Glarine100 IU/ml

Glarine is a long-acting (basal) human insulin analog indicated to improve glycemic control in patients with diabetes mellitus. Its established uses, by strength of evidence, are:

Established / FDA-approved uses

• Type 1 diabetes mellitus (adults and children) — Glarine is used as the basal component of a multiple daily injection regimen, given together with a rapid- or short-acting insulin at mealtimes.
• Type 2 diabetes mellitus requiring insulin therapy (adults, and children per current product labeling) — used alone or in combination with oral antidiabetic agents or other injectable therapies when these are insufficient for glycemic control.

Not indicated for

Glarine is not recommended for the treatment of diabetic ketoacidosis; intravenous short-acting insulin is required in that setting.

Each mL of Insulin Glargine [rDNA] injection contains insulin glargine, a recombinant human insulin analog produced by recombinant DNA (rDNA) technology using a non-pathogenic laboratory strain of Escherichia coli. It is typically formulated as a sterile, clear, colourless-to-almost-colourless aqueous solution for subcutaneous injection, available in strengths such as 100 units/mL (U-100) and, for certain products, 300 units/mL (U-300).

Common excipients include zinc chloride, m-cresol, glycerol (glycerin), polysorbate 20 (in some formulations), hydrochloric acid and/or sodium hydroxide (for pH adjustment), and water for injection.

Glarine is a long-acting, recombinant human insulin analog. It differs from native human insulin by substitution of glycine for asparagine at position A21 and by the addition of two arginine residues to the C-terminus of the B-chain. These modifications shift the isoelectric point of the molecule, making it soluble at an acidic pH (in the injection vial/pen) but forming a microprecipitate in the neutral pH environment of subcutaneous tissue after injection.

This microprecipitate dissolves slowly, releasing small amounts of Glarine continuously, which gives it a relatively flat, peakless time-action profile lasting up to 24 hours with once-daily dosing.

Glarine belongs to the class of long-acting (basal) insulin analogs, a subclass of antidiabetic agents used for the treatment of diabetes mellitus.

Mechanism of Action

The primary activity of Insulin Glargine [rDNA], like other insulins, is regulation of glucose metabolism. Insulin Glargine [rDNA] and its active metabolites lower blood glucose by stimulating peripheral glucose uptake, particularly by skeletal muscle and adipose tissue, and by inhibiting hepatic glucose production. Insulin also inhibits lipolysis and proteolysis while enhancing protein synthesis.

Pharmacodynamics

Insulin Glargine [rDNA] is designed to have low solubility at physiological pH. At the acidic pH of the injection formulation, it is fully soluble; after subcutaneous injection, the acidic solution is neutralized, forming microprecipitates from which small amounts of Insulin Glargine [rDNA] are slowly released. This produces a relatively constant, peakless concentration/time profile over 24 hours, allowing once-daily dosing in most patients.

Pharmacokinetics

Compared with NPH human insulin, Insulin Glargine [rDNA] has a slower, more prolonged absorption and a duration of action of approximately 24 hours, with no pronounced peak. Following subcutaneous injection, Insulin Glargine [rDNA] is rapidly metabolized at the carboxyl terminus of the B-chain to form two active metabolites, M1 and M2.

Glarine is given as a subcutaneous injection once daily, at approximately the same time every day, into the abdominal wall, thigh, or deltoid region. Do not administer intravenously or intramuscularly, and do not use in an insulin infusion pump. Do not mix or dilute Glarine with any other insulin product or solution, as this can alter its time-action profile and reduce glucose control. Inspect the solution before use; it should be clear and colourless — do not use if it appears cloudy, particulate, or coloured. Rotate injection sites with each dose.

Many drugs can affect glucose metabolism and may require Glarine dose adjustment.

Drugs that may increase the blood-glucose-lowering effect (increased hypoglycemia risk)

Other antidiabetic agents, ACE inhibitors, angiotensin receptor blockers, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors (MAOIs), pentoxifylline, propoxyphene, salicylates, and sulfonamide antibiotics.

Drugs that may decrease the blood-glucose-lowering effect (increased hyperglycemia risk)

Corticosteroids, thiazide diuretics, niacin, danazol, protease inhibitors, sympathomimetic agents, atypical antipsychotics, and thyroid hormones — these may increase blood glucose and require dose adjustment of Glarine.

Drugs that may mask the symptoms of hypoglycemia

Beta-blockers (and other sympatholytic agents such as clonidine and guanethidine) can mask the warning signs of hypoglycemia (e.g. tremor, palpitations), making it harder to recognize.

Variable/unpredictable effects

Beta-blockers, clonidine, lithium salts, and alcohol may either potentiate or weaken the glucose-lowering effect of Glarine, with an unpredictable net effect on blood glucose.

Most common

Hypoglycemia is the most common adverse reaction associated with Glarine and may be serious; symptoms can include sweating, tremor, palpitations, hunger, confusion, irritability, and, if severe, seizures, loss of consciousness, or coma.

Other side effects

• Injection site reactions — pain, redness, itching, swelling, or bruising at the injection site.
• Lipodystrophy — thickening or pitting of fat tissue at sites of repeated injection; reduced by rotating injection sites.
• Weight gain, related to the anabolic effects of insulin.
• Peripheral edema, particularly when starting insulin therapy or intensifying glucose control.
• Rare allergic reactions, ranging from local rash or urticaria to, rarely, generalized allergy or anaphylaxis.

Pregnancy

Insulin, including Glarine, is generally the preferred approach for achieving glycemic control during pregnancy when pharmacologic therapy is needed, because good glycemic control is important for maternal and fetal outcomes. However, Glarine should be used during pregnancy only if clearly needed and if the potential benefit justifies the potential risk to the fetus; use only under close medical supervision. Insulin requirements often decrease in the first trimester, increase during the second and third trimesters, and decline rapidly after delivery — frequent monitoring and dose adjustment are essential. Consult a physician before use in pregnancy.

Lactation

Insulin, including Glarine, is generally considered compatible with breastfeeding, as it is not expected to be orally bioavailable to the infant in clinically relevant amounts. Breastfeeding mothers with diabetes may need adjustments to insulin dose, diet, or both. Use only on the advice of a physician.

Do not dilute or mix

Do not dilute or mix Glarine with any other insulin or solution. Mixing or diluting can change its time-action profile in unpredictable ways, and mixing has been associated with a shift in the time-action profile. Glarine must also not be administered intravenously or via an insulin infusion pump, and must not be administered subcutaneously via an insulin pump, because severe hypoglycemia can occur.

Changes in insulin regimen

Any change of insulin type, brand, or manufacturer, or any change in dose, should be made cautiously and only under medical supervision, as it may require a change in dosage.

Hypoglycemia

As with all insulins, the timing of hypoglycemia may differ depending on the insulin regimen. Hypoglycemia may impair concentration and reaction time, which can be hazardous in situations such as driving or operating machinery. Signs of hypoglycemia may be reduced or absent in patients with long-standing diabetes, diabetic neuropathy, or those taking beta-blockers (see Interactions).

Hypersensitivity and allergic reactions

Severe, life-threatening, generalized allergic reactions, including anaphylaxis, can occur with any insulin, including Glarine. Discontinue and seek medical attention if a severe allergic reaction is suspected.

Renal and hepatic impairment

Patients with renal or hepatic impairment may require dose reduction and more frequent glucose monitoring, as insulin requirements may be diminished due to reduced insulin clearance/metabolism.

Do not share devices

Glarine pens/pen devices must never be shared between patients, even if the needle is changed, due to the risk of transmission of blood-borne pathogens.

An excess of Glarine relative to food intake, energy expenditure, or concurrent glucose-lowering therapy can cause hypoglycemia, which may range from mild to severe and life-threatening.

• Mild hypoglycemia can usually be managed by taking oral fast-acting carbohydrates (e.g. glucose tablets, sugary drinks or food).
• Severe hypoglycemia with loss of consciousness, seizures, or neurological impairment is a medical emergency — seek immediate medical attention or contact emergency services; glucagon injection or intravenous glucose administered by a healthcare professional may be required.

Because of the prolonged action of Glarine, recovery from hypoglycemia may be delayed, and the patient should be monitored for an extended period following any overdose.

Unopened (unused) vials or pens: Store in a refrigerator at 2°C to 8°C (36°F to 46°F). Do not freeze; discard if the product has been frozen.

In-use (opened) vials or pens: May be kept at room temperature below 30°C for a limited period, generally up to 28 days per product labeling, then discarded even if some medicine remains. Keep away from direct heat and light. Do not store an in-use pen or cartridge in the refrigerator.

Keep out of reach of children. Do not use if the solution appears cloudy, coloured, or contains particles.

Pediatric use

Safety and efficacy of Glarine have been established in children with type 1 diabetes mellitus within the age ranges specified in product labeling (generally 6 years and older); it has not been adequately studied in children under 6 years of age or in children with type 2 diabetes, so use with caution and only under specialist supervision in these groups.

Elderly (geriatric) patients

Use Glarine with caution in elderly patients. Initiate with conservative dosing, as hypoglycemia may be more difficult to recognize in this population and can be associated with greater risk (e.g. falls, cardiovascular events).

Renal impairment

Insulin requirements may be reduced due to decreased insulin clearance. Glarine is not recommended during periods of rapidly declining renal function because of the risk of prolonged hypoglycemia; dose reduction and close monitoring may be needed.

Hepatic impairment

Insulin requirements may be reduced due to diminished capacity for gluconeogenesis and insulin metabolism. Glarine is not recommended during periods of rapidly declining hepatic function; dose reduction and close monitoring may be needed.

Glarine is generally used as long-term, ongoing basal insulin therapy for chronic management of type 1 or type 2 diabetes mellitus; there is no predefined treatment endpoint. Duration of therapy is determined by the prescribing physician based on ongoing glycemic control, disease progression, and clinical response, and treatment should not be stopped or altered without medical advice.

Insulin Glargine [rDNA] is classified under: Antidiabetic agents → Insulins → Long-acting (basal) insulin analogs.

Insulin Glargine [rDNA] binds to the insulin receptor on target cells (chiefly skeletal muscle and adipose tissue), triggering increased glucose uptake via translocation of GLUT4 glucose transporters, and suppresses hepatic glucose output by inhibiting gluconeogenesis and glycogenolysis. Its distinguishing pharmacologic feature is a delayed, prolonged subcutaneous absorption profile (due to microprecipitate formation at physiological pH) that provides a relatively flat, peakless action lasting approximately 24 hours, mimicking basal endogenous insulin secretion.

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Glarine is approved for use in children with type 1 diabetes mellitus within the age range specified by the product labeling (typically 6 years and older), as part of a basal-bolus insulin regimen. Safety and efficacy in children younger than 6 years, and in children with type 2 diabetes, have not been established — use in these groups should occur only under close pediatric endocrinology supervision. Pediatric dosing is individualized based on weight, blood glucose monitoring, and metabolic needs, following the same principles as in adults, with cautious titration to reduce the risk of hypoglycemia.