What is Ristfor?
Ristfor is a medicine containing two active substances, sitagliptin and metformin hydrochloride. It is available as capsule-shaped tablets (pink: 50 mg of sitagliptin and 850 mg of metformin hydrochloride; red: 50 mg of sitagliptin and 1, 000 mg of metformin hydrochloride).
The medicine is the same as Janumet, already authorized in the European Union (EU). The company that makes Janumet has agreed that its scientific data will be used for Ristfor ("informed consent").
What is Ristfor used for?
Ristfor is used in patients with type 2 diabetes to improve the control of glucose (sugar) levels in the blood. It is used as follows, in addition to diet and exercise:
• in patients who are not satisfactorily controlled on metformin alone (an antidiabetic);
• in patients who are already taking a combination of sitagliptin and metformin as separate tablets;
• in combination with a sulphonylurea, a PPAR-gamma agonist such as a thiazolidinedione, or with insulin (another type of antidiabetic medicine) in patients who are not satisfactorily controlled with this medicine and metformin.
The medicine can only be obtained with a prescription.
The medicine can only be obtained with a prescription.
How is Ristfor used?
Ristfor should be taken twice a day. The dosage of the tablet depends on the dose of the other antidiabetics previously taken by the patient. If Ristfor is taken with a sulphonylurea or with insulin, it may be necessary to lower the dose of the sulphonylurea or insulin to avoid hypoglycaemia (low blood sugar levels).
The maximum dose of sitagliptin is 100 mg a day. Ristfor should be taken after meals to avoid stomach problems caused by metformin.
How does Ristfor work?
Type 2 diabetes is a disease in which the pancreas does not produce enough insulin to control the level of glucose in the blood or where the body is unable to use insulin effectively. Each of the active ingredients of Ristfor, sitagliptin and metformin hydrochloride, has a different action.
Sitagliptin is a dipeptidyl-peptidase-4 inhibitor (DPP-4). It works by inhibiting the breakdown of incretin hormones in the body. These hormones, which are released after a meal, stimulate the pancreas to produce insulin. By increasing the level of incretin in the blood, sitagliptin stimulates the pancreas to produce more insulin when the glycemic rate is high, while it is ineffective when the concentration of glucose in the blood is low. Sitagliptin also reduces the amount of glucose produced by the liver by increasing insulin levels and decreasing the levels of the glucagon hormone. Sitagliptin has been authorized in the European Union (EU) under the names Januvia and Xelevia since 2007 and with the name Tesavel since 2008.
Metformin basically inhibits glucose production and reduces its absorption in the intestine. Metformin has been available in the EU since the 1950s.
The result of the combined action of the two active ingredients is a reduction in the level of glucose present in the blood, thus contributing to the control of type 2 diabetes.
How has Ristfor been studied?
Sitagliptin monotherapy with the names Januvia / Xelevia / Tesavel can be used with metformin and the combination of metformin and a sulphonylurea in patients with type 2 diabetes. The company presented the results of three studies on Januvia / Xelevia for support the use of Ristfor in patients whose ongoing metformin treatment did not provide sufficient disease control. Two of the studies examined sitagliptin administered in addition to metformin: the first compared it with placebo (a dummy treatment) in 701 patients and the second compared it with glipizide (a sulphonylurea) in 1 172 patients. The third study compared sitagliptin with a placebo, when given in addition to glimepiride (another sulphonylurea), with or without metformin, in 441 patients.
The results of three further studies were used to support the use of Ristfor. The first included 1, 091 patients who were not satisfactorily controlled on diet and exercise alone and compared the effect of Ristfor with that of metformin or sitagliptin alone. The second included 278 patients who were not satisfactorily controlled with the combination of metmorphine and rosiglitazone (a PPAR-gamma agonist) and compared the effects of adding sitagliptin or a placebo. The third included 641 patients who were not satisfactorily controlled on a stable dose of insulin, of which three-quarters also took metaphomine. The effects of adding sitagliptin or a placebo were also compared in this study.
In all the studies, the main measure of effectiveness was the change in the blood concentration of a substance called glycosylated hemoglobin (HbA1c), which offers an indication of the effectiveness of blood glucose control.
The company has carried out further studies to show that the active ingredients of Ristfor are assimilated by the body in the same way as the two medicines administered separately.
What benefit has Ristfor shown during the studies?
Ristfor was more effective than metformin alone. The addition of 100 mg of sitagliptin to metformin reduced HbA1c levels by 0.67% (from about 8.0%) after 24 weeks, compared to a decrease of 0.02% in patients who had also taken a placebo. The effectiveness of the addition of sitagliptin to metformin was similar to that of the addition of glipizide. In the study in which sitagliptin was combined with glimepiride and metformin, HbA1c levels decreased by 0.59% after 24 weeks, compared to an increase of 0.30% seen in patients also taking a placebo.
In the first of three further studies, Ristfor was more effective than metformin or sitagliptin alone. In the second, HbA1c levels decreased by 1.03% after 18 weeks in patients who were administered sitagliptin in combination with metformin and rosiglitazone, against a decrease of 0.31% in those also taking a placebo. Finally, they decreased by 0.59% after 24 weeks in patients who added sitagliptin to insulin, compared to a 0.03% decrease in those adding a placebo. Regarding this effect, there was no difference between patients who also took metformin and patients who did not.
What are the risks associated with Ristfor?
The most common side effect with Ristfor (seen in between 1 and 10 patients in 100) is nausea. For the full list of all side effects reported with Ristfor, see the Package Leaflet.
Ristfor should not be used in people who may be hypersensitive (allergic) to sitagliptin, metformin or any of the other ingredients. It must not be used in patients who present with diabetic ketoacidosis or diabetic precoma (dangerous disorders that can occur with diabetes), kidney or liver problems, disorders that may affect the kidneys or a disease that causes a reduction in oxygen supply to tissues such as heart or lung failure or a recent heart attack. It must not be used even in patients who consume excess alcohol or who are suffering from alcoholism, or in breast-feeding women. For the full list of usage restrictions, see the package leaflet.
Why has Ristfor been approved?
The Committee for Medicinal Products for Human Use (CHMP) decided that Ristfor's benefits are greater than its risks and recommended that it be given marketing authorization.
More information on Ristfor
On March 15, 2010, the European Commission issued a marketing authorization for Ristfor, valid throughout the European Union, to Merck Sharp & Dohme Ltd. The marketing authorization is valid for five years, after which it can be renewed.
The full EPAR for Ristfor can be found here. For more information on treatment with Ristfor, please refer to the illustrative fault (included with the EPAR).
Last update of this summary: 01/2010.
