For the use of a Registered Medical Practitioner or a Hospital or a Laboratory only

Dapagliflozin, Sitagliptin and Metformin HCL

DAPASACH MS Extended Release Tablets

Black Box Warning

Warning: Lactic Acidosis

Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. Symptoms included malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Laboratory abnormalities included elevated blood lactate levels, anion gap acidosis, increased lactate/pyruvate ratio, and metformin plasma levels generally >5 mcg/mL.
Risk factors include renal impairment, concomitant use of certain drugs, age ≥65 years old, radiological studies with contrast, surgery and other procedures, hypoxic states, excessive alcohol intake, and hepatic impairment. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high-risk groups are provided in the full prescribing information.
If lactic acidosis is suspected, discontinue Dapagliflozin and metformin hydrochloride and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.

Qualitative and Quantitative Composition

DAPASACH MS 10/100/1000

Dapagliflozin 10 mg, Sitagliptin 100 mg and Metformin Hydrochloride 1000 mg (Extended Release) Tablets

Each film coated bilayer tablet contains:

Dapagliflozin Propanediol monohydrate equivalent to Dapagliflozin…. .10 mg

Sitagliptin Phosphate Monohydrate IP equivalent to Sitagliptin………....100 mg

Metformin Hydrochloride IP (Extended release) .....................................1000 mg

Excipients………………………………………………………………………q.s.

Colours: Indigo carmine aluminium Lake & Titanium dioxide IP

DAPASACH MS 10/100/500

Dapagliflozin 10 mg, Sitagliptin 100 mg and Metformin Hydrochloride 500 mg (Extended Release) Tablets

Each film coated bilayer tablet contains:

Dapagliflozin Propanediol monohydrate equivalent to Dapagliflozin…. 10 mg

Sitagliptin Phosphate Monohydrate IP equivalent to Sitagliptin………...100 mg

Metformin Hydrochloride IP (Extended release) .....................................500 mg

Excipients………………………………………………………………………q.s.

Colours: Ferric Red Oxide USP-NF, Ferric Oxide Yellow USP_NF & Titanium dioxide IP

Dosage Form(S) and Strength(S)

DAPASACH MS film coated bilayer tablets are available as oral tablet containing 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

Clinical Particulars

Therapeutic Indications

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

Posology and Method of Administration

The recommended dose is one tablet daily. Each film coated bilayer tablet contains a fixed dose of Dapagliflozin, Sitagliptin and Metformin Hydrochloride.

It should be given orally once daily.

Contraindications

History of a serious hypersensitivity reaction to dapagliflozin, sitagliptin or metformin hydrochloride
Severe renal impairment (eGFR below 30 mL/min/1.73 m2)
Patients with severe ketosis, acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma, diabetic coma or precoma, type 1 diabetes [Infusion, prompt correction of hyperglycemia with insulin is essential]. Diabetic ketoacidosis should be treated with insulin.
Patients with severe infections, before and after surgery, and with serious trauma [Because glycemic control by insulin injection is desired, administration of this drug is not suitable.]

Special Warnings and Precautions for Use

Dapagliflozin

Volume Depletion

Before initiating, assess volume status and renal function in the elderly, patients with renal impairment or low systolic blood pressure, and in patients on diuretics. Monitor for signs and symptoms during therapy.

Ketoacidosis in Patients with Diabetes Mellitus

Assess patients who present with signs and symptoms of metabolic acidosis for ketoacidosis regardless of blood glucose level. If suspected, discontinue medication, evaluate and treat promptly. Before initiating, consider risk factors for ketoacidosis. Patients on dapagliflozin may require monitoring and temporary discontinuation of therapy in clinical situations known to predispose to ketoacidosis.

Urosepsis and Pyelonephritis

Evaluate for signs and symptoms of urinary tract infections and treat promptly, if indicated.

Hypoglycemia

Consider a lower dose of insulin or the insulin secretagogue to reduce the risk of hypoglycemia when used in combination with drug.

Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)

Serious, life-threatening cases have occurred in patients with diabetes, both females and males. Assess patients presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise. If suspected, institute prompt treatment.

Genital Mycotic Infections

Monitor and treat if indicated.

Sitagliptin

General

Sitagliptin should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

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, sitagliptin and other potentially suspect medicinal products should be discontinued; if acute pancreatitis is confirmed, sitagliptin 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 in clinical trials of sitagliptin as monotherapy and as part of combination therapy with medicinal products not known to cause hypoglycaemia (i.e. metformin and/or a PPARg agonist), rates of hypoglycaemia reported with sitagliptin were similar to rates in patients taking placebo. 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 sulphonylurea or insulin may be considered.

Renal Impairment

Sitagliptin is renally excreted. To achieve plasma concentrations of sitagliptin similar to those in patients with normal renal function, lower dosages are recommended in patients with GFR < 45 mL/min, as well as in ESRD patients requiring haemodialysis or peritoneal dialysis.

When considering the use of sitagliptin in combination with another anti-diabetic medicinal product, its conditions for use in patients with renal impairment should be checked.

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, sitagliptin 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, sitagliptin should be discontinued.

Metformin Hydrochloride

General

Hypoglycaemia with Concomitant Use with Insulin and Insulin Secretagogues

Insulin and insulin secretagogues (e.g., sulfonylurea) are known to cause hypoglycemia. DAPASACH MS may increase the risk of hypoglycemia when combined with insulin and/or an insulin secretagogue. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination.

Vitamin B₁₂

In controlled clinical trials of metformin immediate-release of 29 weeks duration, a decrease to subnormal levels of previously normal serum vitamin B₁₂ levels was observed in approximately 7% of patients. Such decrease, possibly due to interference with B₁₂ absorption from the B₁₂ intrinsic factor complex may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin or vitamin B₁₂ supplementation. Certain individuals (those with inadequate vitamin B₁₂ or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B₁₂ levels. Measure hematologic parameters on an annual basis and vitamin B₁₂ measurements at 2- or 3- year intervals in patients on DAPASACH MS.

Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with metformin hydrochloride.

Lactic Acidosis

There have been post marketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypotension and resistant Brady arrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate: pyruvate ratio; metformin plasma levels were generally >5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk.

If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of Metformin. In Metformin treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery.

Educate patients and their families about the symptoms of lactic acidosis and, if these symptoms occur, instruct them to discontinue Metformin and report these symptoms to their healthcare provider.

For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below:

Renal impairment – The post marketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney.

Use in Special Population

Renal Impairment

Dapagliflozin

Due to limited experience, it is not recommended to initiate treatment with dapagliflozin in patients with GFR <25 mL/min. The glucose lowering efficacy of dapagliflozin is dependent on renal function and is reduced in patients with GFR <45 mL/min and is likely absent in patients with severe renal impairment. In one study in patients with type 2 diabetes mellitus with moderate renal impairment (GFR < 60 mL/min), a higher proportion of patients treated with dapagliflozin had adverse reactions of increase in creatinine, phosphorus, parathyroid hormone (PTH) and hypotension, compared with placebo.

Sitagliptin

Sitagliptin is excreted by the kidney, and sitagliptin exposure is increased in patients with renal impairment. Lower dosages are recommended in patients with eGFR less than 45 mL/min/1.73 m² (moderate and severe renal impairment, as well as in ESRD patients requiring dialysis).

For patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m²) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of Sitagliptin is 25 mg once daily. Sitagliptin may be administered without regard to the timing of dialysis.

Because there is a need for dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of sitagliptin and periodically thereafter. There have been postmarketing reports of worsening renal function in patients with renal impairment, some of whom were prescribed inappropriate doses of sitagliptin. Administration is not recommended.

Metformin Hydrochloride

Metformin is known to be substantially excreted by the kidney and the risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Metformin is contraindicated in severe renal impairment, patients with an eGFR <30 mL/min/1.73 m².

Hepatic Impairment

Dapagliflozin

There is limited experience in clinical studies in patients with hepatic impairment. Dapagliflozin exposure is increased in patients with severe hepatic impairment

Metformin Hydrochloride

Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. Metformin is not recommended in patients with hepatic impairment.

Pregnant Women

There are no data from the use of drug in pregnant women. There are no adequate data from the use of sitagliptin in pregnant women. Studies in animals have shown reproductive toxicity at high doses. The potential risk for humans is unknown. Due to lack of human data, drug should not be used during pregnancy.

Lactating Women

It is unknown whether dapagliflozin (and/or its metabolites) are excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of dapagliflozin/metabolites in milk, as well as pharmacologically-mediated effects in nursing offspring. It is unknown whether sitagliptin is excreted in human milk. It should not be used during breast-feeding.

Pediatric Patients

The safety and efficacy of drug has not yet been established. No data are available.

Geriatric Patients

In Patients ≥ 65 years, It should be used with caution as age increases.

Fertility

The effect of this medicinal product on fertility in humans has not been studied.

Effects of Ability to Drive and Use Machines

Dapagliflozin

Dapagliflozin has no or negligible influence on the ability to drive and use machines. Patients should be alerted to the risk of hypoglycemia when dapagliflozin is used in combination with a sulphonylurea or insulin.

Sitagliptin

Sitagliptin 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. In addition, patients should be alerted to the risk of hypoglycaemia when sitagliptin is used in combination with a sulphonylurea or with insulin.

Metformin Hydrochloride

Metformin monotherapy does not cause hypoglycaemia and, therefore, has no effect on the ability to drive or to use machines. However, patients should be alerted to the risk of hypoglycaemia when metformin is used in combination with other antidiabetic agents (e.g. sulphonylureas, insulin, or meglinitides).

Undesirable Effects

Dapagliflozin

In the clinical studies in type 2 diabetes, >15,000 patients have been treated with dapagliflozin. The primary assessment of safety and tolerability was conducted in a pre-specified pooled analysis of 13 short-term (up to 24 weeks) placebo-controlled studies with 2,360 subjects treated with dapagliflozin 10 mg and 2,295 treated with placebo. In the dapagliflozin cardiovascular outcomes study in type 2 diabetes mellitus (DECLARE study), 8,574 patients received dapagliflozin 10 mg and 8,569 received placebo for a median exposure time of 48 months. In total, there were 30,623 patient-years of exposure to dapagliflozin. The most frequently reported adverse reactions across the clinical studies were genital infections.

Table 1: Adverse reactions in placebo-controlled clinical studies, and postmarketing experience

System organ class	Very common	Common^*	Uncommon^**	Rare	Very rare
Infections and infestations		Vulvovaginitis, balanitis and related genital infections^,b,c Urinary tract infection^,b,d	Fungal infection^**		Necrotising fasciitis of the perineum (Fournier's gangrene)^b,i
Metabolism and nutrition disorders	Hypoglycaemia (when used with SU or insulin)^b		Volume depletionb,^e Thirst^**	Diabetic ketoacidosis (when used in type 2 diabetes mellitus)^b,i,k
Nervous system disorders		Dizziness
Gastrointestinal disorders			Constipation^ Dry mouth^
Skin and subcutaneous tissue disorders		Rash^j			Angioedema
Musculoskeletal and connective tissue disorders		Back pain^*
Renal and urinary disorders		Dysuria Polyuria^*,f	Nocturia^**
Reproductive system and breast disorders			Vulvovaginal pruritus^ Pruritus genital^
Investigations		Haematocrit increased^g Creatinine renal clearance decreased during initial treatment^b Dyslipidaemia^h	Blood creatinine increased during initial treatment^,b Blood urea increased^ Weight decreased^**

^a The table shows up to 24-week (short-term) data regardless of glycaemic rescue.

^b See corresponding subsection below for additional information.

^c Vulvovaginitis, balanitis and related genital infections includes, e.g. the predefined preferred terms: vulvovaginal mycotic infection, vaginal infection, balanitis, genital infection fungal, vulvovaginal candidiasis, vulvovaginitis, balanitis candida, genital candidiasis, genital infection, genital infection male, penile infection, vulvitis, vaginitis bacterial, vulval abscess.

^d Urinary tract infection includes the following preferred terms, listed in order of frequency reported: urinary tract infection, cystitis, Escherichia urinary tract infection, genitourinary tract infection, pyelonephritis, trigonitis, urethritis, kidney infection and prostatitis.

^e Volume depletion includes, e.g. the predefined preferred terms: dehydration, hypovolaemia, hypotension.

^f Polyuria includes the preferred terms: pollakiuria, polyuria, urine output increased.

^g Mean changes from baseline in haematocrit were 2.30% for dapagliflozin 10 mg versus –0.33% for placebo. Haematocrit values >55% were reported in 1.3% of the subjects treated with dapagliflozin 10 mg versus 0.4% of placebo subjects.

^h Mean percent change from baseline for dapagliflozin 10 mg versus placebo, respectively, was: total cholesterol 2.5% versus 0.0%; HDL cholesterol 6.0% versus 2.7%; LDL cholesterol 2.9% versus -1.0%; triglycerides -2.7% versus -0.7%.

ⁱ See below this section for details

^j Adverse reaction was identified through postmarketing surveillance. Rash includes the following preferred terms, listed in order of frequency in clinical studies: rash, rash generalised, rash pruritic, rash macular, rash maculo-papular, rash pustular, rash vesicular, and rash erythematous. In active- and placebo-controlled clinical studies (dapagliflozin, N=5936, All control, N=3403), the frequency of rash was similar for dapagliflozin (1.4%) and all control (1.4%), respectively.

^k Reported in the cardiovascular outcomes study in patients with type 2 diabetes (DECLARE). Frequency is based on annual rate.

* Reported in ≥ 2% of subjects and ≥ 1% more and at least 3 more subjects treated with dapagliflozin 10 mg compared to placebo.

**Reported by the investigator as possibly related, probably related or related to study treatment and reported in ≥ 0.2% of subjects and ≥ 0.1% more and at least 3 more subjects treated with dapagliflozin 10 mg compared to placebo.

Vulvovaginitis, Balanitis and Related Genital Infections

In the 13-study safety pool, vulvovaginitis, balanitis and related genital infections were reported in 5.5% and 0.6% of subjects who received dapagliflozin 10 mg and placebo, respectively. Most infections were mild to moderate, and subjects responded to an initial course of standard treatment and rarely resulted in discontinuation from dapagliflozin treatment. These infections were more frequent in females (8.4% and 1.2% for dapagliflozin and placebo, respectively), and subjects with a prior history were more likely to have a recurrent infection. In the DECLARE study, the numbers of patients with serious adverse events of genital infections were few and balanced: 2 patients in each of the dapagliflozin and placebo groups.

Necrotising Fasciitis of the Perineum (Fournier’s gangrene)

Cases of Fournier’s gangrene have been reported postmarketing in patients taking SGLT2 inhibitors, including dapagliflozin. In the DECLARE study with 17,160 type 2 diabetes mellitus patients and a median exposure time of 48 months, a total of 6 cases of Fournier’s gangrene were reported, one in the dapagliflozin-treated group and 5 in the placebo group.

Hypoglycaemia

The frequency of hypoglycaemia depended on the type of background therapy used in the clinical studies in diabetes mellitus. For studies of dapagliflozin in monotherapy, as add-on to metformin or as add-on to sitagliptin (with or without metformin), the frequency of minor episodes of hypoglycaemia was similar (< 5%) between treatment groups, including placebo up to 102 weeks of treatment. Across all studies, major events of hypoglycaemia were uncommon and comparable between the groups treated with dapagliflozin or placebo. Studies with add-on sulphonylurea and add-on insulin therapies had higher rates of hypoglycaemia. 11 In an add-on to glimepiride study, at weeks 24 and 48, minor episodes of hypoglycaemia were reported more frequently in the group treated with dapagliflozin 10 mg plus glimepiride (6.0% and 7.9%, respectively) than in the placebo plus glimepiride group (2.1% and 2.1%, respectively). In an add-on to insulin study, episodes of major hypoglycaemia were reported in 0.5% and 1.0% of subjects treated with dapagliflozin 10 mg plus insulin at weeks 24 and 104, respectively, and in 0.5% of subjects treated with placebo plus insulin groups at weeks 24 and 104. At weeks 24 and 104, minor episodes of hypoglycaemia were reported, respectively, in 40.3% and 53.1% of subjects who received dapagliflozin 10 mg plus insulin and in 34.0% and 41.6% of the subjects who received placebo plus insulin. In an add-on to metformin and a sulphonylurea study, up to 24 weeks, no episodes of major hypoglycaemia were reported. Minor episodes of hypoglycaemia were reported in 12.8% of subjects who received dapagliflozin 10 mg plus metformin and a sulphonylurea and in 3.7% of subjects who received placebo plus metformin and a sulphonylurea. In the DECLARE study, no increased risk of major hypoglycaemia was observed with dapagliflozin therapy compared with placebo. Major events of hypoglycaemia were reported in 58 (0.7%) patients treated with dapagliflozin and 83 (1.0%) patients treated with placebo.

Volume Depletion

In the 13-study safety pool, reactions suggestive of volume depletion (including, reports of dehydration, hypovolaemia or hypotension) were reported in 1.1% and 0.7% of subjects who received dapagliflozin 10 mg and placebo, respectively; serious reactions occurred in < 0.2% of subjects balanced between dapagliflozin 10 mg and placebo. In the DECLARE study, the numbers of patients with events suggestive of volume depletion were balanced between treatment groups: 213 (2.5%) and 207 (2.4%) in the dapagliflozin and placebo groups, respectively. Serious adverse events were reported in 81 (0.9%) and 70 (0.8%) in the dapagliflozin and placebo group, respectively. Events were generally balanced between treatment groups across subgroups of age, diuretic use, blood pressure and angiotensin converting enzyme inhibitors (ACE-I)/angiotensin II type 1 receptor blockers (ARB) use. In patients with eGFR < 60 mL/min/1.73 m 2 at baseline, there were 19 events of serious adverse events suggestive of volume depletion in the dapagliflozin group and 13 events in the placebo group.

Diabetic Ketoacidosis in Type 2 Diabetes Mellitus

In the DECLARE study, with a median exposure time of 48 months, events of DKA were reported in 27 patients in the dapagliflozin 10 mg group and 12 patients in the placebo group. The events occurred 12 evenly distributed over the study period. Of the 27 patients with DKA events in the dapagliflozin group, 22 had concomitant insulin treatment at the time of the event. Precipitating factors for DKA were as expected in a type 2 diabetes mellitus population.

Urinary Tract Infections

In the 13-study safety pool, urinary tract infections were more frequently reported for dapagliflozin 10 mg compared to placebo 4.7% versus 3.5%, respectively; Most infections were mild to moderate, and subjects responded to an initial course of standard treatment and rarely resulted in discontinuation from dapagliflozin treatment. These infections were more frequent in females, and subjects with a prior history were more likely to have a recurrent infection. In the DECLARE study, serious events of urinary tract infections were reported less frequently for dapagliflozin 10 mg compared with placebo, 79 (0.9%) events versus 109 (1.3%) events, respectively.

Increased Creatinine

Adverse reactions related to increased creatinine were grouped (e.g. decreased renal creatinine clearance, renal impairment, increased blood creatinine and decreased glomerular filtration rate). In the 13-study safety pool, this grouping of reactions was reported in 3.2% and 1.8% of patients who received dapagliflozin 10 mg and placebo, respectively. In patients with normal renal function or mild renal impairment (baseline eGFR ≥ 60 mL/min/1.73 m²) this grouping of reactions were reported in 1.3% and 0.8% of patients who received dapagliflozin 10 mg and placebo, respectively. These reactions were more common in patients with baseline eGFR ≥ 30 and < 60 mL/min/1.73 m2 (18.5% dapagliflozin 10 mg versus 9.3% placebo). Further evaluation of patients who had renal-related adverse events showed that most had serum creatinine changes of ≤ 0.5 mg/dL from baseline. The increases in creatinine were generally transient during continuous treatment or reversible after discontinuation of treatment. In the DECLARE study, including elderly patients and patients with renal impairment (eGFR < 60 mL/min/1.73 m²), eGFR decreased over time in both treatment groups. At 1 year, mean eGFR was slightly lower, and at 4 years, mean eGFR was slightly higher in the dapagliflozin group compared with the placebo group.

Sitagliptin

Adverse reactions reported in ³ 5% of patients treated with Sitagliptin and more commonly than in patients treated with placebo are: upper respiratory tract infection, nasopharyngitis, headache and arthralgia. In the add on to sulfonylurea and add-on to insulin studies, hypoglycemia was also more commonly reported in patients.

Laboratory Tests

Across clinical studies, the incidence of laboratory adverse reactions was similar in patients treated with sitagliptin 100 mg compared to patients treated with placebo. A small increase in white blood cell count (WBC) was observed due to an increase in neutrophils. This increase in WBC (of approximately 200 cells/microL vs placebo, in four pooled placebo-controlled clinical studies, with a mean baseline WBC count of approximately 6600 cells/microL) is not considered to be clinically relevant. In a 12-week study of 91 patients with chronic renal insufficiency, 37 patients with moderate renal insufficiency were randomized to sitagliptin 50 mg daily, while 14 patients with the same magnitude of renal impairment were randomized to placebo. Mean increases in serum creatinine were observed in patients treated with sitagliptin [0.12 mg/dL] and in patients treated with placebo [0.07 mg/dL]. The clinical significance of this added increase in serum creatinine relative to placebo is not known.

Metformin Hydrochloride

The following adverse reactions are also discussed earlier in the labeling:

Lactic Acidosis
Vitamin B12 Deficiency
Hypoglycemia

Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In placebo-controlled trials, 781 patients were administered metformin hydrochloride sustained-release. Adverse reactions reported in greater than 5% of the metformin hydrochloride sustained-release patients, and those were more common in metformin hydrochloride sustained-release - than placebo-treated patients, are listed in table 2.

Table 2: Most common adverse reactions (>5.0%) in placebo-controlled studies of metformin hydrochloride sustained-release in patients with type 2 diabetes mellitus

Adverse Reaction	% of Patients
Adverse Reaction	Metformin Hydrochloride Sustained-Release (N=781)	Placebo (N=195)
Diarrhea	10	3
Nausea/vomiting	7	2

Diarrhea led to discontinuation of study medication in 0.6% of patients treated with metformin hydrochloride sustained-release. Additionally, the following adverse reactions were reported in ≥1.0 to ≤5.0% of metformin hydrochloride sustained-release patients and were more commonly reported with metformin hydrochloride sustained-release than placebo: abdominal pain, constipation, distention abdomen, dyspepsia/heartburn, flatulence, dizziness, headache, upper respiratory infection, taste disturbance.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of metformin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cholestatic, hepatocellular, and mixed hepatocellular liver injury have been reported with postmarketing use of metformin.

Reporting of Significant Adverse Reactions

Reporting significant adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. if you experience any side-effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the national pharmacovigilance program of India by calling on 18001803024 or you can report to Cipla LTD on 18002677779. By reporting side-effects, you can help provide more information on the safety of this product.

Overdose

Dapagliflozin

Dapagliflozin did not show any toxicity in healthy subjects at single oral doses up to 500 mg (50 times the maximum recommended human dose).

Sitagliptin

During controlled clinical trials in healthy subjects, single doses of up to 800 mg Sitagliptin were administered. Maximal mean increases in QTc of 8.0 msec were observed in one study at a dose of 800 mg Sitagliptin, a mean effect that is not considered clinically important. There is no experience with doses above 800 mg in clinical studies. In Phase I multiple-dose studies, there were no dose-related clinical adverse reactions observed with Sitagliptin with doses of up to 600 mg per day for periods of up to 10 days and 400 mg per day for up to 28 days. In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining an electrocardiogram), and institute supportive therapy as dictated by the patient's clinical status. Sitagliptin is modestly dialyzable. In clinical studies, approximately 13.5% of the dose was removed over a 3 to 4 hour hemodialysis session. Prolonged hemodialysis may be considered if clinically appropriate. It is not known if sitagliptin is dialyzable by peritoneal dialysis

Metformin Hydrochloride

Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin hydrochloride has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases. Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.

Pharmacological Properties

Mechanism of Action

DAPASACH MS combines three antihyperglycemic agents with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes mellitus: sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, dapagliflozin, a sodium-glucose cotransporter 2 inhibitors (SGLT2i) and metformin, a member of the biguanide class.

Dapagliflozin

Dapagliflozin is a reversible inhibitor of sodium-glucose co-transporter 2 (SGLT2) that improves glycaemic control in patients with type 2 diabetes mellitus by reducing renal glucose reabsorption leading to urinary excretion of excess glucose (glucuresis).

SGLT2 is selectively expressed in the kidney. SGLT2 is the predominant transporter responsible for reabsorption of glucose from the glomerular filtrate back into the circulation. Dapagliflozin improves both fasting and post-prandial plasma glucose levels by reducing renal glucose reabsorption leading to urinary excretion of excess glucose. The amount of glucose removed by the kidney through this mechanism is dependent upon the blood glucose concentration and GFR. Dapagliflozin does not impair normal endogenous glucose production in response to hypoglycaemia. Dapagliflozin acts independently of insulin secretion and insulin action.

Urinary glucose excretion (glucuresis) induced by Dapagliflozin is associated with caloric loss and reduction in weight. Inhibition of glucose and sodium co-transport by Dapagliflozin is also associated with mild diuresis and transient natriuresis.

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 (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 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 DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.

Metformin Hydrochloride

Metformin improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Metformin does not produce hypoglycemia in either patients with type 2 diabetes or in healthy subjects, except in unusual circumstances 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.

Pharmacodynamic Properties

Dapagliflozin

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

Sitagliptin

General

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.

In studies with healthy subjects, sitagliptin did not lower blood glucose or cause hypoglycemia.

Cardiac Electrophysiology

In a randomized, placebo-controlled crossover study, 79 healthy subjects were administered a single oral dose of sitagliptin 100 mg, sitagliptin 800 mg (8 times the recommended dose), and placebo. At the recommended dose of 100 mg, there was no effect on the QTc interval obtained at the peak plasma concentration, or at any other time during the study. Following the 800-mg dose, the maximum increase in the placebo-corrected mean change in QTc from baseline at 3 hours postdose was 8.0 msec. This increase is not considered to be clinically significant. At the 800-mg dose, peak sitagliptin plasma concentrations were approximately 11 times higher than the peak concentrations following a 100-mg dose.

In patients with type 2 diabetes administered sitagliptin 100 mg (N=81) or sitagliptin 200 mg (N=63) daily, there were no meaningful changes in QTc interval based on ECG data obtained at the time of expected peak plasma concentration.

Metformin Hydrochloride

Metformin lowers both basal and PPG. It works mainly by suppressing excessive hepatic glucose production, through a reduction in gluconeogenesis. Other potential effects of metformin include an increase in glucose uptake, an increase in insulin signaling, a decrease in fatty acid and triglyceride synthesis, and an increase in fatty acid β-oxidation. Metformin may also increase glucose utilization in peripheral tissues, and possibly reduce food intake and intestinal glucose absorption. As metformin does not stimulate endogenous insulin secretion, it does not cause hypoglycemia or hyperinsulinemia, which are common side effects associated with other antidiabetic drugs.

The molecular mechanisms underlying metformin action appear to be complex and remain a topic of considerable debate. However, there is general agreement that the administration of metformin results in the phosphorylation and activation of AMP-activated protein kinase (AMPK) in the liver, which in turn may lead to diverse pharmacologic effects, including inhibition of glucose and lipid synthesis.

Pharmacokinetic Properties

Absorption

Dapagliflozin Following oral administration of dapagliflozin, the maximum plasma concentration (C_max) is usually attained within 2 hours under fasting state. The C_max and AUC values increase dose proportionally with increase in dapagliflozin dose in the therapeutic dose range. The absolute oral bioavailability of dapagliflozin following the administration of a 10 mg dose is 78%. Administration of dapagliflozin with a high-fat meal decreases its C_max by up to 50% and prolongs T_max by approximately 1 hour, but does not alter AUC as compared with the fasted state. These changes are not considered to be clinically meaningful and dapagliflozin can be administered with or without food.

Sitagliptin After oral administration of a 100 mg dose to healthy subjects, sitagliptin was rapidly absorbed with peak plasma concentrations (median T_max) occurring 1 to 4 hours post dose. The absolute bioavailability of sitagliptin is approximately 87%.

Metformin Hydrochloride

Following a single oral dose of metformin extended-release, C_max is achieved with a median value of 7 hours and a range of 4 to 8 hours. The extent of metformin absorption (as measured by AUC) from the metformin extended-release tablet increased by approximately 50% when given with food. There was no effect of food on C_max and T_max of metformin.

Distribution

Dapagliflozin Dapagliflozin is approximately 91% protein bound. Protein binding is not altered in patients with renal or hepatic impairment.

Sitagliptin The mean volume of distribution at steady state following a single 100-mg intravenous dose of sitagliptin to healthy subjects is approximately 198 liters. The fraction of sitagliptin reversibly bound to plasma proteins is low (38%).

Metformin Hydrochloride

Distribution studies with extended-release metformin have not been conducted; however, the apparent volume of distribution (V/F) of metformin following single oral doses of immediate-release metformin 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins, in contrast to sulfonylureas, which are > 90% protein bound. Metformin partitions into erythrocytes.

Metabolism

Dapagliflozin The metabolism of dapagliflozin is primarily mediated by UGT1A9; CYP-mediated metabolism is a minor clearance pathway in humans. Dapagliflozin is extensively metabolized, primarily to yield dapagliflozin 3-O- glucuronide, which is an inactive metabolite. Dapagliflozin 3-O-glucuronide accounted for 61% of a 50 mg [14C]-dapagliflozin dose and is the predominant drug-related component in human plasma.

Sitagliptin Following a [14C] sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.

Metformin Hydrochloride

Intravenous single-dose studies in healthy subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) or biliary excretion.

Metabolism studies with extended-release metformin tablets have not been conducted.

Elimination

Dapagliflozin Dapagliflozin and related metabolites are primarily eliminated via the renal pathway. Following a single 50 mg dose of [14C]-dapagliflozin, 75% and 21% total radioactivity is excreted in urine and feces, respectively. In urine, < 2% of the dose is excreted as parent drug. In feces, approximately 15% of the dose is excreted as parent drug. The mean plasma terminal half-life (t½) for dapagliflozin is approximately 12.9 hours following a single oral dose of dapagliflozin 10 mg.

Sitagliptin Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination. The apparent terminal t½ following a 100 mg oral dose of sitagliptin was approximately 12.4 hours and renal clearance was approximately 350 mL/min.

Metformin Hydrochloride

Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.

Special Populations

Renal impairment

Dapagliflozin

At steady-state (20 mg once-daily dapagliflozin for 7 days), subjects with type 2 diabetes mellitus and mild, moderate or severe renal impairment (as determined by iohexol plasma clearance) had mean systemic exposures of dapagliflozin of 32%, 60% and 87% higher, respectively, than those of subjects with type 2 diabetes mellitus and normal renal function. The steady-state 24-hour urinary glucose excretion was highly dependent on renal function and 85, 52, 18 and 11 g of glucose/day was excreted by subjects with type 2 diabetes mellitus and normal renal function or mild, moderate or severe renal impairment, respectively. The impact of haemodialysis on dapagliflozin exposure is not known. The effect of reduced renal function on systemic exposure was evaluated in a population pharmacokinetic model. Consistent with previous results, model predicted AUC was higher in patients with chronic kidney disease compared with patients with normal renal function, and was not meaningfully different in chronic kidney disease patients with type 2 diabetes mellitus and without diabetes.

Sitagliptin

A single-dose, open-label study was conducted to evaluate the pharmacokinetics of a reduced dose of sitagliptin (50 mg) in patients with varying degrees of chronic renal impairment compared to normal healthy control subjects. The study included patients with mild, moderate, and severe renal impairment, as well as patients with ESRD on haemodialysis. In addition, the effects of renal impairment on sitagliptin pharmacokinetics in patients with type 2 diabetes and mild, moderate, or severe renal impairment (including ESRD) were assessed using population pharmacokinetic analyses. Compared to normal healthy control subjects, plasma AUC of sitagliptin was increased by approximately 1.2-fold and 1.6-fold in patients with mild renal impairment (GFR ≥ 60 to < 90 mL/min) and patients with moderate renal impairment (GFR ≥ 45 to < 60 mL/min), respectively. Because increases of this magnitude are not clinically relevant, dosage adjustment in these patients is not necessary. Plasma AUC of sitagliptin was increased approximately 2-fold in patients with moderate renal impairment (GFR ≥ 30 to < 45 mL/min), and approximately 4-fold in patients with severe renal impairment (GFR < 30 mL/min), including in patients with ESRD on haemodialysis. Sitagliptin was modestly removed by haemodialysis (13.5 % over a 3- to 4-hour haemodialysis session starting 4 hours postdose). To achieve plasma concentrations of sitagliptin similar to those in patients with normal renal function, lower dosages are recommended in patients with GFR < 45 mL/min.

Metformin Hydrochloride

In patients with decreased renal function (based on CLcr), the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased.

Hepatic Impairment

Dapagliflozin

In subjects with mild or moderate hepatic impairment (Child-Pugh classes A and B), mean Cmax and AUC of dapagliflozin were up to 12% and 36% higher, respectively, compared to healthy matched control subjects. These differences were not considered to be clinically meaningful. In subjects with severe hepatic impairment (Child-Pugh class C) mean Cmax and AUC of dapagliflozin were 40% and 67% higher than matched healthy controls, respectively

Sitagliptin

No dose adjustment for sitagliptin is necessary for patients with mild or moderate hepatic impairment (Child-Pugh score £ 9). There is no clinical experience in patients with severe hepatic impairment (Child-Pugh score > 9). However, because sitagliptin is primarily renally eliminated, severe hepatic impairment is not expected to affect the pharmacokinetics of sitagliptin.

Metformin Hydrochloride

No pharmacokinetic studies of metformin have been conducted in patients with hepatic impairment.

Clinical Study

An open label, randomized, balanced, two treatment, two sequence, two period, cross-over, single dose oral relative bioavailability study of Dapagliflozin 10 mg + Sitagliptin 100 mg + Metformin 1000 mg Extended Release Tablets in normal 24 healthy, adult human male subjects under fed condition.

Adverse event of hypoglycemia for subject 006 was recorded in period II. The adverse event was found to be mild in intensity and possibly related to study medication. The adverse event was resolved without any sequale and subject was withdrawn from the study.

There were no serious adverse events or deaths reported in the study.

Both products were found to be safe and well tolerated in participated subjects.

Figure 1: Mean plot for dapagliflozin

Figure 2: Mean plot for sitagliptin

Figure 3: Mean Plot For Metformin Hydrochloride

Drug Interactions

No interaction studies have been performed for Dapagliflozin and Sitagliptin and Metformin ER tablets.

The following statements reflect the information available on the individual active substances.

Dapagliflozin

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.

Carbonic Anhydrase Inhibitors

Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently causes a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with Dapagliflozin and Metformin Hydrochloride Extended release Tablet may increase the risk for lactic acidosis. Consider more frequent monitoring of these patients.

Drugs that Reduce Metformin Clearance

Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors such as ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic exposure to metformin and may increase the risk for lactic acidosis. Consider the benefits and risks of concomitant use.

Alcohol

Alcohol is known to potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake while receiving Dapagliflozin and Metformin Hydrochloride Extended Release Tablet.

Sitagliptin

Digoxin

There was a slight increase in the area under the curve (AUC, 11%) and mean peak drug concentration (C_max, 18%) of digoxin with the co-administration of 100 mg sitagliptin for 10 days. Patients receiving digoxin should be monitored appropriately. No dosage adjustment of digoxin or sitagliptin is recommended.

Insulin Secretagogues or Insulin

Coadministration of sitagliptin with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower doses of the insulin secretagogue or insulin to reduce the risk of hypoglycemia.

Metformin Hydrochloride

Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These medications include thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving Dapagliflozin and Metformin, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving Dapagliflozin and Metformin, observe the patient closely for hypoglycemia.

Nonclinical Properties

Carcinogenesis, Mutagenesis, Impairment of Fertility

Dapagliflozin

In vivo primary pharmacodynamic studies with Dapagliflozin were carried out in single-dose, dose ranging studies in non-diabetic and diabetic rats or mice in order to evaluate the potency, SGLT2-specificity and duration of action in stimulating urinary glucose excretion, and to describe the secondary consequences of urinary glucose excretion, such as changes in urine volume or blood or plasma glucose effects. Subsequently a multiple-dose study was carried out to evaluate the ability of Dapagliflozin to have sustained effects on urinary glucose excretion, urine volume, and fasting plasma glucose in diabetic rats over a two-week dosing period.

Dapagliflozin increased renal glucose excretion in (healthy, non-diabetic) experimental animals. This was accompanied, by osmotic diuresis as measured by increased urine flow. An oral glucose tolerance test was also performed showing that Dapagliflozin was able to significantly reduce glucose area under the curve (AUC), compared to vehicle treatment. A study in knock-out mice lacking the gene for SGLT2 revealed that SGLT2 is indeed the main target for Dapagliflozin at least at lower doses. This study also demonstrated the reversibility of Dapagliflozin’s action towards SGLT2.

Sitagliptin

Reproduction studies have been performed in rats and rabbits. Doses of sitagliptin up to 125 mg/kg (approximately 12 times the human exposure at the maximum recommended human dose) did not impair fertility or harm the fetus. There are, however, no adequate and well-controlled studies with sitagliptin in pregnant women.

Sitagliptin administered to pregnant female rats and rabbits from gestation day 6 to 20 (organogenesis) was not teratogenic at oral doses up to 250 mg/kg (rats) and 125 mg/kg (rabbits), or approximately 30 and 20 times human exposure at the maximum recommended human dose (MRHD) of 100 mg/day based on AUC comparisons. Higher doses increased the incidence of rib malformations in offspring at 1000 mg/kg, or approximately 100 times human exposure at the MRHD.

Sitagliptin administered to female rats from gestation day 6 to lactation day 21 decreased body weight in male and female offspring at 1000 mg/kg. No functional or behavioral toxicity was observed in offspring of rats. Placental transfer of sitagliptin administered to pregnant rats was approximately 45% at 2 hours and 80% at 24 hours postdose. Placental transfer of sitagliptin administered to pregnant rabbits was approximately 66% at 2 hours and 30% at 24 hours

Metformin Hydrochloride

Major target organs of metformin were heart and liver, as evidenced by heart hypertrophy with immune cell infiltration/inflammation and liver hypertrophy with concomitant hepatic injury and elevated LFT biomarkers, starting at approximately 10-times the expected clinical AUC exposures.

Metformin clinical toxicity hallmarks include lactic acidosis and gastrointestinal side effects (e.g., diarrhea, bloating, discomfort).

A notable new toxicity issue was identified in the nonclinical program suggesting potential metformin-induced teratogenicity. Metformin is not listed as teratogenic at approximate clinical exposures (body surface area estimates) on current labels.

Clinical Studies

The firm has conducted Clinical Trial Phase III titled “A Phase III, Randomized, Double Blind, Double Dummy, Active Controlled, Prospective, Parallel Group, Comparative, Multicentric Clinical Study to Evaluate the Efficacy and Safety of Fixed Dose Combination of Dapagliflozin, Sitagliptin and Metformin Hydrochloride ER Tablets in Patients with Type 2 Diabetes Mellitus Inadequately Controlled on Metformin Monotherapy.”

A total of 274 patients with type 2 diabetes mellitus participated in a double-blind, active-controlled trial to evaluate efficacy and safety of fixed dose combination of dapagliflozin (10 mg), sitagliptin (100 mg), metformin XR (1000 mg) compared with sitagliptin (100 mg), metformin XR (1000 mg) in patients inadequately controlled on metformin with an HbA1c between 8.0-10.0% (both inclusive). At week 16, fixed-dose combination of dapagliflozin 10 mg + sitagliptin 100 mg + metformin XR 1000 mg tablets produced statistically significant reductions in HbA1c, fasting plasma glucose & 2-hour post prandial glucose (see table below). Treatment with fixed-dose combination also resulted in a statistically significant reduction in body weight compared to sitagliptin and metformin XR group.

Table 3: Results of the clinical study of FDC of dapagliflozin (10 mg), sitagliptin (100 mg), metformin XR (1000 mg) compared with sitagliptin (100 mg), metformin XR (1000 mg) in patients inadequately controlled on metformin with an HbA1c between 8.0-10.0% (both inclusive).

Study arm	Dapagliflozin + Sitagliptin + Metformin	Sitagliptin + Metformin	Difference [95% CI]
Change from baseline HbA1c {LSM (SE)} (%)	-1.72 (0.04250)	-1.07 (0.04250)	-0.65 (0.06012) [-0.77, -0.53]
Percentage of patients achieving HbA1c <7.0% (%)	54.01	29.93
FPG {LSM (SE)} (mg/dL)	-35.6 (0.7944)	-20.18 (0.7944)	-15.42 (1.12) [-17.6257, -13.2167]
PPG {LSM (SE)} (mg/dL)	-77.88 (1.8704)	-47.5 (1.1.8704)	-30.39 (2.6457) [-35.5861, -25.1920]

For evaluation of safety, frequency of suspected, unanticipated adverse drug reactions reported possibly related to the investigational product up to end of study from start of the treatment was considered. Safety and tolerability of the test and reference products were assessed depending on the outcome from this clinical study. There were events and evidence of adverse reaction observed but were non-significant. Total 34 AEs were reported in 34 patients. 18 AEs were reported in FDC of Dapagliflozin 10 mg + Sitagliptin 100 mg + Metformin XR 1000 mg tablets arm and 16 AEs were reported in Sitagliptin 100 mg + Metformin XR 1000 mg arm. The most common adverse reactions with fixed dose combination of dapagliflozin and sitagliptin (≥2% of patients) were nasopharyngitis (3.88%), headache (2.32%). No SAE was reported during the study.

FDC of Dapagliflozin 10 mg + Sitagliptin 100 mg + Metformin XR 1000 mg Tablets was superior to Sitagliptin Tablets 100 mg + Metformin 1000 mg. There were no deaths or hospitalizations in both the treatment groups. FDC of Dapagliflozin 10 mg + Sitagliptin 100 mg + Metformin 1000 mg Tablets was found to be safe and well tolerated in patients with type 2 diabetes mellitus.

Description

DAPASACH MS tablets for oral use contain three antihyperglycemic drugs: sitagliptin, dapagliflozin and metformin HCl (as extended release).

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]-5,6,7,8tetrahydro-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 Hydrochloride

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:

Pharmaceutical Particulars

Incompatibilities

Not applicable

Shelf-Life

24 months

Packaging Information

Alu-Alu Blister pack

Storage and Handling Instructions

Store below 30° C

This medicinal product does not require any special storage conditions. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Patient Counseling Information

What is DAPASACH MS Tablets?

DAPASACH MS Tablets contains three active substances – dapagliflozin, sitagliptin and Metformin extended release, all of these combinations belong to a group of medicines called “oral antidiabetics”.

Do not take DAPASACH MS:

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 the product, do not take this medicine and talk to your doctor.

Warnings and precautions:

Talk to your doctor, pharmacist or nurse before taking DAPASACH MS:

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, myalgias, 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 / Dapagliflozin/ Metformin individual components but had stopped taking it because of liver disease, you should not take this combination.

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 DAPASACH MS Tablets?

Swallow the tablets whole with some water.

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 DAPASACH MS 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 DAPASACH MS 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.

Details of Manufacturer

Manufactured in India by:

Exemed Pharmaceuticals,

Plot no.133/1 & 133/2, G.I.D.C.,

Selvas Road,

Vapi-396 195, Dist.: Valsad,

INDIA.

Details of Marketing

Cipla House, Peninsula Business Park,

Ganpatrao Kadam Marg, Lower Parel, Mumbai, Maharashtra, INDIA.

Details of Permission or Licence Number with Date

G/25/2011 dates 14.10.2022

Date of Revision

Jan 2023