Insulin Glargine/ Lixisenatide

Registered South African indications:

• Type 2 diabetes mellitus
  - To improve glycaemic control when oral glucose-lowering medicines alone or combined with basal insulin, or basal insulin alone, do not provide adequate glycaemic control

Contraindications

International manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients

South African manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients
• Pregnancy
• Breastfeeding
• Severe renal impairment (CrCl<30ml/min) or end-stage renal disease
• Use during episodes of hypoglycaemia
• Acute pancreatitis

Cautions

International manufacturer recommendations

• Pregnancy
• Breastfeeding
• Renal impairment
• Hepatic impairment
• Elderly
• Type 1 diabetes mellitus
• Diabetic ketoacidosis
• Administration at injection sites with lipodystrophy or cutaneous amyloidosis
• Change in the injection area
• Improved insulin sensitivity (e.g. by removal of stress factors)
• Unaccustomed, increased or prolonged physical activity
• Intercurrent illness (e.g. vomiting, diarrhoea)
• Inadequate food intake
• Missed meals
• Alcohol consumption
• Certain uncompensated endocrine disorders, (e.g. in hypothyroidism and in anterior pituitary or adrenocortical
• History of pancreatitis
• Severe gastrointestinal disease, including severe gastroparesis
• Higher than required dose or dosing errors
• Fluid depletion
• Coadministration with a sulfonylurea
• Coadministration with oral medicinal products that require rapid gastrointestinal absorption, careful clinical monitoring or have a narrow therapeutic ratio
• Coadministration with dipeptidyl peptidase-4 (DPP-4) inhibitors, sulfonylureas, glinides, and pioglitazone
• May impair ability to drive and operate machinery

South African manufacturer recommendations

• Mild to moderate renal impairment (CrCl ≥30ml/min)  
• Hepatic impairment
• Elderly
• Type 1 diabetes mellitus
• Diabetic ketoacidosis
• History of pancreatitis
• Severe gastrointestinal diseases, including severe gastroparesis
• Higher than required dose
• Fluid depletion
• Coadministration with oral medicines that require rapid gastrointestinal absorption, careful clinical monitoring or have a narrow therapeutic ratio
• May impair ability to drive and operate machinery
  - Reduced or absent awareness of the warning symptoms of hypoglycaemia or have frequent episodes of hypoglycaemia

Forms avail. In SA and covered in this monograph: inj

Dosages below include:

• International manufacturer recommendations
• South African manufacturer recommendations

International manufacturer recommendations

Insufficiently controlled type 2 diabetes mellitus (as an adjunct to diet and exercise)
- In addition to metformin with or without sodium-glucose co-transporter-2 (SGLT-2) inhibitors

Insulin naïve patients (Including oral anti-diabetic treatment or a GLP-1 receptor agonist) 

- Insulin glargine 100 units/ml + lixisenatide 50mcg/ml (10-40) pen

• SC: Initial: 10 dose steps (10 units insulin glargine and 5mcg lixisenatide); Titrate according to the individual patient's need for insulin; Max: 40 dose steps/24hrs

Previous therapy with insulin glargine (100units/ml) at ≥20 to <30 units 

- Insulin glargine 100 units/ml +  lixisenatide 50mcg/ml (10-40) pen

• SC: Initial: 20 dose steps (20 units insulin glargine and 10mcg lixisenatide); Titrate according to the individual patient's need for insulin; Max: 40 dose steps/24hrs

Previous therapy with insulin glargine (100 units/ml) at ≥30 to ≤60 units

- Insulin glargine 100 units/ml + lixisenatide 33 mcg/ml (30-60) pen

• SC: Initial: 30 dose steps (30 units insulin glargine and 10mcg lixisenatide); Titrate according to the individual patient's need for insulin; Max: 60 dose steps/24hrs

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To avoid medication errors, the prescriber must make sure that the correct strength and number of dose steps is stated in the prescription

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Therapy with basal insulin or GLP-1 receptor agonist or oral glucose lowering medicinal product (other than metformin and SGLT-2 inhibitors) should be discontinued prior to initiation of insulin glargine/ lixisenatide

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Starting dose: The starting dose is based on previous anti-diabetic treatment, and in order not to exceed the recommended lixisenatide starting dose of 10mcg

Dosage titration: Dose in accordance with the individual patient's need for insulin. It is recommended to optimise glycaemic control via dose adjustment based on fasting plasma glucose

- If the patient starts with the insulin glargine 100 units/ml + lixisenatide 50mcg/ml pen, the dose may be titrated up to 40 dose steps with this pen
- For doses >40 dose steps/day titration must be continued with - insulin glargine 100 units/ml +  lixisenatide 33 mcg/ml pen
- If the patient starts with the insulin glargine 100 units/ml + lixisenatide 33 mcg/ml pen, the dose may be titrated up to 60 dose steps with this pen

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The maximum daily dose is 60 units insulin glargine and 20mcg lixisenatide corresponding to 60 dose steps

For total daily doses >60 dose steps/day, insulin glargine/ lixisenatide must not be used

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If a different basal insulin was used (i.e. other than insulin glargine (100 units/ml):
- For twice daily basal insulin or insulin glargine (300 units/ml), the total daily dose previously used should be reduced by 20% to choose the insulin glargine/ lixisenatide starting dose
-  For any other basal insulin the same rule as for insulin glargine (100 units/ml) should be applied

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Inject once a day within 1hr prior to a meal. It is preferable that the prandial injection is performed before the same meal every day, when the most convenient meal has been chosen

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See additional prescribing points for the method of administration, instructions for handling and explanation of available dosage forms

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South African manufacturer recommendations

Type 2 diabetes mellitus
- When oral glucose-lowering medicines alone or combined with basal insulin, or basal insulin alone, do not provide adequate glycaemic control

Insulin naïve patients (Including oral anti-diabetic agents) 
Previous therapy with insulin glargine (100units/ml) at <20

- Insulin glargine 100 units/ml + lixisenatide 50mcg/ml (10-40) pen

• SC: Initial: 10 dose steps (10 units insulin glargine and 5mcg lixisenatide); Titrate according to the individual patient's need for insulin; Max: 40 dose steps/24hrs

Previous therapy with insulin glargine (100units/ml) at ≥20 to <30 units 

- Insulin glargine 100 units/ml +  lixisenatide 50mcg/ml (10-40) pen

• SC: Initial: 20 dose steps (20 units insulin glargine and 10mcg lixisenatide); Titrate according to the individual patient's need for insulin; Max: 40 dose steps/24hrs

Previous therapy with insulin glargine (100 units/ml) at ≥30 to ≤60 units

- Insulin glargine 100 units/ml + lixisenatide 33 mcg/ml (30-60) pen

• SC: Initial: 30 dose steps (30 units insulin glargine and 10mcg lixisenatide); Titrate according to the individual patient's need for insulin; Max: 60 dose steps/24hrs

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To avoid medicine errors, make sure the correct insulin glargine/ lixisenatide (10-40) pen or (30–60)
pen, is stated in the prescription

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The dose must be individualised based on clinical response and is titrated based on the patient’s need for insulin. The lixisenatide dose is increased or decreased along with insulin glargine dose and also depends on which pen is used

Patients adjusting the amount or timing of dosing should only do so under medical guidance with appropriate glucose monitoring

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Starting dose: The starting dose is  selected based on previous anti-diabetic treatment and in order not to exceed the recommended lixisenatide starting dose of 10mcg

Dosage titration: Dose in accordance with the individual patient's need for insulin. It is recommended to optimise glycaemic control via dose adjustment based on fasting plasma glucose

- If the patient starts with the insulin glargine 100 units/ml + lixisenatide 50mcg/ml pen, the dose may be titrated up to 40 units with this pen
- For total daily doses >40 units/day titration switch to the insulin glargine 100 units/ml +  lixisenatide 33 mcg/ml pen
- If the patient starts with the insulin glargine 100 units/ml + lixisenatide 33 mcg/ml pen, the dose may be titrated up to 60 units with this pen

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The maximum daily dose is 60 units of insulin glargine/ lixisenatide (60 units insulin glargine and 20mcg lixisenatide)

For total daily doses ≥60 units/day, do not use insulin glargine/ lixisenatide

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If a different basal insulin was taken (i.e. other than insulin glargine (U100)):
- For twice daily basal insulin, the total daily dose previously taken should be reduced by 20.0% to choose the insulin glargine/ lixisenatide starting dose
-  For any other basal insulin, the same rule as for insulin glargine (U100) should be applied

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Administer within 1hr prior to any meal ₁

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See additional prescribing points for the method of administration

Not established for use in children

Pregnancy

International manufacturer recommendations

• Caution; not recommended
• There is no clinical data on exposed pregnancies from controlled clinical studies with use of insulin glargine/ lixisenatide, insulin glargine, or lixisenatide
• A large amount of data on pregnant women (more than 1000 pregnancy outcomes) with insulin glargine indicate no specific adverse effects of insulin glargine on pregnancy and no specific malformative nor foeto/ neonatal toxicity of insulin glargine. Animal data do not indicate reproductive toxicity with insulin glargine
• There are no adequate data from the use of lixisenatide in pregnant women. Studies with lixisenatide in animals have shown reproductive toxicity
• Insulin glargine/ lixisenatide should not be used during pregnancy. If a patient wishes to become pregnant, or pregnancy occurs, treatment with insulin glargine/ lixisenatide should be discontinued
• Insulin glargine/ lixisenatide is not recommended in women of childbearing potential not using contraception

South African manufacturer recommendations

• Contraindicated
• Insulin glargine/ lixisenatide use is contraindicated during pregnancy. If a patient wishes to become pregnant, or pregnancy occurs, treatment with insulin glargine/ lixisenatide should be discontinued

Breastfeeding

International manufacturer recommendations

• Caution; not recommended
• It is unknown whether insulin glargine or lixisenatide is excreted in human milk. Insulin glargine/ lixisenatide should not be used during breastfeeding

South African manufacturer recommendations

• Contraindicated
• Insulin glargine/ lixisenatide is contraindicated for a mother who is breastfeeding her infant

Fertility

International manufacturer recommendations

• Animal studies with lixisenatide or insulin glargine do not indicate direct harmful effects with respect to fertility

South African manufacturer recommendations

• Caution; no information available

Renal Impairment

International manufacturer recommendations

• Mild to moderate (CrCl ≥30ml/min): Caution; no dose adjustment recommended
  In patients with renal impairment, insulin requirements may be diminished due to reduced insulin metabolism.
  In patients with mild to moderate renal impairment, frequent glucose monitoring and dose adjustment may be necessary
• Severe (CrCl<30ml/min) and end-stage renal disease: Not recommended for use
  Insulin glargine/ lixisenatide is not recommended in patients with severe renal impairment and end-stage renal disease as there is no sufficient therapeutic experience with use of lixisenatide

South African manufacturer recommendations

• Mild to moderate (CrCl  ≥30ml/min): Caution; no dose adjustment recommended
  In patients with renal impairment, insulin requirements may be diminished due to reduced insulin metabolism
  Frequent glucose monitoring and dose adjustment may be necessary in patients with renal impairment
• Severe (CrCl <30ml/min) and end-stage renal disease: Contraindicated
  There is no therapeutic experience with use of lixisenatide in patients with severe renal impairment (CrCl <30ml/min) or end-stage renal disease and therefore, it is not recommended to use lixisenatide in these populations

Hepatic Impairment

International manufacturer recommendations

• Caution; no dose adjustment recommended
  In patients with hepatic impairment, insulin requirements may be diminished due to reduced capacity for gluconeogenesis and reduced insulin metabolism. Frequent glucose monitoring and dose adjustment may be necessary for insulin glargine/ lixisenatide in patients with hepatic impairment

South African manufacturer recommendations

• Caution; no information available
  The effect of hepatic impairment on the pharmacokinetics of insulin glargine/ lixisenatide has not been studied. In patients with hepatic impairment, insulin requirements may be diminished due to reduced capacity of gluconeogenesis and reduced insulin metabolism. Frequent glucose monitoring and dose adjustment may be necessary for insulin glargine/ lixisenatide in patients with hepatic impairment

Elderly

International manufacturer recommendations

• Caution; no dose adjustment recommended
  The dose should be adjusted on an individual basis, based on glucose monitoring. In the elderly, progressive deterioration of renal function may lead to a steady decrease in insulin requirements
  The therapeutic experience of insulin glargine/ lixisenatide in patients ≥75 years of age is limited

South African manufacturer recommendations

• Caution; no dose adjustment recommended
  Dose should be adjusted on an individual basis, based on glucose monitoring
• The therapeutic experience of insulin glargine/ lixisenatide in patients ≥75 years of age is limited

Drugs in Sport

• Prohibited - At all times

Central Nervous System Disorders

• Dizziness
• Headache
• Fatigue

Cardiovascular Disorders

• Increased heart rate

Respiratory Disorders

• Nasopharyngitis
• Upper respiratory tract infection

Gastrointestinal Disorders

• Nausea and vomiting
• Diarrhoea
• Dyspepsia
• Abdominal pain

Endocrine and Metabolic Disorders

• Hypoglycaemia

Skin and Subcutaneous Tissue Disorders

• Urticaria
• Cutaneous amyloidosis
• Lipodystrophy
• Injection site reactions
  - Erythema
  - Local oedema
  - Pruritus

Immune, Blood and Lymphatic System Disorders

• Generalised allergic reaction
  - Anaphylactic reaction
  - Angioedema
• Formation of antibodies

• Agents that may enhance the blood-glucose-lowering effect and increase susceptibility to hypoglycaemia
• Antihyperglycaemic medicinal products
• Angiotensin-converting enzyme inhibitors
• Disopyramide
• Fibrates
• Fluoxetine
• Monoamine oxidase inhibitors
• Pentoxifylline
• Propoxyphene
• Salicylates
• Sulphonamide antibiotics
• Agents that may reduce the blood-glucose-lowering effect
• Corticosteroids
• Danazol
• Diazoxide
• Diuretics
• Glucagon
• Isoniazid
• Oestrogens
• Progestogens
• Phenothiazine derivatives
• Somatropin
• Sympathomimetic medicinal products
• Epinephrine
• Salbutamol
• Terbutaline
• Thyroid hormones
• Atypical antipsychotic medicinal products
• Clozapine
• Olanzapine
• Protease inhibitors
• Beta-blockers
• Clonidine
• Lithium salts
• Pentamidine
• Guanethidine
• Reserpine
• Oral medicinal products that require rapid gastrointestinal absorption, or are particularly dependent on threshold concentrations for efficacy, or are of a narrow therapeutic ratio or that require careful clinical monitoring (See additional prescribing
• Antibiotics
• Paracetamol (See additional prescribing points)
• Warfarin (See additional prescribing points)

Other interactions

• Alcohol

• Plasma glucose
• Electrolytes
• HbA1c
• Weight

Some cases may require

• Renal function
• Hepatic function
• Potassium (In patients at risk for hypokalemia)

Additional observations

• Signs and symptoms of pancreatitis

Method of administration

• Insulin glargine/ lixisenatide is to be injected subcutaneously in the abdomen, deltoid, or thigh
• The injection sites should be rotated within the same region (abdomen, deltoid, or thigh) from one injection to the next in order to reduce the risk of lipodystrophy and cutaneous amyloidosis
• Patients should be instructed to always use a new needle. The re-use of insulin pen needles increases the risk of blocked needles, which may cause under- or overdosing
• Insulin glargine/ lixisenatide must not be drawn from the cartridge of the pre-filled pen into a syringe to avoid dosing errors and potential overdose

Instructions for handling

• Before first use, the pen must be taken out of the refrigerator and stored below 25°C for 1-2 hours
• The cartridge should be inspected before use. It must only be used if the solution is clear, colourless, with no solid particles visible, and if it is of water-like consistency
• Insulin glargine/ lixisenatide must not be mixed with any other insulin or diluted. Mixing or diluting can change its time/ action profile and mixing can cause precipitation
• A new needle must always be attached before each use. Needles must not be re-used. The patient should discard the needle after each injection
• In the event of blocked needles, patients must follow the instructions described in the accompanying package leaflet
• Empty pens must never be reused and must be properly discarded. To prevent the possible transmission of disease, each pen must be used by one patient only
• The label must always be checked before each injection to avoid medication errors between insulin glargine/ lixisenatide and other injectable antidiabetic medicinal products, including the 2 different pens of insulin glargine/ lixisenatide

Available dosage forms

• Insulin glargine/ lixisenatide is available in two pens, providing different dosing options, i.e. insulin glargine/ lixisenatide (10-40) pen and insulin glargine/ lixisenatide (30-60) pen respectively. The differentiation between the pen strengths is based on the dose range of the pen
• Insulin glargine/ lixisenatide 100 units/ml + 50 mcg/ml pre-filled pen delivers dose steps from 10-40 units of insulin glargine in combination with 5-20 mcg lixisenatide (10-40) pen
• Insulin glargine/ lixisenatide 100 units/ml + 33 mcg/ml pre-filled pen delivers dose steps from 30-60 units of insulin glargine in combination with 10-20 mcg lixisenatide (30-60) pen

Coadministration with oral medicinal products that require rapid gastrointestinal absorption, are particularly dependent on threshold concentrations for efficacy, are of a narrow therapeutic ratio or that require careful clinical monitoring

• The delay of gastric emptying with lixisenatide may reduce the rate of absorption of orally administered medicinal products. Patients receiving medicinal products of either a narrow therapeutic ratio or medicinal products that require careful clinical monitoring should be followed closely, especially at the time of initiation of lixisenatide treatment
• These medicinal products should be taken in a standardised way in relation to lixisenatide. If such medicinal products are to be administered with food, patients should be advised to, if possible, take them with a meal when lixisenatide is not administered
• For oral medicinal products that are particularly dependent on threshold concentrations for efficacy, such as antibiotics, patients should be advised to take those medicinal products at least 1 hour before or 4 hours after lixisenatide injection
• Gastro-resistant formulations containing substances sensitive to stomach degradation should be administered 1 hour before or 4 hours after lixisenatide injection

Coadministration with paracetamol

• No dose adjustment for paracetamol is required but the delayed Tmax observed when paracetamol is administered 1-4 hours after lixisenatide should be taken into account when a rapid onset of action is required for efficacy

Coadministration with warfarin and other coumarin derivatives

• No dose adjustment for warfarin is required when co-administered with lixisenatide; however, frequent monitoring of INR in patients on warfarin and/or coumarin derivatives is recommended at the time of initiation or ending of lixisenatide treatment

Traceability

• In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded

Lixisenatide/ insulin glargine combines two active substances with complementary mechanisms of action to improve glycaemic control. Insulin glargine is a basal insulin analogue (mainly targeting fasting plasma glucose) and lixisenatide is a glucagon-like peptide-1 (GLP-1) receptor agonist (mainly targeting postprandial glucose).

Insulin glargine

The primary activity of insulin, including insulin glargine, is regulation of glucose metabolism. Insulin and its analogues lower blood glucose by stimulating peripheral glucose uptake, especially by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulin inhibits lipolysis and proteolysis, and enhances protein synthesis.

Lixisenatide

Lixisenatide is a GLP-1 receptor agonist. The GLP-1 receptor is the target for native GLP-1, an endogenous incretin hormone that potentiates glucose-dependent insulin secretion from beta cells and suppresses glucagon from alpha cells in the pancreas. Lixisenatide stimulates insulin secretion when blood glucose is increased but not at normoglycaemia, which limits the risk of hypoglycaemia. In parallel, glucagon secretion is suppressed. In case of hypoglycaemia, the rescue mechanism of glucagon secretion is preserved. A postprandial injection of lixisenatide also slows gastric emptying thereby reducing the rate at which meal-derived glucose is absorbed and appears in the circulation.

COMBINATION PREPARATIONS

Insulin Glargine/ Lixisenatide

Injection (per ml) 100u/33.0μg

• Soliqua 33/100 (Sanofi Aventis) originator

Injection (per ml) 100u/50.0μg

• Soliqua 50/100 (Sanofi Aventis) originator