Switching from NPH Insulin to Lantus: Dosage Adjustments and Precautions, Study Guides, Projects, Research of Medicine

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ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Lantus 100 units/ml solution for injection in a vial Lantus 100 units/ml solution for injection in a cartridge Lantus SoloStar 100 units/ml solution for injection in a pre-filled pen

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml contains 100 units insulin glargine* (equivalent to 3.64 mg).

Lantus 100 units/ml solution for injection in a vial Each vial contains 5 ml of solution for injection, equivalent to 500 units, or 10 ml of solution for injection, equivalent to 1000 units.

Lantus 100 units/ml solution for injection in a cartridge, Lantus SoloStar 100 units/ml solution for injection in a pre-filled pen Each cartridge or pen contains 3 ml of solution for injection, equivalent to 300 units.

*Insulin glargine is produced by recombinant DNA technology in Escherichia coli.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Solution for injection.

Clear colourless solution.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Treatment of diabetes mellitus in adults, adolescents and children aged 2 years and above.

4.2 Posology and method of administration

Posology Lantus contains insulin glargine, an insulin analogue, and has a prolonged duration of action. Lantus should be administered once daily at any time but at the same time each day.

The dose regimen (dose and timing) should be individually adjusted. In patients with type 2 diabetes mellitus, Lantus can also be given together with orally active antidiabetic medicinal products. The potency of this medicinal product is stated in units. These units are exclusive to Lantus and are not the same as IU or the units used to express the potency of other insulin analogues (see section 5.1).

Special population Elderly population (≥65 years old) In the elderly, progressive deterioration of renal function may lead to a steady decrease in insulin requirements.

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.

Lantus 100 units/ml solution for injection in a vial For further details on handling, see section 6.6.

Lantus 100 units/ml solution for injection in a cartridge Lantus 100 units/ml in cartridges is only suitable for subcutaneous injections from a reusable pen. If administration by syringe is necessary, a vial should be used (see section 4.4). For further details on handling, see section 6.6.

Lantus SoloStar 100 units/ml solution for injection in a pre-filled pen Lantus SoloStar 100 units/ml in pre-filled pen is only suitable for subcutaneous injections. If administration by syringe is necessary, a vial should be used (see section 4.4). Before using SoloStar, the instructions for use included in the package leaflet must be read carefully (see section 6.6).

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

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.

Lantus is not the insulin of choice for the treatment of diabetic ketoacidosis. Instead, regular insulin administered intravenously is recommended in such cases.

In case of insufficient glucose control or a tendency to hyper- or hypoglycaemic episodes, the patient's adherence to the prescribed treatment regimen, injection sites and proper injection technique and all other relevant factors must be reviewed before dose adjustment is considered.

Transferring a patient to another type or brand of insulin should be done under strict medical supervision. Changes in strength, brand (manufacturer), type (regular, NPH, lente, long-acting, etc.), origin (animal, human, human insulin analogue) and/or method of manufacture may result in the need for a change in dose.

Patients must be instructed to perform continuous rotation of the injection site to reduce the risk of developing lipodystrophy and cutaneous amyloidosis. There is a potential risk of delayed insulin absorption and worsened glycaemic control following insulin injections at sites with these reactions. A sudden change in the injection site to an unaffected area has been reported to result in hypoglycaemia. Blood glucose monitoring is recommended after the change in the injection site, and dose adjustment of antidiabetic medications may be considered.

Hypoglycaemia The time of occurrence of hypoglycaemia depends on the action profile of the insulins used and may, therefore, change when the treatment regimen is changed. Due to more sustained basal insulin supply with Lantus, less nocturnal but more early morning hypoglycaemia can be expected.

Particular caution should be exercised, and intensified blood glucose monitoring is advisable in patients in whom hypoglycaemic episodes might be of particular clinical relevance, such as in patients with significant stenoses of the coronary arteries or of the blood vessels supplying the brain (risk of cardiac or cerebral complications of hypoglycaemia) as well as in patients with proliferative retinopathy, particularly if not treated with photocoagulation (risk of transient amaurosis following hypoglycaemia).

Patients should be aware of circumstances where warning symptoms of hypoglycaemia are diminished. The warning symptoms of hypoglycaemia may be changed, be less pronounced or be absent in certain risk groups. These include patients:

• in whom glycaemic control is markedly improved,
• in whom hypoglycaemia develops gradually,
• who are elderly,
• after transfer from animal insulin to human insulin,
• in whom an autonomic neuropathy is present,
• with a long history of diabetes,
• suffering from a psychiatric illness,
• receiving concurrent treatment with certain other medicinal products (see section 4.5).

Such situations may result in severe hypoglycaemia (and possibly loss of consciousness) prior to the patient's awareness of hypoglycaemia.

The prolonged effect of subcutaneous insulin glargine may delay recovery from hypoglycaemia.

If normal or decreased values for glycated haemoglobin are noted, the possibility of recurrent, unrecognised (especially nocturnal) episodes of hypoglycaemia must be considered.

Adherence of the patient to the dose and dietary regimen, correct insulin administration and awareness of hypoglycaemia symptoms are essential to reduce the risk of hypoglycaemia. Factors increasing the susceptibility to hypoglycaemia require particularly close monitoring and may necessitate dose adjustment. These include:

• 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 insufficiency),
• concomitant treatment with certain other medicinal products (see section 4.5).

Intercurrent illness Intercurrent illness requires intensified metabolic monitoring. In many cases urine tests for ketones are indicated, and often it is necessary to adjust the insulin dose. The insulin requirement is often increased. Patients with type 1 diabetes must continue to consume at least a small amount of carbohydrates on a regular basis, even if they are able to eat only little or no food, or are vomiting etc. and they must never omit insulin entirely.

Insulin antibodies Insulin administration may cause insulin antibodies to form. In rare cases, the presence of such insulin antibodies may necessitate adjustment of the insulin dose in order to correct a tendency to hyper- or hypoglycaemia (see section 5.1).

Pens to be used with Lantus 100 units/ml in cartridges Lantus 100 units/ml in cartridges is only suitable for subcutaneous injections from a reusable pen. If administration by syringe is necessary, a vial should be used. The Lantus cartridges should only be used with the following pens:

• JuniorSTAR which delivers Lantus in 0.5 unit dose increments
• ClikSTAR, Tactipen, Autopen 24, AllStar and AllStar PRO which all deliver Lantus in 1 unit dose increments. These cartridges should not be used with any other reusable pen as the dosing accuracy has only been established with the listed pens.

It is essential for patients with pre-existing or gestational diabetes to maintain good metabolic control throughout pregnancy to prevent adverse outcomes associated with hyperglycemia. Insulin requirements may decrease during the first trimester and generally increase during the second and third trimesters. Immediately after delivery, insulin requirements decline rapidly (increased risk of hypoglycaemia). Careful monitoring of glucose control is essential.

Breast-feeding It is unknown whether insulin glargine is excreted in human milk. No metabolic effects of ingested insulin glargine on the breast-fed newborn/infant are anticipated since insulin glargine as a peptide is digested into aminoacids in the human gastrointestinal tract. Breast-feeding women may require adjustments in insulin dose and diet.

Fertility Animal studies do not indicate direct harmful effects with respect to fertility.

4.7 Effects on ability to drive and use machines

The patient's ability to concentrate and react may be impaired as a result of hypoglycaemia or hyperglycaemia or, for example, as a result of visual impairment. This may constitute a risk in situations where these abilities are of special importance (e.g. driving a car or using machines).

Patients should be advised to take precautions to avoid hypoglycaemia whilst driving. This is particularly important in those who have reduced or absent awareness of the warning symptoms of hypoglycaemia or have frequent episodes of hypoglycaemia. It should be considered whether it is advisable to drive or use machines in these circumstances.

4.8 Undesirable effects

Summary of the safety profile Hypoglycaemia (very common), in general the most frequent adverse reaction of insulin therapy, may occur if the insulin dose is too high in relation to the insulin requirement (see section 4.4).

Tabulated list of adverse reactions The following related adverse reactions from clinical investigations are listed below by system organ class and in order of decreasing incidence (very common: ≥1/10; common: ≥1/100 to <1/10; uncommon: ≥1/1,000 to <1/100; rare: ≥1/10,000 to <1/1,000; very rare: <1/10,000; not known: cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

MedDRA system organ classes

Very common Common Uncommon Rare Very rare Not known

Immune system disorders

Allergic reactions Metabolism and nutrition disorders

Hypoglycaemia

Nervous system disorders

Dysgeusia

Eyes disorders Visual impairment

Retinopathy Skin and subcutaneous tissue disorders

Lipohypertro- phy

Lipoatrophy Cutaneous amyloidosis

Musculoskeletal and connective tissue disorders

Myalgia

General disorders and administration site conditions

Injection site reactions

Oedema

Description of selected adverse reactions Metabolism and nutrition disorders Severe hypoglycaemic attacks, especially if recurrent, may lead to neurological damage. Prolonged or severe hypoglycaemic episodes may be life-threatening.

In many patients, the signs and symptoms of neuroglycopenia are preceded by signs of adrenergic counter-regulation. Generally, the greater and more rapid the decline in blood glucose, the more marked is the phenomenon of counter-regulation and its symptoms (see section 4.4).

Immune system disorders Immediate-type allergic reactions to insulin are rare. Such reactions to insulin (including insulin glargine) or the excipients may, for example, be associated with generalised skin reactions, angio-oedema, bronchospasm, hypotension and shock, and may be life-threatening.

Eyes disorders A marked change in glycaemic control may cause temporary visual impairment, due to temporary alteration in the turgidity and refractive index of the lens.

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 amaurosis.

Skin and subcutaneous tissue disorders Lipodystrophy and cutaneous amyloidosis may occur at the injection site and delay local insulin absorption. Continuous rotation of the injection site within the given injection area may help to reduce or prevent these reactions (see section 4.4).

General disorders and administration site conditions

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 halfmaximal 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.

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

In clinical pharmacology studies, intravenous insulin glargine and human insulin have been shown to be equipotent when given at the same doses. As with all insulins, the time course of action of insulin glargine may be affected by physical activity and other variables.

In euglycaemic clamp studies in healthy subjects or in patients with type 1 diabetes, the onset of action of subcutaneous 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 results from a study in patients:

Activity profile 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 subcutaneous 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 such as insulin glargine may vary considerably in different individuals or within the same individual.

In a clinical study, symptoms of hypoglycaemia or counter-regulatory hormone responses were similar after intravenous insulin glargine and human insulin both in healthy volunteers and patients with type 1 diabetes.

In clinical studies, antibodies that cross-react with human insulin and insulin glargine were observed with the same frequency in both NPH-insulin and insulin glargine treatment groups.

Effects of insulin glargine (once daily) on diabetic retinopathy were evaluated in an open-label 5 year NPH-controlled study (NPH given bid) in 1024 type 2 diabetic patients in which progression of retinopathy by 3 or more steps on the Early Treatment Diabetic Retinopathy Study (ETDRS) scale was investigated by fundus photography. No significant difference was seen in the progression of diabetic retinopathy when insulin glargine was compared to NPH insulin.

The ORIGIN (Outcome Reduction with Initial Glargine INtervention) study was a multicenter, randomised, 2x2 factorial design study conducted in 12,537 participants at high cardiovascular (CV) risk with impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) (12% of participants) or type 2 diabetes mellitus treated with ≤1 antidiabetic oral agent (88% of participants). Participants were randomised (1:1) to receive insulin glargine (n=6264), titrated to reach FPG ≤95 mg/dl (5.3 mM), or standard care (n=6273). The first co-primary efficacy outcome was the time to the first occurrence of CV death, nonfatal myocardial infarction (MI), or nonfatal stroke, and the second co-primary efficacy outcome was the time to the first occurrence of any of the first co-primary events, or revascularisation procedure (coronary, carotid, or peripheral), or hospitalisation for heart failure.

Secondary endpoints included all-cause mortality and a composite microvascular outcome.

Insulin glargine did not alter the relative risk for CV disease and CV mortality when compared to standard of care. There were no differences between insulin glargine and standard care for the two co-primary outcomes; for any component endpoint comprising these outcomes; for all-cause mortality; or for the composite microvascular outcome.

Mean dose of insulin glargine by study end was 0.42 U/kg. At baseline, participants had a median HbA1c value of 6.4% and median on-treatment HbA1c values ranged from 5.9 to 6.4% in the insulin glargine group, and 6.2% to 6.6% in the standard care group throughout the duration of follow-up. The rates of severe hypoglycaemia (affected participants per 100 participant years of exposure) were 1.05 for insulin glargine and 0.30 for standard care group and the rates of confirmed non-severe hypoglycaemia were 7.71 for insulin glargine and 2.44 for standard care group. Over the course of this 6-year study, 42% of the insulin glargine group did not experience any hypoglycaemia.

At the last on-treatment visit, there was a mean increase in body weight from baseline of 1.4 kg in the insulin glargine group and a mean decrease of 0.8 kg in the standard care group.

Paediatric population In a randomised, controlled clinical study, paediatric patients (age range 6 to 15 years) with type 1 diabetes (n=349) were treated for 28 weeks with a basal-bolus insulin regimen where regular human insulin was used before each meal. Insulin glargine was administered once daily at bedtime and NPH human insulin was administered once or twice daily. Similar effects on glycohemoglobin and the incidence of symptomatic hypoglycemia were observed in both treatment groups, however fasting plasma glucose decreased more from baseline in the insulin glargine group than in the NPH group. There was less severe hypoglycaemia in the insulin glargine group as well. One hundred forty three of the patients treated with insulin glargine in this study continued treatment with insulin glargine in an uncontrolled extension study with mean duration of follow-up of 2 years. No new safety signals were seen during this extended treatment with insulin glargine.

A crossover study comparing insulin glargine plus lispro insulin to NPH plus regular human insulin (each treatment administered for 16 weeks in random order) in 26 adolescent type 1 diabetic patients aged 12 to 18 years was also performed. As in the paediatric study described above, fasting plasma glucose reduction from baseline was greater in the insulin glargine group than in the NPH group. HbA1c changes from baseline were similar between treatment groups; however blood glucose values

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

5 ml vial, cartridge, SoloStar pre-filled pen Zinc chloride Metacresol Glycerol Hydrochloric acid (for pH adjustment) Sodium hydroxide (for pH adjustment) Water for injections

10 ml vial Zinc chloride Metacresol Glycerol Hydrochloric acid (for pH adjustment) Polysorbate 20 Sodium hydroxide (for pH adjustment) Water for injections

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products.

Lantus 100 units/ml solution for injection in a vial It is important to ensure that syringes do not contain traces of any other material.

6.3 Shelf-life

Lantus 100 units/ml solution for injection in a vial 5 ml vial 2 years.

10 ml vial 3 years.

Shelf-life after first use of the vial 5 ml vial The medicinal product may be stored for a maximum of 4 weeks not above 25°C and away from direct heat or direct light. Keep the vial in the outer carton in order to protect from light.

10 ml vial The medicinal product may be stored for a maximum of 4 weeks not above 30°C and away from direct heat or direct light. Keep the vial in the outer carton in order to protect from light.

It is recommended that the date of the first use from the vial be noted on the label.

Lantus 100 units/ml solution for injection in a cartridge, Lantus SoloStar 100 units/ml solution for injection in a pre-filled pen 3 years.

Shelf-life after first use of the cartridge or pen The medicinal product may be stored for a maximum of 4 weeks not above 30°C and away from direct heat or direct light. The pen containing a cartridge or the pens in use must not be stored in the refrigerator. The pen cap must be put back on the pen after each injection in order to protect from light.

6.4 Special precautions for storage

Unopened vials, unopened cartridges, not in-use SoloStar pens Store in a refrigerator (2°C-8°C). Do not freeze or place next to the freezer compartment or a freezer pack. Keep the vial, cartridge or SoloStar pre-filled pen in the outer carton in order to protect from light.

Opened vials, in-use cartridges or SoloStar pens For storage conditions after first opening of this medicinal product, see section 6.3.

6.5 Nature and contents of container

Lantus 100 units/ml solution for injection in a vial 5 ml vial Type 1 colourless glass vial with a flanged cap (aluminium), a stopper (chlorobutyl rubber (type 1)) and a tear-off cap (polypropylene) containing 5 ml of solution. Packs of 1, 2, 5 and 10 vials

10 ml vial Type 1 colourless glass vial with a flanged cap (aluminium), a stopper (type 1, laminate of polyisoprene and bromobutyl rubber) and a tear-off cap (polypropylene) containing 10 ml of solution. Pack of 1 vial. Not all pack sizes may be marketed.

Lantus 100 units/ml solution for injection in a cartridge Type 1 colourless glass cartridge with a black plunger (bromobutyl rubber) and a flanged cap (aluminium) with a stopper (bromobutyl or laminate of polyisoprene and bromobutyl rubber) containing 3 ml of solution. Packs of 1, 3, 4, 5, 6, 8, 9 and 10 cartridges. Not all pack sizes may be marketed

Lantus SoloStar 100 units/ml solution for injection in a pre-filled pen Type 1 colourless glass cartridge with a black plunger (bromobutyl rubber) and a flanged cap (aluminium) with a stopper (bromobutyl or laminate of polyisoprene and bromobutyl rubber) containing 3 ml of solution. The cartridge is sealed in a disposable pen injector. Needles are not included in the pack. Packs of 1, 3, 4, 5, 6, 8, 9 and 10 SoloStar pre-filled pens. Not all pack sizes may be marketed

6.6 Special precautions for disposal and other handling

Inspect Lantus 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. Since Lantus is a solution, it does not require resuspension before use. 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. Insulin label must always be checked before each injection to avoid medication errors between insulin glargine and other insulins (see section 4.4).

Lantus 100 units/ml solution for injection in a cartridge Insulin pen Lantus 100 units/ml in cartridges is only suitable for subcutaneous injections from a reusable pen. If administration by syringe is necessary, a vial should be used. The Lantus cartridges are to be used only in conjunction with the pens: ClikSTAR, Autopen 24, Tactipen, AllStar, AllStar PRO or JuniorSTAR (see section 4.2 and 4.4). Not all of these pens may be marketed in your country. The pen should be used as recommended in the information provided by the device manufacturer.

ANNEX II

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE

SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR

BATCH RELEASE

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY

AND USE

C. OTHER CONDITIONS AND REQUIREMENTS OF THE

MARKETING AUTHORISATION

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE

SAFE AND EFFECTIVE USE OF THE MEDICINAL

PRODUCT

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND

MANUFACTURER RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer of the biological active substance

Sanofi-Aventis Deutschland GmbH Industriepark Höchst Brüningstraße 50 D-65926 Frankfurt / Main Germany

Name and address of the manufacturer responsible for batch release

Sanofi-Aventis Deutschland GmbH Industriepark Höchst Brüningstraße 50 D-65926 Frankfurt / Main Germany

The printed package leaflet of the medicinal product must state the name and address of the manufacturer responsible for the release of the concerned batch.

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

Medicinal product subject to medical prescription

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING

AUTHORISATION

• Periodic safety update reports (PSURs)

The marketing authorisation holder shall submit PSURs for this product in accordance with the requirements set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-portal.

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND

EFFECTIVE USE OF THE MEDICINAL PRODUCT

• Risk management plan (RMP)

The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent updates of the RMP.

An updated RMP should be submitted:

• At the request of the European Medicines Agency;
• Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached.

If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the same time.

A. LABELLING

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER CARTON (5 ml vial)

1. NAME OF THE MEDICINAL PRODUCT

Lantus 100 units/ml solution for injection in a vial insulin glargine

2. STATEMENT OF ACTIVE SUBSTANCE(S)

1 ml contains 100 units (3.64 mg) insulin glargine.

3. LIST OF EXCIPIENTS

Excipients: zinc chloride, metacresol, glycerol, hydrochloric acid and sodium hydroxide (for pH adjustment) and water for injections

4. PHARMACEUTICAL FORM AND CONTENTS

Solution for injection 1 vial of 5 ml. 2 vials of 5 ml. 5 vials of 5 ml. 10 vials of 5 ml.

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use. Subcutaneous use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

Use only clear and colourless solutions.

8. EXPIRY DATE

EXP