Zensita-MP 500 Tablets

Sitagliptin, Pioglitazone & Metformin Hydrochloride (Sustained Release) Tablets (15 mg + 100 mg + 500 mg)

Each lm coated bilayered tablet contains :

Sitagliptin Phosphate Monohydrate IP

equivalent to Sitagliptin 100 mg

Pioglitazone Hydrochloride IP

equivalent to Pioglitazone 15 mg

Metformin Hydrochloride IP 500 mg

(As sustained release form)

Colours : Indigo Carmine Lake

& Titanium Dioxide IP

Film coated tablet bilayered tablet, Sitagliptin 100 mg, Pioglitazone 15 mg, Metformin hydrochloride 500 mg

4.1 Therapeutic indication

For the treatment of type 2 diabetes mellitus.

4.2 Posology & method of administration

The usual recommended dose for adults is 1 tablet once daily or as directed by the Physician.

Geriatric use

In general, elderly patients often have physiological hypofunction; & therefore, Sitagliptin should be administered carefully. Start with lowest dose in elderly patients due to higher risks of lactic acidosis, poor renal & hepatic functions.

Pediatric use

Safety & effectiveness of Sitagliptin / Metformin hydrochloride tablets in paediatric patients under 18 years have not been established. Hence, Zensita MP tablet is not recommended in paediatric group. Method of administration : For oral administration only.

Zensita MP tablets must be swallowed whole & not to be chewed or crushed.

4.3 Contraindications

• Known hypersensitivity Pioglitazone, Sitagliptin & Metformin hydrochloride or to any other component of this product.
• Cardiac failure or history of cardiac failure (NYHA stages I-IV), hepatic impairment, diabetic ketoacidosis, current bladder cancer or a history of bladder cancer & un-investigated macroscopic haematuria.
• Renal impairment (e.g. serum creatinine levels ≥ 1.5 mg/dL for men, 1.4 mg/dL for women or abnormal creatinine clearance), which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction & septicemia.
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should be treated with insulin.

4.4 Special warnings & precautions for use

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 & 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 & as part of combination therapy with medicinal products not known to cause hypoglycaemia (i.e. Metformin hydrochloride and/or a PPAR 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 & 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 5 suspected, Sitagliptin should be discontinued. Other potential causes for the event should be assessed, & 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.

Pioglitazone

Warning

Bladder cancer with Pioglitazone advice for healthcare practitioners :

Patients with active bladder cancer or with a history of bladder cancer & those with un-investigated haematuria, should not receive Pioglitazone.

Prescribers should review the safety & efficacy of Pioglitazone in individuals after 3 - 6 months of treatment to ensure that only patients who are deriving benefit continue to be treated. Pioglitazone should be stopped in patients who do not respond adequately to treatment (e.g. reduction in glycosylated haemoglobin, HbA1c).

Before starting Pioglitazone, the following known risk factors for development of bladder cancer should be assessed in individuals : age, current or past history of smoking, exposure to some occupational or chemotherapy agents such as cyclophosphamide or previous irradiation of the pelvic region.

Use in elderly patients should be considered carefully before & during treatment because the risk of bladder cancer increases with age. Elderly patients should start on the lowest possible dose & be regularly monitored because of the risks of bladder cancer & heart failure associated with Pioglitazone.

Fluid retention & cardiac failure

Pioglitazone can cause fluid retention, which may exacerbate or precipitate heart failure. When treating patients who have at least one risk factor for development of congestive heart failure (e.g. prior myocardial infarction or symptomatic coronary artery disease or the elderly), physicians should start with the lowest available dose & increase the dose gradually. Patients should be observed for signs & symptoms of heart failure; weight gain or oedema; particularly those with reduced cardiac reserve. There have been post-marketing cases of cardiac failure reported when Pioglitazone was used in combination with insulin or in patients with a history of cardiac failure.

Patients should be observed for signs & symptoms of heart failure, weight gain & oedema when Pioglitazone is used in combination with insulin. Since Insulin & Pioglitazone are both associated with fluid retention, concomitant administration may increase the risk of oedema. Post marketing cases of peripheral oedema & cardiac failure have also been reported in patients with concomitant use of Pioglitazone & nonsteroidal anti-inflammatory drugs, including selective COX-2 inhibitors. Pioglitazone should be discontinued if any deterioration in cardiac status occurs.

A cardiovascular outcome study of Pioglitazone has been performed in patients under 75 years with type 2 diabetes mellitus & pre-existing major macrovascular disease. Pioglitazone or placebo was added to existing antidiabetic & cardiovascular therapy for up to 3.5 years. This study showed an increase in reports of heart failure; however, this did not lead to an increase in mortality in this study. Significant fluid retention leading to the development / exacerbation of congestive heart failure has been reported with Pioglitazone - avoid its use in patients in heart failure or at risk of developing heart failure.

Elderly

Combination use with insulin should be considered with caution in the elderly because of increased risk of serious heart failure. In light of age- related risks (especially bladder cancer, fractures & heart failure), the balance of benefits & risks should be considered carefully both before & during treatment in the elderly.

Bladder cancer

Cases of bladder cancer were reported more frequently in a meta-analysis of controlled clinical trials with Pioglitazone (19 cases from 12,506 patients, 0.15%) than in control groups (7 cases from 10,212 patients, 0.07%) HR = 2.64 (95% CI 1.11 - 6.31, p = 0.029). After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were 7 cases (0.06%) on Pioglitazone & 2 cases (0.02%) in control groups. Epidemiological studies have also suggested a small increased risk of bladder cancer in diabetic patients treated with Pioglitazone, although not all studies identified a statistically significant increased risk.

Risk factors for bladder cancer should be assessed before initiating Pioglitazone treatment (risks include age, smoking history, exposure to some occupational or chemotherapy agents e.g. cyclophosphamide or prior radiation treatment in the pelvic region). Any macroscopic haematuria should be investigated before starting Pioglitazone therapy. Patients should be advised to promptly seek the attention of their physician if macroscopic haematuria or other symptoms such as dysuria or urinary urgency develop during treatment.

There is some evidence that Pioglitazone may be associated with an increased risk of developing bladder cancer. Pioglitazone should not be used in patients with active bladder cancer & should be used with caution in patients with a history of bladder cancer.

Information for patients

Patients should be informed of the potential risks & benefits of Sitagliptin / Metformin Hydrochloride tablets & of alternative modes of therapy. They should also be informed about the importance of adherence to dietary instructions, of a regular exercise program, & of regular testing of blood glucose, & glycated hemoglobin test.

During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change & patients should be advised to seek medical advice promptly.

The risks of lactic acidosis, its symptoms & conditions that predispose to its development, as noted in the Metformin hydrochloride sections, should be explained to patients.

Patients should be advised to discontinue Metformin hydrochloride immediately & to promptly notify their health practitioner if unexplained hyperventilation, myalgia, malaise, unusual somnolence, or other nonspecific symptoms occur. Once a patient is stabilized on any dose level of Metformin hydrochloride, gastrointestinal symptoms, which are common during initiation of Metformin hydrochloride therapy, are unlikely to recur. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.

Patients should be informed about the importance of regular testing of renal function & hematological parameters when receiving treatment with Sitagliptin / Metformin hydrochloride.

Patients should be counselled against excessive alcohol intake, either acute or chronic, while receiving Sitagliptin / Metformin hydrochloride tablets.

Metformin (Metformin hydrochloride Sustained Release tablets) alone does not usually cause hypoglycemia, although it may occur when Metformin is used in conjunction with insulin secretagogues, such as sulfonylureas & insulin.

Patients should be informed that Sitagliptin / Metformin tablets must be swallowed whole & not crushed or chewed & that the inactive ingredients may occasionally be eliminated in the faeces as a soft mass that may resemble the original tablet.

Patients should be advised to notify their health practitioner immediately in case of Sitagliptin / Metformin hydrochloride overdose.

4.5 Drugs interactions

Sitagliptin

Effects of other medicinal products on Sitagliptin clinical data described below suggest that the risk for clinically meaningful interactions by co-administered medicinal products is low.

In vitro studies indicated that the primary enzyme responsible for the limited metabolism of Sitagliptin is CYP3A4, with contribution from CYP2C8. In patients with normal renal function, metabolism, including via CYP3A4, plays only a small role in the clearance of Sitagliptin. Metabolism may play a more significant role in the elimination of Sitagliptin in the setting of severe renal impairment or end-stage renal disease (ESRD). For this reason, it is possible that potent CYP3A4 inhibitors (i.e. Ketoconazole, Itraconazole, Ritonavir, Clarithromycin) could alter the pharmacokinetics of Sitagliptin in patients with severe renal impairment or ESRD. The effect of potent CYP3A4 inhibitors in the setting of renal impairment has not been assessed in a clinical study.

In vitro transport studies showed that Sitagliptin is a substrate for p-glycoprotein & organic anion transporter-3 (OAT3). OAT3 mediated transport of Sitagliptin was inhibited in vitro by probenecid, although the risk of clinically meaningful interactions is considered to be low. Concomitant administration of OAT3 inhibitors has not been evaluated in vivo.

Metformin hydrochloride

Co-administration of multiple twice-daily doses of 1,000 mg Metformin hydrochloride with 50 mg Sitagliptin did not meaningfully alter the pharmacokinetics of Sitagliptin in patients with type 2 diabetes.

Ciclosporin

A study was conducted to assess the effect of Ciclosporin, a potent inhibitor of p-glycoprotein, on the pharmacokinetics of Sitagliptin. Co-administration of a single 100 mg oral dose of Sitagliptin & a single 600 mg oral dose of Ciclosporin increased the AUC & Cmax of Sitagliptin by approximately 29% & 68%, respectively. These changes in Sitagliptin pharmacokinetics were not considered to be clinically meaningful. The renal clearance of Sitagliptin was not meaningfully altered. Therefore, meaningful interactions would not be expected with other p glycoprotein inhibitors.

Effects of Sitagliptin on other medicinal products

Digoxin

Sitagliptin had a small effect on plasma Digoxin concentrations. Following administration of 0.25 mg Digoxin concomitantly with 100 mg of Sitagliptin daily for 10 days, the plasma AUC of Digoxin was increased on average by 11%, & the plasma Cmax on average by 18%. No dose adjustment of Digoxin is recommended. However, patients at risk of Digoxin toxicity should be monitored for this when Sitagliptin & Digoxin are administered concomitantly. In vitro data suggest that Sitagliptin does not inhibit nor induce CYP450 isoenzymes. In clinical studies, Sitagliptin did not meaningfully alter the pharmacokinetics of Metformin hydrochloride, Glyburide, Simvastatin, Rosiglitazone, Warfarin, or oral contraceptives, providing in vivo evidence of a low propensity for causing interactions with substrates of CYP3A4, CYP2C8, CYP2C9, & organic cationic transporter (OCT). Sitagliptin may be a mild inhibitor of p-glycoprotein in vivo.

Pioglitazone

Interaction studies have shown that Pioglitazone has no relevant effect on either the pharmacokinetics or pharmacodynamics of Digoxin, Warfarin, Phenprocoumon & Metformin hydrochloride. Co-administration of Pioglitazone with sulphonylureas does not appear to affect the pharmacokinetics of the sulphonylurea. Studies in man suggest no induction of the main inducible cytochrome P450, 1A, 2C8/9 & 3A4. In vitro studies have shown no inhibition of any subtype of cytochrome P450. Interactions with substances metabolised by these enzymes, e.g. oral contraceptives, Cyclosporin, Calcium channel blockers, & HMGCoAreductase inhibitors are not to be expected. Co-administration of Pioglitazone with Gemfibrozil (an inhibitor of cytochrome P450 2C8) is reported to result in a 3-fold increase in AUC of Pioglitazone. Since there is a potential for an increase in dose- related adverse events, a decrease in the dose of Pioglitazone may be needed when Gembrozil is concomitantly administered. Close monitoring of glycaemic control should be considered. Co-administration of Pioglitazone with rifampicin (an inducer of cytochrome P450 2C8) is reported to result in a 54% decrease in AUC of Pioglitazone. The Pioglitazone dose may need to be increased when rifampicin is concomitantly administered. Close monitoring of glycaemic control should be considered.

Metformin hydrochloride

Carbonic anhydrase inhibitors

Topiramate or other carbonic anhydrase inhibitors (e.g. Zonisamide, Acetazolamide or Dichlorphenamide) frequently decrease serum bicarbonate & induce non-anion gap, hyperchloremic metabolic acidosis.

Concomitant use of these drugs may induce metabolic acidosis. Use these drugs with caution in patients treated with Metformin hydrochloride, as the risk of lactic acidosis may increase.

Cationic drugs

Cationic drugs (e.g. Amiloride, Digoxin, Morphine, Procainamide, Quinidine, Quinine, Ranitidine, Triamterene, Trimethoprim, or Vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with Metformin hydrochloride by competing for common renal tubular transport systems. Although such interactions remain theoretical (except for cimetidine), careful patient monitoring & dose adjustment of Metformin hydrochloride and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system.

Drugs affecting glycemic control

Certain drugs tend to produce hyperglycemia & may lead to loss of glycemic control. These drugs include the Thiazides & other diuretics, Corticosteroids, Phenothiazines, Thyroid products, Estrogens, Oral contraceptives, Phenytoin, Nicotinic acid, Sympathomimetics, Calcium channel blockers, & Isoniazid. When such drugs are administered to a patient receiving Metformin hydrochloride, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving Metformin hydrochloride, the patient should be observed closely for hypoglycemia.

Concomitant use of Metformin hydrochloride not recommended.

Alcohol

Alcohol intoxication is associated with an increased risk of lactic acidosis, particularly in case of fasting or malnutrition or hepatic insufficiency.

Avoid consumption of Alcohol & Alcohol-containing medications.

Iodinated contrast agents

Metformin hydrochloride must be discontinued prior to, or at the time of the image procedure & not restarted until at least 48 hours after, provided that renal function has been re-evaluated & found to be stable.

Combinations requiring precautions for use

Some medicinal products can adversely affect renal function which may increase the risk of lactic acidosis, e.g. NSAIDs, including selective cyclo-oxygenase (COX) II inhibitors, ACE inhibitors, angiotensin II receptor antagonists & diuretics, especially loop diuretics. When starting or using such products in combination with Metformin hydrochloride, close monitoring of renal function is necessary.

Glucocorticoids (systemic & local routes), beta-2-agonists & diuretics have intrinsic hyperglycaemic activity. Inform the patient & perform more frequent blood glucose monitoring, especially at the beginning of treatment. If necessary, adjust the dosage of the antidiabetic drug during therapy with the other drug & upon its discontinuation. ACE-inhibitors may decrease the blood glucose levels. If necessary, adjust the dosage of the antidiabetic drug during therapy with the other drug & upon its discontinuation.

Metformin hydrochloride may decrease the anticoagulant effect of Phenprocoumon. Therefore, a close monitoring is recommended.

Levothyroxine can reduce the hypoglycemic effect of Metformin hydrochloride. Monitoring of blood glucose levels is recommended, especially when thyroid hormone therapy is initiated or stopped & the dosage of Metformin hydrochloride must be adjusted if necessary.

Organic cation transporters (OCT)

Metformin hydrochloride is a substrate of both transporters OCT1 & OCT2. Co-administration of Metformin hydrochloride with

• Inhibitors of OCT1 (such as Verapamil) may reduce efficacy of Metformin hydrochloride.
• Inducers of OCT1 (such as Rifampicin) may increase gastrointestinal absorption & efficacy of Metformin hydrochloride.
• Inhibitors of OCT2 (such as Cimetidine, Dolutegravir, Ranolazine, Trimethoprim, Vandetanib & Isavuconazole) may decrease the renal elimination of Metformin hydrochloride & thus lead to an increase in Metformin hydrochloride plasma concentration.
• Inhibitors of both OCT1 & OCT2 (such as Crizotinib, Olaparib) may alter efficacy & renal elimination of Metformin hydrochloride.

Caution is therefore advised, especially in patients with renal impairment, when these drugs are co-administered with Metformin hydrochloride, as Metformin hydrochloride plasma concentration may increase. If needed, dose adjustment of Metformin hydrochloride may be considered as OCT inhibitors / inducers may alter the efficacy of Metformin hydrochloride.

4.6 Use in special populations

This tablet must not be taken during pregnancy. The patient must change over to insulin during pregnancy. To prevent possible ingestion with the breast milk & possible harm to the child, this tablet must not be taken by breast-feeding women. If necessary the patient must change over to insulin, or must stop breast-feeding.

Pregnancy

Sitagliptin

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, Sitagliptin should not be used during pregnancy.

Pioglitazone

There are no adequate human data to determine the safety of Pioglitazone during pregnancy. Foetal growth restriction was apparent in animal studies with Pioglitazone. This was attributable to the action of Pioglitazone in diminishing the maternal hyperinsulinaemia & increased insulin resistance that occurs during pregnancy thereby reducing the availability of metabolic substrates for foetal growth. The relevance of such a mechanism in humans is unclear & Pioglitazone should not be used in.

Metformin hydrochloride

Metformin hydrochloride was not teratogenic in rats & rabbits at doses up to 600 mg/kg/day, which represent 3 & 6 times the maximum recommended human daily dose of 2000 mg based on body surface area comparison for rats & rabbits, respectively. However, because animal reproduction studies are not always predictive of human response, Metformin hydrochloride should not be used during pregnancy unless clearly needed. The safety & effectiveness of Metformin hydrochloride used during labor & delivery has not been evaluated in human studies. Fertility of male or female rats was unaffected by Metformin hydrochloride when administered at doses as high as 600 mg/kg/day, which is approximately three times the maximum recommended human daily dose based on body surface area comparisons.

Lactation

It is unknown whether Sitagliptin is excreted in human breast milk. Animal studies have shown excretion of Sitagliptin in breast milk. Sitagliptin should not be used during breast-feeding. Breast-feeding must be discontinued during administration of Sitagliptin tablets in lactating women (transfer to milk in animal studies (rats) has been reported).

Studies in lactating rats show that Metformin hydrochloride is excreted into milk & reaches levels comparable to those in plasma.

Similar studies have not been conducted in nursing mothers. Thus, the potential for hypoglycemia in nursing infants after Metformin hydrochloride oral solution may exist. Metformin hydrochloride is excreted into human breast milk. No adverse effects were observed in breastfed new-borns / infants. However, as only limited data are available, breastfeeding is not recommended during Metformin hydrochloride treatment.

A decision on whether to discontinue breast-feeding should be made, taking into account the benefit of breast-feeding & the potential risk to adverse effect on the child.

Paediatric use

Safety & effectiveness of Sitagliptin in paediatric patients have not been established. The safety of Sitagliptin in low birth weight baby, new-born baby, infant, or little child has not been established. (No usage experience).

The safety & effectiveness in paediatric patients have not been established & Metformin hydrochloride is not recommended in paediatric patients below the age of 18 years. Thus, Sitagliptin / Metformin hydrochloride combination is not recommended in paediatric patients.

Geriatric use

Start with lowest dose in elderly patients due to higher risks of lactic acidosis, poor renal & hepatic functions & therefore, Sitagliptin should be administered carefully. Clinical studies of Metformin hydrochloride did not include sufcient numbers of subjects aged 65 & over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly & younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function & of concomitant disease or other drug therapy & the higher risk of lactic acidosis.

As Metformin hydrochloride is excreted via the kidney & elderly patients have a tendency to decreased renal function, elderly patients taking Sitagliptin / Metformin hydrochloride should have their renal function monitored regularly.

Patients with renal impairment

Sitagliptin / Metformin hydrochloride combination is not recommended in patients with renal impairment (e.g. serum creatinine levels greater than or equal to 1.5 mg/dL for men, greater than or equal to 1.4 mg/dL for women or abnormal creatinine clearance), which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction & septicemia.

The single administration of Sitagliptin at 20 mg in patients with renal impairment revealed no remarkable changes in Cmax & t1/2 corresponding to the level of renal impairment. Compared with healthy adult subjects, the AUC0–∞ of subjects with mild renal impairment (50 ≤ creatinine clearance [Ccr] ≤ 80 mL/minute), moderate renal impairment (30 ≤ Ccr < 50 mL/minute), & severe renal impairment (Ccr < 30 mL/minute) was approximately 1.25 times, 1.68 times, & 1.49 times higher than that of healthy adult subjects, respectively. In addition, the AUC0–43h of patients with end-stage renal failure was approximately 1.16 times higher than that of healthy adult subjects. In addition, 15.6% of the total administration dose of Sitagliptin was eliminated via hemodialysis.

A GFR should be assessed before initiation of treatment with Metformin hydrochloride containing products & at least annually thereafter. In patients at an increased risk of further progression of renal impairment & in the elderly, renal function should be assessed more frequently e.g. every 3 - 6 months.

Patients with hepatic impairment

As determined from the pharmacokinetic characteristics of Sitagliptin, the extent of increase in the exposure level of Sitagliptin in patients with mild to moderate hepatic impairment will not pose any significant safety risk. Thus no dose adjustment is proposed in hepatic impaired patients. There was no clinical experience of Sitagliptin in severe degree hepatic dysfunction patient. The presence of liver disease is a risk-factor for the development of lactic acidosis during Metformin hydrochloride therapy & the drug should be avoided in patients with hepatic insufficiency.

A single administration of Sitagliptin 20 mg in patients with hepatic impairment revealed that the Cmax of subjects with mild hepatic impairment (Child-Pugh classification : total score 5 - 6) & moderate hepatic impairment (Child-Pugh classification : total score 7 - 9) was approximately 1.25 times & 1.38 times that of healthy adult subjects, respectively. Compared to healthy adult subjects, the AUC0–∞of subjects with mild & moderate hepatic impairments was approximately 1.46 times & 1.59 times higher than that of healthy adult subjects, respectively.

There have been no previous clinical studies using Sitagliptin in patients with severe hepatic impairment (Child-Pugh classification : total score was greater than 9). Thus, specific caution is required when the drug is administered to patients with severe hepatic impairment.

4.7 Effects on ability to drive & use machines

Sitagliptin has no or negligible influence on the ability to drive & use machines. However, when driving or using machines, it should be taken into account that dizziness & 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.

Alertness & reactions may be impaired due to hypo- or hyperglycemia, especially when beginning or after altering treatment or when this tablet is not taken regularly. This may, for example, affect the ability to drive or to operate machinery.

Pioglitazone has no or negligible influence on the ability to drive & use machines. However, patients who experience visual disturbance should be cautious when driving or using machines.

Metformin hydrochloride monotherapy does not cause hypoglycaemia & 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 hydrochloride is used in combination with other antidiabetic agents (Sulfonylureas, Insulin, & Repaglinide).

4.8 Undesirable effects

Sitagliptin

Dipeptidyl-peptidase-4 (DPP-4) inhibitors induced arthralgia : Dipeptidyl-peptidase-4 (DPP-4) inhibitors like Sitagliptin, Vildagliptin, Saxagliptin, Sitagliptin etc. induced arthralgia.

Summary of the safety proflle

Serious adverse reactions including pancreatitis & hypersensitivity reactions have been reported. Hypoglycaemia has been reported in combination with sulphonylurea (4.7% - 13.8%) & insulin (9.6%).

Tabulated list of adverse reactions

Adverse reactions are listed below (Table 1) by system organ class & frequency. Frequencies are dened as : Very common (≥ 1/10); Common (≥ 1/100 to < 1/10); Uncommon (≥ 1/1,000 to < 1/100); Rare (≥ 1/10,000 to < 1/1,000); Very rare (< 1/10,000) & Not known (cannot be estimated from the available data).

Table 1 : The frequency of adverse reactions identified from placebo-controlled clinical studies of Sitagliptin monotherapy & post-marketing experience.

* Adverse reactions were identified through post-marketing surveillance.

† See TECOS Cardiovascular Safety Study below.

Description of selected adverse reactions

In addition to the drug-related adverse experiences described above, adverse experiences reported regardless of causal relationship to medication & occurring in at least 5% & more commonly in patients treated with Sitagliptin included upper respiratory tract infection & nasopharyngitis.

Additional adverse experiences reported regardless of causal relationship to medication that occurred more frequently in patients treated with Sitagliptin (not reaching the 5 % level, but occurring with an incidence of > 0.5 % higher with Sitagliptin than that in the control group) included osteoarthritis & pain in extremity.

Pioglitazone

Adverse reactions reported in excess (≥ 0.5%) of placebo & as more than an isolated case in patients receiving Pioglitazone in double-blind studies are listed below as MedDRA preferred term by system organ class & absolute frequency. Frequencies are defined as : Very common (≥ 1/10); Common (≥ 1/100 to < 1/10); Uncommon (≥ 1/1,000 to < 1/100); Rare (≥ 1/10,000 to < 1/1,000); Very rare (< 1/10,000); Not known (cannot be estimated from the available data). Within each system organ class, adverse reactions are presented in order of decreasing incidence followed by decreasing seriousness. Infections & infestations : common : upper respiratory tract infection, bronchitis. Uncommon : sinusitis.

Neoplasms benign, malignant & unspecified (including cysts & polyps) : uncommon bladder cancer.

Blood & lymphatic system disorders : anaemia.

Immune system disorders : not known : Hypersensitivity & allergic reactions ¹.

Metabolism & nutrition disorders : hypoglycaemia, appetite increased. Nervous system disorders : hypo-aesthesia, headache, dizziness, insomnia. Eye disorders : visual disturbance ², macular oedema

Ear & labyrinth disorders : vertigo

Cardiac disorders : heart failure ³

Respiratory, thoracic & mediastinal disorders: dyspnoea.

Gastrointestinal disorders : flatulence

Skin & subcutaneous tissue disorders : sweating

Musculoskeletal & connective tissue disorders : fracture bone, arthralgia, back pain

Renal & urinary disorders : haematuria, glycosuria, proteinuria

Reproductive system & breast disorders : erectile dysfunction. General disorders & administration site conditions: oedema ⁵, fatigue

Investigations : weight increased ⁶, blood creatine phospho-kinase increased, increased lactic dehydro- genase & alanine aminotransferase increased ⁷.

Description of selected adverse reactions :

1. Post-marketing reports of hypersensitivity reactions in patients treated with Pioglitazone have been reported. These reactions include anaphylaxis, angioedema, & urticaria.

2. Visual disturbance has been reported mainly early in treatment & is related to changes in blood glucose due to temporary alteration in the turgidity & refractive index of the lens as seen with other hypoglycaemic treatments.

3. In controlled clinical trials the incidence of reports of heart failure with Pioglitazone treatment was the same as in placebo, Metformin hydrochloride & sulphonylurea treatment groups, but was increased when used in combination therapy with insulin. In an outcome study of patients with pre-existing major macrovascular disease, the incidence of serious heart failure was 1.6% higher with Pioglitazone than with placebo, when added to therapy that included insulin. However, this did not lead to an increase in mortality in this study. In this study in patients receiving Pioglitazone & insulin, a higher percentage of patients with heart failure was observed in patients aged ≥ 65 years compared with those less than 65 years (9.7% compared to 4.0%). In patients on insulin with no Pioglitazone the incidence of heart failure was 8.2% in those ≥ 65 years compared to 4.0% in patients less than 65 years. Heart failure has been reported with marketing use of Pioglitazone, & more frequently when Pioglitazone was used in combination with insulin or in patients with a history of cardiac failure.

4. A pooled analysis was conducted of adverse reactions of bone fractures from randomised, comparator controlled, double blind clinical trials in over 8,100 patients in the Pioglitazone-treated groups & 7,400 in the comparatortreated groups of up to 3.5 years duration. A higher rate of fractures was observed in women taking Pioglitazone (2.6%) versus comparator (1.7%). No increase in fracture rates was observed in men treated with Pioglitazone (1.3%) versus comparator (1.5%).

5. In the 3.5 year PROactive study, 44/870 (5.1%) of Pioglitazone-treated female patients experienced fractures compared to 23/905 (2.5%) of female patients treated with comparator. No increase in fracture rates was observed in men treated with Pioglitazone (1.7%) versus comparator (2.1%). Post- marketing, bone fractures have been reported in both male & female patients.

6. Oedema was reported in 6 - 9% of patients treated with Pioglitazone over one year in controlled clinical trials. The oedema rates for comparator groups (sulphonylurea, Metformin hydrochloride) were 2 - 5%. The reports of oedema were generally mild to moderate & usually did not require discontinuation of treatment.

7. In active comparator controlled trials mean weight increase with Pioglitazone given as monotherapy was 2 - 3 kg over one year. This is similar to that seen in a sulphonylurea active comparator group. In combination trials Pioglitazone added to Metformin hydrochloride resulted in mean weight increase over one year of 1.5 kg & added to a sulphonylurea of 2.8 kg. In comparator group's addition of sulphonylurea to Metformin hydrochloride resulted in a mean weight gain of 1.3 kg & addition of Metformin hydrochloride to a sulphonylurea a mean weight loss of 1.0 kg.

8. In clinical trials with Pioglitazone the incidence of elevations of ALT greater than three times the upper limit of normal was equal to placebo but less than that seen in Metformin hydrochloride or sulphonylurea comparator groups. Mean levels of liver enzymes decreased with treatment with Pioglitazone. Rare cases of elevated liver enzymes & hepatocellular dysfunction have occurred in post-marketing experience. Although in very rare cases fatal outcome has been reported, causal relationship has not been established.

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

• New onset or worsening diabetic macular oedema with decreased visual acuity.
• Fatal & non-fatal hepatic failure.

Post-marketing reports of congestive heart failure have been reported in patients treated with Pioglitazone, both with & without previously known heart disease & both with & without concomitant insulin administration. In post-marketing experience, there have been reports of unusually rapid increases in weight & increases in excess of that generally observed in clinical trials. Patients who experience such increases should be assessed for fluid accumulation & volume-related events such as excessive oedema & congestive heart failure.

Metformin hydrochloride

Gastrointestinal symptoms such as nausea, vomiting, diarrhea, abdominal pain & loss of appetite (> 10%) are very common : these occur most frequently during initiation of therapy & resolve spontaneously in most cases. To prevent these gastrointestinal symptoms, it is recommended that Metformin hydrochloride be taken in 2 or 3 daily doses during or after meals. As low increase of the dose may also improve gastrointestinal tolerability.

• Metallic taste (3%) is common.
• Mild erythema has been reported in some hypersensitive individuals. The incidence of such effects is regarded as very rare (< 0.01%).
• A decrease of vitamin B12 absorption with decrease of serum levels has been observed inpatients treated long-term with Metformin hydrochloride & appears generally to be without clinical significance (< 0.01%).
• However, cases of peripheral neuropathy in patients with Vitamin B12 deficiency have been reported in post-marketing experience (frequency not known).
• Lactic acidosis (0.03 cases / 1000 patient-years) is very rare.
• Hemolytic anemia (frequency unknown)
• Reduction of thyrotropin level in patients with hypothyroidism (frequency unknown)
• Hypomagnesemia in the context of diarrhea (frequency unknown)
• Encephalopathy (frequency unknown)
• Photosensitivity (frequency unknown)
• Hepatobiliary disorders : Reports of liver function tests abnormalities & hepatitis resolving upon Metformin hydrochloride discontinuation.
• In post marketing data & in controlled clinical studies, adverse event reporting in patients treated with Metformin hydrochloride SR was similar in nature & severity to that reported in patients treated with Metformin hydrochloride immediate release.

During treatment initiation, the most common adverse reactions are nausea, vomiting, diarrhoea, abdominal pain & loss of appetite, which resolve spontaneously in most cases.

Laboratory tests

Vitamin B₁₂ concentrations : Metformin hydrochloride may lower serum Vitamin B₁₂ concentrations. Measurement of hematologic parameters on an annual basis is advised in patients on Metformin hydrochloride & any apparent abnormalities should be appropriately investigated & managed.

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

Sitagliptin

During controlled clinical trials in healthy subjects, single doses of up to 800 mg Sitagliptin were administered.

Minimal increases in QTc, not considered to be clinically relevant, were observed in one study at a dose of 800 mg Sitagliptin. 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 & 400 mg per day for periods of 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), & institute supportive therapy if required. Sitagliptin is modestly dialysable. In clinical studies, approximately 13.5 % of the dose was removed over a 3- to 4-hour haemodialysis session. Prolonged haemodialysis may be considered if clinically appropriate. It is not known if Sitagliptin is dialysable by peritoneal dialysis.

Pioglitazone

In clinical studies, patients have taken Pioglitazone at higher than the recommended highest dose of 45 mg daily. The maximum reported dose of 120 mg/day for four days, then 180 mg/day for seven days was not associated with any symptoms. Hypoglycaemia may occur in combination with sulphonylureas or insulin. Symptomatic & general supportive measures should be taken in case of overdose.

Metformin hydrochloride

No cases of overdose were reported during Metformin hydrochloride clinical trials. It would be expected that adverse reactions of a more intense character including epigastric discomfort, nausea, & vomiting followed by diarrhea, drowsiness, weakness, dizziness, malaise & headache might be seen. Should those symptoms persist, lactic acidosis should be excluded.

Overdose of Metformin hydrochloride has occurred, including ingestion of amounts greater than 50 g. 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 hydrochloride overdose cases.

Metformin hydrochloride 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 hydrochloride over dosage is suspected.

5.1 Mechanism of action / pharmacodynamic properties

Sitagliptin

Sitagliptin is a member of a class of oral anti-hyperglycaemic agents called dipeptidyl peptidase 4 (DPP-4) inhibitors.

The improvement in glycaemic control observed with this medicinal product may be mediated by enhancing the levels of active incretin hormones. Incretin hormones, including glucagon-like peptide-1 (GLP-1) & glucose dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, & levels are increased in response to a meal. 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 & GIP increase insulin synthesis & release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. Treatment with GLP-1 or with DPP-4 inhibitors in animal models of type 2 diabetes has been demonstrated to improve beta cell responsiveness to glucose & stimulate insulin biosynthesis & 9 release. With higher insulin levels, tissue glucose uptake is enhanced. In addition, GLP-1 lowers glucagon secretion from pancreatic alpha cells.

Decreased glucagon concentrations, along with higher insulin levels, lead to reduced hepatic glucose production, resulting in a decrease in blood glucose levels. The effects of GLP-1 & GIPare glucose-dependent such that when blood glucose concentrations are low, stimulation of insulin release & suppression of glucagon secretion by GLP-1 are not observed. For both GLP-1 & GIP, stimulation of insulin release is enhanced as glucose rises above normal concentrations. Further, GLP-1 does not impair the normal glucagon response to hypoglycaemia. The activity of GLP-1 & GIP is limited by the DPP-4 enzyme, which rapidly hydrolyzes the incretin hormones to produce inactive products. Sitagliptin prevents the hydrolysis of incretin hormones by DPP-4, thereby increasing plasma concentrations of the active forms of GLP-1 & GIP. By enhancing active incretin levels, Sitagliptin increases insulin release & decreases glucagon levels in a glucose-dependent manner. In patients with type 2 diabetes with hyperglycaemia, these changes in insulin & glucagon levels lead to lower haemoglobin A1c (HbA1c) & lower fasting & postprandial glucose concentrations. The glucose-dependent mechanism of Sitagliptin is distinct from the mechanism of sulphonylureas, which increase insulin secretion even when glucose levels are low & can lead to hypoglycaemia in patients with type 2 diabetes & in normal subjects. Sitagliptin is a potent & highly selective inhibitor of the enzyme DPP-4 & does not inhibit the closely-related enzymes DPP-8 or DPP-9 at therapeutic concentrations.

Pioglitazone

Pioglitazone is a selective agonist at peroxisome proliferator-activated receptor-gamma (PPARγ) in target tissues for insulin action such as adipose tissue, skeletal muscle, & liver. Activation of PPARγ increases the transcription of insulin-responsive genes involved in the control of glucose & lipid production, transport, & utilization. Through this mechanism, Pioglitazone both enhances tissue sensitivity to insulin & reduces the hepatic production of glucose (i.e. gluconeogenesis) - insulin resistance associated with type 2 diabetes mellitus is therefore improved without an increase in insulin secretion by pancreatic beta cells. Pioglitazone enhances cellular responsiveness to insulin, increases insulin-dependent glucose disposal, & improves impaired glucose homeostasis. In patients with type 2 diabetes mellitus, these effects result in lower plasma glucose concentrations, lower plasma insulin concentrations, & lower HbA1c values.

Metformin hydrochloride

Metformin hydrochloride is a biguanide that improves glucose tolerance in patients with type 2 diabetes, lowering both basal & postprandial plasma glucose. Metformin hydrochloride decreases hepatic glucose production, decreases intestinal absorption of glucose, & improves insulin sensitivity by increasing peripheral glucose uptake & utilization. Metformin hydrochloride does not produce hypoglycemia in patients with type 2 diabetes or in healthy subjects except in special circumstances, & does not cause hyperinsulinemia. With Metformin hydrochloride therapy, insulin secretion remains unchanged while fasting insulin levels & daylong plasma insulin response may actually decrease.

5.2 Pharmacokinetic properties

Sitagliptin

Absorption

Following oral administration of a 100-mg dose to healthy subjects, Sitagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1 to 4 hours post-dose, mean plasma AUC of Sitagliptin was 8.52 M•hr, Cmax was 950 nM. The absolute bioavailability of Sitagliptin is approximately 87 %. Since co-administration of a high-fat meal with Sitagliptin had no effect on the pharmacokinetics, Sitagliptin may be administered with or without food. Plasma AUC of Sitagliptin increased in a dose-proportional manner. Dose-proportionality was not established for Cmax & C24hr (Cmax increased in a greater than dose-proportional manner & C24hr increased in a less than dose-proportional manner).

Distribution

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

Biotransformation

Sitagliptin is primarily eliminated unchanged in urine, & metabolism is a minor pathway. Approximately 79% of Sitagliptin is excreted unchanged in the urine. Following a [14C] Sitagliptin oral dose, approximately 16 % of the radioactivity was excreted as metabolites of Sitagliptin. Six metabolites were detected at trace levels & 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. In vitro data showed that Sitagliptin is not an inhibitor of CYP isozymes CYP3A4, 2C8, 2C9, 2D6, 1A2, 2C19 or 2B6, & is not an inducer of CYP3A4 & CYP1A2.

Elimination

Following administration of an oral [14C] Sitagliptin dose to healthy subjects, approximately 100 % of the administered radioactivity was eliminated in faeces (13 %) or urine (87 %) within one week of dosing. The apparent terminal t1/2 following a 100 mg oral dose of Sitagliptin was approximately 12.4 hours. Sitagliptin accumulates only minimally with multiple doses. The renal clearance was approximately 350 mL/min.

Elimination of Sitagliptin occurs primarily via renal excretion & involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of Sitagliptin. The clinical relevance of hOAT-3 in Sitagliptin transport has not been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the renal elimination of Sitagliptin. However, Ciclosporin, a p-glycoprotein inhibitor, did not reduce the renal clearance of Sitagliptin. Sitagliptin is not a substrate for OCT2 or OAT1 or PEPT1/2 transporters. In vitro, Sitagliptin did not inhibit OAT3 (IC50=160 M) or p-glycoprotein (up to 250 M) mediated transport at therapeutically relevant plasma concentrations. In a clinical study Sitagliptin had a small effect on plasma digoxin concentrations indicating that Sitagliptin may be a mild inhibitor of p-glycoprotein.

Pioglitazone

Following oral administration, Pioglitazone is rapidly absorbed, & peak plasma concentrations of unchanged Pioglitazone are usually achieved 2 hours after administration. Proportional increases of the plasma concentration were observed for doses from 2–60 mg. Steady state is achieved after 4 - 7 days of dosing. Repeated dosing does not result in accumulation of the compound or metabolites. Absorption is not influenced by food intake. Absolute bioavailability is greater than 80%. The estimated volume of distribution in humans is 0.25 L/kg. Pioglitazone & all active metabolites are extensively bound to plasma protein (> 99%).

Pioglitazone undergoes extensive hepatic metabolism by hydroxylation of aliphatic methylene groups. This is predominantly via cytochrome P450 2C8 although other isoforms may be involved to a lesser degree. Three of the six identied metabolites are active (M-II, M-III, & M-IV). When activity, concentrations & protein binding is taken into account, Pioglitazone & metabolite M-III contribute equally to efcacy. On this basis M-IV contribution to efficacy is approximately three-fold that of Pioglitazone, whilst the relative efcacy of M-II is minimal.

In vitro studies have shown no evidence that Pioglitazone inhibits any subtype of cytochrome P450. There is no induction of the main inducible P450 isoenzymes 1A, 2C8/9, & 3A4 in man. Interaction studies have shown that Poglitazone has no relevant effect on either the pharmacokinetics or pharmacodynamics of Digoxin, Warfarin, Phenprocoumon & Metformin hydrochloride. Concomitant administration of Pioglitazone with Gembrozil (an inhibitor of cytochrome P450 2C8) or with Rifampicin (an inducer of cytochrome P450 2C8) is reported to increase or decrease, respectively, the plasma concentration of Pioglitazone.

Following oral administration of radiolabelled Pioglitazone to man, recovered label was mainly in faeces (55%) & a lesser amount in urine (45%). In animals, only a small amount of unchanged Pioglitazone can be detected in either urine or faeces. The mean plasma elimination half-life of unchanged Pioglitazone in man is 5 to 6 hours & for its total active metabolites 16 to 23 hours.

Metformin hydrochloride

Following a single oral dose of 1000 mg (2x500 mg tablets) Metformin hydrochloride after a meal, the time to reach maximum plasma Metformin hydrochloride concentration (T_max) is achieved at approximately 7 - 8 hours. In both single & multiple-dose studies in healthy subjects, once daily 1000 mg (2x500 mg tablets) dosing provides equivalent systemic exposure, as measured by areaunder-the-curve (AUC), & up to 35% higher C_max, of Metformin hydrochloride relative to the immediate release given as 500 mg twice daily.

Metformin hydrochloride sustained-release : The absolute bioavailability of a Metformin hydrochloride 500 mg tablet given under fasting conditions is approximately 50 - 60%. Following a single oral dose of Metformin hydrochloride sustained-release, Cmax is achieved within 4 - 8 hours. Peak plasma levels are approximately 20% lower compared to the same dose of Metformin hydrochloride immediate release. Both high & low fat meals had the same effect on the pharmacokinetics of sustained release. The apparent volume of distribution (V/F) of Metformin hydrochloride following single oral doses of 850 mg immediate release Metformin hydrochloride averaged 654 ± 358 L. Metformin hydrochloride is negligibly bound to plasma proteins. Metformin hydrochloride partitions into erythrocytes, most likely as a function of time. At usual clinical doses & dosing schedules of Metformin hydrochloride, steady state plasma concentrations of Metformin hydrochloride are reached within 24 - 48 hours & are generally < 1 µg/mL. During controlled clinical trials, which served as the basis of approval for Metformin hydrochloride, maximum Metformin hydrochloride plasma levels did not exceed 5 µg/mL, even at maximum doses.

Intravenous single-dose studies in healthy subjects demonstrate that Metformin hydrochloride is excreted unchanged in the urine & does not undergo hepatic metabolism (no metabolites have been identied in humans), nor biliary excretion.

Metabolism studies with extended-release Metformin hydrochloride tablets have not been conducted. Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of Metformin hydrochloride 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.

6.1 Animal toxicology or pharmacology

Sitagliptin

Renal & liver toxicity was 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 nding 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 open-mouth breathing, salivation, white foamy emesis, ataxia, trembling, decreased activity, and/or hunched posture were observed in dogs at exposure levels approximately 23 times the clinical exposure level. In addition, very slight to slight skeletal muscle degeneration was also observed histologically at doses resulting in systemic exposure levels of approximately 23 times the human exposure level. A no-effect level for these findings was found at an exposure 6-fold the clinical exposure level. 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 & carcinomas at systemic exposure levels 58 times the human exposure level. Since hepatotoxicity has been shown to correlate with induction of hepatic neoplasia in rats, this increased incidence of hepatic tumours in rats was likely secondary to chronic hepatic toxicity at this high dose.

Because of the high safety margin (19-fold at this no-effect level), these neoplastic changes are not considered relevant for the situation in humans. No adverse effects upon fertility were observed in male & female rats given Sitagliptin prior to & throughout mating. In a pre-/postnatal development study performed in rats Sitagliptin showed no adverse effects. Reproductive toxicity studies showed a slight treatment-related increased incidence of foetal rib malformations (absent, hypoplastic & 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).

Pioglitazone

Heart enlargement has been observed in mice (100 mg/kg), rats (4 mg/kg & above) & dogs (3 mg/kg) treated orally with Pioglitazone hydrochloride (approximately 11, 1, & 2 times the maximum 2 recommended human oral dose for mice, rats, & dogs, respectively, based on mg/m ). In a one-year rat study, drug-related early death due to apparent heart dysfunction occurred at an oral dose of 160 mg/kg/day (approximately 35 times the maximum recommended human oral dose based on mg/m²). Heart enlargement was seen in a 13-week study in monkeys at oral doses of 8.9 mg/kg & above (approximately four times the maximum recommended human oral dose based on mg/m²), but not in a 52-week study at oral doses up to 32 mg/kg (approximately 13 times the maximum recommended human oral dose based on mg/m²)

Metformin hydrochloride

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

This product (tablet) contains : Sitagliptin, Pioglitazone & Metformin hydrochloride as active ingredients. For the treatment of type 2 diabetes mellitus.

Sitagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor which is used in combination with diet & exercise in the therapy of type 2 diabetes, either alone or in combination with other oral hypoglycemic agents.

Molecular formula : C₁₆H₁₅F₆N₅O

Molecular weight : 407.31 g/mol

 

Pioglitazone is an insulin sensitizing agent & thiazolidinedione that is indicated for the treatment of type 2 diabetes.

Molecular formula : C₁₉H₂₀N₂O₃S

Molecular weight : 356.40 g/mol

 

Metformin hydrochloride belong to the biguanide class of antidiabetics with antihyperglycemic activity.

Molecular formula : C₄H₁₁N₅

Molecular weight : 129.16 g/mol

 

8.1 Incompatibilities

Not applicable

8.2 Shelf-life

Refer on the pack.

8.3 Packaging information

Alu-Alu blister strip of 10 tablets.

8.4 Storage & handing instructions

Store below 30°C away from direct sunlight, heat & moisture.

Keep out of reach of children.

Tablet should be swallowed whole & not to be broken, crushed or chewed.

Read this entire leaflet carefully before you start taking this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
• If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.

What Sitagliptin, Pioglitazone & Metformin hydrochloride Tablets is & what it is used for ?

This Product (tablet) contains : Sitagliptin, Pioglitazone & Metformin hydrochloride as active ingredients. For the treatment of type 2 diabetes mellitus.

What you need to know before you take Sitagliptin, Pioglitazone & Metformin hydrochloride Tablets ?

Do not take Sitagliptin, Pioglitazone & Metformin hydrochloride Tablet, if you are :

Having an allergy or hypersensitivity to any of the active ingredients or excipients present in this drug. Sitagliptin is contraindicated in patients with :

• Severe ketosis, diabetic coma (or history of diabetic coma) or pre-coma & also for immediate remedy in type 1 diabetes of hyperglycemias with infusion & insulin.
• Patients with severe infection, surgery, severe trauma (blood sugar control should preferably be done by insulin) are hypersensitive (allergic) to Pioglitazone or any of the other ingredients of Pioglitazone.
• Have heart failure or have had heart failure in the past.
• Have liver disease.
• Have had diabetic ketoacidosis (a complication of diabetes causing rapid weight loss, nausea or vomiting).
• Have or have ever had bladder cancer.
• Have blood in your urine that your doctor has not checked.

Metformin hydrochloride is contraindicated in patients with the following conditions :

• Renal impairment (e.g., serum creatinine levels ≥ 1.5 mg/dL for men, ≥ 1.4 mg/dL for women or abnormal creatinine clearance), which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction & septicemia.
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should be treated with insulin.

Warnings & precautions

Sitagliptin

Sitagliptin should be administered carefully in the following :

Patients with advanced liver failure (safety has not been established).

Patients with congestive heart failure (NYHA category III-IV) (safety has not been established). In patients with pituitary insufficiency or adrenal insufficiency, poor nutritional state, starvation, an irregular dietary intake, or debilitating condition, intense muscle movement or excessive alcohol intake (may cause low blood sugar).

Patients with history of abdominal surgery or with a history of bowel obstruction (may cause bowel obstruction).

In patients with arrhythmia, severe bradycardia or its history, patients with heart disease such as congestive heart failure or patients with low serum Potassium, congenital prolonged QT syndrome, & history of Torsade's de pointes or patients using antiarrhythmic drugs (may cause QT prolongation). Patients using insulin secretagogues (e.g., sulfonylurea) (risk of severe hypoglycaemia).

Acute pancreatitis

Acute pancreatitis has been observed in studies done outside Japan & since acute pancreatitis is also reported with similar molecules, it should not be used in patients with history of acute pancreatitis. In case a patient develops acute pancreatitis the drug should be withdrawn & immediate physician consultation should be done.

In the clinical trial program, pancreatitis was reported in 15.2 cases per 10,000 patient year exposure while being treated with Sitagliptin compared with 3.7 cases per 10,000 patient year exposure while being treated with comparator (placebo & active comparator, sulfonylurea). Three additional cases of pancreatitis were reported following the last administered dose of Sitagliptin.

Hypoglycemia

Hypoglycemia may occur in patients with : Adrenal insufficiency; Malnutrition, starved state, irregular dietary intake, insufficient dietary intake or hyposthenia; Vigorous muscular movement; Patient with excessive alcohol consumption.

Important precautions

The points regarding hypoglycemia & its coping strategy should be sufficiently explained to the patient when using this product. Particularly, when co-administered with sulfonylurea or insulin formulation, there is a possibility of higher risk of hypoglycemia. In order to reduce the risk of hypoglycemia caused by sulfonylurea or insulin formulation, consider decreasing the dose of sulfonylurea or insulin formulation when given in combination with Sitagliptin.

Consider its application only to the patient diagnosed with Type 2 diabetes mellitus (T2DM). In addition to T2DM, pay attention to diseases having symptoms (such as renal glycosuria, thyroid dysfunction) similar to diabetes, such as abnormal glucose tolerance / positive urine sugar.

During administration of Sitagliptin, regularly check the blood sugar; check the effect of the drug. In case, the drug effect is insufficient even after taking this product for 3 months, then change to other treatment.

Metformin hydrochloride

Risk of lactic acidosis.

Metformin hydrochloride may cause a very rare, but very serious side effect called lactic acidosis, particularly if your kidneys are not working properly. The risk of developing lactic acidosis is also increased with uncontrolled diabetes, serious infections, prolonged fasting or alcohol intake, dehydration (see further information below), liver problems & any medical conditions in which a part of the body has a reduced supply of oxygen (such as acute severe heart disease).

If any of the above apply to you, talk to your doctor for further instructions.

Stop taking Metformin hydrochloride for a short time if you have a condition that may be associated with dehydration (significant loss of body fluids) such as severe vomiting, diarrhoea, fever, exposure to heat or if you drink less fluid than normal.

Talk to your doctor for further instructions. Stop taking Metformin hydrochloride & contact a doctor or the nearest hospital immediately if you experience some of the symptoms of lactic acidosis, as this condition may lead to coma.

Symptoms of lactic acidosis include :

• Vomiting
• Stomach ache (abdominal pain).
• Muscle cramps.
• A general feeling of not being well with severe tiredness.
• Difficulty in breathing.
• Reduced body temperature & heartbeat.

Lactic acidosis is a medical emergency & must be treated in a hospital.

If you need to have major surgery you must stop taking Metformin hydrochloride during & for some time after the procedure. Your doctor will decide when you must stop & when to restart your treatment with Metformin hydrochloride. During treatment with Metformin hydrochloride, your doctor will check your kidney function at least once a year or more frequently if you are elderly and/or if you have worsening kidney function. If you are older than 75 years, treatment with Metformin hydrochloride tablet should not be started to lower the risk of developing type 2 diabetes. You may see some remains of the tablets in your stools. Do not worry- this is normal for this type of tablet. You should continue to follow any dietary advice that your doctor has given you & you should make sure that you eat carbohydrates regularly throughout the day. Do not stop taking this medicine without speaking to your doctor.

Other medicines & Sitagliptin, Pioglitazone & Metformin hydrochloride tablets.

Sitagliptin

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. In particular, tell your doctor if you are taking Digoxin (a medicine used to treat irregular heartbeat & other heart problems). The level of digoxin in your blood may need to be checked if taking with Sitagliptin.

Pioglitazone

You can usually continue to take other medicines whilst you are being treated with Pioglitazone. However, certain medicines are especially likely to affect the amount of sugar in your blood :

• Gemfibrozil (used to lower cholesterol)
• Rifampicin (used to treat tuberculosis & other infections) Tell your doctor or pharmacist if you are taking any of these. Your blood sugar will be checked & your dose of Pioglitazone may need to be changed.

Metformin hydrochloride

Tell your doctor if you are taking, have recently taken or might take any other medicines. You may need more frequent blood glucose & kidney function tests, or your doctor may need to adjust the dosage of Metformin hydrochloride SR. It is especially important to mention the following :

• Steroids such as Prednisolone, Mometasone, Beclometasone.
• Medicines which increase urine production (diuretics (water tablets) such as Furosemide).
• Medicines used to treat pain & inflammation (NSAID & COX-2-inhibitors, such as Ibuprofen & Celecoxib)
• Certain medicines for the treatment of high blood pressure (ACE inhibitors & Angiotensin II receptor antagonists)
• Sympathomimetic medicines including epinephrine & dopamine used to treat heart attacks & low blood pressure. Epinephrine is also included in some dental anaesthetics.
• Medicines that may change the amount of Metformin hydrochloride in your blood, especially if you have reduced kidney function (such as Verapamil, Rifampicin, Cimetidine, Dolutegravir, Ranolazine, Trimethoprim, Vandetanib, Isavuconazole, Crizotinib, Olaparib).

Sitagliptin, Pioglitazone & Metformin hydrochloride Tablets with alcohol

Avoid excessive alcohol intake while taking Metformin hydrochloride (Sustained Release) since this may increase the risk of lactic acidosis.

Pregnancy & breast-feeding

Do not take Sitagliptin, Pioglitazone & Metformin hydrochloride Tablets 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.

you think you might be or are planning to become pregnant.

• Are breast-feeding or if you are planning to breastfeed your baby. Your doctor will advise you to discontinue this medicine.

Driving & using machines tablets

Sitagliptin, Pioglitazone & Metformin hydrochloride Tablets taken on its own does not cause 'hypos' (symptoms of low blood sugar or hypoglycaemia, such as faintness, confusion & increased sweating) & therefore should not affect your ability to drive or use machinery. You should be aware, however, that this medicine has no or negligible influence on the ability to drive & use machines. However, dizziness & drowsiness have been reported, which may affect your ability to drive or use machines. Taking this medicine in combination with medicines called sulphonylureas or with insulin can cause hypoglycaemia, which may affect your ability to drive & use machines or work without safe foothold.

Pioglitazone will not affect your ability to drive or use machines but take care if you experience abnormal vision.

Metformin hydrochloride (Sustained Release) taken with other antidiabetic medicines can cause hypos, so in this case you should take extra care when driving or operating machinery.

How to take Sitagliptin, Pioglitazone & Metformin hydrochloride Tablets?

Always take Sitagliptin, Pioglitazone & Metformin hydrochloride tablets exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure.

Posology

The usual recommended dose for adults is 1 tablet once daily or as directed by the Physician.

Method of administration

For oral administration only.

Sitagliptin / Pioglitazone / Metformin hydrochloride tablets must be swallowed whole and not to be chewed or crushed.

Possible side effects

Sitagliptin

Like all medicines, this medicine can cause side effects, although not everybody gets them. STOP taking Sitagliptin & contact a doctor immediately if you notice any of the following serious side effects : Severe & persistent pain in the abdomen (stomach area) which might reach through to your back with or without nausea & vomiting, as these could be signs of an inflamed pancreas (pancreatitis). If you have a serious allergic reaction (frequency not known), including rash, hives, blisters on the skin / peeling skin & swelling of the face, lips, tongue, & throat that may cause difficulty in breathing or swallowing, stop taking this medicine & call your doctor right away. Your doctor may prescribe a medicine to treat your allergic reaction & a different medicine for your diabetes.

Some patients have experienced the following side effects after adding Sitagliptin to Metformin hydrochloride

Common (may affect up to 1 in 10 people) : Low blood sugar, Nausea, Flatulence, Vomiting.

Uncommon (may affect up to 1 in 100 people) : Stomach ache, Diarrhoea, Constipation, Drowsiness

Some patients have experienced different types of stomach discomfort when starting the combination of Sitagliptin & Metformin hydrochloride together (frequency is common).

Some patients have experienced the following side effects while taking Sitagliptin in combination with a sulphonylurea & Metformin hydrochloride :

Very common (may affect more than 1 in 10 people) : Low blood sugar.

Common : Constipation

Some patients have experienced the following side effects while taking Sitagliptin & Pioglitazone

Common : Flatulence, Swelling of the hands or legs.

Some patients have experienced the following side effects while taking Sitagliptin in combination with Pioglitazone & Metformin hydrochloride

Common : Swelling of the hands or legs.

Some patients have experienced the following side effects while taking Sitagliptin in combination with insulin (with or without Metformin hydrochloride)

Common : flu.

Uncommon : dry mouth Some patients have experienced the following side effects while taking.

Sitagliptin alone in clinical studies, or during post-approval use alone and/or with other diabetes medicines

Common : Low blood sugar, Headache, Upper respiratory infection, Stuffy or runny nose & sore throat, Osteoarthritis, Arm or leg pain.

Uncommon : Dizziness, Constipation, Itching.

Rare : Reduced number of platelets.

Frequency not known : Kidney problems (sometimes requiring dialysis), Vomiting, Joint pain, Muscle pain, Back pain, Interstitial lung disease, Bullous pemphigoid (a type of skin blister).

Pioglitazone

Like all medicines, Pioglitazone can cause side effects, although not everybody gets them. In particular, patients have experienced the following serious side effects : Heart failure has been experienced.

commonly (1 to 10 users in 100)

In patients taking Pioglitazone in combination with insulin. Symptoms are unusual shortness of breath or rapid increase in weight or localised swelling (oedema). If you experience any of these, especially if you are over the age of 65, seek medical advice straight away. Bladder cancer has been experienced uncommonly (1 to 10 users in 1000) in patients taking Pioglitazone. Signs & symptoms include blood in your urine, pain when urinating or a sudden need to urinate.

If you experience any of these, talk to your doctor as soon as possible. Localised swelling (oedema) has also been experienced very commonly in patients taking Pioglitazone in combination with insulin. If you experience this side effect, talk to your doctor as soon as possible.

Broken bones have been reported commonly (1 to 10 users in 100) in women patients taking Pioglitazone. If you experience this side effect, talk to your doctor as soon as possible. Blurred vision due to swelling (or fluid) at the back of the eye (frequency not known) has also been reported in patients taking Pioglitazone. If you experience this symptom for the first time, talk to your doctor as soon as possible. Also, if you already have blurred vision & the symptom gets worse, talk to your doctor as soon as possible. The other side effects that have been experienced by some patients taking Pioglitazone are :

Common (affects 1 to 10 users in 100)

• Weight gain
• Respiratory infection
• Numbness
• Abnormal vision
• Bone fracture

Uncommon (affects 1 to 10 users in 1,000)

• Inflammation of the sinuses (sinusitis).
• Difficulty sleeping (insomnia) Not known (frequency cannot be estimated from the available data).
• Blurred vision due to swelling (or fluid) in the back of the eye. If you experience these symptoms for the first time or if they get worse, tell your doctor as soon as possible.
• Increase in liver enzymes The other side effects that have been experienced by some patients when Pioglitazone is taken with other anti-diabetic medicines are :

Very common (affects more than 1 user in 10)

• Decreased blood sugar (hypoglycaemia)
• Localised swelling (oedema)

Common (affects 1 to 10 users in 100)

• Headache
• Dizziness
• Flatulence
• Joint pain
• Impotence
• Blood in urine
• Small reduction in red blood cell count
• Back pain
• Shortness of breath
• Heart failure (when taken with insulin)

Uncommon (affects 1 to 10 users in 1,000)

• Spinning sensation (vertigo)
• Sweating
• Tiredness
• Sugar in urine, proteins in urine
• Increased appetite
• Increase in enzymes

Metformin hydrochloride

Metformin hydrochloride may cause a very rare (may affect up to 1 user in 10,000), but very serious side effect called lactic acidosis. If this happens you must stop taking Metformin hydrochloride & contact a doctor or the nearest hospital immediately, as lactic acidosis may lead to coma. Metformin hydrochloride in may cause abnormal liver function tests & hepatitis (inflammation of the liver) which may result in jaundice (may affect up to 1 user in 10,000). If you develop yellowing of the eyes and/or skin contact your doctor immediately.

Other possible side effects are listed by frequency as follows :

Very common (affects more than 1 person in 10)

• Diarrhoea, nausea, vomiting, stomach ache or loss of appetite. If you get these, do not stop taking the tablets as these symptoms will normally go away in about 2 weeks. It helps if you take the tablets with or immediately after a meal.

Common (affects less than 1 person in 10, but more than 1 person in 100)

• Taste disturbance

Very rare (affects less than 1 person in 10,000)

• Decreased vitamin B12 levels.
• Skin rashes including redness, itching & hives.

How should I store Sitagliptin, Pioglitazone & Metformin hydrochloride Tablets ?

Keep this medicine out of the sight & reach of children.

Store below 30°C away from direct sunlight, heat & moisture.

Do not use this medicine after the expiry date, which is stated on the carton & the container after expiry. The expiry date refers to the last day of that month.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help to protect the environment.

Any other information

Keep this medicine out of the sight & reach of children

17 August 2023