INCRESYNC Film-coated tablet Ref.[51359] Active ingredients: Alogliptin Pioglitazone Pioglitazone and Alogliptin

General

Incresync should not be used in patients with type 1 diabetes mellitus. Incresync is not a substitute for insulin in insulin-requiring patients.

Fluid retention and 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 pioglitazone therapy with the lowest available dose and increase the dose gradually. Patients should be observed for signs and 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 and symptoms of heart failure, weight gain and oedema when pioglitazone is used in combination with insulin. Since insulin and pioglitazone are both associated with fluid retention, concomitant administration may increase the risk of oedema. Post marketing cases of peripheral oedema and cardiac failure have also been reported in patients with concomitant use of pioglitazone and nonsteroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors. Incresync 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 and pre-existing major macrovascular disease. Pioglitazone or placebo was added to existing anti-diabetic and 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.

Elderly patients

In light of age-related risks (especially bladder cancer, fractures and heart failure associated with the pioglitazone component), the balance of benefits and risks should be considered carefully both before and during Incresync treatment in the elderly.

Bladder cancer

Cases of bladder cancer were reported more frequently in a meta-analysis of controlled clinical studies 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 the medicinal product was less than one year at the time of diagnosis of bladder cancer, there were 7 cases (0.06%) on pioglitazone and 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 Incresync treatment (risks include age, smoking history, exposure to some occupational or chemotherapy medicinal products e.g. cyclophosphamide or prior radiation treatment in the pelvic region). Any macroscopic haematuria should be investigated before starting 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.

Monitoring of liver function

There have been rare reports of hepatocellular dysfunction during post-marketing experience with pioglitazone (see section 4.8). Postmarketing reports of hepatic dysfunction including hepatic failure have been received for alogliptin. It is recommended, therefore, that patients treated with Incresync undergo periodic monitoring of liver enzymes. Liver enzymes should be checked prior to the initiation of therapy in all patients. Therapy with Incresync should not be initiated in patients with increased baseline liver enzyme levels (ALT >2.5 x upper limit of normal) or with any other evidence of liver disease.

Following initiation of therapy with Incresync, it is recommended that liver enzymes be monitored periodically based on clinical judgement. If ALT levels are increased to 3 x upper limit of normal during therapy, liver enzyme levels should be reassessed as soon as possible. If ALT levels remain >3 x the upper limit of normal, therapy should be discontinued. If any patient develops symptoms suggesting hepatic dysfunction, which may include unexplained nausea, vomiting, abdominal pain, fatigue, anorexia and/or dark urine, liver enzymes should be checked. The decision whether to continue the patient on therapy with Incresync should be guided by clinical judgement pending laboratory evaluations. If jaundice is observed, the medicinal product should be discontinued.

Renal impairment

As there is a need for dose adjustment of alogliptin in patients with moderate or severe renal impairment, or end-stage renal disease requiring dialysis, appropriate assessment of renal function is recommended prior to initiation of Incresync and periodically thereafter (see section 4.2).

Incresync is not recommended for patients with severe renal impairment or end-stage renal disease requiring dialysis. No information is available on pioglitazone and alogliptin use in dialysed patients and, therefore, co-administered alogliptin plus pioglitazone should not be used in such patients (see sections 4.2 and 5.2).

Weight gain

In clinical studies with pioglitazone, there was evidence of dose-related weight gain, which may be due to fat accumulation and, in some cases, associated with fluid retention. In some cases, weight increase may be a symptom of cardiac failure, therefore weight should be closely monitored. Part of the treatment of diabetes is dietary control. Patients should be advised to adhere strictly to a calorie-controlled diet.

Haematology

There was a small reduction in mean haemoglobin (4% relative reduction) and haematocrit (4.1% relative reduction) during therapy with pioglitazone, consistent with haemodilution. Similar changes were seen in metformin- (haemoglobin 3-4% and haematocrit 3.6-4.1% relative reductions) and to a lesser extent sulphonylurea- and insulin- (haemoglobin 1-2% and haematocrit 1-3.2% relative reductions) treated patients in comparative-controlled studies with pioglitazone.

Use with other antihyperglycaemic medicinal products and hypoglycaemia

Due to the increased risk of hypoglycaemia in combination with metformin, a lower dose of metformin or the pioglitazone component may be considered to reduce the risk of hypoglycaemia when this combination is used (see section 4.2).

Combinations not studied

The efficacy and safety of Incresync as triple therapy with a sulphonylurea has not been established and thus use is not recommended.

Incresync should not be used in combination with insulin, as the safety and efficacy of this combination have not been established.

Eye disorders

Post-marketing reports of new-onset or worsening diabetic macular oedema with decreased visual acuity have been reported with thiazolidinediones, including pioglitazone. Many of these patients reported concurrent peripheral oedema. It is unclear whether or not there is a direct association between pioglitazone and macular oedema but prescribers should be alert to the possibility of macular oedema if patients on Incresync report disturbances in visual acuity; an appropriate ophthalmological referral should be considered.

Hypersensitivity reactions

Hypersensitivity reactions, including anaphylactic reactions, angioedema and exfoliative skin conditions including Stevens-Johnson syndrome and erythema multiforme have been observed for DPP-4 inhibitors and have been spontaneously reported for alogliptin in the post-marketing setting. In clinical studies of alogliptin, anaphylactic reactions were reported with a low incidence.

Acute pancreatitis

Use of DPP-4 inhibitors has been associated with a risk of developing acute pancreatitis. In a pooled analysis of the data from 13 studies, the overall rates of pancreatitis reports in patients treated with 25 mg alogliptin, 12.5 mg alogliptin, active control or placebo were 2, 1, 1 or 0 events per 1,000 patient years, respectively. In the cardiovascular outcomes study the rates of pancreatitis reports in patients treated with alogliptin or placebo were 3 or 2 events per 1,000 patient years, respectively. There have been spontaneously reported adverse reactions of acute pancreatitis in the post-marketing setting. Patients should be informed of the characteristic symptom of acute pancreatitis: persistent, severe abdominal pain, which may radiate to the back. If pancreatitis is suspected, Incresync should be discontinued; if acute pancreatitis is confirmed, Incresync should not be restarted. Caution should be exercised in patients with a history of pancreatitis.

Bullous Pemphigoid

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

Others

An increased incidence in bone fractures in women was seen in a pooled analysis of adverse reactions of bone fracture from randomised, controlled, double-blind clinical studies in over 8,100 pioglitazoneand 7,400 comparator-treated patients, on treatment for up to 3.5 years.

Fractures were observed in 2.6% of women taking pioglitazone compared to 1.7% of women treated with a comparator. No increase in fracture rates was observed in men treated with pioglitazone (1.3%) versus comparator (1.5%).

The fracture incidence calculated was 1.9 fractures per 100 patient years in women treated with pioglitazone and 1.1 fractures per 100 patient years in women treated with a comparator. The observed excess risk of fractures for women in this dataset on pioglitazone is, therefore, 0.8 fractures per 100 patient years of use.

In the 3.5 year cardiovascular risk PROactive study, 44/870 (5.1%; 1.0 fractures per 100 patient years) of pioglitazone-treated female patients experienced fractures compared to 23/905 (2.5%; 0.5 fractures per 100 patient years) of female patients treated with comparator. No increase in fracture rates was observed in men treated with pioglitazone (1.7%) versus comparator (2.1%).

Some epidemiological studies have suggested a similarly increased risk of fracture in both men and women. The risk of fractures should be considered in the long-term care of patients treated with Incresync (see section 4.8).

As a consequence of enhancing insulin action, pioglitazone treatment in patients with polycystic ovarian syndrome may result in resumption of ovulation. These patients may be at risk of pregnancy. Patients should, therefore, be made aware of the risk of pregnancy and if a patient wishes to become pregnant or if pregnancy occurs, Incresync treatment should be discontinued (see section 4.6).

Incresync should be used with caution during concomitant administration of cytochrome P450 2C8 inhibitors (e.g. gemfibrozil) or inducers (e.g. rifampicin). Glycaemic control should be monitored closely. Pioglitazone dose adjustment within the recommended posology or changes in diabetic treatment should be considered (see section 4.5).

Incresync tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

Co-administration of 25 mg alogliptin once daily and 45 mg pioglitazone once daily for 12 days in healthy subjects had no clinically relevant effects on the pharmacokinetics of alogliptin, pioglitazone or their active metabolites.

Specific pharmacokinetic drug interaction studies have not been performed with Incresync. The following section outlines the interactions observed with the individual components of Incresync (alogliptin/pioglitazone) as reported in their respective Summary of Product Characteristics.

Interactions with pioglitazone

Co-administration of pioglitazone with gemfibrozil (an inhibitor of cytochrome P450 2C8) is reported to result in a 3-fold increase in AUC for pioglitazone. Since there is a potential for an increase in dose-related adverse reactions, a decrease in the dose of pioglitazone may be needed when gemfibrozil is concomitantly administered. Close monitoring of glycaemic control should be considered (see section 4.4).

Co-administration of pioglitazone with rifampicin (an inducer of cytochrome P450 2C8) is reported to result in a 54% decrease in AUC for pioglitazone. The pioglitazone dose may need to be increased when rifampicin is concomitantly administered. Close monitoring of glycaemic control should be considered (see section 4.4).

Interaction studies have shown that pioglitazone has no relevant effect on either the pharmacokinetics or pharmacodynamics of digoxin, warfarin, phenprocoumon or metformin. 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 and 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 and HMGCoA reductase inhibitors, are not to be expected.

Effects of other medicinal products on alogliptin

Alogliptin is primarily excreted unchanged in the urine and metabolism by the cytochrome (CYP) P450 enzyme system is negligible (see section 5.2). Interactions with CYP inhibitors are thus not expected and have not been shown.

Results from clinical interaction studies also demonstrate that there are no clinically relevant effects of gemfibrozil (a CYP2C8/9 inhibitor), fluconazole (a CYP2C9 inhibitor), ketoconazole (a CYP3A4 inhibitor), cyclosporine (a p-glycoprotein inhibitor), voglibose (an alpha-glucosidase inhibitor), digoxin, metformin, cimetidine, pioglitazone or atorvastatin on the pharmacokinetics of alogliptin.

Effects of alogliptin on other medicinal products

In vitro studies suggest that alogliptin does not inhibit nor induce CYP 450 isoforms at concentrations achieved with the recommended dose of 25 mg alogliptin (see section 5.2). Interaction with substrates of CYP 450 isoforms are thus not expected and have not been shown. In studies in vitro, alogliptin was found to be neither a substrate nor an inhibitor of key transporters associated with disposition of the active substance in the kidney: organic anion transporter-1, organic anion transporter-3 or organic cationic transporter-2 (OCT2). Furthermore, clinical data do not suggest interaction with p-glycoprotein inhibitors or substrates.

In clinical studies, alogliptin had no clinically relevant effect on the pharmacokinetics of caffeine, (R)-warfarin, pioglitazone, glyburide, tolbutamide, (S)-warfarin, dextromethorphan, atorvastatin, midazolam, an oral contraceptive (norethindrone and ethinyl oestradiol), digoxin, fexofenadine, metformin, or cimetidine, thus providing in vivo evidence of a low propensity to cause interaction with substrates of CYP1A2, CYP3A4, CYP2D6, CYP2C9, p-glycoprotein, and OCT2.

In healthy subjects, alogliptin had no effect on prothrombin time or International Normalised Ratio (INR) when administered concomitantly with warfarin.

Combination of alogliptin with other anti-diabetic medicinal products

Results from alogliptin studies with metformin, pioglitazone (thiazolidinedione), voglibose (alpha-glucosidase inhibitor) and glyburide (sulphonylurea) have shown no clinically relevant pharmacokinetic interactions.

Pregnancy

There are no data from the use of Incresync in pregnant women. Studies in animals with alogliptin plus pioglitazone as combination treatment have shown reproductive toxicity (slight augmentation of pioglitazone-related foetal growth retardation and foetal visceral variations, see section 5.3). Incresync should not be used during pregnancy.

Risk related to alogliptin

There are no data from the use of alogliptin in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).

Risk related to 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 and 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.

Breast-feeding

No studies in lactating animals have been conducted with the combined active substances of Incresync. In studies performed with the individual active substances, both alogliptin and pioglitazone were excreted in the milk of lactating rats. It is unknown whether alogliptin and pioglitazone are excreted in human milk. A risk to the suckling child cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Incresync therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

The effect of Incresync on fertility in humans has not been studied. No adverse effects on fertility were observed in animal studies conducted with alogliptin (see section 5.3). In animal fertility studies conducted with pioglitazone there was no effect on copulation, impregnation or fertility index.

Incresync has no or negligible influence on the ability to drive and use machines. However, patients who experience visual disturbance should be cautious when driving or using machines. Patients should be alerted to the risk of hypoglycaemia when Incresync is used in combination with other anti-diabetic medicinal products known to cause hypoglycaemia.

Summary of the safety profile

Acute pancreatitis is a serious adverse reaction and is attributed to the alogliptin component of Incresync (see section 4.4). Hypersensitivity reactions, including Stevens-Johnson syndrome, anaphylactic reactions, and angioedema are serious and are attributed to the alogliptin component of Incresync (see section 4.4). Other reactions such as upper respiratory tract infections, sinusitis, headache, hypoglycaemia, nausea, weight increase and oedema may occur commonly (≥1/100 to <1/10).

Clinical studies conducted to support the efficacy and safety of Incresync involved the co-administration of alogliptin and pioglitazone as separate tablets. However, the results of bioequivalence studies have demonstrated that Incresync film-coated tablets are bioequivalent to the corresponding doses of alogliptin and pioglitazone co-administered as separate tablets.

The information provided is based on a total of 3,504 patients with type 2 diabetes mellitus, including 1,908 patients treated with alogliptin and pioglitazone, who participated in 4 phase 3 double-blind, placebo- or active-controlled clinical studies. These studies evaluated the effects of co-administered alogliptin and pioglitazone on glycaemic control and their safety as initial combination therapy, as dual therapy in patients initially treated with pioglitazone alone (with or without metformin or a sulphonylurea), and as add-on therapy to metformin.

Tabulated list of adverse reactions

Table 1. Adverse reactions:

The adverse reactions are listed by system organ class and 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 available data).

Description of selected adverse reactions

Post-marketing spontaneous reports of hypersensitivity reactions in patients treated with pioglitazone include anaphylaxis, angioedema, and urticaria.

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

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

A pooled analysis was conducted of adverse reactions of bone fractures from randomised, comparator-controlled, double-blind clinical studies in over 8,100 patients in the pioglitazone-treated groups and 7,400 in the comparator-treated 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%). 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 and female patients (see section 4.4).

In active comparator-controlled studies, 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 studies, pioglitazone added to metformin resulted in mean weight increase over one year of 1.5 kg and added to a sulphonylurea of 2.8 kg. In comparator groups, addition of sulphonylurea to metformin resulted in a mean weight gain of 1.3 kg and addition of metformin to a sulphonylurea a mean weight loss of 1.0 kg.

In clinical studies 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 or sulphonylurea comparator groups. Mean levels of liver enzymes decreased with treatment with pioglitazone. Rare cases of elevated liver enzymes and hepatocellular dysfunction have occurred in post-marketing experience. Although in very rare cases, fatal outcome has been reported, causal relationship has not been established.

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 the national reporting system listed in Appendix V.

Not applicable.