Symptoms
Hypoglycaemia has not been seen with Sophamet hydrochloride doses of up to 85g, although lactic acidosis has occurred in such circumstances. High overdose of Sophamet or concomitant risks may lead to lactic acidosis.
Management
Lactic acidosis is a medical emergency and must be treated in hospital. The most effective method to remove lactate and Sophamet is haemodialysis.
-
- Any type of acute metabolic acidosis (such as lactic acidosis, diabetic ketoacidosis.)
- Severe renal failure (GFR <30 mL/min)
- Acute conditions with the potential to alter renal function such as:
| o dehydration o severe infection o shock |
- Disease which may cause tissue hypoxia (especially acute disease, or worsening of chronic disease) such as:
- Decompensated heart failure o respiratory failure o recent myocardial infarction o shock |
- Hepatic insufficiency, acute alcohol intoxication, alcoholism.
Not applicable.
During treatment initiation, the most common adverse reactions are nausea, vomiting, diarrhoea, abdominal pain and loss of appetite which resolve spontaneously in most cases. To prevent them, it is recommended to take Sophamet in 2 or 3 daily doses and to increase the doses slowly.
Adverse events are which have been associated with Sophamet are given below, listed by system organ class and frequency. Undesirable effects are especially likely to occur at treatment onset or at dose increase.
The following adverse reactions may occur under treatment with Sophamet. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness:
very common (>1/10),
common (>1/100 to <1/10),
uncommon (>1/1000 to<1/100),
rare (>1/10000 to<1/1000),
very rare (<1/10000),
not known (cannot be estimated from the available data).
| System organ class | Frequency | Undesirable effects |
| Metabolism and nutrition disorders | Very rare | Lactic acidosis ( serious metabolic complication, most often occurs at acute worsening of renal function or cardiorespiratory illness or sepsis) |
| Nervous system disorders | Common | Taste disturbance |
| Gastrointestinal disorders | Very common | nausea, vomiting, diarrhoea, abdominal pain and loss of appetite i |
| Hepatobiliary disorders | Very rare | liver function test abnormalities or hepatitisii |
| Skin and subcutaneous tissue disorders | Very rare | Skin reactions such as erythema, pruritus, urticaria |
i) These undesirable effects occur most frequently during initiation of therapy and resolve spontaneously in most cases. To prevent them, it is recommended that Sophamet be taken in 2 or 3 daily doses during or after meals. A slow increase of the dose may also improve gastrointestinal tolerability.
ii) Isolated reports of liver function test abnormalities or hepatitis resolving upon Sophamet discontinuation
Paediatric population
In published and post marketing data and in controlled clinical studies in a limited paediatric population aged 10-16 years treated during 1 year, adverse event reporting was similar in nature and severity to that reported in adults.
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: www.mhra.gov.uk/yellowcard
Non clinical data reveal no special hazard for humans based on conventional studies on safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, reproductive toxicity.
Treatment of type 2 diabetes mellitus, particularly in overweight patients, when dietary management and exercise alone does not result in adequate glycaemic control.
Adults
- In adults, Sophamet hydrochloride may be used as monotherapy or in combination with other oral anti-diabetic agents or with insulin.
A reduction of diabetic complications has been shown in overweight type 2 diabetic adult patients treated with Sophamet as first-line therapy after diet failure.
Paediatric population
- In children from 10 years of age and adolescents, Sophamet hydrochloride may be used as monotherapy or in combination with insulin.
Pharmacotherapeutic group: Blood glucose lowering drugs, Biguanides
ATC Code: A10B A02
Mechanism of action
Sophamet hydrochloride is a biguanide with antihyperglycaemic effects, lowering both basal and postprandial plasma glucose. It does not stimulate insulin secretion and therefore does not produce hypoglycaemia.
Pharmacodynamic effect
Sophamet hydrochloride may act via 3 mechanisms:
(1) reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis (2) in muscle, by increasing insulin sensitivity, improving peripheral glucose uptake and utilisation (3) delay of intestinal glucose absorption.
Sophamet hydrochloride stimulates intracellular glycogen synthesis by acting on glycogen synthase.
Sophamet hydrochloride increases the transport capacity of all types of membrane glucose transporters (GLUT) known to date.
In clinical studies, use of Sophamet was associated with either a stable body weight or modest weight loss.
In humans, independently of its action on glycaemia, Sophamet has favourable effects on lipid metabolism. This has been shown at therapeutic doses in controlled, medium-term or long-term clinical studies: Sophamet hydrochloride reduces total cholesterol, LDL cholesterol and triglyceride levels.
Clinical efficacy and safety:
The prospective randomised (UKPDS) study has established the long-term benefit of intensive blood glucose control in adult patients with type 2 diabetes.
Analysis of the results for overweight patients treated with Sophamet after failure of diet alone showed:
- a significant reduction of the absolute risk of any diabetes-related complication in the Sophamet group (29.8 events/1000 patient-years) versus diet alone (43.3 events/1000 patient-years), p=0.0023, and versus the combined sulphonylurea and insulin monotherapy groups (40.1 events/1000 patient-years), p=0.0034;
- a significant reduction of the absolute risk of diabetes-related mortality: Sophamet 7.5 events/1000 patient-years, diet alone 12.7 events/1000 patient-years, p=0.017;
- a significant reduction of the absolute risk of overall mortality: Sophamet 13.5 events/1000 patient-years versus diet alone 20.6 events/1000 patient-years (p=0.011), and versus the combined sulphonylurea and insulin monotherapy groups 18.9 events/1000 patient-years (p=0.021);
- a significant reduction in the absolute risk of myocardial infarction: Sophamet 11 events/1000 patient-years, diet alone 18 events/1000 patient-years (p=0.01).
Benefit regarding clinical outcome has not been shown for Sophamet used as second-line therapy, in combination with a sulfonylurea.
In type 1 diabetes, the combination of Sophamet hydrochloride and insulin has been used in selected patients, but the clinical benefit of this combination has not been formally established.
Paediatric population
Controlled clinical studies in a limited paediatric population aged 10-16 years treated during 1 year demonstrated a similar response in glycaemic control to that seen in adults.
Absorption:
After an oral dose of Sophamet hydrochloride, Tmax is reached approximately in 2.5 hours. Absolute bioavailability of a 500mg or 850mg Sophamet hydrochloride tablet is approximately 50-60% in healthy subjects. After an oral dose, the non-absorbed fraction recovered in faeces was 20-30%.
After oral administration, Sophamet hydrochloride absorption is saturable and incomplete. It is assumed that the pharmacokinetics of Sophamet absorption is non-linear.
At the recommended Sophamet doses and dosing schedules, steady state plasma concentrations are reached within 24 to 48 hours and are generally less than 1μg/ml. In controlled clinical trials, maximum Sophamet hydrochloride plasma levels (Cmax) did not exceed 5μg/ml, even at maximum doses.
Food decreases the extent and slightly delays the absorption of Sophamet. Following administration of a dose of 850mg, a 40% lower plasma peak concentration, a 25% decrease in AUC (area under the curve) and a 35 minute prolongation of time to peak plasma concentration were observed. The clinical relevance of these findings is unknown.
Distribution:
Plasma protein binding is negligible. Sophamet hydrochloride partitions into erythrocytes. The blood peak is lower than the plasma peak and appears at approximately the same time. The red blood cells most likely represent a secondary compartment of distribution. The mean volume of distribution (Vd) ranged between 63-276L.
Biotransformation:
Sophamet hydrochloride is excreted unchanged in the urine. No metabolites have been identified in humans.
Elimination:
Renal clearance of Sophamet is >400ml/min, indicating that Sophamet is eliminated by glomerular filtration and tubular secretion. Following an oral dose, the apparent terminal elimination half-life is approximately 6.5 hours.
When renal function is impaired, renal clearance is decreased in proportion to that of creatinine and thus the elimination half-life is prolonged, leading to increased levels of Sophamet in plasma.
Characteristics in specific groups of patients
Renal impairment
The available data in subjects with moderate renal insufficiency are scarce and no reliable estimation of the systemic exposure to Sophamet in this subgroup as compared to subjects with normal renal function could be made. Therefore, the dose adaptation should be made upon clinical efficacy/tolerability considerations.
Paediatric population:
Single dose study: After single doses of Sophamet hydrochloride 500mg, paediatric patients have shown similar pharmacokinetic profiles to that observed in healthy adults.
Multiple dose study: Data are restricted to one study. After repeated doses of 500mg twice daily for 7 days, in paediatric patients, the peak plasma concentration (Cmax) and systemic exposure (AUC0-t) were reduced by approximately 33% and 40%, respectively, compared to diabetic adults who received repeated doses of 500mg twice daily for 14 days. As the dose is individually titrated based on glycaemic control, this is of limited clinical relevance.
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. Sophamet accumulation occurs at acute worsening of renal function and increases the risk of lactic acidosis.
Reported cases of lactic acidosis in patients on Sophamet have occurred primarily in diabetic patients with impaired renal failure or acute worsening of renal function. Special caution should be paid to situations where renal function may become impaired, for example in case of dehydration (severe diarrhoea or vomiting, fever or reduced fluid intake), or when initiating antihypertensive therapy or diuretic therapy and when starting therapy with a non-steroidal anti-inflammatory drug (NSAID). In the acute conditions listed, Sophamet should be temporarily discontinued.
Other associated risk factors should be considered to avoid lactic acidosis such as poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, hepatic insufficiency and any condition associated with hypoxia (such as decompensated heart failure, acute myocardial infarction).
The risk of lactic acidosis must be considered in the event of non-specific signs such as muscle cramps, digestive disorders as abdominal pain and severe asthenia. Patients should be instructed to notify these signs immediately to their physicians if they occur, notably if patients had a good tolerance to Sophamet before. Sophamet should be discontinued, at least temporarily, until the situation is clarified. Reintroduction of Sophamet should then be discussed taking into account the benefit/risk ratio in an individual basis as well as renal function.
Diagnosis:
Medicinal products that can acutely impair renal function (such as antihypertensives, diuretics and NSAIDs) should be initiated with caution in Sophamet 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.
Patients and/or care-givers should be informed on the risk of lactic acidosis.
Lactic acidosis is characterised by acidotic dyspnoea, abdominal pain 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. In case of lactic acidosis, the patient should be hospitalised immediately.
Physicians should alert the patients on the risk and on the symptoms of lactic acidosis.
Renal function
As Sophamet is excreted by the kidney, creatinine clearance (this can be estimated from serum creatinine levels by using the Cockcroft-Gault formula) or eGFR should be determined before initiating treatment and regularly thereafter:
- at least annually in patients with normal renal function;
- at least two to four times a year in patients with serum creatinine levels at the lower limit of normal and in elderly subjects.
Decreased renal function in elderly subjects is frequent and asymptomatic. Special caution should be exercised in situations where renal function may become impaired, for example when initiating antihypertensive therapy, diuretic therapy or when starting therapy with a non-steroidal anti-inflammatory drug (NSAID).
In these cases, it is also recommended to check renal function before initiating treatment with Sophamet.
Cardiac function
Patients with heart failure are more at risk of hypoxia and renal insufficiency. In patients with stable chronic heart failure, Sophamet may be used with a regular monitoring of cardiac and renal function.
For patients with acute and unstable heart failure, Sophamet is contraindicated.
Administration of iodinated contrast media
Intravascular administration of iodinated contrast agents may lead to contrast induced nephropathy, resulting in Sophamet accumulation and an increased risk of lactic acidosis.5.
In patients with moderate renal impairment (eGFR between 45 and 60 ml/min/1.73m2), Sophamet must be discontinued 48 hours before administration of iodinated contrast media and not be reinstituted until at least 48 hours afterwards and only after renal function has been re-evaluated and has not deteriorated further.
Surgery
Sophamet 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.
Paediatric population
The diagnosis of type 2 diabetes mellitus should be confirmed before treatment with Sophamet is initiated.
No effect of Sophamet on growth and puberty has been detected during controlled clinical studies of one year duration, but no long term data on these specific points are available. Therefore, a careful follow-up of the effect of Sophamet hydrochloride on these parameters, in Sophamet hydrochloride treated children, especially pre-pubescent children, is recommended.
Children aged between 10 and 12 years:
Only 15 subjects aged between 10 and 12 years were included in the controlled clinical studies conducted in children and adolescents. Although efficacy and safety of Sophamet in these children did not differ from efficacy and safety in older children and adolescents, particular caution is recommended when prescribing to children aged between 10 and 12 years.
Other precautions
All patients should continue their diet with a regular distribution of carbohydrate intake during the day. Overweight patients should continue their energy-restricted diet.
The usual laboratory tests for diabetes monitoring should be performed regularly.
Sophamet hydrochloride alone does not cause hypoglycaemia, but caution is advised when it is used in combination with insulin or other oral antidiabetics (e.g. sulphonylureas or meglitinides).
Excipient warnings
This product contains:
- Sodium methyl and propyl parahydroxybenzoates. These may cause allergic reactions (possibly delayed).
- Liquid maltitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine.
- Sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrose-isomaltase insufficiency should not take this medicine. Sucrose may also be harmful to teeth.
- Sodium - 7mg per 5ml dose. To be taken into consideration by patients on a controlled sodium diet.
- Potassium - 14.5mg per 5ml dose. To be taken into consideration by patients with reduced kidney function or patients on controlled potassium diets.
- Sodium sulphite. This may rarely cause severe hypersensitivity (allergic) reactions and bronchospasm.
- Ethanol. This medicinal product contains small amounts of ethanol (alcohol), less than 100mg per 10ml.
Sophamet has no influence on the ability to drive and use machines.
Sophamet monotherapy does not cause hypoglycaemia and therefore has no effect on the ability to drive or to use machines.
However, patients should be alerted to the risk of hypoglycaemia when Sophamet is used in combination with other antidiabetic agents (e.g. sulphonylureas, insulin, meglitinides).
Posology
Adults (with normal renal function, GFR> 90 mL/min):
Monotherapy and combination with other oral antidiabetic agents:
- The usual starting dose is 500mg (5ml) or 850mg (8.5ml) Sophamet hydrochloride 2 or 3 times daily given during or after meals.
- After 10 to 15 days the dose should be adjusted on the basis of blood glucose measurements. A slow increase of dose may improve gastrointestinal tolerability. In patients receiving a high Sophamet hydrochloride dose (2 to 3 grams per day), it is possible to replace two Sophamet hydrochloride 500mg doses (5ml) with one Sophamet hydrochloride 1000mg (10ml) dose. The maximum recommended dose of Sophamet is 3g (30ml) daily, taken as 3 divided doses.
- If transfer from another oral antidiabetic agent is intended, discontinue the other agent and initiate Sophamet at the dose indicated above.
Combination with insulin:
Sophamet and insulin may be used in combination therapy to achieve better blood glucose control. Sophamet hydrochloride is given at the usual starting dose of 500mg (5ml) or 850mg (8.5ml) 2-3 times daily, while insulin dosage is adjusted on the basis of blood glucose measurements.
Patients with renal impairment
A GFR should be assessed before initiation of treatment with Sophamet 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.
Sophamet may be used in patients with moderate renal impairment, stage 3a (creatinine clearance [CrCl] 45-59 ml/min or estimated glomerular filtration rate [eGFR] 45-59 ml/min/1.73m2) only in the absence of other conditions that may increase the risk of lactic acidosis and with the following dose adjustments:
| GFR mL/min | Total maximum daily dose (to be divided into 2-3 daily doses) | Additional considerations |
| 60-89 | 3000 mg | Dose reduction may be considered in relation to declining renal function. |
| 45-59 | 2000 mg | Factors that may increase the risk of lactic acidosis (see 4.4) should be reviewed before considering initiation of Sophamet. The starting dose is at most half of the maximum dose. |
| 30-44 | 1000 mg | |
| <30 | - | Sophamet is contraindicated. |
Sophamet is contraindicated in patients with severe renal failure (GFR <30 mL/min).
Elderly:
Due to the potential for decreased renal function in elderly subjects, the Sophamet dosage should be adjusted based on renal function. Regular assessment of renal function is necessary.
Paediatric population
Monotherapy and combination with insulin
- Sophamet hydrochloride can be used in children from 10 years of age and adolescents.
- The usual starting dose is 500mg (5ml) or 850mg (8.5ml) once daily, given during meals or after meals.
- After 10 to 15 days the dose should be adjusted on the basis of blood glucose measurements. A slow increase of dose may improve gastrointestinal tolerability. The maximum recommended dose of Sophamet is 2g (20ml) daily, taken as 2 or 3 divided doses.
Method of administration
Sophamet oral solution is for oral administration.
Any unused product or waste material should be disposed of in accordance with local requirements.
