SAP-Nr.: 153763_A Schriftgröße: 8.5 Punkt Z-Nr.: 013003-007156-0B01c Code: L1384 OL Erstellt am: 10. September 2003 Auftrags-Nummer: 075850 Zeilenabstand: 8.2 Punkt Druckfarben: Reflex Blue Prozent: 100 Version: 3 / PC2-A Technische Freigabe: Text Freigabe: Gesamtfreigabe: Druckfertig Ja Nein 153763 /2 Pakistan/Lantus 153763 A This package insert is continually updated: please read carefully before using a new pack. In case of any question, please con- tact your physician or pharmacist. ® 100 IU/ml (Insulin glargine) Composition Each ml of the solution for injection contains 100 IU of insulin glargine. Excipients: Zinc chloride, m-cresol, glycerol, hydrochloric acid and sodium hydroxide for pH adjustment, and water for injections. Properties Pharmaco-therapeutic class: Long-acting insu- lin (A: Insulins and analogues). Lantus is an antidiabetic agent which contains insulin glargine. Insulin glargine is a human insulin analogue designed to have a low solu- bility at neutral pH. At pH 4, insulin glargine injection solution is completely soluble. After injection into the subcutaneous tissue, the acidic solution is neutralised, leading to the formation of micro-precipitates from which small amounts of insulin glargine are released continuously, 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, the onset of action of subcutaneous insulin glargine 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 below shows the activity profiles over time of insulin glargine and NPH insulin in patients with type 1 diabetes: * determined as amount of glucose infused to maintain constant plasma glucose levels (hourly mean values). The longer duration of action of insulin glargine is directly related to its slower rate of absorption and supports once daily adminis- tration. The time course of action of insulin and insulin analogues such as insulin glargine may vary considerably in different individuals or within the same individual. Insulin glargine has less intra- and inter-indi- vidual variability in pharmacokinetic profile compared to human ultralente (a slow-acting) insulin. There were no clinically relevant differences in serum insulin levels after abdominal, deltoid or thigh administration of insulin glargine. When should this drug be used (Therapeutic indications) Diabetes mellitus, where treatment with insulin is required. How should this drug be used Strictly follow the recommended dosage unless directed otherwise by the physician. Dosage Given its prolonged duration of action, Lantus should be injected once daily every evening. The physician will adjust the dosage individu- ally, and will also give guidance on where to inject Lantus, when blood sugar measure- ments are to be performed and whether urine tests are necessary. The physician may prescribe Lantus with either a short-acting insulin or an oral anti- diabetic. When changing from a treatment regimen with an intermediate or a long-acting insulin to a regimen with Lantus, a change of the dose of the basal insulin may be required and the concomitant antidiabetic treatment may need to be adjusted (dose and timing of additional short-acting insulins or fast-acting insulin analogues or the dose of oral antidiabetic agents). When twice-daily NPH insulin treatment is substituted with once daily Lantus treatment, the dose should be reduced by approximately 20% during the first week of treatment, and then adjusted based on patient response. This reduction should be compensated, at least partially, by an increase in mealtime insulin. Thereafter, the dosage should again be ad- justed individually. As with other insulin analogues, patients with high insulin doses because of antibodies to human insulin may experience an improved insulin response with Lantus. Metabolic con- trol, particularly in such patients, should be closely monitored during the transition and in the 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 and precautions). Administration Lantus 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 INTRAVENOUS USE since it could result in severe hypoglycae- mia. Inspect each vial before use. Only use it if the solution 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 may change the effectiveness of Lantus or cause it to precipitate and must therefore be avoided. The date of the first withdrawal from the vial should be noted on the label. When should this drug not be used (Contraindications) Hypersensitivity to insulin glargine or to any of the excipients (see Composition). Warnings and precautions General Patients must be instructed in the skills neces- sary for the self-management of diabetes, such as blood sugar monitoring, proper injection technique, 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 handle special situations such as skipped, inadequate or increased insulin doses, inadequate food in- take or missed meals. Moreover, patients and their relatives must learn how to recognise the signs and symptoms of hypo- or hyperglycae- mia, what corrective actions need to be taken and when they must speak with their physi- cian. In the event of insufficient blood sugar control or a tendency to hypo- or hyperglycaemic epi- sodes, possible underlying factors (such as pa- tient compliance, choice of injection site and proper technique) must be excluded prior to considering prescription of a dose adjustment. Due to limited experience the efficacy and safety of Lantus could not be assessed in chil- dren, in patients with impaired liver function or in patients with moderate to severe renal impairment. In patients with renal impairment, insulin requirements may be diminished due to re- duced insulin metabolism. In the elderly, pro- gressive deterioration of renal function may lead to a steady decrease in insulin require- ments. In patients with severe liver impairment, insulin requirements may be diminished due to reduced capacity for gluconeogenesis and reduced insulin metabolism. Hypoglycaemia The time of occurrence of hypoglycaemia de- pends on the action profile of the insulins used and may, therefore, change when the treatment regimen is changed. The likelihood of hypoglycaemia in conjunction with Lantus is, given its more constant and prolonged ef- fect, less during the night but greater in the early morning. Patients in whom hypoglycaemic episodes might be of particular clinical relevance in- clude those with significant narrowing of the coronary arteries or of the blood vessels sup- plying the brain (risk of cardiac or cerebral complications of hypoglycaemia), or those with a certain eye disease related to diabetes (proliferative retinopathy), particularly when not treated with photocoagulation (risk of transient blindness). Particular caution should be exercised and intensified blood sugar monitoring is advisable in such patients. Hypoglycaemia is more likely to occur at the start of insulin treatment, following transfer to a different insulin preparation, where meta- bolic control is unstable, or in severe kidney or liver diseases. ‘ Symptoms that may indicate the onset of hypoglycaemia may be: Sweating, clammy skin, anxiety, fast heart beat, high blood pressure, palpitations and irregular heart beat, chest pain (angina pec- toris). In many patients, these signs and symp- toms often develop before those of a low sugar level 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 of speech), visual disorders, trembling, paralysis, tingling sensations (paraesthesiae), numbness and tingling sensations in the area of the mouth, dizziness, loss of self-control, inability to look after oneself, convulsions, and loss of consciousness. ‘ The initial symptoms pointing to the onset of hypoglycaemia may change, be milder, or be 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 (see Interactions). In such circumstances, severe hypoglycaemia (and even loss of conscious- ness) may develop without the patient notic- ing it. Affected patients should try to keep familiar at all times with their individual warn- ing symptoms. More frequent blood sugar test- ing can help to identify mild hypoglycaemic episodes which otherwise might be over- looked. Patients not confident of recognising their warning symptoms should avoid situa- tions (e.g. driving a car) that might result in danger to themselves or others. ‘ Compliance of the patient with the dosage and dietary regimen, correct insulin adminis- tration and awareness of hypoglycaemia symptoms are essential to reduce the risk of hypoglycaemia. ‘ All factors increasing such risk require par- ticularly close monitoring and may necessitate dose 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 or such with less carbohydrate content than normal (sweet and starchy food), changes in diet, – Consumption of alcohol, – Certain uncompensated endocrine disorders such as, e.g., reduced thyroid function or anterior pituitary or adrenocortical insuffi- ciency, – Concurrent use of other medicines (see Interactions). ‘ A hypoglycaemic attack can be corrected by immediately taking sugar, e.g., in the form of glucose, sugar cubes or sugar-sweetened beverages. In this regard, please note that food or 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 be taken. If hypoglycaemia comes back again, another 10 to 20 g of sugar should be taken. If a hypoglycaemic attack cannot be corrected or if it recurs, speak to a physician immediately. Always carry at least 20 grams of sugar with you, together with some information identify- ing you as a diabetic. Inability to swallow or unconsciousness will make necessary injec- tions of glucose solution or glucagon (a medi- cine increasing blood sugar), even where the presence of hypoglycaemia is uncertain. It is advisable to test your blood sugar immedi- ately after taking glucose to check that you really have hypoglycaemia. The prolonged action of Lantus may delay recovery from hypoglycaemia. Hyperglycemia Hyperglycaemia 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 (see Interactions). Thirst, increased need to pass water, tiredness, dry skin, reddening of the face, loss of appe- tite, low blood pressure, fast heart beat and high concentrations of sugar and ketone bodies 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 urine must 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 illness Please inform your physician if you are ill, since this situation may necessitate intensified metabolic monitoring and, possibly, further special measures (e.g., dose adjustment, urine tests for ketones). Operating a vehicle or performing other hazardous tasks As a result, e.g., of hypoglycaemia, hypergly- caemia or visual impairment (see Undesirable effects), the ability to concentrate and react may be affected, possibly constituting a risk in situations where these abilities are of parti- cular importance (e.g. operating a vehicle or machinery). Overdose Insulin overdose may lead to severe and some- times life-threatening hypoglycaemia. Mild episodes of hypoglycaemia can usually be treated with oral carbohydrates. Adjust- ments in dosage, meal patterns or physical activity 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 after apparent clinical recovery. Interactions In order to avoid possible interactions with other medicines, inform your physician or phar- macist about any other current treatment. Certain medicines affect glucose metabolism and require insulin dose adjustment and par- ticularly close monitoring. ‘ An increase in the blood-sugar-lowering effect and in susceptibility to hypoglycaemia may occur in concomitant use of, e.g., oral antidiabetics, ACE inhibitors, disopyramide, fibrates, fluoxetine, MAO inhibitors, pentoxi- fylline, propoxyphene, salicylates, or sulfon- amide antibiotics. ‘ A decrease in the blood-sugar-lowering effect may occur in concomitant use of corti- costeroids, danazol, diazoxide, diuretics, glu- cagon, isoniazid, oestrogens and progestogens (e.g. in oral contraceptives), phenothiazine derivatives, somatropin, sympathomimetic agents such as [epinephrine (adrenaline), sal- butamol, terbutaline], or thyroid hormones. ‘ Beta-blockers, clonidine, lithium salts or alcohol may either potentiate or weaken the blood-sugar-lowering effect of insulin. Penta- midine may cause hypoglycaemia, sometimes followed by hyperglycaemia. Moreover, beta- blockers, in common with other sympatholytic medicines (e.g., clonidine, guanethidine, reserpine) may weaken or even suppress entirely the warning symptoms of a hypogly- caemic reaction. Pregnancy and lactation Women with pre-existing or gestational dia- betes must maintain good metabolic control during pregnancy. In the first three months, insulin requirements may decrease and gener- ally increase during the second and third trimesters. Immediately after delivery, insulin requirements then decrease again rapidly (increased risk of hypoglycaemia). Therefore, careful blood sugar monitoring is essential. If you are pregnant or are planning pregnancy, please inform your physician. Adjustments in dosage and diet may be neces- sary in breast-feeding women. Undesirable effects Please tell your physician or pharmacist, if you experience any adverse effect with the use of this product. ‘ Hypoglycaemia (see Warnings and precau- tions) may occur if the insulin dose exceeds the requirement. Hypoglycaemia may lead to unconsciousness and, if severe, may cause a heart attack or brain damage and may be life- threatening. ‘ A marked change in blood sugar level may cause temporary visual impairment. Long- term improved glycemic control decreases the risk of progression of diabetic retinopathy. However, intensification of insulin therapy with abrupt improvement in glycemic control may be associated with temporary worsening of diabetic retinopathy. In patients with prolif- erative retinopathy, particularly if not treated with photocoagulation, severe hypoglycemic episodes may result in transient loss of vision. ‘ Fatty tissue under the skin may shrink or swell (lipoatrophy or lipohypertrophy) at the injection site and delay insulin absorption and its effect. Selecting a different site for each injection may help to reduce or prevent these reactions. 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 reactions usually disappear within a few days or weeks. ‘ In rare cases, severe allergic reactions to insulins and their excipients may occur. These may include large-scale skin reactions, severe swelling 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 reactions Insulin administration may cause insulin anti- bodies to form. In clinical studies, antibodies that cross-react with human insulin and insulin glargine were observed with the same frequency in both NPH and insulin glargine groups. In rare cases, the presence of such insulin antibodies may necessitate dose ad- justment. Rarely, insulin may cause sodium and fluid retention into the tissues (edema), particularly after significant improvement of metabolic control in association with intensified insulin therapy. Storage Store at + 2°C to + 8°C. Do not freeze. Protect from light. Avoid direct contact of the vial with freezer compartment or freezer packs. Once opened, the vial may be used for up to four weeks when stored below 25°C and pro- tected from direct heat and light. Keep out of the reach of children. Expiry date Do not use later than the date of expiry. Presentation 1 vial containing 10 ml (1000 IU). Manufacturer/Marketing Authorization Holder Aventis Pharma Deutschland GmbH D-65926 Frankfurt am Main, Germany Date of issue: June 2002.