4.1. Therapeutic indications

Vildagliptin/Metformin is indicated as an adjunct to diet and exercise to improve glycaemic control in adults with type 2 diabetes mellitus:

- in patients who are inadequately controlled with metformin hydrochloride alone.

- in patients who are already being treated with the combination of vildagliptin and metformin hydrochloride, as separate tablets.

- in combination with other medicinal products for the treatment of diabetes, including insulin, when these do not provide adequate glycaemic control (see sections 4.4, 4.5 and 5.1 for available data on different combinations).

4.2. Posology and method of administration

Posology

Adults with normal renal function (GFR ≥ 90 ml/min)

The dose of antihyperglycaemic therapy with Vildagliptin/Metformin should be individualised on the basis of the patient's current regimen, effectiveness and tolerability while not exceeding the maximum recommended daily dose of 100 mg vildagliptin. Vildagliptin/Metformin may be initiated at either the 50 mg/850 mg or 50 mg/1000 mg tablet strength twice daily, one tablet in the morning and the other in the evening.

- For patients inadequately controlled at their maximal tolerated dose of metformin monotherapy:

The starting dose of Vildagliptin/Metformin should provide vildagliptin as 50 mg twice daily (100 mg total daily dose) plus the dose of metformin already being taken.

- For patients switching from co-administration of vildagliptin and metformin as separate tablets:

Vildagliptin/Metformin should be initiated at the dose of vildagliptin and metformin already being taken.

- For patients inadequately controlled on dual combination with metformin and a sulphonylurea:

The doses of Vildagliptin/Metformin should provide vildagliptin as 50 mg twice daily (100 mg total daily dose) and a dose of metformin similar to the dose already being taken. When Vildagliptin/Metformin is used in combination with a sulphonylurea, a lower dose of the sulphonylurea may be considered to reduce the risk of hypoglycaemia.

- For patients inadequately controlled on dual combination therapy with insulin and the maximal tolerated dose of metformin:

The dose of Vildagliptin/Metformin should provide vildagliptin dosed as 50 mg twice daily (100 mg total daily dose) and a dose of metformin similar to the dose already being taken.

The safety and efficacy of vildagliptin and metformin as triple oral therapy in combination with a thiazolidinedione have not been established.

Special populations

Elderly (≥ 65 years)

As metformin is excreted via the kidney, and elderly patients have a tendency to decreased renal function, elderly patients taking Vildagliptin/Metformin should have their renal function monitored regularly (see sections 4.4 and 5.2).

Renal impairment

A GFR should be assessed before initiation of treatment with metformin-containing 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 (see section 4.4) should be reviewed before considering initiation of metformin in patients with GFR<60 ml/min.

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

GFR ml/min

Metformin

Vildagliptin

60-89

Maximum daily dose is 3000 mg.

Dose reduction may be considered in relation to declining renal function.

No dose adjustment.

45-59

Maximum daily dose is 2000 mg.

The starting dose is at most half of the maximum dose.

Maximal daily dose is 50 mg.

30-44

Maximum daily dose is 1000 mg.

The starting dose is at most half of the maximum dose.

<30

Metformin is contraindicated.

Hepatic impairment

Vildagliptin/Metformin should not be used in patients with hepatic impairment, including those with pre-treatment alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 times the upper limit of normal (ULN) (see sections 4.3, 4.4 and 4.8).

Paediatric population

Vildagliptin/Metformin is not recommended for use in children and adolescents (< 18 years). The safety and efficacy of Vildagliptin/Metformin in children and adolescents (< 18 years) have not been established. No data are available.

Method of administration

Oral use.

Taking Vildagliptin/Metformin with or just after food may reduce gastrointestinal symptoms associated with metformin (see also section 5.2).

4.3. Contraindications

- Hypersensitivity to the active substances or to any of the excipients listed in section 6.1

- Any type of acute metabolic acidosis (such as lactic acidosis, diabetic ketoacidosis)

- Diabetic pre-coma

- Severe renal failure (GFR < 30 ml/min) (see section 4.4)

- Acute conditions with the potential to alter renal function, such as:

- dehydration,

- severe infection,

- shock,

- intravascular administration of iodinated contrast agents (see section 4.4).

- Acute or chronic disease which may cause tissue hypoxia, such as:

- cardiac or respiratory failure,

- recent myocardial infarction,

- shock.

- Hepatic impairment (see sections 4.2, 4.4 and 4.8)

- Acute alcohol intoxication, alcoholism

- Breast-feeding (see section 4.6)

4.4. Special warnings and precautions for use

The safety and efficacy of amlodipine in hypertensive crisis have not been established.

Pregnancy

Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

Sodium- and/or volume-depleted patients

Excessive hypotension was seen in 0.4% of patients with uncomplicated hypertension treated with amlodipine/valsartan in placebo-controlled studies. In patients with an activated renin-angiotensin system (such as volume- and/or salt-depleted patients receiving high doses of diuretics) who are receiving angiotensin receptor blockers, symptomatic hypotension may occur. Correction of this condition prior to administration of amlodipine/valsartan or close medical supervision at the start of treatment is recommended.

If hypotension occurs with amlodipine/valsartan, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. Treatment can be continued once blood pressure has been stabilised.

Hyperkalaemia

Concomitant use with potassium supplements, potassium-sparing diuretics, salt substitutes containing potassium, or other medicinal products that may increase potassium levels (heparin, etc.) should be undertaken with caution and with frequent monitoring of potassium levels.

Renal artery stenosis

Amlodipine/valsartan should be used with caution to treat hypertension in patients with unilateral or bilateral renal artery stenosis or stenosis to a solitary kidney since blood urea and serum creatinine may increase in such patients.

Kidney transplantation

To date there is no experience of the safe use of amlodipine/valsartan in patients who have had a recent kidney transplantation.

Hepatic impairment

Valsartan is mostly eliminated unchanged via the bile. The half life of amlodipine is prolonged and AUC values are higher in patients with impaired liver function; dosage recommendations have not been established. Particular caution should be exercised when administering amlodipine/valsartan to patients with mild to moderate hepatic impairment or biliary obstructive disorders.

In patients with mild to moderate hepatic impairment without cholestasis, the maximum recommended dose is 80 mg valsartan.

Renal impairment

No dosage adjustment of amlodipine/valsartan is required for patients with mild to moderate renal impairment (GFR >30 ml/min/1.73 m2). Monitoring of potassium levels and creatinine is advised in moderate renal impairment.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism should not be treated with the angiotensin II antagonist valsartan as their renin-angiotensin system is affected by the primary disease.

Angioedema

Angioedema, including swelling of the larynx and glottis, causing airway obstruction and/or swelling of the face, lips, pharynx and/or tongue, has been reported in patients treated with valsartan. Some of these patients previously experienced angioedema with other medicinal products, including ACE inhibitors. Amlodipine/valsartan should be discontinued immediately in patients who develop angioedema and should not be re-administered.

Intestinal angioedema

Intestinal angioedema has been reported in patients treated with angiotensin II receptor antagonists, including valsartan (see section 4.8). These patients presented with abdominal pain, nausea, vomiting and diarrhoea. Symptoms resolved after discontinuation of angiotensin II receptor antagonists. If intestinal angioedema is diagnosed, valsartan should be discontinued and appropriate monitoring should be initiated until complete resolution of symptoms has occurred.

Heart failure/post-myocardial infarction

As a consequence of the inhibition of the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with ACE inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotaemia and (rarely) with acute renal failure and/or death. Similar outcomes have been reported with valsartan. Evaluation of patients with heart failure or post-myocardial infarction should always include assessment of renal function.

In a long-term, placebo-controlled study (PRAISE-2) of amlodipine in patients with NYHA (New York Heart Association Classification) III and IV heart failure of non-ischaemic aetiology, amlodipine was associated with increased reports of pulmonary oedema despite no significant difference in the incidence of worsening heart failure as compared to placebo.

Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure, as they may increase the risk of future cardiovascular events and mortality.

Aortic and mitral valve stenosis

As with all other vasodilators, special caution is indicated in patients suffering from mitral stenosis or significant aortic stenosis that is not high grade.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

There is evidence that the concomitant use of ACE inhibitors, ARBs or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE inhibitors, ARBs or aliskiren is therefore not recommended (see sections 4.5 and 5.1).

If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure. ACE inhibitors and ARBs should not be used concomitantly in patients with diabetic nephropathy.

Amlodipine/valsartan has not been studied in any patient population other than hypertension.

Patients with known or suspected mitochondrial diseases:

In patients with known mitochondrial diseases such as Mitochondrial Encephalopathy with Lactic Acidosis, and Stroke-like episodes (MELAS) syndrome and Maternal inherited diabetes and deafness (MIDD), metformin is not recommended due to the risk of lactic acidosis exacerbation and neurologic complications which may lead to worsening of the disease.

In case of signs and symptoms suggestive of MELAS syndrome or MIDD after the intake of metformin, treatment with metformin should be withdrawn immediately and prompt diagnostic evaluation should be performed.

4.5. Interaction with other medicinal products and other forms of interaction

There have been no formal interaction studies for Vildagliptin/Metformin. The following statements reflect the information available on the individual active substances.

Vildagliptin

Vildagliptin has a low potential for interactions with co-administered medicinal products. Since vildagliptin is not a cytochrome P (CYP) 450 enzyme substrate and does not inhibit or induce CYP 450 enzymes, it is not likely to interact with active substances that are substrates, inhibitors or inducers of these enzymes.

Results from clinical trials conducted with the oral antidiabetics pioglitazone, metformin and glyburide in combination with vildagliptin have shown no clinically relevant pharmacokinetic interactions in the target population.

Drug-drug interaction studies with digoxin (P-glycoprotein substrate) and warfarin (CYP2C9 substrate) in healthy subjects have shown no clinically relevant pharmacokinetic interactions after co-administration with vildagliptin.

Drug-drug interaction studies in healthy subjects were conducted with amlodipine, ramipril, valsartan and simvastatin. In these studies, no clinically relevant pharmacokinetic interactions were observed after co-administration with vildagliptin. However, this has not been established in the target population.

Combination with ACE inhibitors

There may be an increased risk of angioedema in patients concomitantly taking ACE inhibitors. (see section 4.8).

As with other oral antidiabetic medicinal products the hypoglycaemic effect of vildagliptin may be reduced by certain active substances, including thiazides, corticosteroids, thyroid products and sympathomimetics.

Metformin

Combinations not recommended

Alcohol

Alcohol intoxication is associated with an increased risk of lactic acidosis, particularly in cases of fasting, malnutrition or hepatic impairment.

Iodinated contrast agents

Metformin 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).

Combinations requiring precautions for use

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, 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, 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. If necessary, the dosage of Vildagliptin/Metformin may need to be adjusted during concomitant therapy and on its discontinuation.

Angiotensin converting enzyme (ACE) inhibitors may decrease the blood glucose levels. If necessary, the dosage of the antihyperglycaemic medicinal product should be adjusted during therapy with the other medicinal product and on its discontinuation.

Concomitant use of medicinal products that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g. organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors such as ranolazine, vandetanib, dolutegravir and cimetidine) could increase systemic exposure to metformin.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no adequate data from the use of Vildagliptin/Metformin in pregnant women. For vildagliptin studies in animals have shown reproductive toxicity at high doses. For metformin, studies in animals have not shown reproductive toxicity. Studies in animals performed with vildagliptin and metformin have not shown evidence of teratogenicity, but foetotoxic effects at maternotoxic doses (see section 5.3). The potential risk for humans is unknown. Vildagliptin/Metformin should not be used during pregnancy.

Breast-feeding

Studies in animals have shown excretion of both metformin and vildagliptin in milk. It is unknown whether vildagliptin is excreted in human milk, but metformin is excreted in human milk in low amounts. Due to both the potential risk of neonate hypoglycaemia related to metformin and the lack of human data with vildagliptin, Vildagliptin/Metformin should not be used during breast-feeding (see section 4.3).

Fertility

No studies on the effect on human fertility have been conducted for Vildagliptin/Metformin (see section 5.3).

4.7. Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. Patients who may experience dizziness as an adverse reaction should avoid driving vehicles or using machines.

4.8. Undesirable effects

Summary of the safety profile

Safety data were obtained from a total of 6 197 patients exposed to vildagliptin/metformin in randomised placebo‑controlled trials. Of these patients, 3 698 patients received vildagliptin/metformin and 2 499 patients received placebo/metformin.

There have been no therapeutic clinical trials conducted with vildagliptin/metformin. However, bioequivalence of vildagliptin/metformin with co-administered vildagliptin and metformin has been demonstrated (see section 5.2).

The majority of adverse reactions were mild and transient, not requiring treatment discontinuations. No association was found between adverse reactions and age, ethnicity, duration of exposure or daily dose. Vildagliptin use is associated with the risk of development of pancreatitis. Lactic acidosis has been reported following the use of metformin, especially in patients with underlying renal impairment (see section 4.4).

Tabulated list of adverse reactions

Adverse reactions reported in patients who received vildagliptin in double-blind clinical trials as monotherapy and add-on therapies are listed below by system organ class and absolute 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 the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1 Adverse reactions reported in patients who received vildagliptin and metformin (as mono-components or as fixed dose combination), or in combination with other anti-diabetic treatments, in clinical trials and in post-marketing experience

System organ class - adverse reaction

Frequency

Infections and infestations

Upper respiratory tract infection

Common

Nasopharyngitis

Common

Metabolism and nutrition disorders

Hypoglycaemia

Uncommon

Loss of appetite

Uncommon

Decrease of vitamin B12 absorption and lactic acidosis

Very rare*

Nervous system disorders

Dizziness

Common

Headache

Common

Tremor

Common

Metallic taste

Uncommon

Gastrointestinal disorders

Vomiting

Common

Diarrhoea

Common

Nausea

Common

Gastro-oesophageal reflux disease

Common

Flatulence

Common

Constipation

Common

Abdominal pain including upper

Common

Pancreatitis

Uncommon

Hepatobiliary disorders

Hepatitis

Uncommon

Skin and subcutaneous tissue disorders

Hyperhidrosis

Common

Pruritis

Common

Rash

Common

Dermatitis

Common

Erythema

Uncommon

Urticaria

Uncommon

Exfoliative and bullous skin lesions, including bullous pemphigoid

Not known†

Cutaneous vasculitis

Not known†

Musculoskeletal and connective tissue disorders

Arthalgia

Common

Myalgia

Uncommon

General disorders and administration site conditions

Asthenia

Common

Fatigue

Uncommon

Chills

Uncommon

Oedema peripheral

Uncommon

Investigations

Abnormal liver function tests

Uncommon

* Adverse reactions reported in patients who received metformin as monotherapy and that were not observed in patients who received vildalgiptin+metformin fixed dose combination. Refer to summary of product characteristics for metformin for additional information.

† Based on post‑marketing experience.

Description of selected adverse reactions

Vildagliptin

Hepatic impairment

Rare cases of hepatic dysfunction (including hepatitis) have been reported with vildagliptin. In these cases, the patients were generally asymptomatic without clinical sequelae and liver function returned to normal after discontinuation of treatment. In data from controlled monotherapy and add-on therapy trials of up to 24 weeks in duration, the incidence of ALT or AST elevations ≥ 3x ULN (classified as present on at least 2 consecutive measurements or at the final on-treatment visit) was 0.2%, 0.3% and 0.2% for vildagliptin 50 mg once daily, vildagliptin 50 mg twice daily and all comparators, respectively. These elevations in transaminases were generally asymptomatic, non-progressive in nature and not associated with cholestasis or jaundice.

Angioedema

Rare cases of angioedema have been reported on vildagliptin at a similar rate to controls. A greater proportion of cases were reported when vildagliptin was administered in combination with an ACE inhibitor. The majority of events were mild in severity and resolved with ongoing vildagliptin treatment.

Hypoglycaemia

Hypoglycaemia was uncommon when vildagliptin (0.4%) was used as monotherapy in comparative controlled monotherapy studies with an active comparator or placebo (0.2%). No severe or serious events of hypoglycaemia were reported. When used as add-on to metformin, hypoglycaemia occurred in 1% of vildagliptin‑treated patients and in 0.4% of placebo‑treated patients. When pioglitazone was added, hypoglycaemia occurred in 0.6% of vildagliptin‑treated patients and in 1.9% of placebo‑treated patients. When sulphonylurea was added, hypoglycaemia occurred in 1.2% of vildagliptin treated patients and in 0.6% of placebo‑treated patients. When sulphonylurea and metformin were added, hypoglycaemia occurred in 5.1% of vildagliptin‑treated patients and in 1.9% of placebo‑treated patients. In patients taking vildagliptin in combination with insulin, the incidence of hypoglycaemia was 14% for vildagliptin and 16% for placebo.

Metformin

Decrease of vitamin B12 absorption

A decrease in vitamin B12 absorption with decrease in serum levels has been observed very rarely in patients who have been treated with metformin over a long period. Consideration of such aetiology is recommended if a patient presents with megaloblastic anaemia.

Liver function

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

Gastrointestinal disorders

Gastrointestinal adverse reactions occur most frequently during initiation of therapy and resolve spontaneously in most cases. To prevent them, it is recommended that metformin be taken in 2 daily doses during or after meals. A slow increase in the dose may also improve gastrointestinal tolerability.

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

No data are available with regard to overdose of Vildagliptin/Metformin.

Vildagliptin

Information regarding overdose with vildagliptin is limited.

Symptoms

Information on the likely symptoms of overdose with vildagliptin was taken from a rising dose tolerability study in healthy subjects given vildagliptin for 10 days. At 400 mg, there were three cases of muscle pain, and individual cases of mild and transient paraesthesia, fever, oedema and a transient increase in lipase levels. At 600 mg, one subject experienced oedema of the feet and hands, and increases in creatine phosphokinase (CPK), AST, C-reactive protein (CRP) and myoglobin levels. Three other subjects experienced oedema of the feet, with paraesthesia in two cases. All symptoms and laboratory abnormalities resolved without treatment after discontinuation of the study medicinal product.

Metformin

A large overdose of metformin (or co-existing risk of lactic acidosis) may lead to lactic acidosis, which is a medical emergency and must be treated in hospital.

Management

The most effective method of removing metformin is haemodialysis. However, vildagliptin cannot be removed by haemodialysis, although the major hydrolysis metabolite (LAY 151) can. Supportive management is recommended.