Summary of Product Characteristics Updated 29-Jun-2015 | Novartis Pharmaceuticals UK Ltd
Excipient with known effect:Lactose monohydrate: 283 mg per tablet.For the full list of excipients, see section 6.1.
PosologyNateglinide should be taken within 1 to 30 minutes before meals (usually breakfast, lunch and dinner).The dosage of nateglinide should be determined by the physician according to the patient's requirements.The recommended starting dose is 60 mg three times daily before meals, particularly in patients who are near goal HbA1c. This may be increased to 120 mg three times daily.Dose adjustments should be based on periodic glycosylated haemoglobin (HbA1c) measurements. Since the primary therapeutic effect of Starlix is to reduce mealtime glucose, (a contributor to HbA1c), the therapeutic response to Starlix may also be monitored with 12 hour post-meal glucose.The recommended maximum daily dose is 180 mg three times daily to be taken before the three main meals.Special populations ElderlyThe clinical experience in patients over 75 years of age is limited.
Paediatric populationThere are no data available on the use of nateglinide in patients under 18 years of age, and therefore its use in this age group is not recommended.
Patients with hepatic impairmentNo dose adjustment is necessary for patients with mild to moderate hepatic impairment. As patients with severe liver disease were not studied, nateglinide is contraindicated in this group.
Patients with renal impairmentNo dose adjustment is necessary in patients with mild to moderate renal impairment. Although there is a 49% decrease in Cmax of nateglinide in dialysis patients, the systemic availability and half-life in diabetic subjects with moderate to severe renal insufficiency (creatinine clearance 1550 ml/min) was comparable between renal subjects requiring haemodialysis and healthy subjects. Although safety was not compromised in this population dose adjustment may be required in view of low Cmax.
OthersIn debilitated or malnourished patients the initial and maintenance dosage should be conservative and careful titration is required to avoid hypoglycaemic reactions.
GeneralNateglinide should not be used in monotherapy.Like other insulin secretagogues, nateglinide is capable of producing hypoglycaemia.Hypoglycaemia has been observed in patients with type 2 diabetes on diet and exercise, and in those treated with oral antidiabetic agents (see section 4.8). Elderly, malnourished patients and those with adrenal or pituitary insufficiency or severe renal impairment are more susceptible to the glucose-lowering effect of these treatments. The risk of hypoglycaemia in type 2 diabetic patients may be increased by strenuous physical exercise, or ingestion of alcohol.Symptoms of hypoglycaemia (unconfirmed by blood glucose levels) were observed in patients whose baseline HbA1c was close to the therapeutic target (HbA1c <7.5%).Combination with metformin is associated with an increased risk of hypoglycaemia compared to monotherapy.Hypoglycaemia may be difficult to recognise in subjects receiving beta blockers.When a patient stabilised on any oral hypoglycaemic agent is exposed to stress such as fever, trauma, infection or surgery, a loss of glycaemic control may occur. At such times, it may be necessary to discontinue oral hypoglycaemic treatment and replace it with insulin on a temporary basis.Starlix contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, of the Lapp lactase deficiency or of glucose-galactose malabsorption should not take this medicine.
Special populationsNateglinide should be used with caution in patients with moderate hepatic impairment.No clinical studies have been conducted in patients with severe hepatic impairment or children and adolescents. Treatment is therefore not recommended in these patient groups.
PregnancyStudies in animals have shown developmental toxicity (see section 5.3). There is no experience in pregnant women, therefore the safety of Starlix in pregnant women cannot be assessed. Starlix, like other oral antidiabetic agents, must not be used in pregnancy.
Breast-feedingNateglinide is excreted in the milk following a peroral dose to lactating rats. Although it is not known whether nateglinide is excreted in human milk, the potential for hypoglycaemia in breast-fed infants may exist and therefore nateglinide should not be used in lactating women.
HypoglycaemiaAs with other antidiabetic agents, symptoms suggestive of hypoglycaemia have been observed after administration of nateglinide. These symptoms included sweating, trembling, dizziness, increased appetite, palpitations, nausea, fatigue, and weakness. These were generally mild in nature and easily handled by intake of carbohydrates when necessary. In completed clinical trials, symptoms of hypoglycaemia were reported in 10.4% with nateglinide monotherapy, 14.5% with nateglinide+metformin combination, 6.9% with metformin alone, 19.8% with glibenclamide alone, and 4.1% with placebo.
Immune system disordersRare: Hypersensitivity reactions such as rash, itching and urticaria.
Metabolism and nutrition disordersCommon: Symptoms suggestive of hypoglycaemia.
Gastrointestinal disordersCommon: Abdominal pain, diarrhoea, dyspepsia, nausea.Uncommon: Vomiting.
Hepatobiliary disordersRare: Elevations in liver enzymes.
Other eventsOther adverse events observed in clinical studies were of a similar incidence in Starlix-treated and placebo-treated patients.Post-marketing data revealed very rare cases of erythema multiforme.
Reporting of suspected adverse reactionsReporting 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.
AbsorptionNateglinide is rapidly absorbed following oral administration of Starlix tablets prior to a meal, with mean peak drug concentration generally occurring in less than 1 hour. Nateglinide is rapidly and almost completely (≥ 90%) absorbed from an oral solution. Absolute oral bioavailability is estimated to be 72%. In type 2 diabetic patients given Starlix over the dose range 60 to 240 mg before three meals per day for one week, nateglinide showed linear pharmacokinetics for both AUC and Cmax, and tmax was independent of dose.
DistributionThe steady-state volume of distribution of nateglinide based on intravenous data is estimated to be approximately 10 litres. In vitro studies show that nateglinide is extensively bound (9799%) to serum proteins, mainly serum albumin and to a lesser extent alpha1-acid glycoprotein. The extent of serum protein binding is independent of drug concentration over the test range of 0.110 μg Starlix/ml.
BiotransformationNateglinide is extensively metabolised. The main metabolites found in humans result from hydroxylation of the isopropyl side-chain, either on the methine carbon, or one of the methyl groups; activity of the main metabolites is about 56 and 3 times less potent than nateglinide, respectively. Minor metabolites identified were a diol, an isopropene and acyl glucuronide(s) of nateglinide; only the isopropene minor metabolite possesses activity, which is almost as potent as nateglinide. Data available from both in vitro and in vivo experiments indicate that nateglinide is predominantly metabolised by CYP2C9 with involvement of CYP3A4 to a smaller extent.
EliminationNateglinide and its metabolites are rapidly and completely eliminated. Most of the [14C] nateglinide is excreted in the urine (83%), with an additional 10% eliminated in the faeces. Approximately 75% of the administered [14C] nateglinide is recovered in the urine within six hours post-dose. Approximately 616% of the administered dose was excreted in the urine as unchanged drug. Plasma concentrations decline rapidly and the elimination half-life of nateglinide typically averaged 1.5 hours in all studies of Starlix in volunteers and type 2 diabetic patients. Consistent with its short elimination half-life, there is no apparent accumulation of nateglinide upon multiple dosing with up to 240 mg three times daily.
Food effectWhen given post-prandially, the extent of nateglinide absorption (AUC) remains unaffected. However, there is a delay in the rate of absorption characterised by a decrease in Cmax and a delay in time to peak plasma concentration (tmax). It is recommended that Starlix be administered prior to meals. It is usually taken immediately (1 minute) before a meal but may be taken up to 30 minutes before meals.
ElderlyAge did not influence the pharmacokinetic properties of nateglinide.
Hepatic impairmentThe systemic availability and half-life of nateglinide in non-diabetic subjects with mild to moderate hepatic impairment did not differ to a clinically significant degree from those in healthy subjects.
Renal impairmentThe systemic availability and half-life of nateglinide in diabetic patients with mild, moderate (creatinine clearance 3150 ml/min) and severe (creatinine clearance 1530 ml/min) renal impairment (not undergoing dialysis) did not differ to a clinically significant degree from those in healthy subjects. There is a 49% decrease in Cmax of nateglinide in dialysis-dependent diabetic patients. The systemic availability and half-life in dialysis-dependent diabetic patients was comparable with healthy subjects. Although safety was not compromised in this population dose adjustment may be required in view of low Cmax.Gender No clinically significant differences in nateglinide pharmacokinetics were observed between men and women.