Source: European Medicines Agency (EU) Revision Year: 2018 Publisher: Novartis Europharm Limited, Vista Building, Elm Park, Merrion Road, Dublin 4, Ireland
Starlix is contraindicated in patients with:
Nateglinide 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.
Patients with severe renal impairment (see section 5.2) who have not undergone haemodialysis are more susceptible to the glucose-lowering effect of Starlix. Discontinuation should be considered in patients with severe renal impairment who present with potentiation of the hypoglycaemic effect.
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.
Nateglinide should be used with caution in patients with moderate hepatic impairment.
No clinical studies have been conducted in patients with severe hepatic impairment, or in children and adolescents. Treatment is therefore not recommended in these patient groups.
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 (e.g. methandrostenolone).
The following agents may reduce the hypoglycaemic effect of nateglinide: diuretics, corticosteroids, beta2 agonists, somatropin, somatostatin analogues (e.g. lanreotide, octreotide), rifampin, phenytoin and St. John’s Wort (Hypericum perforatum).
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, gemfibrozil or sulfinpyrazone), or in patients known to be poor metabolisers for CYP2C9 substrates.
Interaction studies with a CYP3A4 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.
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, must not be used in pregnancy.
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.
Nateglinide did not impair fertility in male or female rats (see section 5.3).
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. 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.
Based on the experience with nateglinide and with other hypoglycaemic agents, the following adverse reactions have been seen. 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).
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.
Rare: Hypersensitivity reactions such as rash, itching and urticaria.
Common: Symptoms suggestive of hypoglycaemia. Gastrointestinal disorders
Common: Abdominal pain, diarrhoea, dyspepsia, nausea. Uncommon: Vomiting.
Rare: Elevations in liver enzymes.
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.
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 the national reporting system listed in Appendix V.
Not applicable.
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