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Active substance(s): INSULIN HUMAN (PYR)

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Human Mixtard 30 Pen 100 IU/ml
Suspension for injection in a pre-filled pen


Insulin human, rDNA (produced by recombinant DNA technology in Saccharomyces
1 ml contains 100 IU of insulin human
1 pre-filled pen contains 3 ml equivalent to 300 IU
One IU (International Unit) corresponds to 0.035 mg of anhydrous human insulin.
Mixtard is a mixture of dissolved insulin and isophane (NPH) insulin.
Mixtard 30 consists of 30% dissolved insulin and 70% isophane insulin.
For excipients, see Section 6.1 List of excipients.


Suspension for injection in a pre-filled pen.
Mixtard is a cloudy, white, aqueous suspension.




Therapeutic indications
Treatment of diabetes mellitus.


Posology and method of administration
Mixtard is a dual-acting insulin. It is biphasic formulation containing fast-acting and longacting insulin.
Premixed insulins are usually given once or twice daily when a rapid initial effect together
with a more prolonged effect is desired.
Dosage is individual and determined by the physician in accordance with the needs of the
The average range of total daily insulin requirement for maintenance therapy in type 1
diabetic patients lies between 0.5 and 1.0 IU/kg. In pre-pubertal children it usually varies
from 0.7 to 1.0 IU/kg. .During the period of partial remission, the insulin requirements can

be much lower, whereas in insulin resistant states, e.g. during puberty or due to obesity, the
daily insulin requirement may be substantially higher.
Initial dosages for type 2 diabetic patients are often lower, e.g. 0.3 to 0.6 IU/kg/day.
In patients with diabetes mellitus optimised glycaemic control delays the onset and slows the
progression of late diabetic complications. Blood glucose monitoring is therefore
An injection should be followed within 30 minutes by a meal or snack containing
Dosage adjustment
Concomitant illness, especially infections and feverish conditions, usually increases the
patient's insulin requirement.
Renal or hepatic impairment may reduce insulin requirement.
Adjustment of dosage may also be necessary if patients change physical activity or their
usual diet.
Dosage adjustment may be necessary when transferring patients from one insulin
preparation to another (see section 4.4 Special warnings and special precautions for use).
For subcutaneous use.
Mixtard is usually administered subcutaneously in the thigh or abdominal wall. If
convenient, the gluteal region or the deltoid region may also be used.
Subcutaneous injection into the abdominal wall ensures a faster absorption than from other
injection sites.
Injection into a lifted skin fold minimises the risk of unintended intramuscular injection.
Keep the needle under the skin for at least 6 seconds to make sure the entire dose is injected.
Injection sites should be rotated within an anatomic region in order to avoid lipodystrophy.
Insulin suspensions are never to be administered intravenously.
Mixtard is accompanied by a package leaflet with detailed instruction for use to be followed.
Human Mixtard Pen is designed to be used with NovoFine needles.
The Pen device delivers 2-78 units in increments of 2 units.
The pens should be primed before injection so that the dose selector returns to zero and a
drop of insulin appears at the needle top.
The dose is set by turning the selector, which returns to zero during the injection.


Hypersensitivity to human insulin or to any of the excipients (see section 6.1 List of


Special Warnings and Special Precautions for Use
Inadequate dosage or discontinuation of treatment, especially in type 1 diabetes, may lead to
hyperglycaemia and diabetic ketoacidosis.
Usually the first symptoms of hyperglycaemia set in gradually, over a period of hours or
days. They include thirst, increased frequency of urination, nausea, vomiting, drowsiness,
flushed dry skin, dry mouth, loss of appetite as well as acetone odour of breath (see section
4.8 Undesirable effects).
In type 1 diabetes, untreated hyperglycaemic events eventually lead to diabetic ketoacidosis,
which is potentially lethal.
Hypoglycaemia may occur if the insulin dose is too high in relation to the insulin
Hypoglycaemia can generally be corrected by immediate carbohydrate intake. In order to be
able to take action immediately, patients should carry glucose with them at all times.
Omission of a meal or unplanned, strenuous physical exercise may lead to hypoglycaemia.
Patients whose blood glucose control is greatly improved e.g. by intensified insulin therapy,
may experience a change in their usual warning symptoms of hypoglycaemia and should be
advised accordingly (see section 4.8 Undesirable effects).
Usual warning symptoms may disappear in patients with longstanding diabetes.
Transferring a patient to another type or brand of insulin should be done under strict medical
supervision. Changes in strength, brand (manufacturer), type (fast-, dual-, long-acting
insulin etc.), species (animal, human or analogue insulin) and/or method of manufacture
(recombinant DNA versus animal source insulin) may result in a change in dosage.
If an adjustment is needed when switching the patients to Mixtard, it may occur with the
first dose or during the first several weeks or months.
A few patients who have experienced hypoglycaemic reactions after transfer from animal
source insulin have reported that early warning symptoms of hypoglycaemia were less
pronounced or different from those experienced with their previous insulin.
Before travelling between different time zones, the patient should be advised to consult the
doctor, since this may mean that the patient has to take insulin and meals at different times.
Insulin suspensions are not to be used in insulin infusion pumps.
Mixtard contains metacresol, which may cause allergic reactions.


Interaction with other Medicinal Products and Other Forms of Interaction
A number of medicinal products are known to interact with the glucose metabolism. The
physician must therefore take possible interactions into account and should always ask their
patients about any medicinal products they take.
The following substances may reduce insulin requirement:
Oral hypoglycaemic agents (OHA), monoamine oxidase inhibitors (MAOI), non-selective
beta-blocking agents, angiotensin converting enzyme (ACE) inhibitors, salicylates and
The following substances may increase insulin requirement:

Thiazides, glucocorticoids, thyroid hormones and beta-sympathomimetics, growth hormone
and danazol.
Beta-blocking agents may mask the symptoms of hypoglycaemia and delay recovery from
Octreotide/lanreotide may both decrease and increase insulin requirement.
Alcohol may intensify and prolong the hypoglycaemic effect of insulin.


Pregnancy and Lactation
There are no restrictions on treatment of diabetes with insulin during pregnancy, as insulin
does not pass the placental barrier.
Both hypoglycaemia and hyperglycaemia, which can occur in inadequately controlled
diabetes therapy, increase the risk of malformations and death in utero. Intensified control in
the treatment of pregnant women with diabetes is therefore recommended throughout
pregnancy and when contemplating pregnancy.
Insulin requirements usually fall in the first trimester and increase subsequently during the
second and third trimesters.
After delivery, insulin requirements return rapidly to pre-pregnancy values.
Insulin treatment of the nursing mother presents no risk to the baby. However, the Mixtard
dosage may need to be adjusted.


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.


Undesirable effects
The most often seen undesirable effect in insulin-treated patients is a change in blood
glucose levels. From clinical investigations it is known that major hypoglycaemia, defined
as need for assistance in treatment, occurs in approximately 20% of well-controlled patients.
Based on post-marketing experience adverse drug reactions including hypoglycaemia have
been reported rarely (>1/10,000 <1/1,000). The listings below are all based on postmarketing experience and is subject to underreporting and should be interpreted in that light.
Metabolism and nutrition disorders
(>1/10,000 <1/1,000)
Change in blood


Symptoms of hypoglycaemia usually occur suddenly. They
may include cold sweats, cool pale skin, fatigue,
nervousness or tremor, anxiousness, unusual tiredness or
weakness, confusion, difficulty in concentration,
drowsiness, excessive hunger, vision changes, headache,
nausea and palpitation. Severe hypoglycaemia may lead to
unconsciousness and/or convulsions and may result in
temporary or permanent impairment of brain function or
even death.
Usually the first symptoms of hyperglycaemia set in
gradually, over a period of hours or days. They include
thirst, increased frequency of urination, nausea, vomiting,
drowsiness, flushed dry skin, dry mouth, loss of appetite as
well as acetone odour of breath.
In type 1 diabetes, untreated hyperglycaemic events
eventually lead to diabetic ketoacidosis which is potentially
For precautions see section 4.4 Special warnings and
special precautions for use.

Eye disorders
Very rare

Refraction anomalies may occur upon initiation of insulin
therapy. These symptoms are usually of transitory nature.

General disorders and administration site
Very rare

Very rare
Very rare

Very rare


Local hypersensitivity reactions (redness, swelling and
itching at the injection site) may occur during treatment
with insulin. These reactions are usually transitory and
normally they disappear during continued treatment.
Lipodystrophy may occur at the injection site as a
consequence of failure to rotate injection sites within an
Symptoms of generalised hypersensitivity may include
generalised skin rash, itching, sweating, gastrointestinal
upset, angioneurotic oedema, difficulties in breathing,
palpitation, reduction in blood pressure and fainting/loss of
consciousness. Generalised hypersensitivity reactions are
potentially life threatening.
Oedema may occur upon initiation of insulin therapy.
These symptoms are usually of transitory nature.

A specific overdose of insulin cannot be defined. However, hypoglycaemia may develop
over sequential stages:
Mild hypoglycaemic episodes can be treated by oral administration of glucose or sugary
products. It is therefore recommended that the diabetic patient constantly carries some sugar
lumps, sweets, biscuits or sugary fruit juice.

Severe hypoglycaemic episodes, where the patient has become unconscious, can be treated
by glucagon (0.5 to 1 mg) given intramuscularly or subcutaneously by a person who has
received appropriate instruction, or by glucose given intravenously by a medical
professional. Glucose must also be given intravenously, if the patient does not respond to
glucagon within 10 to 15 minutes.
Upon regaining consciousness, administration of oral carbohydrate is recommended for the
patient in order to prevent relapse.
After an injection of glucagon, the patient should be monitored in a hospital in order to find
the reason for this severe hypoglycaemia and prevent other similar episodes.




Pharmacodynamic properties
Pharmacotherapeutic group: antidiabetic agent. ATC code: A10A D01.
The blood glucose lowering effect of insulin is due to the facilitated uptake of glucose
following binding of insulin to receptors on muscle and fat cells and to the simultaneous
inhibition of glucose output from the liver.
Mixtard is a dual-acting insulin.
Onset of action is within ½ hour, reaches a maximum effect within 2-8 hours and the entire
time of duration is up to 24 hours.


Pharmacokinetic properties
Insulin in the blood stream has a half-life of a few minutes. Consequently, the time-action
profile of an insulin preparation is determined solely by its absorption characteristics.
This process is influenced by several factors (e.g. insulin dosage, injection route and site,
thickness of subcutaneous fat, type of diabetes). The pharmacokinetics of insulins is
therefore affected by significant intra- and inter-individual variation.
The absorption profile is due to the product being a mixture of insulins with fast and
protracted absorption respectively. The maximum plasma concentration of Mixtard is
reached within 1.5-2.5 hours after subcutaneous administration.
No profound binding to plasma proteins, except circulating insulin antibodies (if present)
has been observed.
Human insulin is reported to be degraded by insulin protease or insulin-degrading enzymes
and possibly protein disulfide isomerase. A number of cleavage (hydrolysis) sites on the
human insulin molecule have been proposed; none of the metabolites formed following the
cleavage are active.

The terminal half-life is determined by the rate of absorption from the subcutaneous tissue.
The terminal half-life (t½) is therefore a measure of the absorption rather than of the
elimination per se of insulin from plasma (insulin in the blood stream has a t½ of a few
minutes). Trials have indicated a t½ of about 5-10 hours.


Preclinical safety data
Preclinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to




List of excipients
Zinc chloride
Disodium phosphate dihydrate
Sodium hydroxide or/and hydrochloric acid (for pH adjustment)
Protamine sulphate
Water for injections


Insulin suspensions should not be added to infusion fluids.
Medicinal products added to the insulin suspension may cause degradation of the insulin,
e.g. if the medicinal products contain thiols or sulphites.


Shelf life
30 months.
After first opening: 6 weeks.


Special precautions for storage
Store at 2°C - 8°C (in a refrigerator) not near a freezing compartment.
Do not freeze.
During use: do not refrigerate. Do not store above 30°C.
Keep the pen cap on in order to protect the insulin from light.
Protect from excessive heat and sunlight.


Nature and contents of container
Pre-filled pen (multidose disposable pen) comprising a pen injector with a cartridge (3 ml).
The cartridge is made of glass (type 1), containing a bromobutyl rubber plunger and a
bromobutyl/polyisoprene rubber stopper. The cartridge contains a glass ball to facilitate the
re-suspension. The pen injector is made of plastic.
Pack size: 5 x 3 ml pre-filled pens.


Instructions for use and handling
Pens should only be used in combination with products that are compatible with them and
allow the pens to function safely and effectively.
Human Mixtard Pen is for single person use only. The container must not be refilled.
Insulin preparations, which have been frozen, must not be used.
Insulin suspensions should not be used if they do not appear uniformly white and cloudy
after re-suspension.


Novo Nordisk Limited
Broadfield Park
Brighton Road
West Sussex, RH11 9RT


PL 3132/0070


Marketing authorisation renewed 1 February 2004


November 2004

POM (Prescription-Only Medicine)

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