4.1. Therapeutic indications

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

Method of administration

Oral use.

Taking Vildagliptin/Metformin Krka 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

General

Vildagliptin/Metformin Krka is not a substitute for insulin in insulin-requiring patients and should not be used in patients with type 1 diabetes.

Lactic acidosis

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 or reduced fluid intake), metformin 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 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 of 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 metformin 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.

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.

Administration of iodinated contrast agents

Intravascular administration of iodinated contrast agents may lead to contrast-induced nephropathy, resulting in metformin accumulation and increased risk of lactic acidosis. Metformin 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).

Renal function

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).

Concomitant medicinal products that may affect renal function, result in significant haemodynamic change, or inhibit renal transport and increase metformin systemic exposure, should be used with caution (see section 4.5).

Hepatic impairment

Patients with hepatic impairment, including those with pre-treatment ALT or AST > 3x ULN, should not be treated with Vildagliptin/Metformin Krka (see sections 4.2, 4.3 and 4.8).

Liver enzyme monitoring

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 tests (LFTs) returned to normal after discontinuation of treatment. LFTs should be performed prior to the initiation of treatment with Vildagliptin/Metformin Krka in order to know the patient's baseline value. Liver function should be monitored during treatment with Vildagliptin/Metformin Krka at three-month intervals during the first year and periodically thereafter. Patients who develop increased transaminase levels should be monitored with a second liver function evaluation to confirm the finding and be followed thereafter with frequent LFTs until the abnormality(ies) return(s) to normal. Should an increase in AST or in ALT of 3x ULN or greater persist, withdrawal of Vildagliptin/Metformin Krka therapy is recommended. Patients who develop jaundice or other signs suggestive of liver dysfunction should discontinue Vildagliptin/Metformin Krka.

Following withdrawal of treatment with Vildagliptin/Metformin Krka and LFT normalisation, treatment with Vildagliptin/Metformin Krka should not be re-initiated.

Skin disorders

Skin lesions, including blistering and ulceration have been reported with vildagliptin in extremities of monkeys in non-clinical toxicology studies (see section 5.3). Although skin lesions were not observed at an increased incidence in clinical trials, there was limited experience in patients with diabetic skin complications. Furthermore, there have been post-marketing reports of bullous and exfoliative skin lesions. Therefore, in keeping with routine care of the diabetic patient, monitoring for skin disorders, such as blistering or ulceration, is recommended.

Acute pancreatitis

Use of vildagliptin has been associated with a risk of developing acute pancreatitis. Patients should be informed of the characteristic symptom of acute pancreatitis.

If pancreatitis is suspected, vildagliptin should be discontinued; if acute pancreatitis is confirmed, vildagliptin should not be restarted. Caution should be exercised in patients with a history of acute pancreatitis.

Hypoglycaemia

Sulphonylureas are known to cause hypoglycaemia. Patients receiving vildagliptin in combination with a sulphonylurea may be at risk for hypoglycaemia. Therefore, a lower dose of sulphonylurea may be considered to reduce the risk of hypoglycaemia.

Surgery

Metformin must be discontinued at the time of surgery under general, spinal or epidural anaesthesia. 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.

Sodium

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

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

There have been no formal interaction studies for Vildagliptin/Metformin Krka. 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 coadministration 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 Krka 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 Krka 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 Krka 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 Krka 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 Krka (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 the vildagliptin/metformin combination. However, bioequivalence of vildagliptin/metformin combination 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 studies 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

Pruritus

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

Arthralgia

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 Yellow Card Scheme Website: yellowcard.mhra.gov.uk 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 Krka.

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.