NovoMix 30

NovoMix 30

insulin aspart + insulin aspart protamine

Manufacturer:

Novo Nordisk

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Insulin aspart.
Description
Each flexpen of suspension for injection contains 30% soluble insulin aspart and 70% protamine crystallised insulin aspart.
It also contains the following excipients: Glycerol, phenol, metacresol, zinc (as chloride), sodium chloride, disodium phosphate dihydrate, protamine sulfate, sodium hydroxide and hydrochloric acid (for pH adjustment), and water for injections.
Insulin aspart is produced by recombinant DNA technology in Saccharomyces cerevisiae.
One unit of insulin aspart corresponds to 6 nmol, salt-free anhydrous insulin aspart 0.035 mg.
One pre-filled pen contains 3 mL equivalent to 300 U.
Action
Pharmacotherapeutic Group: Antidiabetic agent. Insulins and analogues for injection, intermediate-acting combined with fast-acting. ATC Code: A10AD05.
Pharmacology: Pharmacodynamics: Novomix 30 is a biphasic suspension of insulin aspart (rapid-acting human insulin analogue) and protamine-crystallised insulin aspart (intermediate-acting human insulin analogue).
The blood glucose-lowering effect of insulin occurs when the molecules facilitate the uptake of glucose by binding to insulin receptors on muscle and fat cells, and simultaneously inhibit the output of glucose from the liver.
NovoMix 30 is a biphasic insulin which contains 30% soluble insulin aspart. This has a rapid onset of action, thus allowing it to be given closer to a meal (within 0-10 min of the meal) when compared to soluble human insulin. The crystalline phase (70%) consists of protamine-crystallised insulin aspart which has an activity profile that is similar to that of human neutral protamine hagedorn (NPH) insulin.
When NovoMix 30 is injected SC, the onset of action will occur within 10-20 min of injection. The maximum effect is exerted between 1 and 4 hrs after injection. The duration of action is up to 24 hrs.
In a 3-month trial in patients with types 1 and 2 diabetes, NovoMix 30 showed equal control of glycosylated haemoglobin compared to treatment with biphasic human insulin 30. Insulin aspart is equipotent to human insulin on a molar basis.
In 1 study, 341 patients with type 2 diabetes were randomised to treatment with NovoMix 30 either alone or in combination with metformin or to metformin together with sulfonylurea. The primary efficacy variable glycosylated haemoglobin (HbA1C) after 16 weeks of treatment did not differ between patients with Novomix 30 combined with metformin and patients with metformin plus sulfonylurea. In this trial, 57% of the patients had baseline HbA1C above 9%; in these patients treatment with NovoMix 30 in combination with metformin resulted in significantly lower HbA1C than metformin in combination with sulfonylurea.
In 1 study, patients with type 2 diabetes, insufficiently controlled on oral hypoglycaemic agents alone, were randomised to treatment with NovoMix 30 twice daily (117 patients) or insulin glargine once daily (116 patients). After 28 weeks treatment following the dosing guideline, the mean reduction in HbA1C was 2.8% with NovoMix 30 (mean at baseline=9.7%). With NovoMix 30, 66% and 42% of the patients reached HbA1C levels <7% and 6.5%, respectively, and the mean FPG was reduced about 7 mmol/L (from 14 mmol/L at baseline to 7.1 mmol/L).
Children and Adolescents: A 16-week clinical trial comparing postprandial glycaemic control of meal-related NovoMix 30 with meal-related human insulin/biphasic human insulin 30 and bedtime NPH insulin was performed in 167 subjects 10-18 years. Mean HbA1C remained similar to baseline throughout the trial in both treatment groups, and there was no difference in hypoglycaemia rate with NovoMix 30 or biphasic human insulin 30.
In a smaller (54 subjects) and younger (6-12 years) population, treated in a double-blind, cross-over trial (12 weeks on each treatment) the rate of hypoglycaemic episodes and the postprandial glucose increase was significantly lower with NovoMix 30 compared to biphasic human insulin 30. Final HbA1C was significantly lower in the biphasic human insulin 30-treated group compared with NovoMix 30.
Pharmacokinetics: In insulin aspart, substitution of amino acid proline with aspartic acid at position B28 reduces the tendency to form hexamers in the soluble fraction of NovoMix 30, as compared with soluble human insulin. The insulin aspart in the soluble phase of NovoMix 30 comprises 30% of the total insulin; this is absorbed more rapidly from the subcutaneous layer than the soluble insulin component of biphasic human insulin. The remaining 70% is in crystalline form as protamine-crystallised insulin aspart; this has a prolonged absorption profile similar to human NPH insulin.
The maximum serum insulin concentration is, on average, 50% higher with NovoMix 30 than with biphasic human insulin 30. The time to maximum concentration is, on average, ½ of that for biphasic human insulin 30. In healthy volunteers, a mean maximum serum concentration of 140±32 pmol/L was reached about 60 min after SC dose of 0.2 units/kg body weight. The mean t½ of NovoMix 30, reflecting the absorption rate of the protamine bound fraction, was about 8-9 hrs. Serum insulin levels returned to baseline 15-18 hrs after SC dose. In type 2 diabetic patients, the maximum concentration was reached about 95 min after dosing, and concentrations well >0 for not less than 14 hrs post-dosing were measured.
Children and Adolescents: The pharmacokinetics of NovoMix 30 has not been investigated in children or adolescents. However, the pharmacokinetic and pharmacodynamic properties of soluble insulin aspart have been investigated in children 6-12 years and adolescents 13-17 years with type 1 diabetes. Insulin aspart was rapidly absorbed in both age groups, with similar tmax as in adults. However, peak plasma concentration (Cmax) differed between the age groups, stressing the importance of the individual titration of insulin aspart.
The pharmacokinetics of NovoMix 30 has not been investigated in elderly or patients with impaired renal or liver function.
Toxicology: Preclinical Safety Data: Nonclinical data with insulin aspart reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated-dose toxicity, genotoxicity and toxicity to reproduction.
In in vitro tests, including binding to insulin and IGF-1 receptor sites and effects on cell growth, insulin aspart behaved in a manner that closely resembled human insulin. Studies also demonstrate that the dissociation of binding to the insulin receptor of insulin aspart is equivalent to human insulin.
Indications/Uses
Treatment of diabetes mellitus.
Dosage/Direction for Use
Dosage of NovoMix 30 is individual and determined in accordance with the needs of the patient.
In patients with type 2 diabetes, NovoMix 30 can be given in monotherapy or in combination with metformin when the blood glucose is inadequately controlled with oral antidiabetic drugs alone. For patients with type 2 diabetes, the recommended starting dose of NovoMix 30 is 6 units at breakfast and 6 units at dinner (evening meal). NovoMix 30 can also be initiated once daily 12 units at dinner (evening meal). When using NovoMix 30 once daily, it is generally recommended to move to twice daily when reaching 30 units splitting the dose to equal breakfast and dinner doses. If twice-daily dosing with NovoMix 30 results in recurrent daytime hypoglycaemic episodes, the morning dose can be split into morning and lunchtime doses (thrice-daily dosing).
The following titration guideline is recommended for dose adjustment: (See table.)

Click on icon to see table/diagram/image

The lowest of the 3 previous days' pre-meal levels should be used. The dose should not be increased if hypoglycaemia occurred within these days. Dose adjustments can be made once a week until target HbA1C is reached. Pre-meal blood glucose levels should be used to evaluate the adequacy of the preceding dose.
In patients with type 1 diabetes, the individual insulin requirement is usually between 0.5 unit/kg/day and 1 unit/kg/day. NovoMix 30 may fully or partially meet its requirement. The daily insulin requirement may be higher in patients with insulin resistance (eg, due to obesity) and lower in patients with residual endogenous insulin production. NovoMix 30 can be used in elderly patients; however, there is limited experience with the use of NovoMix 30 in combination with metformin in patients >75 years.
Administration: NovoMix 30 has a faster onset of action than biphasic human insulin and should generally be given immediately before a meal. When necessary, NovoMix 30 can be given soon after a meal.
NovoMix 30 is administered SC in the thigh or in the abdominal wall. If convenient, the gluteal or deltoid region may be used. Injection sites should be rotated within the same region. As with all insulins, the duration of action will vary according to the dose, injection site, blood flow, temperature and level of physical activity. The influence of different injection sites on the absorption of NovoMix 30 has not been investigated. NovoMix 30 should never be administered IV.
Renal or hepatic impairment may reduce the patient's insulin requirements.
NovoMix 30 can be used in children and adolescents ≥10 years with type 1 diabetes when premixed insulin is preferred. For children 6-9 years, limited clinical data exists.
Overdosage
A specific overdose for insulin cannot be defined, however, hypoglycaemia may develop over sequential stages if too high doses relative to the patient's requirements are administered: Mild hypoglycaemic episodes can be treated by oral administration of glucose or sugary products. It is therefore recommended that the diabetic patient constantly carries sugar-containing products.
Severe hypoglycaemic episodes, where the patient has become unconscious, can be treated by glucagon (0.5-1 mg) given IM or SC by a trained person, or glucose given IV by a medical professional. Glucose must also be given IV if the patient does not respond to glucagon within 10-15 min. Upon regaining consciousness, administration of oral carbohydrate is recommended for the patient in order to prevent relapse.
Contraindications
Hypersensitivity to insulin aspart or any of the excipients of NovoMix 30. Hypoglycaemia.
Special Precautions
Inadequate dosing or discontinuation of treatment especially insulin-dependent diabetics may lead to hyperglycaemia and diabetic ketoacidosis; conditions which are potentially lethal.
Omission of a meal or unplanned, strenuous physical exercise may lead to hypoglycaemia.
Compared with biphasic human insulin, NovoMix 30 may have a more pronounced glucose lowering effect up to 6 hrs after injection. This may have to be compensated for by the individual patient, through adjustment of insulin dose and/or food intake.
Patients whose blood glucose control is greatly improved eg, by intensified insulin therapy, may experience a change in their usual warning symptoms of hypoglycaemia and should be advised accordingly.
Tighter control of glucose levels can increase the potential for hypoglycaemic episodes and therefore require special attention during dose intensification.
NovoMix 30 should be administered in immediate relation to a meal. The rapid onset of action should therefore be considered in patients with concomitant diseases or treatment with other medicinal products where a delayed absorption of food might be expected.
Concomitant illness, especially infections, usually increases the patient's insulin requirements.
When patients are transferred between different types of insulin products, the early warning symptoms of hypoglycaemia may change or become less pronounced than those experienced with their previous insulin.
Transferring a patient to a new type or brand of insulin should be done under strict medical supervision. Changes in strength, brand (manufacturer), type, origin (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. Patients taking NovoMix 30 may need a change in dosage from that used with their usual insulins. If dosage adjustment is needed, it may be done with the 1st dose or during the 1st few weeks or months.
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.
Insulin suspensions are not to be used in insulin infusion pumps.
As with any insulin therapy, injection site reactions may occur and include pain, itching, hives, swelling and inflammation. Continuous rotation of the injection site within a given area may help to reduce or prevent these reactions. Reactions usually resolve in a few days to a few weeks. On rare occasions, injection site reactions may require discontinuation of NovoMix 30.
Effects on the Ability to Drive or Operate Machinery: No studies on the effects on the ability to drive and use machines have been reported.
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 (eg, driving a car or operating machinery).
Patients should be advised to take precautions in order 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.
Use in pregnancy & lactation: There is limited clinical experience with NovoMix 30 in pregnancy.
Animal reproduction studies have not revealed any differences between insulin aspart and human insulin regarding embryotoxicity or teratogenicity.
In general, intensified blood glucose control and monitoring of pregnant women with diabetes are recommended throughout pregnancy and when contemplating pregnancy. Insulin requirements usually fall in the 1st trimester and increase subsequently during the 2nd and 3rd trimesters. After delivery, insulin requirements return rapidly to pre-pregnancy levels.
There are no restrictions on treatment with NovoMix 30 during lactation. Insulin treatment of the breastfeeding mother presents no risk to the baby. However, the NovoMix 30 dosage may need to be adjusted.
Use in children: No studies have been performed with NovoMix 30 in children <6 years.
Use In Pregnancy & Lactation
There is limited clinical experience with NovoMix 30 in pregnancy.
Animal reproduction studies have not revealed any differences between insulin aspart and human insulin regarding embryotoxicity or teratogenicity.
In general, intensified blood glucose control and monitoring of pregnant women with diabetes are recommended throughout pregnancy and when contemplating pregnancy. Insulin requirements usually fall in the 1st trimester and increase subsequently during the 2nd and 3rd trimesters. After delivery, insulin requirements return rapidly to pre-pregnancy levels.
There are no restrictions on treatment with NovoMix 30 during lactation. Insulin treatment of the breastfeeding mother presents no risk to the baby. However, the NovoMix 30 dosage may need to be adjusted.
Adverse Reactions
Adverse drug reactions observed in patients using NovoMix 30 are mainly dose-dependent and due to the pharmacologic effect of insulin. As for other insulin products, hypoglycaemia, in general is the most frequently adverse reaction. It may occur if the insulin dose is too high in relation to the insulin requirement and therefore require special attention during dose intensification. Severe hypoglycaemia may lead to unconsciousness and/or convulsions and may result in temporary or permanent impairment of brain function or even death.
In clinical trials and during marketed use the frequency varies with patient population and dose regimens, therefore, no specific frequency can be presented.
During clinical trials, the overall rates of hypoglycaemia did not differ between patients treated with insulin aspart compared to human insulin.
Frequencies of adverse drug reactions from clinical trials, which by an overall judgement are considered related to insulin aspart are listed as follows: The frequencies are defined as: Uncommon (>1/1000, <1/100) and rare (>1/10,000, <1/1000). Isolated spontaneous cases are presented as very rare defined as (<1/10,000) including isolated reports. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Immune System Disorders: Uncommon: Urticaria, rash, eruptions. Very Rare: Anaphylactic reactions. Symptoms of generalised hypersensitivity may include generalised skin rash, itching, sweating, gastrointestinal upset, angioneurotic oedema, difficulties in breathing, palpitation and reduction in blood pressure. Generalised hypersensitivity reactions are potentially life-threatening.
Nervous System Disorders: Rare: Peripheral neuropathy. Fast improvement in blood glucose control may be associated with a condition termed acute painful neuropathy, which is usually reversible.
Eye Disorders: Uncommon: Refraction disorder. Refraction anomalies may occur upon initiation of insulin therapy. These symptoms are usually of transitory nature. Uncommon: Diabetic retinopathy. 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 worsening of diabetic retinopathy.
Skin and Subcutaneous Tissue Disorders: Uncommon: Lipodystrophy. Lipodystrophy may occur at the injection site as a consequence of failure to rotate injection sites within an area. Uncommon: Local hypersensitivity. Local hypersensitivity reactions (redness, swelling and itching at the injection site) may occur during treatment with insulin. These reactions are usually transitory and they normally disappear during continued treatment.
General Disorders and Administration Site Conditions: Uncommon: Oedema. Oedema may occur upon initiation of insulin therapy. These symptoms are usually of transitory nature. Oedema and weight increase may occur when NovoMix 30 is used in combination with oral antidiabetic drugs.
Drug Interactions
A number of medicinal products are known to interact with the glucose metabolism.
The following substances may reduce the patient's insulin requirements: Oral antidiabetic drugs (OADs), monoamine oxidase inhibitors (MAOIs), nonselective β-adrenergic blocking agents, angiotensin-converting enzyme (ACE) inhibitors, salicylates, alcohol, anabolic steroids and sulfonamides.
The following substances may increase the patient's insulin requirements: Oral contraceptives, thiazides, glucocorticoids, thyroid hormones, sympathomimetics, growth hormone and danazol.
Beta-blocking agents may mask the symptoms of hypoglycaemia and delay recovery from hypoglycaemia.
Octreotide/lanreotide may both increase and decrease insulin requirement.
Alcohol may intensify and prolong the glucose lowering effect of insulin.
Incompatibilities: In the absence of compatibility studies, NovoMix 30 must not be mixed with other medicinal products.
Caution For Usage
Instructions for Use, Handling & Disposal: NovoMix 30 FlexPen is a unique dial-a-dose insulin pen. Doses from 1-60 units in increments of 1 unit can be selected. NovoMix 30 FlexPen is designed to be used with NovoFine or NovoTwist disposable needles up to length of 8 mm. As a precautionary measure, always carry a spare insulin delivery device in case NovoMix 30 FlexPen is lost or damaged.
Getting Started: Check the label to ensure the correct type of insulin. Always use a new needle for each injection to prevent contamination.
Preparing NovoMix 30 FlexPen: Before the 1st injection with a new NovoMix 30 Flexpen, the insulin must be re-suspended. Let the insulin reach room temperature before using it. This makes it easier to re-suspend. Pull off the pen cap.
Roll the pen between the palms 10 times. It is important that the pen is kept horizontal.
Then move the pen up and down 10 times between 2 positions, so the glass ball moves from 1 end of the cartridge to the other. Repeat rolling and moving the pen until the liquid appears uniformly white and cloudy.
For every following injection, move the pen up and down between the 2 positions at least 10 times until the liquid appears uniformly white and cloudy. After having re-suspended the insulin, complete all the following steps of injection without delay.
Always check if there are at least 12 units of insulin left in the cartridge to allow re-suspension. If there are <12 units left, use a new FlexPen.
Attaching a Needle: Disinfect the rubber membrane with a medicinal swab.
Remove the protective tab from a new disposable needle. Screw the needle straight and tightly onto NovoMix 30 FlexPen.
Pull off the big outer needle cap and keep it for later.
Pull off the inner needle cap and dispose of it.
Always use a new needle for each injection to prevent contamination. Be careful not to bend or damage the needle before use. To reduce the risk of unexpected needle sticks, never put the inner needle cap back on when removing it from the needle.
Checking the Insulin Flow: Prior to each injection, small amounts of air may collect in the cartridge during normal use. To avoid injection of air and ensure proper dosing: Turn the dose selector to select 2 units.
Hold NovoMix 30 FlexPen with the needle pointing upwards and tap the cartridge gently with a finger a few times to make any air bubbles collect at the top of the cartridge.
Keeping the needle upwards, press the push-button all the way in. The dose selector returns to 0. A drop of insulin should appear at the needle tip. If not, change the needle and repeat the procedure no more than 6 times.
If a drop of insulin still does not appear, the pen is defective, and a new 1 must be used.
Selecting the Dose: Check that the dose selector is set at 0.
Turn the dose selector to select the number of units needed to inject.
The dose can be corrected either up or down by turning the dose selector in either direction until the correct dose lines up with the pointer. When turning the dose selector, be careful not to push the push-button as insulin will come out.
A dose larger than the number of units left in the cartridge cannot be selected.
Do not use the residual scale to measure the dose of insulin.
Making the Injection: Insert the needle into the skin. Use the injection technique shown by the doctor or nurse.
Inject the dose by pressing the push-button all the way in until 0 lines up with the pointer. Be careful only to push the push-button when injecting.
Turning the dose selector will not inject insulin.
Keep the push-button fully depressed after the injection until the needle has been withdrawn from the skin.
The needle must remain under the skin for at least 6 sec. This will ensure that the full dose has been injected.
Lead the needle tip into the big outer needle cap without touching the big outer needle cap. When the needle is covered, carefully push the big outer needle cap completely on and then unscrew the needle.
Dispose it carefully and put the pen cap back on.
Always remove the needle after each injection and store NovoMix 30 FlexPen without the needle attached. Otherwise, the liquid may leak out which can cause inaccurate dosing.
Caregivers should be most careful when handling used needles to avoid needle sticks.
Dispose the used FlexPen carefully without the needle attached.
Do not share NovoMix 30 FlexPen with anyone else.
Maintenance: NovoMix 30 FlexPen is designed to work accurately and safely. It must be handled with care. If it is dropped or crushed, there is a risk of damage and leakage of insulin.
Clean the exterior of NovoMix 30 FlexPen by wiping it with a medicinal swab.
Do not soak it, wash or lubricate it as it may damage the pen.
Do not refill NovoMix 30 FlexPen.
Do Not Use NovoMix 30: In insulin infusion pumps; if FlexPen is dropped, damaged or crushed as there is a risk of leakage of insulin; if it has not been stored correctly or has been frozen; if the insulin is not uniformly white and cloudy when it is re-suspended and if clumps of material are present or if solid white particles stick to the bottom or the wall of the cartridge giving a frosted appearance.
NovoMix 30 FlexPen is for SC injection. Never inject the insulin directly into a vein or muscle.
Always vary the sites to inject, to avoid lumps. The best places to give an injection are: The front of the waist (abdomen); the buttocks; the front of the thighs or upper arms. The insulin will work more quickly if injected around the waist.
Special Precautions for Disposal and Other Handling: NovoFine and NovoTwist needles are designed to be used with the pre-filled pen. Detailed instructions accompanying the NovoMix 30 FlexPen must be followed.
NovoMix 30 FlexPen is for use by 1 person only.
The NovoMix 30 FlexPen must not be refilled.
The necessity of re-suspending the NovoMix 30 suspension immediately before use is to be stressed to the patient. The re-suspended liquid must appear uniformly white and cloudy.
NovoMix 30 FlexPen which has been frozen must not be used.
The patient should be advised to discard the needle after each injection.
Any unused product or waste material should be disposed of in accordance with local requirements.
Storage
Store at 2-8°C not in or near the freezer section or cooling element (in a refrigerator). Do not freeze.
In order to protect from light, keep the cap on when NovoMix 30 FlexPen is not in use. Protect from light. After removing NovoMix 30 FlexPen from the refrigerator, it is recommended to allow it to reach room temperature before re-suspending the insulin as instructed for the 1st time use.
NovoMix 30 FlexPen in use or carried as a spare can be kept at ambient temperature (below 30°C). Do not refrigerate. The in-use shelf-life is 4 weeks.
ATC Classification
A10AD05 - insulin aspart ; Belongs to the class of intermediate-acting combined with fast-acting insulins and analogues. Used in the treatment of diabetes.
Presentation/Packing
FlexPen susp for inj (pre-filled pen, white) 3 mL x 5's.
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