Metformin and Alogliptin

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

The maximum daily dose of metformin should preferably be divided into 2-3 daily doses. Factors that may increase the risk of lactic acidosis should be reviewed before considering initiation of metformin in patients with GFR<60 mL/min.

If no adequate strength of alogliptin/metformin is available, individual monocomponents should be used instead of the fixed dose combination.

^* Alogliptin dose adjustment is based on a pharmacokinetic study where kidney function was assessed using creatinine clearance (CrCl) levels estimated from the Cockcroft-Gault equation.

ACE inhibitors may decrease blood glucose levels. If necessary, the dose of alogliptin/metformin should be adjusted during therapy with the other medicinal product and upon its discontinuation.

Glucocorticoids (given by systemic and local routes), beta-2-agonists and diuretics have intrinsic hyperglycaemic activity. The patient should be informed and more frequent blood glucose monitoring performed, especially at the beginning of treatment with such medicinal products. If necessary, the dose of alogliptin/metformin should be adjusted during therapy with the other medicinal product and upon its discontinuation.

Cationic substances that are eliminated by renal tubular secretion (e.g. cimetidine) may interact with metformin by competing for common renal tubular transport systems. A study conducted in seven normal healthy volunteers showed that cimetidine (400 mg twice daily) increased metformin systemic exposure (area under the curve, AUC) by 50% and C_max by 81%. Therefore, close monitoring of glycaemic control, dose adjustment within the recommended posology and changes in diabetic treatment should be considered when cationic medicinal products that are eliminated by renal tubular secretion are co-administered.

There are no data from the use of metformin/alogliptin in pregnant women. Studies in pregnant rats with alogliptin plus metformin as combination treatment have shown reproductive toxicity at approximately 5-20 times (for metformin and alogliptin respectively) the human exposure at the recommended dose.

Metformin/alogliptin 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 metformin

A limited amount of data from the use of metformin in pregnant women does not indicate an increased risk of congenital abnormalities. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity at clinically relevant doses.

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

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

Fertility

The effect of metformin/alogliptin on fertility in humans has not been studied. No adverse effects on fertility were observed in animal studies conducted with alogliptin or with metformin.

Metformin/alogliptin has no or negligible influence on the ability to drive and use machines. However, patients should be alerted to the risk of hypoglycaemia especially when used in combination with insulin or pioglitazone.

Summary of the safety profile

Acute pancreatitis is a serious adverse reaction and is attributed to the alogliptin component of alogliptin/metformin combination. Hypersensitivity reactions, including Stevens-Johnson syndrome, anaphylactic reactions, and angioedema are serious and are attributed to the alogliptin component of alogliptin/metformin combination. Lactic acidosis is a serious adverse reaction, which may occur very rarely (<1/10,000), and is attributed to the metformin component of alogliptin/metformin combination. Other reactions such as upper respiratory tract infections, nasopharyngitis, headache, gastroenteritis, abdominal pain, diarrhoea, vomiting, gastritis, gastroesophageal reflux disease, pruritus, rash, hypoglycaemia may occur commonly (≥1/100 to <1/10) which are attributed to alogliptin/metformin combination.

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

The information provided is based on a total of 7,150 patients with type 2 diabetes mellitus, including 4,201 patients treated with alogliptin and metformin, who participated in 7 phase 3 double-blind, placebo- or active-controlled clinical studies. These studies evaluated the effects of co-administered alogliptin and metformin on glycaemic control and their safety as initial combination therapy, as dual therapy in patients initially treated with metformin alone, and as add-on therapy to a thiazolidinedione or insulin.

Tabulated list of 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).

Adverse reactions:

Description of selected adverse reactions

Lactic acidosis: 0.03 cases/1,000 patient-years.

Long-term treatment with metformin has been associated with a decrease in vitamin B₁₂ absorption and appears generally to be without clinical significance. However, it may very rarely result in clinically significant vitamin B₁₂ deficiency (e.g. megaloblastic anaemia).

Gastrointestinal symptoms occur most frequently during initiation of therapy and resolve spontaneously in most cases. These may be prevented by taking metformin in 2 daily doses during or after meals.

Isolated cases of hepatitis or liver function test abnormalities resolving on discontinuation of metformin have been reported.