Lantus

Insulin glargine.

Lantus also contains the following excipients: Zinc chloride, m-cresol, glycerol, hydrochloric acid and sodium hydroxide for pH adjustment and water for injections.

Pharmacotherapeutic Group: Long-acting insulins (A: Insulins and analogues).
Pharmacology: Pharmacodynamics: Lantus is an antidiabetic agent, which contains insulin glargine. Insulin glargine is a human insulin analogue designed to have a low solubility 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 microprecipitates from which small amounts of insulin glargine are released continuously, yielding a smooth, peakless, predictable concentration/time profile with a prolonged duration of action.
Insulin glargine is metabolised into 2 active metabolites M1 and M2 (see Pharmacokinetics: Metabolism as follows).
Insulin Receptor Binding: In vitro studies indicate that the affinity of insulin glargine and its metabolites M1 and M2 for the human insulin receptor is similar to the 1 of human insulin.
IGF-1 Receptor Binding: The affinity of insulin glargine for the human IGF-1 receptor is approximately 5- to 8-fold greater than that of human insulin (but approximately 70- to 80-fold lower than the one of IGF-1), whereas M1 and M2 bind the IGF-1 receptor with slightly lower affinity compared to human insulin.
The total therapeutic insulin concentration (insulin glargine and its metabolites) found in type 1 diabetic patients was markedly lower than what would be required for a half-maximal occupation of the IGF-1 receptor and the subsequent activation of the mitogenic-proliferative pathway initiated by the IGF-1 receptor. Physiological concentrations of endogenous IGF-1 may activate the mitogenic-proliferative pathway; however, the therapeutic concentrations found in insulin therapy, including in Lantus therapy, are considerably lower than the pharmacological concentrations required to activate the IGF-1 pathway.
In euglycaemic clamp studies in healthy subjects or in patients with type 1 diabetes, the onset of action of SC insulin glargine was slower than with human NPH insulin, its effect profile was smooth and peakless and the duration of its effect was prolonged. The following graph shows the activity profiles over time of insulin glargine and NPH insulin in patients with type 1 diabetes: See figure.

Click on icon to see table/diagram/image

The longer duration of action of insulin glargine is directly related to its slower rate of absorption and supports once-daily administration. The time course of action of insulin and insulin analogues eg, insulin glargine may vary considerably in different individuals or within the same individual.
There were no clinically relevant differences in serum insulin levels after abdominal, deltoid or thigh administration of insulin glargine.
Clinical Efficacy: Type 1 Paediatric Diabetes (1-6 Years): A 24-week parallel group study was conducted in 125 children with type 1 diabetes mellitus 1-6 years (61 children from 2-5 in the insulin glargine group and 64 children from 1-6 in the NPH insulin group), comparing insulin glargine given once daily in the morning to NPH insulin given once or twice daily as basal insulin. Both groups received bolus insulin before meals.
Comparison of the 2 treatment regimens in terms of hypoglycemia was the primary objective of the study. The composite primary outcome consisted of continuous glucose monitoring excursions below 70 mg/dL (3.9 mM), confirmed by fingerstick blood glucose (FSBG) measurements; other FSBG measurements <70 mg/dL; and episodes of symptomatic hypoglycemia. Overall, the event rate ratio of this composite outcome for once daily Lantus compared to NPH (given twice daily in most patients) was 1.18 (95% CI: 0.97-1.44), therefore, not meeting the non-inferiority margin of 1.15.
The rate of symptomatic hypoglycemia events is the most commonly used and clinically relevant component of the composite outcome. Rates of symptomatic hypoglycemia events were numerically lower in the insulin glargine group, both overall (25.5 episodes per patient-year vs 33 for NPH) and overnight (2.38 episodes per patient-year vs 3.65 for NPH).
Glycohaemoglobin and glucose variabilities were comparable in both treatment groups. No new safety signals were observed in this trial.
Pharmacokinetics: Distribution: After SC injection of insulin glargine in healthy subjects and diabetic patients, the insulin serum concentrations indicated a slower and much more prolonged absorption and a lack of a peak in comparison to human NPH insulin. Concentrations were, thus, consistent with the time profile of the pharmacodynamic activity of insulin glargine.
After SC injection of 0.3 units/kg insulin glargine in diabetic patients, a concentration-time profile without pronounced peak as compared to NPH-insulin has been observed.
When given IV, the concentration profiles and the apparent elimination half-life of insulin glargine and human insulin were comparable.
Metabolism: After SC injection of Lantus in healthy subjects and diabetic patients, insulin glargine is rapidly metabolized at the carboxyl terminus of the β-chain with formation of 2 active metabolites M1 (21A-Gly-insulin) and M2 (21A-Gly-des-30B-Thr-insulin). In plasma, the principal circulating compound is the metabolite M1. The exposure to M1 increases with the administered dose of Lantus. The pharmacokinetic and pharmacodynamic findings indicate that the effect of the SC injection with Lantus is principally based on exposure to M1. Insulin glargine and the metabolite M2 were not detectable in the vast majority of subjects and, when they were detectable their concentration was independent of the administered dose of Lantus.
Diabetic Retinopathy: Effects of insulin glargine on diabetic retinopathy were evaluated in a large 5-year NPH controlled study in which progression of retinopathy was investigated by fundus photography using a grading protocol derived from the early treatment diabetic retinopathy study (ETDRS). The primary outcome in this study was progression by 3 or more steps on the ETDRS scale at study endpoint. The results of this analysis are shown in the table below for both the per-protocol (primary) and intent-to-treat (ITT) populations and indicate noninferiority of insulin glargine to NPH in the progression of diabetic retinopathy as assessed by this outcome. See table.

Click on icon to see table/diagram/image

Special Populations: Children : Pharmacokinetics in children 2 to <6 years with type 1 diabetes mellitus was assessed in 1 clinical study (see previous text on Pharmacodynamics). Plasma “trough” levels of insulin glargine and its main metabolites M1 and M2 were measured in children treated with insulin glargine, revealing plasma concentration patterns similar to adults and providing no evidence for accumulation of insulin glargine or its metabolites with chronic dosing.

Treatment of adults, adolescents and children ≥2 years with diabetes mellitus, where treatment with insulin is required.

Strictly follow the recommended dosage unless otherwise directed by the physician.
Given its prolonged duration of action, Lantus should be injected once daily at the same time everyday. The physician will adjust the dosage individually and will also give guidance on where to inject Lantus, when blood sugar measurements are to be performed and whether urine tests are necessary. The physician may prescribe Lantus with either a short-acting insulin or an oral antidiabetic.
When changing from a treatment regimen with an intermediate or another 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 initial dose should be reduced by approximately 20% (compared to total daily iu of NPH insulin), 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 adjusted 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 control, particularly in such patients, should be closely monitored during the transition and in the initial weeks thereafter.
With improved metabolic control and resultant increase in insulin sensitivity (reduced insulin requirements), further adjustment of the doses of Lantus and other insulins or oral antidiabetic agents in the regimen may become necessary. Dose adjustment may also be required in conjunction with eg, weight or lifestyle changes, change of timing of insulin dose or other circumstances which may promote increased susceptibility to hypo- or hyperglycaemia or concomitant illness (see Precautions). Any change of insulin dose should be made under medical supervision.
Children: Lantus can be administrated to children ≥2 years. Administration to children <2 years has not been studied.
Administration: Vial: Lantus is given by SC injection. Within the given injection area, choose a different site for each injection.
Since its prolonged duration of action is dependent on SC administration, Lantus is not intended for IV use since it could result in severe hypoglycaemia.
Inspect each vial before use. Use only if the solution is clear, colorless, with no solid particles visible and if it is of a water-like consistency. As it is a solution, Lantus requires no resuspension prior to use. Syringes must not contain 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 1st withdrawal should be noted on the label.
SoloStar: Lantus is administered SC. It should not be administered IV. The prolonged duration of action of Lantus is dependent on its injection into subcutaneous tissue. IV administration of the usual SC dose could result in severe hypoglycaemia.
There are no clinically relevant differences in serum insulin or glucose levels after abdominal, deltoid or thigh administration of Lantus. Injection sites must be rotated within a given injection area from one injection to the next.
Lantus must not be mixed with any other insulin or diluted. Mixing or diluting can change its time/action profile and mixing can cause precipitation.
Before using SoloStar, the Instruction for Use included in the package leaflet must be read carefully.

Insulin overdosage may lead to severe and sometimes life-threatening hypoglycaemia.
Mild episodes of hypoglycaemia can usually be treated with oral carbohydrates. Adjustments in dosage, meal patterns or physical activity may be necessary. More severe episodes with coma, seizure or neurologic impairment may be treated with glucagon (IM or SC) or concentrated glucose solution (IV). Sustained carbohydrate intake and observation may be necessary because hypoglycaemia may recur after apparent clinical recovery.

Hypersensitivity to insulin glargine or to any of the excipients of Lantus.

General: Patients must be instructed on the skills necessary for the self-management of diabetes eg, blood sugar monitoring, proper injection technique, measures for recognizing and managing reduced or increased blood sugar levels (hypo- or hyperglycaemia) as described as follows. In addition, they must learn how to handle special situations eg, skipped, inadequate or increased insulin doses, inadequate food intake or missed meals. Moreover, patients and their relatives must learn how to recognize the signs and symptoms of hypo- or hyperglycaemia, what corrective actions need to be taken and when they must speak with their physician.
In the event of insufficient blood sugar control or a tendency to hypo- or hyperglycaemic episodes, possible underlying factors (eg, patient compliance, choice of injection site and proper technique, handling of the pen) 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 children <2 years, 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 reduced insulin metabolism. In the elderly, progressive deterioration of renal function may lead to a steady decrease in insulin requirements.
In patients with severe liver impairment, insulin requirements may be diminished due to reduced capacity for gluconeogenesis and reduced insulin metabolism.
Hypoglycaemia: The time to occurrence of hypoglycaemia depends on the action profile of the insulins use 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 effect, less during the night but greater in the early morning.
Patients in whom hypoglycaemic episodes might be of particular clinical relevance include those with significant narrowing of the coronary arteries or of the blood vessels supplying 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 metabolic 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 pectoris). In many patients, these signs and symptoms 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 absent in certain risk groups. These include patients: In whom blood sugar control is markedly improved, in whom hypoglycaemia develops gradually, who are elderly, in whom a certain type of nervous disease (autonomic neuropathy) is present, with a long history diabetes, suffering from a psychiatric illness or receiving concurrent treatment with certain other medicines (see Interactions). In such circumstances, severe hypoglycaemia (and even loss of consciousness) may develop without the patient noticing it. Affected patients should try to keep familiar at all times with their individual warning symptoms. More frequent blood sugar testing can help to identify mild hypoglycaemic episodes which otherwise might be overlooked. Patients not confident of recognizing their warning symptoms should avoid situations (eg, driving a car) that might result in danger to themselves or others.
Compliance of the patient with the dosage and dietary regimen, correct insulin administration and awareness of hypoglycaemia symptoms are essential in reducing the risk of hypoglycaemia.
All factors increasing such risk require particularly close monitoring and may necessitate dose adjustment. These include: Change in the injection area (eg, from the thigh to the upper arm); improved insulin sensitivity eg, by removal of stress factors; unaccustomed or increased physical activity; concomitant illness (eg, vomiting, diarrhoea); inadequate food intake eg, 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 eg, reduced thyroid function or anterior pituitary or adrenocortical insufficiency; concurrent use of other medicines (see Interactions).
A hypoglycaemic attack can be corrected by immediately taking sugar eg, in the form of glucose, sugar cubes or sugar-sweetened beverages. In this regard, note that food or beverages containing artificial sweeteners (eg, diet foods and drinks) are not suitable. Then, some food having long-acting blood sugar-raising effect (eg, bread) should be taken. If hypoglycaemia comes back again, another 10-20 g of sugar should be taken. If a hypoglycaemic attack cannot be corrected or if it recurs, speak to a physician immediately.
The patient should always carry at least 20 g of sugar at all times, together with some information identifying the patient as diabetic. Inability to swallow or unconsciousness will make necessary injections of glucose solution or glucagon (a medicine increasing blood sugar), even where the presence of hypoglycaemia is uncertain.
It is advisable to test the patient's blood sugar immediately after taking glucose to check if it is really hypoglycaemia.
The prolonged action of Lantus may delay recovery from hypoglycaemia.
Hyperglycaemia: Hyperglycaemia may occur under certain circumstances. These include: Omission or reduction of injections or decrease in insulin effectiveness (eg, due to incorrect storage); pen malfunction; decreased physical activity, stress situations (emotional distress, excitement), injuries, operations, feverish illnesses or certain other diseases; concurrent use of other medicines (see Interactions).
Thirst, increased need to pass water, tiredness, dry skin, reddening of the face, loss of appetite, low blood pressure, fast heart beat and high concentrations of sugar and ketone bodies in the urine may be signs of hyperglycaemia. Stomach pain, fast and deep breathing, 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 symptoms occur. Severe hyperglycaemia or ketoacidosis must always be treated by a physician, normally in a hospital.
Concomitant Illness: Inform the physician if the patient is ill, since this situation may necessitate intensified metabolic monitoring and, possibly, further special measures (eg, dose adjustment, urine tests for ketones).
Pens to be Used with Lantus Cartridges: The Lantus cartridges should only be used with the following pens: ClickSTAR and Optipen, and should not be used with any other reusable pen as the dosing accuracy has only been established with the listed pen.
Effects on the Ability to Drive or Operate Machinery: As a result eg, of hypoglycaemia, hyperglycaemia or visual impairment (see Adverse Reactions), the ability to concentrate and react may be affected, possibly constituting a risk in situations where these abilities are of particular importance (eg, operating a vehicle or machinery).
Use in Pregnancy & Lactation: For insulin glargine, no clinical data on exposed pregnancies from controlled clinical trials are available. A limited number of exposed pregnancies from post-marketing surveillance indicate no adverse effects of insulin glargine on pregnancy or on the health of the foetus and neonates. To date, no other relevant epidemiological data are available.
Women with preexisting or gestational diabetes must maintain good metabolic control during pregnancy. In the first 3 months, insulin requirements may decrease and generally increase during the 2nd and 3rd trimesters. Immediately after delivery, insulin requirements then decrease again rapidly (increased risk of hypoglycaemia). Therefore, careful blood sugar monitoring is essential. If pregnant or planning a pregnancy, inform the physician.
Adjustments in dosage and diet may be necessary in breastfeeding women.
Use in Children: In general, the side effects in patients ≤18 years are similar to those seen in adults. Complaints of injection site reactions and skin reactions are reported relatively more frequently in patients of ≤18 years than in adult patients. No clinical study safety data are available in patients <2 years.

For insulin glargine, no clinical data on exposed pregnancies from controlled clinical trials are available. A limited number of exposed pregnancies from post-marketing surveillance indicate no adverse effects of insulin glargine on pregnancy or on the health of the foetus and neonates. To date, no other relevant epidemiological data are available.
Women with preexisting or gestational diabetes must maintain good metabolic control during pregnancy. In the first 3 months, insulin requirements may decrease and generally increase during the 2nd and 3rd trimesters. Immediately after delivery, insulin requirements then decrease again rapidly (increased risk of hypoglycaemia). Therefore, careful blood sugar monitoring is essential. If pregnant or planning a pregnancy, inform the physician.
Adjustments in dosage and diet may be necessary in breastfeeding women.

Inform the physician or pharmacist if any adverse effect is experienced with the use of Lantus.
Hypoglycaemia (see Precautions) 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 glycaemic control decreases the risk of progression of diabetic retinopathy. However, intensification of insulin therapy with abrupt improvement in glycaemic control may be associated with temporary worsening of diabetic retinopathy. In patients with proliferative retinopathy, particularly if not treated with photocoagulation, severe hypoglycaemic 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 injection site and may also spread into the surrounding area. These include reddening, unusually 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's edema), shortness of breath (bronchospasm), a fall in blood pressure and circulatory collapse (shock). Severe allergic reactions may under certain circumstances become life-threatening.
Other Reactions: Insulin administration may cause insulin antibodies 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 adjustment.
Rarely, insulin may cause sodium and fluid retention into the tissues (edema), particularly after significant improvement of metabolic control in association with intensified therapy.
Medication errors have been reported in which other insulins, particularly short-acting insulins, have been accidentally administered instead of insulin glargine.

In order to avoid possible interactions with other medicines, inform the physician or pharmacist about any other current treatment.
Certain medicines affect glucose metabolism and require insulin dose adjustment and particularly close monitoring.
An increase in the blood sugar-lowering effect and in susceptibility to hypoglycaemia may occur in concomitant use of eg, oral antidiabetics, ACE inhibitors, disopyramide, fibrates, fluoxetine, MAO inhibitors, pentoxifylline, propoxyphene, salicylates or sulfonamide antibiotics.
A decrease in the blood sugar-lowering effect may occur in concomitant use of corticosteroids, danazol, diazoxide, diuretics, glucagon, isoniazid, oestrogens and progestogens (eg, in oral contraceptives), phenothiazine derivatives, somatropin, sympathomimetic agents [eg, epinephrine (adrenaline), salbutamol, terbutaline], thyroid hormones, atypical antipsychotics (eg, clozapine and olanzapine) and protease inhibitors.
Beta-blockers, clonidine, lithium salts or alcohol may either potentiate or weaken the blood sugar-lowering effect of insulin. Pentamidine may cause hypoglycaemia, sometimes followed by hyperglycaemia. Moreover, β-blockers, in common with other sympatholytic medicines (eg, clonidine, guanethidine, reserpine) may weaken or even suppress entirely the warning symptoms of a hypoglycaemic reaction.

Unopened/Not in Use: Store in a refrigerator between 2-8°C. Protect from light. Do not freeze, discard if frozen. Ensure that the container is not directly touching the freezer compartment or freezer packs.
Before first use, SoloStar must be stored at room temperature for 1-2 hrs.
Opened/In Use: Do not freeze, discard if frozen. The vial whether or not refrigerated, must be discarded after 28 days from the first use. If refrigeration is not possible, the opened vial can be kept unrefrigerated for up to 28 days away from direct heat and light below 25°C.
Unrefrigerated vial, whether in use or not, must be discarded after 28 days.
If the SoloStar pen has been taken out of cool storage, either for use or to be carried as spare, it can be used up to 28 days. During this time, it can be safely kept at room temperature up to 25°C protected from light and must not be stored in the refrigerator. Do not use it after this time.

Insulin Preparations

A10AE04 - insulin glargine ; Belongs to the class of long-acting insulins and analogues for injection. Used in the treatment of diabetes.

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