STARLIX 60mg tablets medication leaflet

STARLIX 60 mg film-coated tablets

STARLIX 120 mg film-coated tablets

STARLIX 180 mg film-coated tablets

STARLIX 60 mg film-coated tablets

Each film-coated tablet contains 60 mg nateglinide.

Lactose monohydrate: 141.5 mg per tablet.

STARLIX 120 mg film-coated tablets

Each film-coated tablet contains 120 mg nateglinide.

Lactose monohydrate: 283 mg per tablet.

STARLIX 180 mg film-coated tablets

Each film-coated tablet contains 180 mg nateglinide.

Lactose monohydrate: 214 mg per tablet.

For the full list of excipients, see section 6.1.

Film-coated tablet.

STARLIX 60 mg film-coated tablets60 mg pink, round, bevelled-edge tablets with “STARLIX” marked on one side and “60” on the other.

STARLIX 120 mg film-coated tablets120 mg yellow, ovaloid tablets with “STARLIX” marked on one side and “120” on the other.

STARLIX 180 mg film-coated tablets180 mg red, ovaloid tablets with “STARLIX” marked on one side and “180” on the other.

Nateglinide is indicated for combination therapy with metformin in type 2 diabetic patientsinadequately controlled despite a maximally tolerated dose of metformin alone.

Nateglinide 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’srequirements.

The recommended starting dose is 60 mg three times daily before meals, particularly in patients whoare 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 1-2 hour post-meal glucose.

The recommended maximum daily dose is 180 mg three times daily to be taken before the three mainmeals.

The clinical experience in patients over 75 years of age is limited.

No dose adjustment is necessary in patients with mild to moderate renal impairment. Although there isa 49% decrease in Cmax of nateglinide in dialysis patients, the systemic availability and half-life indiabetic subjects with moderate to severe renal insufficiency (creatinine clearance 15-50 ml/min) wascomparable between renal subjects requiring haemodialysis and healthy subjects. Although safety wasnot compromised in this population dose adjustment may be required in view of low Cmax.

No dose adjustment is necessary for patients with mild to moderate hepatic impairment. As patientswith severe liver disease were not studied, nateglinide is contraindicated in this group.

There are no data available on the use of nateglinide in patients under 18 years of age, and therefore itsuse in this age group is not recommended.

In debilitated or malnourished patients the initial and maintenance dosage should be conservative andcareful titration is required to avoid hypoglycaemic reactions.

Starlix is contraindicated in patients with:

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

- Type 1 diabetes (C-peptide negative)

- Diabetic ketoacidosis, with or without coma

- Pregnancy and breast-feeding (see section 4.6)

- Severe hepatic impairment

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 thosetreated with oral antidiabetic agents (see section 4.8). Elderly, malnourished patients and those withadrenal 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 beincreased by strenuous physical exercise, or ingestion of alcohol.

Patients with severe renal impairment (see section 5.2) who have not undergone haemodialysis aremore susceptible to the glucose-lowering effect of Starlix. Discontinuation should be considered inpatients with severe renal impairment who present with potentiation of the hypoglycaemic effect.

Symptoms of hypoglycaemia (unconfirmed by blood glucose levels) were observed in patients whosebaseline HbA1c was close to the therapeutic target (HbA1c <7.5%).

Combination with metformin is associated with an increased risk of hypoglycaemia compared tomonotherapy.

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 todiscontinue oral hypoglycaemic treatment and replace it with insulin on a temporary basis.

Starlix contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance,total lactase deficiency or of glucose-galactose malabsorption should not take this medicinal product.

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially‘sodium free’.

Nateglinide should be used with caution in patients with moderate hepatic impairment.

Severe hepatic impairment, children and adolescents

No clinical studies have been conducted in patients with severe hepatic impairment, or in children andadolescents. Treatment is therefore not recommended in these patient groups.

A number of medicinal products influence glucose metabolism and possible interactions shouldtherefore be taken into account by the physician.

Combination with ACE-inhibitors, NSAIDs, salicylates, monoamine oxidase inhibitors, non-selectivebeta-adrenergic-blocking agents and anabolic hormones

The following agents may enhance the hypoglycaemic effect of nateglinide: angiotensin-convertingenzyme inhibitors (ACEI), non-steroidal anti-inflammatory agents, salicylates, monoamine oxidaseinhibitors, non-selective beta-adrenergic-blocking agents and anabolic hormones (e.g.

methandrostenolone).

Diuretics, corticosteroids, beta2 agonists, somatropin, somatostatin analogues, rifampin, phenytoin and

St. John’s Wort (Hypericum perforatum)

The following agents may reduce the hypoglycaemic effect of nateglinide: diuretics, corticosteroids,beta2 agonists, somatropin, somatostatin analogues (e.g. lanreotide, octreotide), rifampin, phenytoinand St. John’s Wort (Hypericum perforatum).

When these medicinal products - that enhance or reduce the hypoglycaemic effect of nateglinide - areadministered to or withdrawn from patients receiving nateglinide, the patient should be observedclosely for changes in glycaemic control.

CYP2C9 and CYP3A4 substrates

Data available from both in vitro and in vivo experiments indicate that nateglinide is predominantlymetabolised 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 eliminationhalf-life. A more prolonged effect and possibly a risk of hypoglycaemia cannot be excluded in patientswhen nateglinide is co-administered with CYP2C9 inhibitors.

Particular caution is recommended when nateglinide is co-administered with other more potentinhibitors of CYP2C9 (e.g. fluconazole, gemfibrozil or sulfinpyrazone), or in patients known to bepoor 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 productsmetabolised by CYP2C9 and CYP3A4. The pharmacokinetics of warfarin (a substrate for CYP3A4and CYP2C9), diclofenac (a substrate for CYP2C9), and digoxin were unaffected by coadministrationwith nateglinide. Conversely, these medicinal products had no effect on the pharmacokinetics ofnateglinide. 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 clinicallysignificant pharmacokinetic interaction of Starlix with other oral antidiabetic agents such as metforminor 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 inpregnant women, therefore the safety of Starlix in pregnant women cannot be assessed. Starlix, likeother 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 knownwhether nateglinide is excreted in human milk, the potential for hypoglycaemia in breast-fed infantsmay 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 isparticularly important in those who have reduced or absent awareness of the warning signs ofhypoglycaemia or have frequent episodes of hypoglycaemia. The advisability of driving should beconsidered in these circumstances.

Based on the experience with nateglinide and with other hypoglycaemic agents, the following adversereactions 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); notknown (cannot be estimated from the available data).

As with other antidiabetic agents, symptoms suggestive of hypoglycaemia have been observed afteradministration of nateglinide. These symptoms included sweating, trembling, dizziness, increasedappetite, palpitations, nausea, fatigue, and weakness. These were generally mild in nature and easilyhandled by intake of carbohydrates when necessary. In completed clinical trials, symptoms ofhypoglycaemia were reported in 10.4% with nateglinide monotherapy, 14.5% withnateglinide+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.

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 andplacebo-treated patients.

Post-marketing data revealed very rare cases of erythema multiforme.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

In a clinical study in patients, Starlix was administered in increasing doses up to 720 mg a day for7 days and was well tolerated. There is no experience of an overdose of Starlix in clinical trials.

However, an overdose may result in an exaggerated glucose-lowering effect, with the development ofhypoglycaemic symptoms. Hypoglycaemic symptoms without loss of consciousness or neurologicalfindings should be treated with oral glucose and adjustments in dosage and/or meal patterns. Severehypoglycaemic reactions with coma, seizure or other neurological symptoms should be treated withintravenous glucose. As nateglinide is highly protein-bound, dialysis is not an efficient means ofremoving it from the blood.

Pharmacotherapeutic group: D-phenylalanine derivative, ATC code: A10 BX 03

Nateglinide is an amino acid (phenylalanine) derivative, which is chemically and pharmacologicallydistinct from other antidiabetic agents. Nateglinide is a rapid, short-acting oral insulin secretagogue.

Its effect is dependent on functioning beta cells in the pancreas islets.

Early insulin secretion is a mechanism for the maintenance of normal glycaemic control. Nateglinide,when taken before a meal, restores early or first phase insulin secretion, which is lost in patients withtype 2 diabetes, resulting in a reduction in post-meal glucose and HbA1c.

Nateglinide closes ATP-dependent potassium channels in the beta-cell membrane with characteristicsthat distinguish it from other sulphonylurea receptor ligands. This depolarises the beta cell and leads toan opening of the calcium channels. The resulting calcium influx enhances insulin secretion.

Electrophysiological studies demonstrate that nateglinide has 45-300-fold selectivity for pancreaticbeta cell versus cardiovascular K+

ATP channels.

In type 2 diabetic patients, the insulinotropic response to a meal occurs within the first 15 minutesfollowing an oral dose of nateglinide. This results in a blood-glucose-lowering effect throughout themeal period. Insulin levels return to baseline within 3 to 4 hours, reducing post-mealhyperinsulinaemia.

Nateglinide-induced insulin secretion by pancreatic beta cells is glucose-sensitive, such that lessinsulin is secreted as glucose levels fall. Conversely, the coadministration of food or a glucoseinfusion results in an enhancement of insulin secretion.

In combination with metformin, which mainly affected fasting plasma glucose, the effect ofnateglinide on HbA1c was additive compared to either agent alone.

Nateglinide efficacy was inferior to that of metformin in monotherapy (decrease in HbA1c (%) withmetformin 500 mg three times daily monotherapy: -1.23 [95% CI: -1.48; -0.99] and with nateglinide120 mg three times daily monotherapy -0.90 [95% CI: -1.14; -0.66]).

The efficacy of nateglinide in combination with metformin has been compared to the combination ofgliclazide plus metformin in a 6-month randomised, double-blind trial in 262 patients using asuperiority design. The decrease from baseline in HbA1c was -0.41% in the nateglinide plus metformingroup and -0.57% in the gliclazide plus metformin group (difference 0.17%, [95% CI -0.03, 0.36]).

Both treatments were well tolerated.

An outcome study has not been conducted with nateglinide, therefore the long-term benefits associatedwith improved glycaemic control have not been demonstrated.

Nateglinide is rapidly absorbed following oral administration of Starlix tablets prior to a meal, withmean peak drug concentration generally occurring in less than 1 hour. Nateglinide is rapidly andalmost completely ( 90%) absorbed from an oral solution. Absolute oral bioavailability is estimatedto be 72%.

The steady-state volume of distribution of nateglinide based on intravenous data is estimated to beapproximately 10 litres. In vitro studies show that nateglinide is extensively bound (97-99%) to serumproteins, mainly serum albumin and to a lesser extent alpha1-acid glycoprotein. The extent of serumprotein binding is independent of drug concentration over the test range of 0.1-10 g Starlix/ml.

Nateglinide is extensively metabolised. The main metabolites found in humans result fromhydroxylation 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; onlythe isopropene minor metabolite possesses activity, which is almost as potent as nateglinide. Dataavailable from both in vitro and in vivo experiments indicate that nateglinide is predominantlymetabolised by CYP2C9 with involvement of CYP3A4 to a smaller extent.

Nateglinide and its metabolites are rapidly and completely eliminated. Most of the [14C] nateglinide isexcreted in the urine (83%), with an additional 10% eliminated in the faeces. Approximately 75% ofthe administered [14C] nateglinide is recovered in the urine within six hours post-dose. Approximately6-16% of the administered dose was excreted in the urine as unchanged drug. Plasma concentrationsdecline 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 isno apparent accumulation of nateglinide upon multiple dosing with up to 240 mg three times daily.

In patients with type 2 diabetes who were given Starlix with a dose range of 60 mg to 240 mg beforemeals three times a day for one week, nateglinide showed linear pharmacokinetics for both AUC and

Cmax. Tmax was independent of dose.

Age did not influence the pharmacokinetic properties of nateglinide.

The systemic availability and half-life of nateglinide in non-diabetic subjects with mild to moderatehepatic impairment did not differ to a clinically significant degree from those in healthy subjects.

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 systemicavailability 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 oflow Cmax.

Repeated dosing with 90 mg once daily for 1 to 3 months in diabetic patients with end-stage renaldisease (ESRD) showed pronounced M1 metabolite accumulation up to 1.2 ng/ml despite the reduceddose. M1 concentration decreased markedly after haemodialysis. Although M1 metabolites show onlyslight hypoglycaemic activity (approximately 5 times lower than nateglinide), metaboliteaccumulation might increase the hypoglycaemic effect of the administered dose. Therefore, dosediscontinuation is advisable in patients with severe renal impairment who present with potentiation ofhypoglycaemic effect while on Starlix.

No clinically significant differences in nateglinide pharmacokinetics were observed between men andwomen.

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 peakplasma concentration (tmax). It is recommended that Starlix be administered prior to meals. It is usuallytaken immediately (1 minute) before a meal but may be taken up to 30 minutes before meals.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to fertility andpost-natal development. Nateglinide was not teratogenic in rats. In rabbits, embryonic developmentwas adversely affected and the incidence of gallbladder agenesis or small gallbladder was increased atdoses of 300 and 500 mg/kg (approximately 24 and 28 times the human therapeutic exposure with amaximum recommended nateglinide dose of 180 mg, three times daily before meals), but not at150 mg/kg (approximately 17 times the human therapeutic exposure with a maximum recommendednateglinide dose of 180 mg, three times daily before meals).

STARLIX 60 mg film-coated tablets

Lactose monohydrate

Cellulose, microcrystalline

Povidone

Croscarmellose sodium

Magnesium stearate

Red iron oxide (E172)

Hypromellose

Titanium dioxide (E171)

Talc

Macrogol

Silica, colloidal anhydrous

STARLIX 120 mg film-coated tablets

Lactose monohydrate

Cellulose, microcrystalline

Povidone

Croscarmellose sodium

Magnesium stearate

Yellow iron oxide (E172)

Hypromellose

Titanium dioxide (E171)

Talc

Macrogol

Silica, colloidal anhydrous

STARLIX 180 mg film-coated tablets

Lactose monohydrate

Cellulose, microcrystalline

Povidone

Croscarmellose sodium

Magnesium stearate

Red iron oxide (E172)

Hypromellose

Titanium dioxide (E171)

Talc

Macrogol

Silica, colloidal anhydrous

Not applicable

3 years

Do not store above 30°C.

Store in the original package.

Blisters: PVC/PE/PVDC blisters, backed with a heat-sealable lacquered aluminium foil.

Packs contain 12, 24, 30, 60, 84, 120 and 360 tablets.

Not all pack sizes or tablet strengths may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Novartis Europharm Limited

Vista Building

Elm Park, Merrion Road

Dublin 4

Ireland

STARLIX 60 mg film-coated tablets

EU/1/01/174/001-007

STARLIX 120 mg film-coated tablets

EU/1/01/174/008-014

STARLIX 180 mg film-coated tablets

EU/1/01/174/015-021

Date of first authorisation: 03 April 2001

Date of latest renewal: 24 April 2006

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu