1. Name of the medicinal product Humalog Mix50 100 units/ml suspension for injection in cartridge Humalog Mix50 100 units/ml KwikPen suspension for injection in a pre-filled pen 2. Qualitative and quantitative composition Each ml contains 100 units insulin lispro* (equivalent to 3.5 mg). Humalog Mix50 consists of 50 % insulin lispro solution and 50 % insulin lispro protamine suspension. Cartridge Each cartridge contains 300 units of insulin lispro in 3 ml suspension. KwikPen Each pre-filled pen contains 300 units of insulin lispro in 3 ml suspension. Each KwikPen delivers 1 - 60 units in steps of 1 unit. *produced in E.coli by recombinant DNA technology. For a full list of excipients, see section 6.1. 3. Pharmaceutical form Suspension for injection. White suspension. 4. Clinical particulars 4.1 Therapeutic indications Humalog Mix50 is indicated for the treatment of patients with diabetes mellitus who require insulin for the maintenance of normal glucose homeostasis. 4.2 Posology and method of administration Posology The dosage should be determined by the physician, according to the requirement of the patient. Humalog Mix50 may be given shortly before meals. When necessary, Humalog Mix50 can be given soon after meals. Humalog Mix50 should only be given by subcutaneous injection. Under no circumstances should Humalog Mix50 be given intravenously. The rapid onset and early peak of activity of Humalog itself is observed following the subcutaneous administration of Humalog Mix50. This allows Humalog Mix50 to be given very close to mealtime. The duration of action of the insulin lispro protamine suspension component of Humalog Mix50 is similar to that of a basal insulin (NPH [isophane]). The time course of action of any insulin may vary considerably in different individuals or at different times in the same individual. As with all insulin preparations, the duration of action of Humalog Mix50 is dependent on dose, site of injection, blood supply, temperature, and physical activity. Special populations Renal impairment Insulin requirements may be reduced in the presence of renal impairment. Hepatic impairment Insulin requirements may be reduced in patients with hepatic impairment due to reduced capacity for gluconeogenesis and reduced insulin breakdown; however, in patients with chronic hepatic impairment, an increase in insulin resistance may lead to increased insulin requirements. Paediatric population Administration of Humalog Mix50 to children below 12 years of age should be considered only in case of an expected benefit when compared to soluble insulin. Method of administration Subcutaneous administration should be in the upper arms, thighs, buttocks, or abdomen. Use of injection sites should be rotated so that the same site is not used more than approximately once a month, in order to reduce the risk of lipodystrophy and cutaneous amyloidosis (see section 4.4 and 4.8). When administered subcutaneously care should be taken when injecting Humalog Mix50 to ensure that a blood vessel has not been entered. After injection, the site of injection should not be massaged. Patients must be educated to use the proper injection techniques. KwikPen The KwikPen delivers 1 – 60 units in steps of 1 unit in a single injection. The needed dose is dialled in units. The number of units is shown in the dose window of the pen. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Hypoglycaemia. 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. Under no circumstances should Humalog Mix50 be given intravenously. Transferring a patient to another type or brand of insulin Transferring a patient to another type or brand of insulin should be done under strict medical supervision. Changes in strength, brand (manufacturer), type (regular/soluble, NPH/isophane, etc.), species (animal, human, human insulin analogue), and/or method of manufacture (recombinant DNA versus animal-source insulin) may result in the need for a change in dosage. Hypoglycaemia and hyperglycaemia Conditions which may make the early warning symptoms of hypoglycaemia different or less pronounced include long duration of diabetes, intensified insulin therapy, diabetic nerve disease or medications such as beta-blockers. A few patients who have experienced hypoglycaemic reactions after transfer from animal-source insulin to human insulin have reported that the early warning symptoms of hypoglycaemia were less pronounced or different from those experienced with their previous insulin. Uncorrected hypoglycaemic or hyperglycaemic reactions can cause loss of consciousness, coma, or death. The use of dosages which are inadequate or discontinuation of treatment, especially in insulin-dependent diabetics, may lead to hyperglycaemia and diabetic ketoacidosis; conditions which are potentially lethal. Injection technique 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. Insulin requirements and dosage adjustment Insulin requirements may be increased during illness or emotional disturbances. Adjustment of dosage may also be necessary if patients undertake increased physical activity or change their usual diet. Exercise taken immediately after a meal may increase the risk of hypoglycaemia. Combination of Humalog Mix50 with pioglitazone Cases of cardiac failure have been reported when pioglitazone was used in combination with insulin, especially in patients with risk factors for development of cardiac heart failure. This should be kept in mind, if treatment with the combination of pioglitazone and Humalog Mix50 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. Avoidance of medication errors Patients must be instructed to always check the insulin label before each injection to avoid accidental mix-ups between the two different strengths of Humalog KwikPen as well as other insulin products. Patients must visually verify the dialled units on the dose counter of the pen. Therefore, the requirement for patients to self-inject is that they can read the dose counter on the pen. Patients who are blind or have poor vision must be instructed to always get help/assistance from another person who has good vision and is trained in using the insulin device. Excipients This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e., essentially “sodium-free”. 4.5 Interaction with other medicinal products and other forms of interaction Insulin requirements may be increased by substances with hyperglycaemic activity, such as oral contraceptives, corticosteroids, or thyroid replacement therapy, danazol, beta2 stimulants (such as ritodrine, salbutamol, terbutaline). Insulin requirements may be reduced in the presence of substances with hypoglycaemic activity, such as oral hypoglycaemics, salicylates (for example, acetylsalicylic acid), sulpha antibiotics, certain antidepressants, (monoamine oxidase inhibitors, selective serotonin reuptake inhibitors), certain angiotensin converting enzyme inhibitors (captopril, enalapril), angiotensin II receptor blockers, beta-blockers, octreotide or alcohol. Mixing Humalog Mix50 with other insulins has not been studied. The physician should be consulted when using other medications in addition to Humalog Mix50 (see section 4.4). 4.6 Fertility, pregnancy and lactation Pregnancy Data on a large number of exposed pregnancies do not indicate any adverse effect of insulin lispro on pregnancy or on the health of the foetus/newborn. It is essential to maintain good control of the insulin-treated (insulin-dependent or gestational diabetes) patient throughout pregnancy. Insulin requirements usually fall during the first trimester and increase during the second and third trimesters. Patients with diabetes should be advised to inform their doctor if they are pregnant or are contemplating pregnancy. Careful monitoring of glucose control, as well as general health, is essential in pregnant patients with diabetes. Breast-feeding Patients with diabetes who are breast-feeding may require adjustments in insulin dose, diet or both. Fertility Insulin lispro did not induce fertility impairment in animal studies (see section 5.3). 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. This may constitute a risk in situations where these abilities are of special importance (e.g. driving a car or operating machinery). 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 signs of hypoglycaemia or have frequent episodes of hypoglycaemia. The advisability of driving should be considered in these circumstances. 4.8 Undesirable effects Summary of safety profile Hypoglycaemia is the most frequent undesirable effect of insulin therapy that a patient with diabetes may suffer. Severe hypoglycaemia may lead to loss of consciousness, and in extreme cases, death. No specific frequency for hypoglycaemia is presented, since hypoglycaemia is a result of both the insulin dose and other factors e.g. a patient`s level of diet and exercise. Tabulated list of adverse reactions The following related adverse reactions from clinical trials are listed below as MedDRA preferred term 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 form the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.