Pioglitazone and Alogliptin

For patients with moderate renal impairment (CrCl ≥30 to ≤50 mL/min), one-half of the recommended dose of alogliptin should be administered. Therefore, 12.5 mg of alogliptin and 30 mg of pioglitazone once daily is recommended in patients with moderate renal impairment.

Appropriate assessment of renal function is recommended prior to initiation of alogliptin/pioglitazone and periodically thereafter.

Alogliptin/pioglitazone combination is not recommended for patients with severe renal impairment (CrCl <30 mL/min) or end-stage renal disease requiring dialysis.

There are no data from the use of alogliptin/pioglitazone 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). Alogliptin/pioglitazone 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.

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.

No studies in lactating animals have been conducted with the combined active substances of alogliptin/pioglitazone. 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 alogliptin/pioglitazone therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

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

Alogliptin/pioglitazone combination 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 alogliptin/pioglitazone 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 alogliptin/pioglitazone fixed-dose combination. Hypersensitivity reactions, including Stevens-Johnson syndrome, anaphylactic reactions, and angioedema are serious and are attributed to the alogliptin. 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 alogliptin/pioglitazone involved the co-administration of alogliptin and pioglitazone as separate tablets. However, the results of bioequivalence studies have demonstrated that alogliptin/pioglitazone fixed-dose combination 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

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.

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.