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INSULATARD PENFILL 3ML

Active substance(s): INSULIN HUMAN (PYR)

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1.

NAME OF THE MEDICINAL PRODUCT
Insulatard Penfill 3ml 100 IU/ml
Suspension for injection in a cartridge

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION
Insulin human, rDNA (produced by recombinant DNA technology in Saccharomyces
cerevisiae).
1 ml contains 100 IU of insulin human
1 cartridge contains 3 ml equivalent to 300 IU
One IU (International Unit) corresponds to 0.035 mg of anhydrous human insulin.
Insulatard is a suspension of isophane (NPH) insulin.
For excipients, see Section 6.1 List of excipients.

3.

PHARMACEUTICAL FORM
Suspension for injection in cartridge.
Insulatard is a cloudy, white, aqueous suspension.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications
Treatment of diabetes mellitus.

4.2

Posology and method of administration
Insulatard is a long-acting insulin.
Dosage
Dosage is individual and determined by the physician in accordance with the needs of the
patient.
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.

The physician determines whether one or several daily injections are necessary. Insulatard
may be used alone or mixed with fast-acting insulin. In intensive insulin therapy the
suspension may be used as basal insulin (evening and/or morning injection) with fast-acting
insulin given at meals.
In patients with diabetes mellitus optimised glycaemic control delays the onset and slows the
progression of late diabetic complications. Blood glucose monitoring is therefore
recommended.
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).
Administration
For subcutaneous use.
Insulatard is usually administered subcutaneously in the thigh. If convenient, the abdominal
wall, the gluteal region or the deltoid region may also be used.
Subcutaneous injection into the thigh results in a slower and less variable absorption
compared to the 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.
Insulatard is accompanied by a package leaflet with detailed instruction for use to be
followed.
The cartridges are designed to be used with Novo Nordisk delivery systems (durable devices
for repeated use) and NovoFine needles. Detailed instruction accompanying the delivery
system must be followed.

4.3

Contraindications
Hypoglycaemia
Hypersensitivity to human insulin or to any of the excipients (see section 6.1 List of
excipients).

4.4

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
requirement.
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 Insulatard, 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.
Insulatard contains metacresol, which may cause allergic reactions.

4.5

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
alcohol.
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
hypoglycaemia.
Octreotide/lanreotide may both decrease and increase insulin requirement.
Alcohol may intensify and prolong the hypoglycaemic effect of insulin.

4.6

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 Insulatard
dosage may need to be adjusted.

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
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
Rare (>1/10,000 <1/1,000)
Change in blood glucose

Hypoglycaemia:
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.
Hyperglycaemia:
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 lethal.
For precautions see section 4.4 Special warnings
and special precautions for use.
Eye disorders
Very rare (<1/10,000)

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

General disorders and administration site
conditions
Very rare (<1/10,000)
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.
Very rare (<1/10,000)

Lipodystrophy may occur at the injection site as a
consequence of failure to rotate injection sites
within an area.

Very rare (<1/10,000)

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.

Very rare (<1/10,000)

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

4.9

Overdose
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.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: antidiabetic agent. ATC code: A10A C01.
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.
Insulatard is a long-acting insulin.
Onset of action is within 1½ hours, reaches a maximum effect within 4-12 hours and the
entire time of duration is approximately 24 hours.

5.2

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.
Absorption
The maximum plasma concentration of the insulin is reached within 2-18 hours after
subcutaneous administration.
Distribution
No profound binding to plasma proteins, except circulating insulin antibodies (if present)
has been observed.
Metabolism

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.
Elimination
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.

5.3

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
reproduction.

6.

PHARMACEUTICAL PARTICULARS

6.1

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

6.2

Incompatibilities
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.

6.3

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

6.4

Special precautions for storage
Store at 2°C - 8°C (in a refrigerator) not near a freezing compartment.
Do not freeze.

Keep the container in the outer carton in order to protect from light.
During use: do not refrigerate. Do not store above 30°C.
Protect from excessive heat and sunlight.

6.5

Nature and contents of container
Glass cartridge (type 1) with a bromobutyl rubber plunger and a bromobutyl/polyisoprene
rubber stopper. The cartridge contains a glass ball to facilitate the re-suspension.
Pack size: 5 x 3 ml cartridges.

6.6

Instructions for use and handling
Cartridges should only be used in combination with products that are compatible with them
and allow the cartridge to function safely and effectively.
Insulatard Penfill 3ml 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.

7.

MARKETING AUTHORISATION HOLDER
Novo Nordisk Limited
Broadfield Park
Brighton Road
Crawley
West Sussex, RH11 9RT

8.

MARKETING AUTHORISATION NUMBER(S)
PL 3132/0091

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Marketing authorisation renewed 1 February 2004

10.

DATE OF REVISION OF THE TEXT
November 2004

LEGAL STATUS
POM (Prescription-Only Medicine)

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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