ingredients of this medicine. If you think you may be allergic to Sitagliptin / Dapagliflozin / Metformin or any of the other ingredients of do not take this medicine and talk to your doctor.

Warnings and precautions :

Talk to your doctor, before taking Sitagliptin / Dapagliflozin / Metformin :

• if you have type 1 diabetes (i.e., your body does not produce insulin) or if you have a condition called diabetic ketoacidosis.
• if you are taking an anti-diabetic medicine known as sulphonylurea (your doctor may want to reduce your dose of the sulphonylurea when you take it together with Sitagliptin in order to avoid low blood glucose [hypoglycaemia]).
• if you have moderate or severe kidney disease (you will need to take a lower dose of this combination).
• if you are on dialysis.
• if you have liver disease.
• if you suffer from heart failure.
• if you have or have had a disease of the pancreas.
• if you have malaise, myalgia, abdominal pain, respiratory distress, or increased somnolence; however, hypotension and resistant Brady arrhythmias have occurred with severe acidosis.
• if you have significant renal impairment
• If you have previously taken Sitagliptin / Dapaglilozin/ Metformin individual components but had stopped taking it because of liver disease, you should not take this combination.

Major side effects to be explained

Lactic acidosis, pancreatitis etc.

Diabetic skin lesions are a common complication of diabetes. You are advised to follow the recommendations for skin and foot care that you are given by your doctor or nurse. You are also advised to pay particular attention to new onset of blisters or ulcers while taking Sitagliptin. Should these occur, you should promptly consult your doctor. A test to determine your liver function will be performed before the start of Sitagliptin treatment, at three-month intervals for the first year and periodically thereafter. This is so that signs of increased liver enzymes can be detected as early as possible.

Children and adolescents

The use of this combination product in children and adolescents up to 18 years of age is not recommended.

Other medicines and Sitagliptin and Metformin Extended Release and Dapagliflozin Tablets

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. Your doctor may wish to alter your dose of Sitagliptin if you are taking other medicines such as :

• Thiazides or other diuretics (also called water tablets)
• Corticosteroid (generally used to treat inflammation)
• Thyroid medicines
• Certain medicines affecting the nervous system.

Pregnancy, breast feeding and fertility

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Driving and using machines

If you feel dizzy while taking this medicine, do not drive or use machines. How should I take Dapagliflozin and Sitagliptin and Metformin Extended-Release Tablets?

Swallow the tablets whole with some water once daily.

If you have taken too many tablets?

Contact your doctor immediately or go to the nearest hospital casualty department taking any remaining medication and this patient information leaflet with you.

If you forget to take Dapagliflozin and Sitagliptin and Metformin Extended-Release Tablets?

If you miss a dose of Dapagliflozin, Sitagliptin and Metformin Extended-Release Tablets, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular schedule. Do not double the dose.

What are the possible side effects of Dapagliflozin, Sitagliptin and Metformin Extended-Release Tablets?

Like all medicines, this medicine can cause side effects, although not everybody gets them. Stop taking this medicine and consult your doctor immediately if any of the following occur-you may need medical treatment. The most common side effects with the combination include nasopharyngitis and headache.

18 November 2022