Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Takeda Pharma A/S, Delta Park 45, 2665 Vallensbaek Strand, Denmark
Vipdomet should not be used in patients with type 1 diabetes mellitus. Vipdomet is not a substitute for insulin in insulin-requiring patients.
Lactic acidosis, a very rare but serious metabolic complication, most often occurs at acute worsening of renal function or cardiorespiratory illness or sepsis. Metformin accumulation occurs at acute worsening of renal function and increases the risk of lactic acidosis.
In case of dehydration (severe diarrhoea or vomiting, fever, heat, reduced fluid intake) Vipdomet should be temporarily discontinued and contact with a health care professional is recommended.
Medicinal products that can acutely impair renal function (such as antihypertensives, diuretics and nonsteroidal anti-inflammatory drugs (NSAIDs)) should be initiated with caution in metformin-treated patients. Other risk factors for lactic acidosis are excessive alcohol intake, hepatic insufficiency, inadequately controlled diabetes, ketosis, prolonged fasting and any conditions associated with hypoxia, as well as concomitant use of medicinal products that may cause lactic acidosis (see sections 4.3 and 4.5).
Patients and/or care-givers should be informed on the risk of lactic acidosis. Lactic acidosis is characterised by acidotic dyspnoea, abdominal pain, muscle cramps, asthenia and hypothermia followed by coma. In case of suspected symptoms, the patient should stop taking Vipdomet and seek immediate medical attention. Diagnostic laboratory findings are decreased blood pH (<7.35), increased plasma lactate levels (>5 mmol/L) and an increased anion gap and lactate/pyruvate ratio.
Intravascular administration of iodinated contrast media may lead to contrast induced nephropathy, resulting in metformin accumulation and an increased risk of lactic acidosis. Vipdomet should be discontinued prior to or at the time of the imaging procedure and not restarted until at least 48 hours after, provided that renal function has been re-evaluated and found to be stable, see sections 4.2 and 4.5.
GFR should be assessed before treatment initiation and regularly thereafter (see section 4.2). Metformin is contraindicated in patients with GFR <30 mL/min and should be temporarily discontinued in the presence of conditions that alter renal function (see section 4.3).
Decreased renal function in elderly patients is frequent and asymptomatic. Special caution should be exercised in situations where renal function may become impaired, for example when initiating antihypertensive or diuretic therapy or when starting treatment with a nonsteroidal anti-inflammatory drug (NSAID).
As Vipdomet contains metformin it must be discontinued at the time of surgery under general, spinal or epidural anesthesia. Therapy may be restarted no earlier than 48 hours following surgery or resumption of oral nutrition and provided that renal function has been re-evaluated and found to be stable.
Alogliptin has not been studied in patients with severe hepatic impairment (Child-Pugh score >9) and is, therefore, not recommended for use in such patients (see sections 4.2, 4.3 and 5.2).
Insulin is known to cause hypoglycaemia. Therefore, a lower dose of insulin may be considered to reduce the risk of hypoglycaemia when this medicinal product is used in combination with Vipdomet (see section 4.2).
Due to the increased risk of hypoglycaemia in combination with pioglitazone, a lower dose of pioglitazone may be considered to reduce the risk of hypoglycaemia when this medicinal product is used in combination with Vipdomet (see section 4.2).
Vipdomet should not be used in combination with a sulphonylurea, as the safety and efficacy of this combination have not been fully established.
As Vipdomet contains metformin, any patient with type 2 diabetes mellitus previously well controlled on Vipdomet who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate and metformin levels. If acidosis of either form occurs, Vipdomet must be stopped immediately and other appropriate corrective measures initiated.
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.
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, Vipdomet should be discontinued; if acute pancreatitis is confirmed, Vipdomet should not be restarted. Caution should be exercised in patients with a history of pancreatitis.
Postmarketing reports of hepatic dysfunction including hepatic failure have been received. A causal relationship has not been established. Patients should be observed closely for possible liver abnormalities. Obtain liver function tests promptly in patients with symptoms suggestive of liver injury. If an abnormality is found and an alternative etiology is not established, consider discontinuation of alogliptin treatment.
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.
Co-administration of 100 mg alogliptin once daily and 1,000 mg metformin hydrochloride twice daily for 6 days in healthy subjects had no clinically relevant effects on the pharmacokinetics of alogliptin or metformin.
Specific pharmacokinetic drug interaction studies have not been performed with Vipdomet. The following section outlines the interactions observed with the individual components of Vipdomet (alogliptin/metformin) as reported in their respective Summary of Product Characteristics.
Alcohol intoxication is associated with an increased risk of lactic acidosis, particularly in case of fasting, malnutrition or hepatic impairment.
Vipdomet must be discontinued prior to or at the time of the imaging procedure and not restarted until at least 48 hours after, provided that renal function has been re-evaluated and found to be stable, see sections 4.2 and 4.4.
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 Cmax 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.
Some medicinal products can adversely affect renal function which may increase the risk of lactic acidosis, e.g. NSAIDs, including selective cyclo-oxygenase (COX) II inhibitors, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists and diuretics, especially loop diuretics. When starting or using such products in combination with metformin, close monitoring of renal function is necessary.
Glucocorticoids (given by systemic and local routes), beta-2-agonists and diuretics (see also section 4.4) 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 Vipdomet should be adjusted during therapy with the other medicinal product and upon its discontinuation.
ACE inhibitors may decrease blood glucose levels. If necessary, the dose of Vipdomet should be adjusted during therapy with the other medicinal product and upon its discontinuation.
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.
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.
Results from studies with metformin, pioglitazone (thiazolidinedione), voglibose (alpha-glucosidase inhibitor) and glyburide (sulphonylurea) have shown no clinically relevant pharmacokinetic interactions.
There are no data from the use of Vipdomet in pregnant women. Studies in pregnant rats with alogliptin plus metformin as combination treatment have shown reproductive toxicity (see section 5.3) at approximately 5-20 times (for metformin and alogliptin respectively) the human exposure at the recommended dose.
Vipdomet should not be used during pregnancy.
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).
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 (see section 5.3).
No studies in lactating animals have been conducted with the combined active substances of Vipdomet. 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 Vipdomet therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
The effect of Vipdomet on fertility in humans has not been studied. No adverse effects on fertility were observed in animal studies conducted with alogliptin or with metformin (see section 5.3).
Vipdomet 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.
Acute pancreatitis is a serious adverse reaction and is attributed to the alogliptin component of Vipdomet (see section 4.4). Hypersensitivity reactions, including Stevens-Johnson syndrome, anaphylactic reactions, and angioedema are serious and are attributed to the alogliptin component of Vipdomet (see section 4.4). Lactic acidosis is a serious adverse reaction, which may occur very rarely (<1/10,000), and is attributed to the metformin component of Vipdomet (see section 4.4). 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) (see section 4.4) which are attributed to Vipdomet.
Clinical studies conducted to support the efficacy and safety of Vipdomet involved the co-administration of alogliptin and metformin as separate tablets. However, the results of bioequivalence studies have demonstrated that Vipdomet 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.
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).
Table 1. Adverse reactions:
| System organ class Adverse reaction | Frequency of adverse reactions | ||
|---|---|---|---|
| Alogliptin | Metformin | Vipdomet | |
| Infections and infestations | |||
| Upper respiratory tract infections | common | common | |
| Nasopharyngitis | common | common | |
| Immune system disorders | |||
| Hypersensitivity | not known | ||
| Metabolism and nutrition disorders | |||
| Lactic acidosis | very rare | ||
| Vitamin B12 deficiency | very rare | ||
| Hypoglycaemia | common | common | |
| Nervous system disorders | |||
| Headache | common | common | |
| Metallic taste | common | ||
| Gastrointestinal disorders | |||
| Gastroenteritis | common | ||
| Abdominal pain | common | very common | common |
| Diarrhoea | common | very common | common |
| Vomiting | very common | common | |
| Gastritis | common | ||
| Gastroesophageal reflux disease | common | common | |
| Loss of appetite | very common | ||
| Nausea | very common | ||
| Acute pancreatitis | not known | ||
| Hepatobiliary disorders | |||
| Hepatitis | very rare | ||
| Liver function test abnormalities | very rare | ||
| Hepatic dysfunction including hepatic failure | not known | ||
| Skin and subcutaneous tissue disorders | |||
| Pruritus | common | very rare | common |
| Rash | common | common | |
| Erythema | very rare | ||
| Exfoliative skin conditions including Stevens- Johnson syndrome | not known | ||
| Erythema multiforme | not known | ||
| Angioedema | not known | ||
| Urticaria | not known | very rare | |
| Bullous pemphigoid | not known | ||
| Renal and urinary disorders | |||
| Interstitial nephritis | not known | ||
Lactic acidosis: 0.03 cases/1,000 patient-years (see section 4.4).
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.
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.
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