Source: Health Products Regulatory Authority (ZA) Revision Year: 2022 Publisher: Novartis South Africa (Pty) Ltd., Magwa Crescent West, Waterfall City, Jukskei View, Johannesburg, 2090
JALRAMET is contraindicated in patients with known hypersensitivity to vildagliptin or metformin hydrochloride or to any of the excipients of JALRAMET.
JALRAMET is contraindicated in patients with severe renal impairment (GFR <30 ml/min) (see section 4.2 and 4.4).
JALRAMET is contraindicated in patients with hepatic impairment, including patients with a pretreatment ALT or AST >2,5 x the upper limit of normal (see section 4.4).
JALRAMET is contraindicated in patients with congestive heart failure requiring pharmacological treatment (see section 4.4).
JALRAMET is contraindicated in patients with acute or chronic metabolic acidosis, including lactic acidosis or diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.
JALRAMET is not a substitute for insulin in patients requiring insulin. JALRAMET should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
If metabolic acidosis is suspected, treatment with JALRAMET should be discontinued and the patient hospitalised immediately (see section 4.9).
JALRAMET should be discontinued if evidence of renal impairment is present.
Alcohol is known to potentiate the effect of metformin hydrochloride on lactate metabolism. Patients should be warned against excessive alcohol intake while receiving metformin containing products (such as JALRAMET).
Alcohol intoxication is associated with an increased risk of lactic acidosis, particularly in cases of fasting, malnutrition or hepatic impairment.
JALRAMET should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function and increase the risk of lactic acidosis. In patients undergoing such studies, JALRAMET should be temporarily discontinued at the time of or prior to the procedure, withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been re-evaluated and found to be normal.
Vildagliptin is not recommended in patients with hepatic impairment, including patients with pretreatment ALT or AST >2,5 x the ULN (see section 4.3).
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 JALRAMET. LFTs should be monitored during JALRAMET treatment 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 liver function tests until the abnormality(ies) return to normal. Should an increase in AST or ALT of 3 x ULN or greater persist, withdrawal of therapy with JALRAMET is recommended. Patients who develop jaundice or other signs suggestive of liver dysfunction should discontinue JALRAMET and contact their physician immediately. Following withdrawal of treatment with JALRAMET and LFT normalisation, JALRAMET should not be reinitiated.
A clinical study of vildagliptin in patients with New York Heart Association (NYHA) functional class I-III showed that treatment with vildagliptin was not associated with a change in left-ventricular function or worsening of pre-existing congestive heart failure (CHF) versus placebo. Clinical experience in patients with NYHA functional class III treated with vildagliptin is still limited and results are inconclusive.
There is no experience of vildagliptin use in clinical studies in patients with NYHA functional class IV and therefore use is not recommended in these patients.
Vildagliptin as contained in JALRAMET may cause arthralgia that can be severe.
Severe cutaneous adverse reactions (SCARs) such as toxic epidermal necrolysis (TEN), StevenJohnson syndrome, erythema multiforme, acute generalised exanthematous pustulosis, erythroderma (generalised exfoliative dermatitis) and pemphigoid have been reported in patients treated with DPP-4 inhibitors including JALRAMET. SCARs are regarded as a class effect of DPP-4 inhibitors such as JALRAMET. If a patient develops SCAR, treatment with DPP-4 inhibitors such as JALRAMET must immediately be discontinued and appropriate treatment instituted. Patients should continue with an alternative class of anti-diabetic medicines.
Rhabdomyolysis has been reported during use of DPP-4 inhibitor containing products such as JALRAMET. However, causality could not be assessed due to confounding factors such as concomitant use of medicines (statins, colchicine, etc.) or co-morbid conditions (Renal failure, hypovolemia, etc.), known to cause or predispose to development of rhabdomyolysis. Close monitoring of patients using DPP-4 inhibitor containing products in presence of predisposing risk factors is recommended.
Lactic acidosis is a serious metabolic complication that most often occurs with acute worsening of renal function, or cardiorespiratory illness or sepsis. Metformin accumulation occurs with acute worsening of renal function and increases the risk of lactic acidosis.
In case of dehydration (e.g. due to severe diarrhoea or vomiting, fever or reduced fluid intake), the patient should stop taking metformin-containing products (such as JALRAMET) and seek immediate medical attention.
Medicinal products that can acutely impair renal function (such as antihypertensives, diuretics and NSAIDs) should be initiated with caution in patients treated with metformin-containing products (such as JALRAMET). Other risk factors for lactic acidosis are excessive alcohol intake, hepatic impairment, 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 section 4.3 and 4.5).
Patients and/or caregivers 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. 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. If metabolic acidosis is suspected, treatment with metformin-containing products (such as JALRAMET) should be discontinued and the patient should be immediately hospitalised.
GFR should be assessed before treatment initiation and regularly thereafter (see section 4.2). Metformin-containing products (such as JALRAMET) are 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).
Metformin hydrochloride is substantially excreted by the kidneys, and the risk of metformin hydrochloride accumulation and lactic acidosis increases with the degree of renal function impairment. Since advancing age is associated with reduced renal function, metformin-containing products (such as JALRAMET) should be carefully titrated in the elderly to establish the minimum dose for adequate glycaemic effect, and renal function should be monitored regularly (see section 4.2).
Concomitant medications that may affect renal function, result in significant haemodynamic change or interfere with the disposition of metformin hydrochloride, such as cationic medicines that are eliminated by renal tubular secretion should be used with caution (see section 4.5).
Cardiovascular collapse (shock), acute congestive heart failure, acute myocardial infarction and other conditions characterized by hypoxaemia have been associated with lactic acidosis and may also cause prerenal uraemia. If such events occur in patients receiving JALRAMET therapy, the medication should be promptly discontinued.
Use of JALRAMET should be temporarily suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient’s oral intake has resumed and renal function has been evaluated as normal.
Since impaired hepatic function has been associated with some cases of lactic acidosis, a risk associated with metformin hydrochloride, metformin-containing products (such as JALRAMET) should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.
The metformin component of JALRAMET has been associated with a decrease in serum vitamin B12 levels without clinical manifestations, in approximately 7% of patients. Such decrease, is very rarely associated with anaemia and appears to be rapidly reversible with discontinuation of metformin hydrochloride and/or vitamin B12 supplementation. Measurement of haematological parameters on at least an annual basis is advised for patients receiving metformin-containing products (such as JALRAMET) and any apparent abnormalities should be appropriately investigated and managed. Certain individuals (e.g. those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. In these patients, routine serum vitamin B12 measurements at minimally two-to-three-year intervals may be useful.
A patient with type 2 diabetes previously well-controlled on JALRAMET who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should promptly be evaluated for ketoacidosis and/or lactic acidosis. If acidosis of either form occurs, JALRAMET must be stopped immediately and appropriate measures initiated.
Hypoglycaemia does not usually occur in patients receiving JALRAMET alone, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or ethanol use. Elderly, debilitated or malnourished patients and those with adrenal or pituitary insufficiency or alcohol intoxication are susceptible to hypoglycaemic effects. Hypoglycaemia may be difficult to recognize in the elderly and in people taking beta-adrenergic blocking medicines.
Hypoglycaemia may occur when JALRAMET is used as add-on therapy to other anti-diabetic medicines.
When a patient stabilised on any diabetic regimen is exposed to stress such as fever, trauma, infection, surgery, etc., a temporary loss of glycaemic control may occur. At such times, it may be necessary to withhold JALRAMET and temporarily administer insulin. JALRAMET may be reinstituted after the acute episode is resolved.
No clinically relevant pharmacokinetic interaction was observed when vildagliptin (100 mg once daily) was co-administered with metformin hydrochloride (1000 mg once daily). Medicine interactions for each component of JALRAMET have been extensively studied. However, the concomitant use of the active substances in patients in clinical studies and in widespread clinical use has not resulted in any unexpected interactions.
The following statements reflect the information available on the individual active substances (vildagliptin and metformin).
Vildagliptin, as contained in JALRAMET, has a low potential for medicine interactions. Since vildagliptin is not a cytochrome P (CYP) 450 enzyme substrate nor does it inhibit nor induces CYP 450 enzymes, it is not likely to interact with co-medications that are substrates, inhibitors or inducers of these enzymes. Furthermore, vildagliptin does not affect metabolic clearance of co-medications metabolised by CYP 1A2, CYP 2C8, CYP 2C9, CYP 2C19, CYP 2D6, CYP 2E1, and CYP 3A4/5. Medicine-medicine interaction studies were conducted with commonly co-prescribed medications for patients with type 2 diabetes or medications with a narrow therapeutic window. As a result of these studies no clinically relevant interactions with other oral antidiabetics (glibenclamide, pioglitazone, and metformin hydrochloride), amlodipine, digoxin, ramipril, simvastatin, valsartan or warfarin were observed after coadministration with vildagliptin.
The following is known about metformin:
Furosemide - Furosemide increased Cmax and blood AUC of metformin with no change in renal clearance of metformin. Metformin decreased Cmax blood AUC of furosemide, with no change in renal clearance of furosemide.
Nifedipine - Nifedipine increased absorption, Cmax and AUC of metformin, and increased excretion of metformin in urine. Metformin had minimal effects on nifedipine.
Glyburide - Glyburide produced no changes in metformin PK/PD parameters. Decreases in Cmax blood AUC of glyburide were observed, but were highly variable. Therefore the clinical significance of this finding was unclear.
Cationic medicines - Cationic medicines (e.g. amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. Thus, with cimetidine increases in metformin plasma/blood concentration and AUC were observed to be 60 % and 40 % respectively. Metformin had no effect on cimetidine PK. Although such interactions remain theoretical (except for cimetidine), careful monitoring of patients and doses of metformin-containing products (such as JALRAMET) and such medications are recommended.
Other - Some medicines 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-containing products (such as JALRAMET), close monitoring of renal function is necessary. Certain medicines tend to cause hyperglycaemia and may lead to loss of glycaemic control. These medicines include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, oestrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking medicines, and isoniazid. Close monitoring of glycaemic control and metformin dose adjustments are recommended when such medicines are administered or withdrawn for these patients.
There is an increased risk of lactic acidosis in acute alcohol intoxication (particularly in the case of fasting, malnutrition or hepatic impairment) due to metformin. Avoid consumption of alcohol and medicinal products containing alcohol (see section 4.4).
Safety in pregnancy has not been established.
Safety in lactation has not been established.
JALRAMET should not be administered to breastfeeding women.
JALRAMET may cause dizziness. Patients who experience dizziness should avoid driving vehicles or using machines.
The data presented here refers to the administration of vildagliptin and metformin as a free or fixed combination.
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 angiotensin converting enzyme inhibitor (ACE-Inhibitor). The majority of events were mild in severity and resolved with ongoing vildagliptin treatment.
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. In data from controlled monotherapy and add-on therapy studies lasting up to 24 weeks in duration, the incidence of ALT or AST elevations ≥3 x 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 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.
In clinical studies with JALRAMET 0,4% of patients withdrew due to adverse reactions in the vildagliptin 50 mg once daily + metformin treatment group, and no withdrawal due to adverse reactions was reported in either the vildagliptin 50 mg bid + metformin or the placebo + metformin treatment groups.
In clinical studies, the incidence of hypoglycaemia was uncommon in patients receiving vildagliptin 50 mg once daily in combination with metformin (0,9%), patients receiving vildagliptin 50 mg twice daily in combination with metformin (0,5%) and in patients receiving placebo and metformin (0,4%). No severe hypoglycaemic events were reported in the vildagliptin arms.
Adverse reactions reported in patients who received vildagliptin in double-blind studies as add-on to metformin and as monotherapy, are listed below, for each indication, by system organ class and absolute frequency. Frequencies are defined as: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000); very rare (<1/10000), including isolated reports. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Table 1. Other adverse reactions reported in patients who received vildagliptin 50 mg once daily (n = 233) or 50 mg twice daily (n = 183) as add-on therapy metformin compared to placebo plus metformin in double-blind studies:
Common: Tremor, dizziness, headache.
Long term clinical studies of up to more than 2 years did not show any additional safety signal or unforeseen risks when vildagliptin was added on to metformin.
When vildagliptin was studied as initial combination therapy with metformin, no additional safety signal or unforeseen risk was observed.
Table 2. Adverse reactions reported in patients who received Galvus (vildagliptin) 50 mg twice daily in combination with insulin (with or without metformin) (n = 371):
Common: Headache
Common: Nausea, gastroesophageal reflux disease
Uncommon: Diarrhoea, flatulence
Common: Chills
Common: Hypoglycaemia
Table 3. Adverse reactions reported in patients who received Galvus (vildagliptin) 50 mg twice daily in combination with metformin and sulphonylurea (with or without metformin) (n = 157):
Common: Dizziness, tremor
Common: Asthenia
Common: Hypoglycaemia
Common: Hyperhidrosis
Adverse reactions for vildagliptin component from monotherapy double blind studies in Table 4.
Table 4. Adverse reactions reported in patients who received vildagliptin 50 mg once daily (n = 409) or 50 mg twice daily (n = 1373) as monotherapy in double-blind studies:
Common: Dizziness
Uncommon: Headache
Uncommon: Constipation
Uncommon: Oedema peripheral
During post-marketing experience the following additional adverse drug reactions have been reported:
Severe cutaneous adverse reactions (SCARs) such as toxic epidermal necrolysis (TEN), Steven-Johnson syndrome, erythema multiforme, acute generalised exanthematous pustulosis, erythroderma (generalised exfoliative dermatitis) and pemphigoid have been reported in patients treated with DPP-4 inhibitors including JALRAMET.
Known adverse reactions for metformin component are summarized in Table 5.
Table 5. Known adverse reactions for metformin:
Very common: Decreased appetite
Very rare: Lactic acidosis
Common: Metallic taste
Very common: Flatulence, nausea, vomiting, diarrhoea, abdominal pain
Very rare: Liver function test abnormalities, hepatitis**
Very rare: Skin reactions such as erythema, pruritus, urticaria
Very rare: Decrease of vitamin B12 absorption*
* A decrease of vitamin B12 absorption with decrease of serum levels has been very rarely observed in patients treated long-term with metformin and appears generally to be without clinical significance. Consideration of such aetiology is recommended if a patient presents with megaloblastic anaemia.
** Isolated cases of liver function test abnormalities or hepatitis resolving upon metformin discontinuation have been reported.
Gastrointestinal adverse effects occur most frequently during initiation of therapy and resolve spontaneously in most cases.
Severe cutaneous adverse reactions (SCARs) such as toxic epidermal necrolysis (TEN), StevenJohnson syndrome, erythema multiforme, acute generalised exanthematous pustulosis, erythroderma (generalised exfoliative dermatitis) and pemphigoid have been reported in patients treated with DPP-4 inhibitors including JALRAMET.
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare providers are asked to report any suspected adverse reactions to SAHPRA via the “6.04 Adverse Drug Reactions Reporting Form”, found online under SAHPRA’s publications: https://www.sahpra.org.za/Publications/Index/8.
Not applicable.
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