SAP-Nr.:

153763_ASchriftgröße:

8.5Punkt

Z-Nr.:

013003-007156-0B01c

Code:L1384

OL

Erstelltam

:10.

September

2003

Auftrags-Num

mer:

075850Zeilenabstand:

8.2Punkt

Druckfarben:

ReflexBlue

Prozent:100

Version:3

/PC2-A

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153763/2

Pakistan/Lantus153763

A

This package insert is continually updated:please read carefully before using a newpack. In case of any question, please con-tact your physician or pharmacist.

®

100 IU/ml( I n s u l i n g l a r g i n e )

CompositionEach ml of the solution for injection contains100 IU of insulin glargine.Excipients: Zinc chloride, m-cresol, glycerol,hydrochloric acid and sodium hydroxide forpH adjustment, and water for injections.

PropertiesPharmaco-therapeutic class: Long-acting insu-lin (A: Insulins and analogues).Lantus is an antidiabetic agent which containsinsulin glargine. Insulin glargine is a humaninsulin analogue designed to have a low solu-bility at neutral pH. At pH 4, insulin glargineinjection solution is completely soluble. Afterinjection into the subcutaneous tissue, theacidic solution is neutralised, leading to theformation of micro-precipitates from whichsmall amounts of insulin glargine are releasedcontinuously, yielding a smooth, peakless, pre-dictable concentration/time profile with a pro-longed duration of action.

In euglycaemic clamp studies in healthy sub-jects or in patients with type 1 diabetes, theonset of action of subcutaneous insulinglargine was slower than with human NPH in-sulin, its effect profile was smooth and peak-less, and the duration of its effect was pro-longed. To illustrate this, the graph belowshows the activity profiles over time of insulinglargine and NPH insulin in patients with type1 diabetes:

* determined as amount of glucose infused to maintainconstant plasma glucose levels (hourly mean values).

The longer duration of action of insulinglargine is directly related to its slower rate ofabsorption and supports once daily adminis-tration. The time course of action of insulinand insulin analogues such as insulin glarginemay vary considerably in different individualsor within the same individual.Insulin glargine has less intra- and inter-indi-vidual variability in pharmacokinetic profilecompared to human ultralente (a slow-acting)insulin.There were no clinically relevant differences inserum insulin levels after abdominal, deltoidor thigh administration of insulin glargine.

When should this drug be used(Therapeutic indications)Diabetes mellitus, where treatment withinsulin is required.

How should this drug be usedStrictly follow the recommended dosage unlessdirected otherwise by the physician.

DosageGiven its prolonged duration of action, Lantusshould be injected once daily every evening.The physician will adjust the dosage individu-ally, and will also give guidance on where toinject Lantus, when blood sugar measure-ments are to be performed and whether urinetests are necessary.The physician may prescribe Lantus witheither a short-acting insulin or an oral anti-diabetic.When changing from a treatment regimenwith an intermediate or a long-acting insulinto a regimen with Lantus, a change of the doseof the basal insulin may be required and theconcomitant antidiabetic treatment may needto be adjusted (dose and timing of additionalshort-acting insulins or fast-acting insulinanalogues or the dose of oral antidiabeticagents).When twice-daily NPH insulin treatment issubstituted with once daily Lantus treatment,the dose should be reduced by approximately20% during the first week of treatment, andthen adjusted based on patient response. Thisreduction should be compensated, at leastpartially, by an increase in mealtime insulin.Thereafter, the dosage should again be ad-justed individually.As with other insulin analogues, patients withhigh insulin doses because of antibodies tohuman insulin may experience an improvedinsulin response with Lantus. Metabolic con-trol, particularly in such patients, should beclosely monitored during the transition and inthe initial weeks thereafter.

With improved metabolic control and result-ant increase in insulin sensitivity, a further ad-justment of the dose may become necessary.Dose adjustment may also be required in con-junction with, e.g., weight or life-style changes,other circumstances which may promote in-creased susceptibility to hypo- or hyperglycae-mia or concomitant illness (see Warnings andprecautions).

AdministrationLantus is given by subcutaneous injection.Within the given injection area, choose a dif-ferent site for each injection.Since its prolonged duration of action is de-pendent on subcutaneous administration,Lantus is NOT INTENDED FOR INTRAVENOUSUSE since it could result in severe hypoglycae-mia.Inspect each vial before use. Only use it if thesolution is clear, colourless, with no solid parti-cles visible and if it is of a water-like consisten-cy. As it is a solution, Lantus requires no re-sus-pension prior to use. Syringes must not con-tain any other medicines or traces thereof.Mixing or dilution with any other product maychange the effectiveness of Lantus or cause itto precipitate and must therefore be avoided.The date of the first withdrawal from the vialshould be noted on the label.

When should this drug not be used(Contraindications)Hypersensitivity to insulin glargine or to any ofthe excipients (see Composition).

Warnings and precautionsGeneralPatients must be instructed in the skills neces-sary for the self-management of diabetes, suchas blood sugar monitoring, proper injectiontechnique, measures for recognising and man-aging reduced or increased blood sugar levels

(hypo- or hyperglycaemia) as described below.In addition, they must learn how to handlespecial situations such as skipped, inadequateor increased insulin doses, inadequate food in-take or missed meals. Moreover, patients andtheir relatives must learn how to recognise thesigns and symptoms of hypo- or hyperglycae-mia, what corrective actions need to be takenand when they must speak with their physi-cian.In the event of insufficient blood sugar controlor a tendency to hypo- or hyperglycaemic epi-sodes, possible underlying factors (such as pa-tient compliance, choice of injection site andproper technique) must be excluded prior toconsidering prescription of a dose adjustment.Due to limited experience the efficacy andsafety of Lantus could not be assessed in chil-dren, in patients with impaired liver functionor in patients with moderate to severe renalimpairment.In patients with renal impairment, insulinrequirements may be diminished due to re-duced insulin metabolism. In the elderly, pro-gressive deterioration of renal function maylead to a steady decrease in insulin require-ments.In patients with severe liver impairment,insulin requirements may be diminished dueto reduced capacity for gluconeogenesis andreduced insulin metabolism.

HypoglycaemiaThe time of occurrence of hypoglycaemia de-pends on the action profile of the insulinsused and may, therefore, change when thetreatment regimen is changed. The likelihoodof hypoglycaemia in conjunction with Lantusis, given its more constant and prolonged ef-

fect, less during the night but greater in theearly morning.Patients in whom hypoglycaemic episodesmight be of particular clinical relevance in-clude those with significant narrowing of thecoronary arteries or of the blood vessels sup-plying the brain (risk of cardiac or cerebralcomplications of hypoglycaemia), or thosewith a certain eye disease related to diabetes(proliferative retinopathy), particularly whennot treated with photocoagulation (risk oftransient blindness). Particular caution shouldbe exercised and intensified blood sugarmonitoring is advisable in such patients.Hypoglycaemia is more likely to occur at thestart of insulin treatment, following transfer toa different insulin preparation, where meta-bolic control is unstable, or in severe kidney orliver diseases.

‘ Symptoms that may indicate the onset ofhypoglycaemia may be:Sweating, clammy skin, anxiety, fast heartbeat, high blood pressure, palpitations andirregular heart beat, chest pain (angina pec-toris). In many patients, these signs and symp-toms often develop before those of a low sugarlevel in the brain. The latter include headache,intense hunger, nausea, vomiting, tiredness,sleepiness, sleep disturbances, restlessness,aggressive behaviour, lapses in concentration,impaired reactions, depression, confusion,speech disturbances (sometimes total loss ofspeech), visual disorders, trembling, paralysis,tingling sensations (paraesthesiae), numbnessand tingling sensations in the area of themouth, dizziness, loss of self-control, inabilityto look after oneself, convulsions, and loss ofconsciousness.

‘ The initial symptoms pointing to the onsetof hypoglycaemia may change, be milder, orbe entirely absent, e.g., in the following cir-cumstances: markedly improved blood sugar

control, slow-developing hypoglycaemia, ad-vanced age, a certain type of nervous disease(autonomic neuropathy), long-standing diabe-tes or concurrent use of other medicines (seeInteractions). In such circumstances, severehypoglycaemia (and even loss of conscious-ness) may develop without the patient notic-ing it. Affected patients should try to keepfamiliar at all times with their individual warn-ing symptoms. More frequent blood sugar test-ing can help to identify mild hypoglycaemicepisodes which otherwise might be over-looked. Patients not confident of recognisingtheir warning symptoms should avoid situa-tions (e.g. driving a car) that might result indanger to themselves or others.‘ Compliance of the patient with the dosageand dietary regimen, correct insulin adminis-tration and awareness of hypoglycaemiasymptoms are essential to reduce the risk ofhypoglycaemia.‘ All factors increasing such risk require par-ticularly close monitoring and may necessitatedose adjustment. These include:– Change in the injection area (e.g. from the

thigh to the upper arm),– Improved insulin sensitivity by, e.g., removal

of stress factors,– Unaccustomed or increased physical activity,_ Concomitant illness (e.g. vomiting, diar-

rhoea),– Inadequate food intake such as: missed or

delayed meals, smaller than usual meals orsuch with less carbohydrate content thannormal (sweet and starchy food), changes indiet,

– Consumption of alcohol,– Certain uncompensated endocrine disorders

such as, e.g., reduced thyroid function oranterior pituitary or adrenocortical insuffi-ciency,

– Concurrent use of other medicines (seeInteractions).

‘ A hypoglycaemic attack can be corrected byimmediately taking sugar, e.g., in the form ofglucose, sugar cubes or sugar-sweetenedbeverages. In this regard, please note that foodor beverages containing artificial sweeteners(e.g. diet foods and drinks) are not suitable.Then, some food having a long-acting blood-sugar-raising effect (e.g. bread) should betaken. If hypoglycaemia comes back again,another 10 to 20 g of sugar should be taken. Ifa hypoglycaemic attack cannot be corrected orif it recurs, speak to a physician immediately.Always carry at least 20 grams of sugar withyou, together with some information identify-ing you as a diabetic. Inability to swallow orunconsciousness will make necessary injec-tions of glucose solution or glucagon (a medi-cine increasing blood sugar), even where thepresence of hypoglycaemia is uncertain.It is advisable to test your blood sugar immedi-ately after taking glucose to check that youreally have hypoglycaemia.The prolonged action of Lantus may delayrecovery from hypoglycaemia.HyperglycemiaHyperglycaemia may occur under certain cir-cumstances. These include:‘ Omission or reduction of injections or de-crease in insulin effectiveness (e.g. due to in-correct storage),‘ Decreased physical activity, stress situations(emotional distress, excitement), injuries, op-erations, feverish illnesses,‘ Concurrent use of other medicines (seeInteractions).Thirst, increased need to pass water, tiredness,dry skin, reddening of the face, loss of appe-tite, low blood pressure, fast heart beat andhigh concentrations of sugar and ketonebodies in the urine may be signs of hypergly-caemia. Stomach pain, fast and deep breath-ing, sleepiness or even loss of consciousness

may be signs of a serious metabolic condition(ketoacidosis) resulting from lack of insulin.Blood sugar testing or tests for ketones in urinemust be carried out as soon as any such symp-toms occur. Severe hyperglycaemia or ketoaci-dosis must always be treated by a physician,normally in a hospital.

Concomitant illnessPlease inform your physician if you are ill,since this situation may necessitate intensifiedmetabolic monitoring and, possibly, furtherspecial measures (e.g., dose adjustment, urinetests for ketones).

Operating a vehicle or performing otherhazardous tasksAs a result, e.g., of hypoglycaemia, hypergly-caemia or visual impairment (see Undesirableeffects), the ability to concentrate and reactmay be affected, possibly constituting a risk insituations where these abilities are of parti-cular importance (e.g. operating a vehicle ormachinery).

OverdoseInsulin overdose may lead to severe and some-times life-threatening hypoglycaemia.Mild episodes of hypoglycaemia can usuallybe treated with oral carbohydrates. Adjust-ments in dosage, meal patterns or physicalactivity may be necessary. More severe epi-sodes with coma, seizure or neurologic impair-ment may be treated with glucagon (intramus-cular or subcutaneous) or concentrated glu-cose solution (intravenous). Sustained carbo-hydrate intake and observation may be neces-sary because hypoglycaemia may recur afterapparent clinical recovery.

InteractionsIn order to avoid possible interactions withother medicines, inform your physician or phar-macist about any other current treatment.Certain medicines affect glucose metabolismand require insulin dose adjustment and par-ticularly close monitoring.‘ An increase in the blood-sugar-loweringeffect and in susceptibility to hypoglycaemiamay occur in concomitant use of, e.g., oralantidiabetics, ACE inhibitors, disopyramide,fibrates, fluoxetine, MAO inhibitors, pentoxi-fylline, propoxyphene, salicylates, or sulfon-amide antibiotics.‘ A decrease in the blood-sugar-loweringeffect may occur in concomitant use of corti-costeroids, danazol, diazoxide, diuretics, glu-cagon, isoniazid, oestrogens and progestogens(e.g. in oral contraceptives), phenothiazinederivatives, somatropin, sympathomimeticagents such as [epinephrine (adrenaline), sal-butamol, terbutaline], or thyroid hormones.‘ Beta-blockers, clonidine, lithium salts oralcohol may either potentiate or weaken theblood-sugar-lowering effect of insulin. Penta-midine may cause hypoglycaemia, sometimesfollowed by hyperglycaemia. Moreover, beta-blockers, in common with other sympatholyticmedicines (e.g., clonidine, guanethidine,reserpine) may weaken or even suppressentirely the warning symptoms of a hypogly-caemic reaction.

Pregnancy and lactationWomen with pre-existing or gestational dia-betes must maintain good metabolic controlduring pregnancy. In the first three months,insulin requirements may decrease and gener-ally increase during the second and thirdtrimesters. Immediately after delivery, insulinrequirements then decrease again rapidly(increased risk of hypoglycaemia). Therefore,careful blood sugar monitoring is essential. Ifyou are pregnant or are planning pregnancy,please inform your physician.Adjustments in dosage and diet may be neces-sary in breast-feeding women.

Undesirable effectsPlease tell your physician or pharmacist, if youexperience any adverse effect with the use ofthis product.‘ Hypoglycaemia (see Warnings and precau-tions) may occur if the insulin dose exceeds therequirement. Hypoglycaemia may lead tounconsciousness and, if severe, may cause aheart attack or brain damage and may be life-threatening.‘ A marked change in blood sugar level maycause temporary visual impairment. Long-term improved glycemic control decreases therisk of progression of diabetic retinopathy.However, intensification of insulin therapywith abrupt improvement in glycemic controlmay be associated with temporary worseningof diabetic retinopathy. In patients with prolif-erative retinopathy, particularly if not treatedwith photocoagulation, severe hypoglycemicepisodes may result in transient loss of vision.‘ Fatty tissue under the skin may shrink orswell (lipoatrophy or lipohypertrophy) at theinjection site and delay insulin absorption andits effect. Selecting a different site for eachinjection may help to reduce or prevent thesereactions. Other reactions may occur at the in-jection site and may also spread into the sur-rounding area. These include reddening, unu-sually intense pain on injection, itching, hives,swelling or inflammation. Such reactionsusually disappear within a few days or weeks.‘ In rare cases, severe allergic reactions toinsulins and their excipients may occur. Thesemay include large-scale skin reactions, severeswelling of skin or mucous membranes(Quincke edema), shortness of breath (bron-chospasm), a fall in blood pressure, and circu-latory collapse (shock). Severe allergic reac-tions may under certain circumstances be-come life-threatening.‘ Other reactionsInsulin administration may cause insulin anti-bodies to form. In clinical studies, antibodiesthat cross-react with human insulin andinsulin glargine were observed with the samefrequency in both NPH and insulin glarginegroups. In rare cases, the presence of suchinsulin antibodies may necessitate dose ad-justment.Rarely, insulin may cause sodium and fluidretention into the tissues (edema), particularlyafter significant improvement of metaboliccontrol in association with intensified insulintherapy.

StorageStore at +2°C to +8°C. Do not freeze. Protectfrom light. Avoid direct contact of the vial withfreezer compartment or freezer packs.Once opened, the vial may be used for up tofour weeks when stored below 25°C and pro-tected from direct heat and light.

Keep out of the reach of children.

Expiry dateDo not use later than the date of expiry.

Presentation1 vial containing 10 ml (1000 IU).

Manufacturer/Marketing Authorization HolderAventis Pharma Deutschland GmbHD-65926 Frankfurt am Main, Germany

Date of issue: June 2002.

SAP-Nr.:

153763_ASchriftgröße:

8.5Punkt

Z-Nr.:

013003-007156-0B01c

Code:L1384

OL

Erstelltam

:10.

September

2003

Auftrags-Num

mer:

075850Zeilenabstand:

8.2Punkt

Druckfarben:

ReflexBlue

Prozent:100

Version:3

/PC2-A

TechnischeFreigabe:

TextFreigabe:

Gesamtfreigabe:

Druckfertig

JaN

ein

153763/3

153763/4