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XULTOPHY ® 100/3.6
2017-05-29 20:19:14 来源: 作者: 【 】 浏览:816次 评论:0
Xultophy 100 units/ml insulin degludec + 3.6 mg/mL liraglutide solution for injection in a pre-filled pen 
1. Name of the medicinal product

Xultophy 100 units/mL + 3.6 mg/mL solution for injection.

2. Qualitative and quantitative composition

1 mL solution contains 100 units insulin degludec* and 3.6 mg liraglutide*.

*Produced in Saccharomyces cerevisiae by recombinant DNA technology.

One pre-filled pen contains 3 mL equivalent to 300 units insulin degludec and 10.8 mg liraglutide.

One dose step contains 1 unit of insulin degludec and 0.036 mg of liraglutide.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Solution for injection.

Clear, colourless, isotonic solution.

4. Clinical particulars
 
4.1 Therapeutic indications

Xultophy is indicated for the treatment of adults with type 2 diabetes mellitus to improve glycaemic control in combination with oral glucose-lowering medicinal products when these alone or combined with a GLP-1 receptor agonist or basal insulin do not provide adequate glycaemic control (see sections 4.4 and 5.1 for available data on the different combinations).

4.2 Posology and method of administration

Posology

Xultophy is given once daily by subcutaneous administration. Xultophy can be administered at any time of the day, preferably at the same time of the day.

Xultophy is to be dosed in accordance with the individual patient's needs. It is recommended to optimise glycaemic control via dose adjustment based on fasting plasma glucose.

Adjustment of dose may be necessary if patients undertake increased physical activity, change their usual diet or during concomitant illness.

Patients who forget a dose are advised to take it upon discovery and then resume their usual once-daily dosing schedule. A minimum of 8 hours between injections should always be ensured. This also applies when administration at the same time of the day is not possible.

Xultophy is administered as dose steps. One dose step contains 1 unit of insulin degludec and 0.036 mg of liraglutide. The pre-filled pen can provide from 1 up to 50 dose steps in one injection in increments of one dose step. The maximum daily dose of Xultophy is 50 dose steps (50 units insulin degludec and 1.8 mg liraglutide). The dose counter on the pen shows the number of dose steps.

Add-on to oral glucose lowering medicinal products

The recommended starting dose of Xultophy is 10 dose steps (10 units insulin degludec and 0.36 mg liraglutide).

Xultophy can be added to existing oral anti-diabetic treatment. When Xultophy is added to sulphonylurea therapy, a reduction in the dose of sulphonylurea should be considered (see section 4.4).

Transfer from GLP-1 receptor agonist

Therapy with GLP-1 receptor agonists should be discontinued prior to initiation of Xultophy. When transferring from a GLP-1 receptor agonist, the recommended starting dose of Xultophy is 16 dose steps (16 units insulin degludec and 0.6 mg liraglutide) (see section 5.1). The recommended starting dose should not be exceeded. If transferring from a long-acting GLP-1 receptor agonist (e.g. once-weekly dosing), the prolonged action should be considered. Treatment with Xultophy should be initiated at the moment the next dose of the long-acting GLP-1 receptor agonist would have been taken. Close glucose monitoring is recommended during the transfer and in the following weeks.

Transfer from basal insulin

Therapy with basal insulin should be discontinued prior to initiation of Xultophy. When transferring from basal insulin therapy, the recommended starting dose of Xultophy is 16 dose steps (16 units insulin degludec and 0.6 mg liraglutide) (see section 4.4 and 5.1). The recommended starting dose should not be exceeded. Close glucose monitoring is recommended during the transfer and in the following weeks.

Special populations

Elderly patients (≥ 65 years old)

Xultophy can be used in elderly patients. Glucose monitoring is to be intensified and the dose adjusted on an individual basis. The therapeutic experience in patients ≥75 years of age is limited.

Renal impairment

When Xultophy is used in patients with mild or moderate renal impairment, glucose monitoring is to be intensified and the dose adjusted on an individual basis. Xultophy cannot be recommended for use in patients with severe renal impairment including patients with end-stage renal disease (see section 5.2).

Hepatic impairment

The therapeutic experience with Xultophy in patients with hepatic impairment is currently too limited to recommend the use in these patients (see section 5.2).

Paediatric population

There is no relevant use of Xultophy in the paediatric population.

Method of administration

Xultophy is for subcutaneous use only. Xultophy must not be administered intravenously or intramuscularly.

Xultophy is administered subcutaneously by injection in the thigh, the upper arm or the abdomen. Injection sites are always to be rotated within the same region in order to reduce the risk of lipodystrophy. For further instructions on administration, see section 6.6.

4.3 Contraindications

Hypersensitivity to either or both active substances or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

Xultophy should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.

Hypoglycaemia

Hypoglycaemia may occur if the dose of Xultophy is higher than required. Omission of a meal or unplanned strenuous physical exercise may lead to hypoglycaemia. In combination with sulphonylurea, the risk of hypoglycaemia may be lowered by a reduction in the dose of sulphonylurea. Concomitant diseases in the kidney, liver or diseases affecting the adrenal, pituitary or thyroid gland may require changes of the Xultophy dose. Patients whose blood-glucose control is greatly improved (e.g. by intensified therapy) may experience a change in their usual warning symptoms of hypoglycaemia, and must be advised accordingly. Usual warning symptoms (see section 4.8) of hypoglycaemia may disappear in patients with long-standing diabetes. The prolonged effect of Xultophy may delay recovery from hypoglycaemia.

Hyperglycaemia

Inadequate dosing and/or discontinuation of anti-diabetic treatment may lead to hyperglycaemia and potentially to hyperosmolar coma. In case of discontinuation of Xultophy, ensure that instruction for initiation of alternative anti-diabetic medication is followed. Furthermore, concomitant illness, especially infections, may lead to hyperglycaemia and thereby cause an increased requirement for anti-diabetic treatment. Usually, the first symptoms of hyperglycaemia develop gradually over a period of hours or days. They include thirst, increased frequency of urination, nausea, vomiting, drowsiness, flushed dry skin, dry mouth, and loss of appetite as well as acetone odour of breath.

Administration of rapid-acting insulin should be considered in situations of severe hyperglycaemia. Untreated hyperglycaemic events eventually lead to hyperosmolar coma/diabetic ketoacidosis, which is potentially lethal.

Combination of pioglitazone and insulin medicinal products

Cases of cardiac failure have been reported when pioglitazone was used in combination with insulin medicinal products, especially in patients with risk factors for development of cardiac failure. This should be kept in mind if treatment with the combination of pioglitazone and Xultophy is considered. If the combination is used, patients should be observed for signs and symptoms of heart failure, weight gain and oedema. Pioglitazone should be discontinued if any deterioration in cardiac symptoms occurs.

Eye disorder

Intensification of therapy with insulin, a component of Xultophy, with abrupt improvement in glycaemic control may be associated with temporary worsening of diabetic retinopathy, while long-term improved glycaemic control decreases the risk of progression of diabetic retinopathy.

Antibody formation

Administration of Xultophy may cause formation of antibodies against insulin degludec and/or liraglutide. In rare cases, the presence of such antibodies may necessitate adjustment of the Xultophy dose in order to correct a tendency to hyper- or hypoglycaemia. Very few patients developed insulin degludec specific antibodies, antibodies cross-reacting to human insulin or anti-liraglutide antibodies following treatment with Xultophy. Antibody formation has not been associated with reduced efficacy of Xultophy.

Acute pancreatitis

Use of GLP-1 receptor agonists including liraglutide, a component of Xultophy, has been associated with a risk of developing acute pancreatitis. There have been few reported events of acute pancreatitis. Patients should be informed of the characteristic symptoms of acute pancreatitis. If pancreatitis is suspected, Xultophy should be discontinued; if acute pancreatitis is confirmed, Xultophy should not be restarted. Caution should be exercised in patients with a history of pancreatitis.

Thyroid adverse events

Thyroid adverse events, including increased blood calcitonin, goitre and thyroid neoplasm have been reported in clinical trials with GLP-1 receptor agonists including liraglutide, a component of Xultophy, in particular in patients with pre-existing thyroid disease, and Xultophy should therefore be used with caution in these patients.

Inflammatory bowel disease and diabetic gastroparesis

There is no experience with Xultophy in patients with inflammatory bowel disease and diabetic gastroparesis. Xultophy is therefore not recommended in these patients.

Dehydration

Signs and symptoms of dehydration, including renal impairment and acute renal failure have been reported in clinical trials with GLP-1 receptor agonists including liraglutide, a component of Xultophy. Patients treated with Xultophy should be advised of the potential risk of dehydration in relation to gastrointestinal side effects and take precautions to avoid fluid depletion.

Avoidance of medication errors

Patients must be instructed to always check the pen label before each injection to avoid accidental mix-ups between Xultophy and other injectable diabetes medicinal products.

Populations not studied

Transfer to Xultophy from doses of basal insulin < 20 and > 50 units has not been studied.

Xultophy has not been studied in combination with dipeptidyl peptidase 4 (DPP-4) inhibitors, glinides or prandial insulin.

There is limited experience in patients with congestive heart failure New York Heart Association (NYHA) class I-II and Xultophy should therefore be used with caution in these patients. There is no experience in patients with congestive heart failure NYHA class III-IV and Xultophy is therefore not recommended in these patients.

Excipients

Xultophy contains less than 1 mmol sodium (23 mg) per dose, therefore the medicinal product is essentially 'sodium-free'.

4.5 Interaction with other medicinal products and other forms of interaction

Pharmacodynamic interactions

Interaction studies with Xultophy have not been performed.

A number of substances affect glucose metabolism and may require dose adjustment of Xultophy.

The following substances may reduce the Xultophy requirement:

Anti-diabetic medicinal products, monoamine oxidase inhibitors (MAOI), beta-blockers, angiotensin converting enzyme (ACE) inhibitors, salicylates, anabolic steroids and sulphonamides.

The following substances may increase the Xultophy requirement:

Oral contraceptives, thiazides, glucocorticoids, thyroid hormones, sympathomimetics, growth hormones and danazol.

Beta-blockers may mask the symptoms of hypoglycaemia.

Octreotide/lanreotide may either increase or decrease the Xultophy requirement.

Alcohol may intensify or reduce the hypoglycaemic effect of Xultophy.

Pharmacokinetic interactions

In vitro data suggest that the potential for pharmacokinetic drug interactions related to CYP interaction and protein binding is low for both liraglutide and insulin degludec.

The small delay of gastric emptying with liraglutide may influence absorption of concomitantly administered oral medicinal products. Interaction studies did not show any clinically relevant delay of absorption.

Warfarin and other coumarin derivatives

No interaction study has been performed. A clinically relevant interaction with active substances with poor solubility or with narrow therapeutic index such as warfarin cannot be excluded. Upon initiation of Xultophy treatment in patients on warfarin or other coumarin derivatives more frequent monitoring of INR (International Normalised Ratio) is recommended.

Paracetamol

Liraglutide did not change the overall exposure of paracetamol following a single dose of 1,000 mg. Paracetamol Cmax was decreased by 31% and median tmax was delayed up to 15 min. No dose adjustment for concomitant use of paracetamol is required.

Atorvastatin

Liraglutide did not change the overall exposure of atorvastatin to a clinical relevant degree following single dose administration of atorvastatin 40 mg. Therefore, no dose adjustment of atorvastatin is required when given with liraglutide. Atorvastatin Cmax was decreased by 38% and median tmax was delayed from 1 h to 3 h with liraglutide.

Griseofulvin

Liraglutide did not change the overall exposure of griseofulvin following administration of a single dose of griseofulvin 500 mg. Griseofulvin Cmax increased by 37% while median tmax did not change. Dose adjustments of griseofulvin and other compounds with low solubility and high permeability are not required.

Digoxin

A single dose administration of digoxin 1 mg with liraglutide resulted in a reduction of digoxin AUC by 16%; Cmax decreased by 31%. Digoxin median time to maximum concentration (tmax) was delayed from 1 h to 1.5 h. No dose adjustment of digoxin is required based on these results.

Lisinopril

A single dose administration of lisinopril 20 mg with liraglutide resulted in a reduction of lisinopril AUC by 15%; Cmax decreased by 27%. Lisinopril median tmax was delayed from 6 h to 8 h with liraglutide. No dose adjustment of lisinopril is required based on these results.

Oral contraceptives

Liraglutide lowered ethinylestradiol and levonorgestrel Cmax by 12 and 13%, respectively, following administration of a single dose of an oral contraceptive product. Tmax was delayed by 1.5 h with liraglutide for both compounds. There was no clinically relevant effect on the overall exposure of either ethinylestradiol or levonorgestrel. The contraceptive effect is therefore anticipated to be unaffected when co-administered with liraglutide.

4.6 Fertility, pregnancy and lactation

Pregnancy

There is no clinical experience with use of Xultophy, insulin degludec or liraglutide in pregnant women. If a patient wishes to become pregnant, or pregnancy occurs, treatment with Xultophy should be discontinued.

Animal reproduction studies with insulin degludec have not revealed any differences between insulin degludec and human insulin regarding embryotoxicity and teratogenicity. Animal studies with liraglutide have shown reproductive toxicity, see section 5.3. The potential risk for humans is unknown.

Breast-feeding

There is no clinical experience with use of Xultophy during breast-feeding. It is not known whether insulin degludec or liraglutide is excreted in human milk. Because of lack of experience, Xultophy should not be used during breast-feeding.

In rats, insulin degludec was secreted in milk; the concentration in milk was lower than in plasma. Animal studies have shown that the transfer of liraglutide and metabolites of close structural relationship into milk was low. Non-clinical studies with liraglutide have shown a treatment-related reduction of neonatal growth in suckling rat pups (see section 5.3).

Fertility

There is no clinical experience with Xultophy in relation to fertility.

Animal reproduction studies with insulin degludec have not revealed any adverse effects on fertility. Apart from a slight decrease in the number of live implants, animal studies with liraglutide did not indicate harmful effects with respect to fertility.

4.7 Effects on ability to drive and use machines

The patient's ability to concentrate

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