4.5 Interaction with other medicinal products and other forms of interaction
A number of medicinal products influence glucose metabolism and possible interactions should therefore be taken into account by the physician:
The following agents may enhance the hypoglycaemic effect of nateglinide: angiotensin-converting enzyme inhibitors (ACEI), non-steroidal anti-inflammatory agents, salicylates, monoamine oxidase inhibitors, non-selective beta-adrenergic-blocking agents and anabolic hormones (eg. methandrostenolone).
The following agents may reduce the hypoglycaemic effect of nateglinide: diuretics, corticosteroids, and beta2 agonists, somatropin, somatostatin analogues (eg. lanreotide, octreotide), rifampin, phenytoin and St John’s wort.
When these medicinal products - that enhance or reduce the hypoglycaemic effect of nateglinide - are administered to or withdrawn from patients receiving nateglinide, the patient should be observed closely for changes in glycaemic control.
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.
In an interaction trial with sulfinpyrazone, a CYP2C9 inhibitor, a modest increase in nateglinide AUC (~28%) was observed in healthy volunteers, with no changes in the mean Cmax and elimination half‑life. A more prolonged effect and possibly a risk of hypoglycaemia cannot be excluded in patients when nateglinide is co-administered with CYP2C9 inhibitors.
Particular caution is recommended when nateglinide is co-administered with other more potent inhibitors of CYP2C9, (e.g. fluconazole, or gemfibrozil or sulfinpyrazone), or in patients known to be poor metabolisers for CYP2C9.
Interaction studies with a 3A4 inhibitor have not been carried out in vivo.
In vivo, nateglinide has no clinically relevant effect on the pharmacokinetics of medicinal products metabolised by CYP2C9 and CYP3A4. The pharmacokinetics of warfarin (a substrate for CYP3A4 and CYP2C9), diclofenac (a substrate for CYP2C9), and digoxin were unaffected by coadministration with nateglinide. Conversely, these medicinal products had no effect on the pharmacokinetics of nateglinide. Thus, no dosage adjustment is required for digoxin, warfarin or other drugs that are CYP2C9 or CYP3A4 substrates upon coadministration with Starlix. Similarly, there was no clinically significant pharmacokinetic interaction of Starlix with other oral antidiabetic agents such as metformin or glibenclamide.
Nateglinide has shown a low potential for protein displacement in in vitro studies.
4.6 Fertility, pPregnancy and lactation
Pregnancy
Studies 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, is not recommended for use in pregnancy.
Breast-feeding
Nateglinide 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.
4.7 Effects on ability to drive and use machines
The effect of Starlix on the ability to drive or operate machinery has not been studied.
Patients should be advised to take precautions to avoid hypoglycaemia whilst driving or operating machinery. This is particularly important in those who have reduced or absent awareness of the warning signs of hypoglycaemia or have frequent episodes of hypoglycaemia. The advisability of driving should be considered in these circumstances.
4.8 Undesirable effects
Based on the experience with nateglinide and with other hypoglycaemic agents, the following adverse reactions have been seen. Frequencies are defined as: very common (³1/10); common (³>1/100, to <1/10); uncommon (³>1/1,000, to <1/100); rare (³>1/10,000, to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).
Hypoglycaemia
As 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 disorders
Rare: Hypersensitivity reactions such as rash, itching and urticaria.
Metabolism and nutrition disorders
Common: Symptoms suggestive of hypoglycaemia.
Gatrointestinal disorders
Common: Abdominal pain, diarrhoea, dyspepsia, nausea.
Uncommon: Vomiting.
Hepatobiliary disorders
Rare: Elevations in liver enzymes.
Other events
Other 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.
5.2 Pharmacokinetic properties
Absorption and bioavailability
Nateglinide 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 (³ 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.
Distribution
The 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 (97–99%) 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 0.1–10 mg Starlix/ml.
BiotransformationMetabolism
Nateglinide 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 5–6 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.
EliminationExcretion
Nateglinide 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 6–16% 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 effect
When 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.
Sub-populations
Elderly: Age did not influence the pharmacokinetic properties of nateglinide.
Hepatic impairment: The 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 impairment: The systemic availability and half-life of nateglinide in diabetic patients with mild, moderate (creatinine clearance 31–50 ml/min) and severe (creatinine clearance 15–30 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.
5.3 Preclinical safety data
Preclinical Non-clinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to fertility and post-natal development. Nateglinide was not teratogenic in rats. In rabbits, embryonic development was adversely affected and the incidence of gallbladder agenesis or small gallbladder was increased at doses of 300 and 500 mg/kg (approximately 24 and 28 times the human therapeutic exposure with a maximum recommended nateglinide dose of 180 mg, three times daily before meals), but not at 150 mg/kg (approximately 17 times the human therapeutic exposure with a maximum recommended nateglinide dose of 180 mg, three times daily before meals).
9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION
Date of first authorisation: 03 April .04.2001
Date of latestfirst renewal: 03 April .04.2006
10. DATE OF REVISION OF THE TEXT
24 October 2011
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu
