For the use of a Registered Medical Practitioner or a Hospital or a Laboratory only TENELIGLIPTIN, PIOGLITAZONE HYDROCHLORIDE AND PROLONGED RELEASE METFORMIN HYDROCHLORIDE TABLETS 1. THE DRUG SHOULD BE USED AT FIRST LINE OF THERAPY FOR DIABETES. 2. ADVICE FOR HEALTHCARE PROFESSIONALS • Patients with active bladder cancer or with a history of bladder cancer and those with uninvestigated haematuria should not receive pioglitazone. • Prescribers should review the safety and efficacy of pioglitazone in individuals after 3-6 month 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 and during treatment because the risk of bladder cancer increases with age. Elderly patients should start on the lowest possible dose and be regularly monitored because of the risks of bladder cancer and heart failure associated with pioglitazone. COMPOSITION Each uncoated bilayered tablet contains: . 20 mg (InTeneligliptin Prolonged IP release .………………………..……………….. form) PioglitazoneMetformin Hydrochloride Hydrochloride IP IP …………………..…... equivalent to mg Pio . 15 mg .s Colour:glitazone Quinoline ………………………….…………………… Yellow Excipients ………………………….……………………..... q CLINICAL PHARMACOLOGY Biotenly®-MP contains three oral anti-hyperglycaemic drugs teneligliptin, pioglitazone and metformin hydrochloride used in the management of type-2 diabetes (NIDDM). MECHANISM OF ACTION/PHARMACODYNEMICS Teneligliptin 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 teneligliptin, 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 signalling 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, teneligliptin increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Metformin prolonged release: decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Pioglitazone selectively stimulates the nuclear receptor peroxisome proliferator- activated receptor gamma (PPAR- and to a lesser extent PPAR- It modulates the transcription of the insulin-sensitive genes involved in the control of glucose and lipid metabolism in the muscle, adiposeγ tissue, and the liver. As a γ.result, pioglitazone reduces insulin resistance in the liver and peripheral tissues; increases the expense of insulin-dependent glucose; decreases withdrawal of glucose from the liver; reduces quantity of glucose, insulin and glycated haemoglobin in the bloodstream. The combination of teneligliptin, pioglitazone and metformin prolonged-release complements each other and provides better glycemic control in the management of type-2 diabetes and probably in the prevention of its associated macrovascular and microvascular complications. PHARMACOKINETICS Teneligliptin: After oral administration of a 20 mg dose of teneligliptin to healthy subjects, teneligliptin was rapidly absorbed, with peak plasma concentrations (mean T max) occurring at 1.8 hours and 1 hour post dose. Plasma AUC of teneligliptin increased in a dose-proportional manner. Following oral 20 mg dose to healthy volunteers, mean plasma AUC of teneligliptin was 2028.9 ng*hr/ml, Cmax was 187.2 ng/ml, and apparent terminal half-life (t1/2) was 24.2 hours. Plasma AUC of teneligliptin increased following 20 mg doses at steady-state compared to the first dose. Co administration with food reduces the Cmax by 20%, increases the Tmax from 1.1 to 2.6 hours but does not affect the AUC of teneligliptin as compared to that in the fasting state. The plasma protein binding rate is 77.6 82.2%. Following a 20 mg single oral dose of [14C] teneligliptin, 5 metabolites M1, M2, M3, M4 and M5 were observed. In vitro studies indicated that CYP3A4 and flavin-containing– monooxygenase (FMO1 and FMO3) are involved in the metabolism of teneligliptin. Teneligliptin does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C8/9, CYP2C19, CYP2E1, is a weak inhibitor of CYP2D6, CYP3A4, and FMO (IC50 value：489.4, 197.5 and 467.2 µmol/l) and does not induce CYP3A4 and CYP1A2. Following a 20 mg single oral dose of [14C] teneligliptin, 45.4% of administered radioactivity was excreted in urine and 46.5% in faeces till 216 hours after dose. The cumulative urinary excretion rates for up to 120 hours for un-metabolized, M1, M2, and M3 were 14.8%, 17.7%, 1.4% and 1.9% respectively while the cumulative faecal excretion rates for un-metabolized, M1, M3, M4 and M5 were 26.1%, 4.0%, 1.6%, 0.3% and 1.3% respectively. The single administration of teneligliptin at 20 mg in patients with renal impairment revealed no remarkable changes in Cmax and t1/2 corresponding to the level of renal impairment. Compared with healthy adult subjects, the AUC0 mL/minute), and severe renal impairment–∞ of subjects(Ccr < 30 with mL/minute) mild renal was impairment approximately 1.25creatinine times, clearance 1.68 times, [Ccr] and 8 1.49 mL/minute, times higher moderate than renalthat impairmentof healthy adult subjects,Ccr < respectively. A single administration of teneligliptin 20 mg in patients with hepatic impairment revealed that the Cmax of subjects with mild hepatic impairment and moderate hepatic impairment. approximately 1.25 times and 1.38 times that of healthy adult subjects, respectively. Compared to healthy adult subjects, respectively. Compared to healthy adult subjects, the AUC0 hepatic impairments was approximately 1.46 times and 1.59 times higher than that of healthy adult subjects, respectively. There have–∞ ofbeen subjects no previouswith mild clinical and moderate studies using teneligliptin in patients with severe hepatic impairment. Metformin prolonged release: The absolute bioavailability of a metformin 500-mg tablet given under fasting conditions is approximately 50-60%. Following a single oral dose of metformin prolonged-release, Cmax is achieved within 4-8 hours. Peak plasma levels are approximately 20% lower compared to the same dose of metformin immediate release, however, the extent of absorption (as measured by AUC) is similar to immediate release. Both high and low fat meals had the same effect on the pharmacokinetics of extended release. Metformin is negligibly bound to plasma proteins, in contrast to sulphonylureas, which are more than 90% protein bound. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of immediate-release metformin, steady state plasma concentrations of metformin are reached within 24-48 hours and are generally <1 During controlled clinical trials of immediate-release metformin, maximum metformin plasma levels did not exceed 5 even at maximum doses. Metabolism studiesμg/mL. with metformin prolonged- release have not been conducted. However, intravenous single-dose studies in normalμg/mL, subjects demonstrate that metformin immediate release does not undergo hepatic metabolism or biliary excretion. 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. Pioglitazone: Following oral administration, in the fasting state, pioglitazone is first measurable in serum within 30 minutes, with peak concentrations observed within 2 hours. Food slightly delays the time to peak serum concentration [3 to 4 hours], but does not alter the extent of absorption. The mean apparent volume of distribution (Vd/F) of pioglitazone following single dose administration is 0.63 ± 0.41 (mean ± SD) L/kg of body weight. Pioglitazone is extensively protein bound (>99%) in human serum, principally to serum albumin. Pioglitazone also binds to other serum proteins, but with lower affinity. Metabolites M-III and M-IV also are extensively bound (>98%) to serum albumin. Pioglitazone is extensively metabolized by hydroxylation and oxidation; the metabolites also partly convert to glucuronide or sulfate conjugates. Metabolites M-II and M-IV (hydroxy derivatives of pioglitazone) and M-III (keto derivative of pioglitazone) are pharmacologically