ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
Optimark 500 micromol/ml solution for injection in a pre-filled syringe
1 ml contains 330.9 mg gadoversetamide, equivalent to 500 micromol.
For a full list of excipients, see section 6.1.
3. PHARMACEUTICALFORM
Solution for injection.
Clear, colourless to pale yellow solution.
pH: 6.0 – 7.5
Osmolality (37°C): 1000 – 1200 mOsm/kg
4. CLINICALPARTICULARS
This medicinal product is for diagnostic use only.
Optimark is indicated for use with magnetic resonance imaging (MRI) of the central nervous system
(CNS) and liver. It provides contrast enhancement and facilitates visualization and helps with the
characterization of focal lesions and abnormal structures in the CNS and liver in patients with known
or highly suspected pathology.
Optimark should only be administered by physicians experienced in clinical MRI practice.
The agent should be administered as a bolus peripheral intravenous injection at a dose of 0.2 ml/kg
(100 micromol/kg) body weight. To ensure complete injection of the contrast medium, the injection
should be followed by a 5 ml flush of sodium chloride 9 mg/ml (0.9 %) injection. The imaging
procedure should be completed within 1 hour of administration of the contrast medium.
In cranial MRI, if a strong clinical suspicion of a lesion persists despite a single dose contrast-
enhanced MRI or when more accurate information on the number, size or extent of lesions might
influence management or therapy of the patient, in subjects with normal renal function, a second
bolus injection of 100 micromol/kg may be administered within 30 minutes of the first injection as it
may increase the diagnostic yield of the examination. The safety of repeat doses has not been
established in children and adolescents, in patients with renal impairment, or the elderly.
Limited data with other gadolinium contrast agents suggests that for the exclusion of additional
cranial metastases in a patient with a known solitary resectable metastasis, an MR exam with the
injection of the dose of 300 micromol/kg body weight of Optimark may lead to higher diagnostic
confidence.
2
Special Populations
Renal impairment
Optimark is contraindicated in patients with severe renal impairment (GFR < 30 ml/min/1.73m
2
) and
in patients who have had liver transplantation or in patients in the perioperative liver transplantation
period (see section 4.3). Optimark should only be used after careful risk/benefit evaluation in patients
with moderate renal impairment (GFR 30-59 ml/min/1.73m
2
) at a dose not exceeding
100 micromol/kg body weight (see section 4.4). More than one dose should not be used during a scan.
Because of the lack of information on repeated administration, Optimark injections should not be
repeated unless the interval between injections is at least 7 days.
Neonates up to 4 weeks of age, infants up to 1 year of age and children
Optimark is contraindicated in neonates up to 4 weeks of age (see section 4.3). Use of Optimark is not
recommended in children less than 2 years of age
because the safety, efficacy, and impact of
immature kidney function have not been studied in this age group. Optimark has been studied in
children of 2 years and older with a similar safety profile as shown in the adult population.
Elderly (aged 65 years and above)
No dosage adjustment is considered necessary. Caution should be exercised in elderly patients (see
section 4.4).
The container and the solution should be inspected prior to use as described in section 6.6.
Insertion of a flexible in-dwelling venous catheter is recommended, see section 4.4.
Hypersensitivity to gadoversetamide or to any of the excipients or to other gadolinium containing
products.
Optimark is contraindicated in patients with severe renal impairment (GFR <30ml/min/1.73m
2
), in
patients who have had liver transplantation or in patients in the perioperative liver transplantation
period and in neonates up to 4 weeks of age (see section 4.4).
As with any paramagnetic contrast agent, enhancement of MRI with gadoversetamide may impair the
visualization of existing lesions. Some of these lesions may be seen on unenhanced, non-contrast
MRI. Therefore, caution should be exercised when contrast enhanced scan interpretation is made in
the absence of a companion unenhanced MRI.
Before the examination, care must be taken that patients are sufficiently hydrated. The usual
contraindications of MR examinations must be applied, such as exclusion of patients with infusion
pumps, pacemakers, ferro-magnetic clips etc.
Hypersensitivity
Allergoid and other idiosyncratic reactions may occur with all contrast media for intravenous
application, also with gadoversetamide, which could become manifest in form of cardiovascular,
respiratory and skin reactions (see section 4.8). Most of these reactions occur within half an hour after
administering the contrast medium. As with all other contrast media of the same class, late reactions
may occur (after hours or days) in rare cases; however, none were reported in the completed clinical
trials.
If hypersensitivity reactions occur, the administration of the contrast medium must be discontinued
immediately and intravenous treatment initiated, if necessary.
During the examination, supervision by a physician is necessary and insertion of a flexible in-
dwelling catheter is recommended. To enable immediate action in emergencies, the necessary
3
•
medicinal products (e.g. epinephrine/adrenaline, theophylline, antihistamines, corticosteroids and
atropines), endotracheal tube and ventilator must be immediately available.
The risk of hypersensitivity reactions is increased in the following cases:
-
patients with allergic predisposition
-
patients with bronchial asthma; in these patients it is especially the risk of bronchospasm which is
increased
-
patients with a history of reactions to contrast agents, including a previous history of reaction to
iodine-based contrast agents
Before the injection of contrast media, patients should be asked whether they have any allergies (e.g.
allergies to seafood or medicinal products, hay fever, urticaria), whether they are hypersensitive to
contrast media and whether they have bronchial asthma. Premedication with antihistamines and/or
glucocorticoids may be considered.
•
Patients with cardiovascular disease
In this group of patients hypersensitivity reactions may be severe. Especially in patients with serious
heart diseases (e.g. severe heart failure, coronary artery disease) cardiovascular reactions may
deteriorate. However, these were not evident from clinical trials with Optimark.
•
Central nervous system disorders
In patients suffering from epilepsy or brain lesions the likelihood of convulsions during the
examination may be increased. Precautions are necessary when examining these patients (e.g.
monitoring of the patient) and the equipment and medicinal products needed for the rapid treatment of
possible convulsions should be available.
•
Impaired renal function
Prior to administration of Optimark, all patients should be screened for renal dysfunction by obtaining
laboratory tests.
There have been reports of nephrogenic systemic fibrosis (NSF) associated with use of Optimark and
some gadolinium-containing contrast agents in patients with acute or chronic severe renal impairment
(GFR <30ml/min/1.73m
2
). Patients who have had or are undergoing liver transplantation are at
particular risk since the incidence of acute renal failure is high in this group. Therefore, Optimark
must not be used in patients who have had or are undergoing liver transplantation and in neonates (see
section 4.3).
The risk for development of NSF in patients with moderate renal impairment (GFR 30–59
ml/min/1.73 m
2
) is unknown, therefore Optimark should only be used after careful risk-benefit
evaluation in patients with moderate renal impairment.
Gadoversetamide is dialysable. Haemodialysis shortly after Optimark administration may be useful at
removing Optimark from the body. There is no evidence to support the initiation of haemodialysis for
prevention or treatment of NSF in patients not already undergoing haemodialysis.
•
Children
Optimark must not be administered with an autoinjector. The required dose should be administered by
hand to children to avoid overdosage by mistake.
•
Neonates and infants
Optimark should not be used in children below the age of two years. Safety and efficacy have not
been studied in this age group.
•
Elderly
As the renal clearance of gadoversetamide may be impaired in the elderly, it is particularly important
to screen patients aged 65 years and older for renal dysfunction.
•
Sodium
This medicinal product contains less than 1 mmol sodium (23 mg) per dose of up to 17 ml, i.e.
essentially ‘sodium- free’. Higher doses contain 1 mmol of sodium or more, which should be taken
into consideration for patients on a controlled sodium diet.
•
Serum iron and zinc
Caution should be exercised because transient decreases in serum iron and zinc parameters have been
observed in clinical trials. The clinical significance of this is unknown.
4
Patients taking beta-blockers
It should be noted that patients using beta-blockers do not necessarily respond to the beta-agonists
usually used for the treatment of hypersensitivity reactions.
•
No formal interaction studies have been performed.
Optimark has been shown to cause interference in the measurement of serum calcium using the ortho-
cresolphthalein complexone (OCP) colorimetric method. However, the administration of
gadoversetamide does not cause a true decrease in serum calcium. In the presence of
gadoversetamide, the OCP technique produces an erroneous, low value for plasma calcium. The
magnitude of this measurement artefact is proportional to the concentration of gadoversetamide in the
blood, and in patients with normal renal clearance accurate values can be obtained approximately 90
minutes following injection. In patients with compromised renal function, clearance of
gadoversetamide will be slowed and the interference with calcium determination by OCP prolonged.
Gadoversetamide does not affect other methods of measuring serum calcium, such as the arsenazo III
colorimetric method, atomic absorption spectroscopy, and inductively coupled plasma mass
spectroscopy.
4.6 Pregnancy and Lactation
Pregnancy
There are no data from the use of gadoversetamide in pregnant women. Animal studies do not indicate
direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). Optimark
should not be used during pregnancy unless the clinical condition of the women requires use of
gadoversetamide.
Lactation
It is unknown whether gadoversetamide is excreted in human milk. There is insufficient information
on the excretion of gadoversetamide in animal milk. A risk to the suckling child cannot be excluded.
Breast-feeding should be discontinued for at least 24 hours after the administration of Optimark.
No studies on the effects on the ability to drive and use machines have been performed. Ambulant
patients while driving vehicles or operating machinery should take into account that dizziness may
incidentally occur.
4.8 Undesirable Effects
Most of the undesirable effects were of mild to moderate intensity and transient in nature. The most
common undesirable effects were dysgeusia, feeling hot, headache and dizziness.
The majority of adverse reactions observed after the use of gadoversetamide were found to be adverse
reactions of the nervous system, followed by general adverse reactions, gastrointestinal disorders/skin
and subcutaneous tissue disorders.
The following drug-related adverse reactions have been reported from clinical trials and from post-
marketing use of gadoversetamide. Within each frequency grouping, undesirable effects are presented
in order of decreasing seriousness.
System Organ
Class
(MedDRA)
Common
(≥1/100,
<1/10)
Uncommon
(≥1/1,000,
<1/100)
Rare
(≥1/10,000, <1/1,000)
Very Rare
(<1/10,000)
Immune System
Disorders
Anaphylactic
reaction
5
System Organ
Class
(MedDRA)
Common
(≥1/100,
<1/10)
Uncommon
(≥1/1,000,
<1/100)
Rare
(≥1/10,000, <1/1,000)
Very Rare
(<1/10,000)
Metabolism and
Nutrition
Disorders
Decreased appetite
Psychiatric
Disorders
Anxiety, Sleep disorder Confusionalstate
Nervous System
Disorders
Dizziness,
Headache,
Dysgeusia
Hypoaesthesia,
Paraesthesia,
Parosmia
Syncope, Tremor,
Somnolence, Burning
sensation
Convulsion
Erythema of eyelid,
Eye pain, Vision
blurred
Eye Disorders
Ocular hyperaemia
Ear and
Labyrinth
Disorders
Tinnitus
Cardiac
Disorders
Tachycardia,
Palpitations, AV block
first degree,
Extrasystoles
Arrhythmia
Vascular
Disorders
Flushing
Hypotension,
Hypertension
Respiratory,
Thoracic and
Mediastinal
Disorders
Nasal
congestion,
Throat irritation
Dyspnoea, Dysphonia,
Cough, Rhinorrhoea,
Throat tightness
Bronchospasm,
Pharyngeal oedema,
Pharyngitis,
Rhinitis, Sneezing
Gastrointestinal
Disorders
Nausea,
Diarrhoea
Salivary
hypersecretion,,
Vomiting, Abdominal
pain, Constipation, Dry
mouth
Skin and
Subcutaneous
Tissue Disorders
Urticaria,
Pruritus, Rash
Cold sweat, Erythema,
Hyperhidrosis
Periorbital oedema
Renal and
Urinary
Disorders
Blood creatinine
increased, Hematuria
General
Disorders and
Administration
Site Conditions
Feeling hot
Chest
discomfort,
Feeling cold,
Administration
site reactions
Pain, Chest pain, Face
oedema, Fatigue, Fever,
Oedema peripheral,
Peripheral coldness
Malaise, Feeling
abnormal,
ALT increased, Urine
analysis abnormal,
Urine electrolytes
abnormal CPK
Increased,
Haemoglobin
decreased, Blood
calcium abnormal
Investigations
Electrocardiogram
QT prolonged
Serious adverse reactions have been reported and include anaphylactic reactions, cardiovascular
reactions, and allergic respiratory disorders. Treatment should be symptomatic and immediate access
to necessary medicinal products and emergency equipment should be available should a serious event
6
occur. Local reactions have occurred at the injection site and may lead to local irritation type
reactions.
Cases of Nephrogenic Systemic Fibrosis (NSF) have been reported with Optimark (see section 4.4).
Gadoversetamide has been tested in humans in doses up to 700 micromol/kg (seven times the standard
dose). Clinical consequences of an overdose have not been reported. Acute toxicity symptoms are
unlikely to occur in patients with normal renal function. Optimark can be removed by haemodialysis.
However, there is no evidence that haemodialysis is suitable for prevention of Nephrogenic Systemic
Fibrosis (NSF).
5. PHARMACOLOGICALPROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic Group: Paramagnetic MRI contrast media, ATC code: V08C A06
Gadoversetamide is a chelate containing gadolinium - which has paramagnetic properties and is
responsible for the contrast enhancement effect in MRI - and the ligand versetamide.
The purpose of an MRI contrast agent is to induce signal intensity changes within the lesion thereby
facilitating its recognition from the surrounding normal structures. The use of a contrast agent may
therefore reduce the threshold for lesion detection and visualization. Gadolinium containing MRI
contrast agents (gadolinium-based chelates) are designed to act indirectly on the local magnetic
environment by altering proton T1 (spin-lattice) and T2 (spin-spin) relaxation times and at the usual
concentration of 100 micromol/kg, the T1 shortening predominates, and the T2 shortening is not
significant using T1-weighted sequences.
Gadoversetamide, an extracellular gadolinium chelate, after intravenous administration, equilibrates
rapidly within the extracellular fluid/space and is eliminated primarily by glomerular filtration.
As a result of these characteristics, the timing of the image acquisition after contrast administration is
critical in liver imaging. For liver metastases, the signal difference between the tumour and
surrounding liver tissue is significantly improved during the first 90 seconds after an extracellular
gadolinium contrast agent is administered. Therefore, a rapid imaging sequence should be initiated 20
seconds after bolus injection of the contrast agent when the agent is predominately in the hepatic
arteries and then again at 60 seconds after injection during the dominant portal venous phase. Since
the hepatic artery and portal venous system supply approximately 20% and 80% of the hepatic blood
supply, respectively, the earlier (hepatic arterial phase) images provide optimal lesion conspicuity for
hypervascular lesions and the portal venous phase images are useful for hypovascular lesions (most
metastatic lesions are relatively hypovascular and are better demonstrated during the portal venous
phase, manifesting as areas of lower signal intensity compared with the markedly enhanced liver).
Lesion conspicuity of hypo- and hypervascular lesions may be reduced if imaging is delayed more
than 3 minutes due to the diffusion of the contrast agent into the interstitial spaces of both the liver
parenchyma and lesion (e.g. metastasis) making the lesion isointense with the normal liver
parenchyma. Delayed post-contrast or equilibrium images (> 5 minutes after dosing) assist in the
characterization of lesions, e.g. the centre of a metastasis may accumulate contrast in the interstitial
space of the lesion and become hyperintense to the normal liver. This difference in enhancement
pattern is useful in formulating a differential diagnosis based on lesion characterization and diagnostic
confidence.
The enhancement of brain tumours using a gadolinium (or iodine) containing contrast agent depends
on the disruption of the blood brain barrier (BBB). As a result, these agents have been referred to as
markers for sites of abnormal BBB breakdown. When the BBB is disrupted, the gadoversetamide
7
molecules diffuse into the interstitial compartment thereby producing the characteristic paramagnetic
effect of T1 and T2 shortening. In general, the addition of contrast to MRI, at the standard clinical
dose of 100 micromol/kg, has led to a significantly improved lesion detection, sensitivity and
diagnostic accuracy.
5.2 Pharmacokinetic properties
Distribution
The pharmacokinetics of gadoversetamide conforms to a two compartment open-model. At the 100
micromol/kg dose, the mean distribution half life in normal subjects calculated by the method of
residuals in 12 normal volunteers is 13.3 ± 6.8 min. Mean volume of distribution at the 100
micromol/kg dose in non-renally impaired patients (including both normal subjects and patients with
CNS or liver pathology) was 158.7 ± 29.0 to 214.3 (range 116.4 to 295.0) ml/kg. This volume of
distribution (approximately 10-15 l for a body weight of 70 kg) is consistent with a medicinal product
which distributes into the extracellular fluid. Dose level has no consistent effect on the volume of
distribution in any of the studies. Gadoversetamide does not undergo protein binding in vitro.
Elimination
The elimination half life at the 100 micromol/kg dose ranges from 1.49 ± 0.15 h in healthy volunteers
to 2.11 ± 0.62 h in non-renally impaired patients (including normal subjects and patients with CNS or
liver pathology).
The mean plasma clearance of gadoversetamide in healthy subjects (111.0 ± 14.1 ml/min/1.73m²
BSA) is not significantly different from the mean renal clearance. Similar results are obtained in
normal subjects and patients with various combinations of liver, CNS and renal dysfunctions with
renal clearance of gadoversetamide being approximately 95% of the total plasma clearance. Such
results (ratio renal clearance/total plasma clearance close to 1) indicate that gadoversetamide is
essentially cleared through the kidneys.
There was no systematic difference in any of the kinetic parameters as a function of dose level (100 to
700 micromol/kg). Therefore, within this dose range, the kinetics of gadoversetamide appear to be
linear.
Metabolism
The high accountability for the dose as intact complex in urine suggests that no significant
metabolism of gadoversetamide occurs in humans.
Special Populations
Effect of Gender:
Adult male and female subjects were enrolled in two pharmacokinetic studies. No significant
differences in pharmacokinetics based on gender were identified.
Effects of Age:
When corrected for body weight, the total body clearance of gadoversetamide is greater in the 2 to 11
year age group (143 ± 27.9 ml/h/kg) than that observed in the 12 to 18 year age group (117 ± 26.1
ml/h/kg) and the two adult populations (82.1 ± 16.8 and 56.5 ± 9.7 ml/h/kg in the 19 to 64 and ≥ 65
year of age groups, respectively).
The elimination half life in the 2 to 11 and 12 to 18 year age groups (1.4 ± 0.3 and 1.6± 0.3 h
-1
,
respectively) is shorter than that observed in the two adult populations (1.9 ± 0.5 and 2.5± 0.5 h
-1
in
the 19 to 64 and ≥ 65 year of age groups, respectively). The number of elderly patients in whom the
pharmacokinetics were determined was limited (over 65 years, N=3).
8
Effect of Renal Impairment
Gadoversetamide plasma levels increase linearly with decreasing renal function; in patients with
severe renal impairment (Cr
Cl
<30 ml/min) this even leads to a six-fold decreased gadoversetamide
clearance and a corresponding six-fold increased extent of exposure AUC and t
½
. Since
gadoversetamide is only administered as a single dose this will lead to a longer and higher exposure
for a limited duration. Still, after 72 hours even in patients with severe renal impairment nearly the
whole dose is recovered in the urine and in healthy populations up to 500 micromol/kg doses were
administered without safety issues. Nevertheless, because of reported cases of NSF that may be
associated with renal impairment for other gadolinium containing contrast agents and for
gadoversetamide, Optimark should not be used in these patients.
5.3 Preclinical safety data
Nonclinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology, acute toxicity, reproductive toxicity, local tolerance, antigenicity, and genotoxicity. No
carcinogenicity studies were performed.
Repeated-dose toxicity studies in rats and dogs revealed vacuolation of the tubular cells of the
kidneys, with strong evidence for reversibility of the effect. No functional impairment was observed.
6.1 List of excipients
Versetamide
Calcium hydroxide
Calcium chloride dihydrate
Sodium hydroxide and/or hydrochloric acid for pH adjustment.
Water for injections.
6.2 Incompatibilities
In the absence of compatibility studies, Optimark should not be mixed with other medicinal products.
6.3 Shelf-life
3 years.
Chemical and physical in-use stability has been demonstrated for 24 hours at up to 25°C.
From a microbiological point of view, the product should be used immediately. If not used
immediately, in-use storage times and conditions prior to use are the responsibility of the user.
6.4 Special precautions for storage
Keep the syringe in the outer carton in order to protect from light.
Do not refrigerate or freeze.
6.5 Nature and contents of container
Optimark is filled in pre-filled syringes made of polypropylene. Syringe tip cap and piston are made
of bromobutyl rubber.
9
Pack sizes:
1 x 10 ml 10 x 10 ml
1 x 15 ml 10 x 15 ml
1 x 20 ml 10 x 20 ml
1 x 30 ml 10 x 30 ml
Not all pack-sizes may be marketed
.
Optimark is also available in glass vials of 10 ml, 15 ml and 20 ml.
6.6 Special precautions for disposal and other handling
Optimark is intended for single use only; any unused portions should be discarded.
Do not use the solution if it is discoloured or particulate matter is present. If non-disposable
equipment is used, scrupulous care should be taken to prevent residual contamination with traces of
cleansing agents.
Pre-filled syringes:
Assembly and Inspection
Inspect the syringe for signs of leakage. Do not use if leakage is observed.
After screwing the push rod into the syringe
piston, it is important to
turn the push rod an
additional ½ turn
so that the grey piston
rotates freely
Prior to using the syringe, twist off grey tip
cap and discard. Syringe is now ready for
needle or infusion tubing attachment.
Discard syringe and unused portion of the solution after use.
Any unused product or waste material should be disposed of in accordance with local requirements.
The peel-off tracking label on the pre-filled syringes should be stuck onto the patient record to enable
accurate recording of the gadolinium contrast agent used. The dose used should also be recorded.
7. MARKETINGAUTHORISATIONHOLDER
Covidien Deutschland GmbH
Gewerbepark 1
93333 Neustadt/Donau
Germany
10
8. MARKETINGAUTHORISATIONNUMBER(S)
1 x 10 ml: EU/1/07/398/007
10 x 10 ml: EU/1/07/398/008
1 x 15 ml: EU/1/07/398/009
10 x 15 ml: EU/1/07/398/010
1 x 20 ml: EU/1/07/398/011
10 x 20 ml: EU/1/07/398/012
1 x 30 ml: EU/1/07/398/013
10 x 30 ml EU/1/07/398/014
9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION
23/07/2007
11
1.
Optimark 500 micromol/ml solution for injection in a vial
1 ml contains 330.9 mg gadoversetamide, equivalent to 500 micromol.
For a full list of excipients, see section 6.1.
3. PHARMACEUTICALFORM
Solution for injection.
Clear, colourless to pale yellow solution.
pH: 6.0 – 7.5
Osmolality (37°C): 1000 – 1200 mOsm/kg
4. CLINICALPARTICULARS
This medicinal product is for diagnostic use only.
Optimark is indicated for use with magnetic resonance imaging (MRI) of the central nervous system
(CNS) and liver. It provides contrast enhancement and facilitates visualization and helps with the
characterization of focal lesions and abnormal structures in the CNS and liver in patients with known
or highly suspected pathology.
Optimark should only be administered by physicians experienced in clinical MRI practice.
The agent should be administered as a bolus peripheral intravenous injection at a dose of 0.2 ml/kg
(100 micromol/kg) body weight. To ensure complete injection of the contrast medium, the injection
should be followed by a 5 ml flush of sodium chloride 9 mg/ml (0.9 %) injection. The imaging
procedure should be completed within 1 hour of administration of the contrast medium.
In cranial MRI, if a strong clinical suspicion of a lesion persists despite a single dose contrast-
enhanced MRI or when more accurate information on the number, size or extent of lesions might
influence management or therapy of the patient, in subjects with normal renal function, a second
bolus injection of 100 micromol/kg may be administered within 30 minutes of the first injection as it
may increase the diagnostic yield of the examination. The safety of repeat doses has not been
established in children and adolescents, in patients with renal impairment, or the elderly.
Limited data with other gadolinium contrast agents suggests that for the exclusion of additional
cranial metastases in a patient with a known solitary resectable metastasis, an MR exam with the
injection of the dose of 300 micromol/kg body weight of Optimark may lead to higher diagnostic
confidence.
12
Special Populations
Renal impairment
Optimark is contraindicated in patients with severe renal impairment (GFR < 30 ml/min/1.73m
2
) and
in patients who have had liver transplantation or in patients in the perioperative liver transplantation
period (see section 4.3). Optimark should only be used after careful risk/benefit evaluation in patients
with moderate renal impairment (GFR 30-59 ml/min/1.73m
2
) at a dose not exceeding
100 micromol/kg body weight (see section 4.4). More than one dose should not be used during a scan.
Because of the lack of information on repeated administration, Optimark injections should not be
repeated unless the interval between injections is at least 7 days.
Neonates up to 4 weeks of age, infants up to 1 year of age and children
Optimark is contraindicated in neonates up to 4 weeks of age (see section 4.3). Use of Optimark is not
recommended in children less than 2 years of age because the safety, efficacy, and impact of
immature kidney function have not been studied in this age group. Optimark has been studied in
children of 2 years and older with a similar safety profile as shown in the adult population.
Elderly (aged 65 years and above)
No dosage adjustment is considered necessary. Caution should be exercised in elderly patients (see
section 4.4).
The container and the solution should be inspected prior to use as described in section 6.6.
Insertion of a flexible in-dwelling venous catheter is recommended, see section 4.4.
Hypersensitivity to gadoversetamide or to any of the excipients or to other gadolinium containing
products.
Optimark is contraindicated in patients with severe renal impairment (GFR <30ml/min/1.73m
2
), in
patients who have had liver transplantation or in patients in the perioperative liver transplantation
period and in neonates up to 4 weeks of age (see section 4.4).
As with any paramagnetic contrast agent, enhancement of MRI with gadoversetamide may impair the
visualization of existing lesions. Some of these lesions may be seen on unenhanced, non-contrast
MRI. Therefore, caution should be exercised when contrast enhanced scan interpretation is made in
the absence of a companion unenhanced MRI.
Before the examination, care must be taken that patients are sufficiently hydrated. The usual
contraindications of MR examinations must be applied, such as exclusion of patients with infusion
pumps, pacemakers, ferro-magnetic clips etc.
Hypersensitivity
Allergoid and other idiosyncratic reactions may occur with all contrast media for intravenous
application, also with gadoversetamide, which could become manifest in form of cardiovascular,
respiratory and skin reactions (see section 4.8). Most of these reactions occur within half an hour after
administering the contrast medium. As with all other contrast media of the same class, late reactions
may occur (after hours or days) in rare cases; however, none were reported in the completed clinical
trials.
If hypersensitivity reactions occur, the administration of the contrast medium must be discontinued
immediately and intravenous treatment initiated, if necessary.
During the examination, supervision by a physician is necessary and insertion of a flexible in-
dwelling catheter is recommended. To enable immediate action in emergencies, the necessary
13
•
medicinal products (e.g. epinephrine/adrenaline, theophylline, antihistamines, corticosteroids and
atropines), endotracheal tube and ventilator must be immediately available.
The risk of hypersensitivity reactions is increased in the following cases:
-
patients with allergic predisposition
-
patients with bronchial asthma; in these patients it is especially the risk of bronchospasm which is
increased
-
patients with a history of reactions to contrast agents, including a previous history of reaction to
iodine-based contrast agents
Before the injection of contrast media, patients should be asked whether they have any allergies (e.g.
allergies to seafood or medicinal products, hay fever, urticaria), whether they are hypersensitive to
contrast media and whether they have bronchial asthma. Premedication with antihistamines and/or
glucocorticoids may be considered.
•
Patients with cardiovascular disease
In this group of patients hypersensitivity reactions may be severe. Especially in patients with serious
heart diseases (e.g. severe heart failure, coronary artery disease) cardiovascular reactions may
deteriorate. However, these were not evident from clinical trials with Optimark.
•
Central nervous system disorders
In patients suffering from epilepsy or brain lesions the likelihood of convulsions during the
examination may be increased. Precautions are necessary when examining these patients (e.g.
monitoring of the patient) and the equipment and medicinal products needed for the rapid treatment of
possible convulsions should be available.
•
Impaired renal function
Prior to administration of Optimark, all patients should be screened for renal dysfunction by obtaining
laboratory tests.
There have been reports of nephrogenic systemic fibrosis (NSF) associated with use of Optimark and
some gadolinium-containing contrast agents in patients with acute or chronic severe renal impairment
(GFR <30ml/min/1.73m
2
). Patients who have had or are undergoing liver transplantation are at
particular risk since the incidence of acute renal failure is high in this group. Therefore, Optimark
must not be used in patients who have had or are undergoing liver transplantation and in neonates (see
section 4.3).
The risk for development of NSF in patients with moderate renal impairment (GFR 30–59
ml/min/1.73 m
2
) is unknown, therefore Optimark should only be used after careful risk-benefit
evaluation in patients with moderate renal impairment.
Gadoversetamide is dialysable. Haemodialysis shortly after Optimark administration may be useful at
removing Optimark from the body. There is no evidence to support the initiation of haemodialysis for
prevention or treatment of NSF in patients not already undergoing haemodialysis.
•
Children
Optimark must not be administered with an autoinjector. The required dose should be administered by
hand to children to avoid overdosage by mistake.
•
Neonates and infants
Optimark should not be used in children below the age of two years. Safety and efficacy have not
been studied in this age group.
•
Elderly
As the renal clearance of gadoversetamide may be impaired in the elderly, it is particularly important
to screen patients aged 65 years and older for renal dysfunction.
•
Sodium
This medicinal product contains less than 1 mmol sodium (23 mg) per dose of up to 17 ml, i.e.
essentially ‘sodium- free’. Higher doses contain 1 mmol of sodium or more, which should be taken
into consideration for patients on a controlled sodium diet.
•
Serum iron and zinc
Caution should be exercised because transient decreases in serum iron and zinc parameters have been
observed in clinical trials. The clinical significance of this is unknown.
14
Patients taking beta-blockers
It should be noted that patients using beta-blockers do not necessarily respond to the beta-agonists
usually used for the treatment of hypersensitivity reactions.
•
No formal interaction studies have been performed.
Optimark has been shown to cause interference in the measurement of serum calcium using the ortho-
cresolphthalein complexone (OCP) colorimetric method. However, the administration of
gadoversetamide does not cause a true decrease in serum calcium. In the presence of
gadoversetamide, the OCP technique produces an erroneous, low value for plasma calcium. The
magnitude of this measurement artefact is proportional to the concentration of gadoversetamide in the
blood, and in patients with normal renal clearance accurate values can be obtained approximately 90
minutes following injection. In patients with compromised renal function, clearance of
gadoversetamide will be slowed and the interference with calcium determination by OCP prolonged.
Gadoversetamide does not affect other methods of measuring serum calcium, such as the arsenazo III
colorimetric method, atomic absorption spectroscopy, and inductively coupled plasma mass
spectroscopy.
4.6 Pregnancy and Lactation
Pregnancy
There are no data from the use of gadoversetamide in pregnant women. Animal studies do not indicate
direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). Optimark
should not be used during pregnancy unless the clinical condition of the women requires use of
gadoversetamide.
Lactation
It is unknown whether gadoversetamide is excreted in human milk. There is insufficient information
on the excretion of gadoversetamide in animal milk. A risk to the suckling child cannot be excluded.
Breast-feeding should be discontinued for at least 24 hours after the administration of Optimark.
No studies on the effects on the ability to drive and use machines have been performed. Ambulant
patients while driving vehicles or operating machinery should take into account that dizziness may
incidentally occur.
4.8 Undesirable Effects
Most of the undesirable effects were of mild to moderate intensity and transient in nature. The most
common undesirable effects were dysgeusia, feeling hot, headache and dizziness.
The majority of adverse reactions observed after the use of gadoversetamide were found to be adverse
reactions of the nervous system, followed by general adverse reactions, gastrointestinal disorders/skin
and subcutaneous tissue disorders.
The following drug-related adverse reactions have been reported from clinical trials and from post-
marketing use of gadoversetamide. Within each frequency grouping, undesirable effects are presented
in order of decreasing seriousness.
System Organ
Class
(MedDRA)
Common
(≥1/100,
<1/10)
Uncommon
(≥1/1,000,
<1/100)
Rare
(≥1/10,000, <1/1,000)
Very Rare
(<1/10,000)
Immune System
Disorders
Anaphylactic
reaction
15
System Organ
Class
(MedDRA)
Common
(≥1/100,
<1/10)
Uncommon
(≥1/1,000,
<1/100)
Rare
(≥1/10,000, <1/1,000)
Very Rare
(<1/10,000)
Metabolism and
Nutrition
Disorders
Decreased appetite
Psychiatric
Disorders
Anxiety, Sleep
disorder
Confusional state
Nervous System
Disorders
Dizziness,
Headache,
Dysgeusia
Hypoaesthesia,
Paraesthesia,
Parosmia
Syncope, Tremor,
Somnolence, Burning
sensation
Convulsion
Erythema of eyelid,
Eye pain, Vision
blurred
Eye Disorders
Ocular hyperaemia
Ear and
Labyrinth
Disorders
Tinnitus
Cardiac
Disorders
Tachycardia,
Palpitations, AV block
first degree,
Extrasystoles
Arrhythmia
Vascular
Disorders
Flushing
Hypotension,
Hypertension
Respiratory,
Thoracic and
Mediastinal
Disorders
Nasal congestion,
Throat irritation
Dyspnoea, Dysphonia,
Cough, Rhinorrhoea,
Throat tightness
Bronchospasm,
Pharyngeal oedema,
Pharyngitis, Rhinitis,
Sneezing
Gastrointestinal
Disorders
Nausea,
Diarrhoea
Salivary
hypersecretion,,
Vomiting, Abdominal
pain, Constipation,
Dry mouth
Skin and
Subcutaneous
Tissue Disorders
Urticaria,
Pruritus, Rash
Cold sweat, Erythema,
Hyperhidrosis
Periorbital oedema
Renal and
Urinary Disorders
Blood creatinine
increased, Hematuria
General
Disorders and
Administration
Site Conditions
Feeling hot
Chest discomfort,
Feeling cold,
Administration
site reactions
Pain, Chest pain, Face
oedema, Fatigue,
Fever, Oedema
peripheral, Peripheral
coldness
Malaise, Feeling
abnormal,
ALT increased, Urine
analysis abnormal,
Urine electrolytes
abnormal CPK
Increased,
Haemoglobin
decreased, Blood
calcium abnormal
Investigations
Electrocardiogram
QT prolonged
Serious adverse reactions have been reported and include anaphylactic reactions, cardiovascular
reactions, and allergic respiratory disorders. Treatment should be symptomatic and immediate access
to necessary medicinal products and emergency equipment should be available should a serious event
16
occur. Local reactions have occurred at the injection site and may lead to local irritation type
reactions.
Cases of Nephrogenic Systemic Fibrosis (NSF) have been reported with Optimark (see section 4.4).
Gadoversetamide has been tested in humans in doses up to 700 micromol/kg (seven times the standard
dose). Clinical consequences of an overdose have not been reported. Acute toxicity symptoms are
unlikely to occur in patients with normal renal function. Optimark can be removed by haemodialysis.
However, there is no evidence that haemodialysis is suitable for prevention of Nephrogenic Systemic
Fibrosis (NSF).
5. PHARMACOLOGICALPROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic Group: Paramagnetic MRI contrast media, ATC code: V08C A06
Gadoversetamide is a chelate containing gadolinium - which has paramagnetic properties and is
responsible for the contrast enhancement effect in MRI - and the ligand versetamide.
The purpose of an MRI contrast agent is to induce signal intensity changes within the lesion thereby
facilitating its recognition from the surrounding normal structures. The use of a contrast agent may
therefore reduce the threshold for lesion detection and visualization. Gadolinium containing MRI
contrast agents (gadolinium-based chelates) are designed to act indirectly on the local magnetic
environment by altering proton T1 (spin-lattice) and T2 (spin-spin) relaxation times and at the usual
concentration of 100 micromol/kg, the T1 shortening predominates, and the T2 shortening is not
significant using T1-weighted sequences.
Gadoversetamide, an extracellular gadolinium chelate, after intravenous administration, equilibrates
rapidly within the extracellular fluid/space and is eliminated primarily by glomerular filtration.
As a result of these characteristics, the timing of the image acquisition after contrast administration is
critical in liver imaging. For liver metastases, the signal difference between the tumour and
surrounding liver tissue is significantly improved during the first 90 seconds after an extracellular
gadolinium contrast agent is administered. Therefore, a rapid imaging sequence should be initiated 20
seconds after bolus injection of the contrast agent when the agent is predominately in the hepatic
arteries and then again at 60 seconds after injection during the dominant portal venous phase. Since
the hepatic artery and portal venous system supply approximately 20% and 80% of the hepatic blood
supply, respectively, the earlier (hepatic arterial phase) images provide optimal lesion conspicuity for
hypervascular lesions and the portal venous phase images are useful for hypovascular lesions (most
metastatic lesions are relatively hypovascular and are better demonstrated during the portal venous
phase, manifesting as areas of lower signal intensity compared with the markedly enhanced liver).
Lesion conspicuity of hypo- and hypervascular lesions may be reduced if imaging is delayed more
than 3 minutes due to the diffusion of the contrast agent into the interstitial spaces of both the liver
parenchyma and lesion (e.g. metastasis) making the lesion isointense with the normal liver
parenchyma. Delayed post-contrast or equilibrium images (> 5 minutes after dosing) assist in the
characterization of lesions, e.g. the centre of a metastasis may accumulate contrast in the interstitial
space of the lesion and become hyperintense to the normal liver. This difference in enhancement
pattern is useful in formulating a differential diagnosis based on lesion characterization and diagnostic
confidence.
The enhancement of brain tumours using a gadolinium (or iodine) containing contrast agent depends
on the disruption of the blood brain barrier (BBB). As a result, these agents have been referred to as
markers for sites of abnormal BBB breakdown. When the BBB is disrupted, the gadoversetamide
17
molecules diffuse into the interstitial compartment thereby producing the characteristic paramagnetic
effect of T1 and T2 shortening. In general, the addition of contrast to MRI, at the standard clinical
dose of 100 micromol/kg, has led to a significantly improved lesion detection, sensitivity and
diagnostic accuracy.
5.2 Pharmacokinetic properties
Distribution
The pharmacokinetics of gadoversetamide conforms to a two compartment open-model. At the 100
micromol/kg dose, the mean distribution half life in normal subjects calculated by the method of
residuals in 12 normal volunteers is 13.3 ± 6.8 min. Mean volume of distribution at the 100
micromol/kg dose in non-renally impaired patients (including both normal subjects and patients with
CNS or liver pathology) was 158.7 ± 29.0 to 214.3 (range 116.4 to 295.0) ml/kg. This volume of
distribution (approximately 10-15 l for a body weight of 70 kg) is consistent with a medicinal product
which distributes into the extracellular fluid. Dose level has no consistent effect on the volume of
distribution in any of the studies. Gadoversetamide does not undergo protein binding in vitro.
Elimination
The elimination half life at the 100 micromol/kg dose ranges from 1.49 ± 0.15 h in healthy volunteers
to 2.11 ± 0.62 h in non-renally impaired patients (including normal subjects and patients with CNS or
liver pathology).
The mean plasma clearance of gadoversetamide in healthy subjects (111.0 ± 14.1 ml/min/1.73m²
BSA) is not significantly different from the mean renal clearance. Similar results are obtained in
normal subjects and patients with various combinations of liver, CNS and renal dysfunctions with
renal clearance of gadoversetamide being approximately 95% of the total plasma clearance. Such
results (ratio renal clearance/total plasma clearance close to 1) indicate that gadoversetamide is
essentially cleared through the kidneys.
There was no systematic difference in any of the kinetic parameters as a function of dose level (100 to
700 micromol/kg). Therefore, within this dose range, the kinetics of gadoversetamide appear to be
linear.
Metabolism
The high accountability for the dose as intact complex in urine suggests that no significant
metabolism of gadoversetamide occurs in humans.
Special Populations
Effect of Gender:
Adult male and female subjects were enrolled in two pharmacokinetic studies. No significant
differences in pharmacokinetics based on gender were identified.
Effects of Age:
When corrected for body weight, the total body clearance of gadoversetamide is greater in the 2 to 11
year age group (143 ± 27.9 ml/h/kg) than that observed in the 12 to 18 year age group (117 ± 26.1
ml/h/kg) and the two adult populations (82.1 ± 16.8 and 56.5 ± 9.7 ml/h/kg in the 19 to 64 and ≥ 65
year of age groups, respectively).
The elimination half life in the 2 to 11 and 12 to 18 year age groups (1.4 ± 0.3 and 1.6± 0.3 h
-1
,
respectively) is shorter than that observed in the two adult populations (1.9 ± 0.5 and 2.5± 0.5 h
-1
in
the 19 to 64 and ≥ 65 year of age groups, respectively). The number of elderly patients in whom the
pharmacokinetics were determined was limited (over 65 years, N=3).
18
Effect of Renal Impairment
Gadoversetamide plasma levels increase linearly with decreasing renal function; in patients with
severe renal impairment (Cr
Cl
<30 ml/min) this even leads to a six-fold decreased gadoversetamide
clearance and a corresponding six-fold increased extent of exposure AUC and t
½
. Since
gadoversetamide is only administered as a single dose this will lead to a longer and higher exposure
for a limited duration. Still, after 72 hours even in patients with severe renal impairment nearly the
whole dose is recovered in the urine and in healthy populations up to 500 micromol/kg doses were
administered without safety issues. Nevertheless, because of reported cases of NSF that may be
associated with renal impairment for other gadolinium containing contrast agents and for
gadoversetamide, Optimark should not be used in these patients.
5.3 Preclinical safety data
Nonclinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology, acute toxicity, reproductive toxicity, local tolerance, antigenicity, and genotoxicity. No
carcinogenicity studies were performed.
Repeated-dose toxicity studies in rats and dogs revealed vacuolation of the tubular cells of the
kidneys, with strong evidence for reversibility of the effect. No functional impairment was observed.
6.1 List of excipients
Versetamide
Calcium hydroxide
Calcium chloride dihydrate
Sodium hydroxide and/or hydrochloric acid for pH adjustment.
Water for injections.
6.2 Incompatibilities
In the absence of compatibility studies, Optimark should not be mixed with other medicinal products.
6.3 Shelf-life
3 years.
Chemical and physical in-use stability has been demonstrated for 24 hours at up to 25°C.
From a microbiological point of view, the product should be used immediately. If not used
immediately, in-use storage times and conditions prior to use are the responsibility of the user.
6.4 Special precautions for storage
Keep the vial in the outer carton in order to protect from light.
Do not refrigerate or freeze.
6.5 Nature and contents of container
Optimark is filled in vials made of colourless highly resistant borosilicate glass (EP Type I). The vials
are fitted with bromobutyl rubber closures, aluminium cap seals, and plastic flip caps.
Pack sizes:
1 x 10 ml 10 x 10 ml
1 x 15 ml 10 x 15 ml
1 x 20 ml 10 x 20 ml
19
Not all pack-sizes may be marketed
.
Optimark is also available in pre-filled syringes of 10 ml, 15 ml, 20 ml and 30 ml.
6.6 Special precautions for disposal and other handling
Optimark is intended for single use only; any unused portions should be discarded.
Do not use the solution if it is discoloured or particulate matter is present. If non-disposable
equipment is used, scrupulous care should be taken to prevent residual contamination with traces of
cleansing agents.
Optimark should be drawn into the syringe and used immediately.
If frozen, presentations of gadoversetamide in glass containers may be warmed to room temperature
and shaken vigorously. The product must be examined before use to confirm that all solids are
dissolved and that the container and closure are undamaged. If solids remain, the vial must be
discarded.
Discard syringe and unused portion of the solution after use.
Any unused product or waste material should be disposed of in accordance with local requirements.
The peel-off tracking label on the vials should be stuck onto the patient record to enable accurate
recording of the gadolinium contrast agent used. The dose used should also be recorded.
7. MARKETINGAUTHORISATIONHOLDER
Covidien Deutschland GmbH
Gewerbepark 1
93333 Neustadt/Donau
Germany
8. MARKETINGAUTHORISATIONNUMBER(S)
1 x 10 ml: EU/1/07/398/001
10 x 10 ml: EU/1/07/398/002
1 x 15 ml: EU/1/07/398/003
10 x 15 ml: EU/1/07/398/004
1 x 20 ml: EU/1/07/398/005
10 x 20 ml: EU/1/07/398/006
9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION
23/07/2007
20
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
21
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Mallinckrodt Medical Imaging Ireland
Damastown
Mulhuddart
Dublin 15
Ireland
B. CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to restricted medical prescription. (See Annex I: Summary of Product
Characteristics, section 4.2).
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Prior to the launch, the MAA shall provide to all potential prescribers a copy of the SPC with a cover
letter highlighting the safety information included in Sections 4.3 and 4.4. The text shall be agreed by
the CHMP and shall also contain the following key element:
•
Optimark is not recommended for use in children below the age of two years because the
safety, efficacy, and impact of immature kidney function have not been studied in this
age group. Optimark has been studied in children of 2 years and older with a similar
safety profile as shown in the adult population.
As per decision on the Article 20 of Regulation (EC) No 726/2004 the MAH should:
•
Submit a cumulative review on nephrogenic systemic fibrosis (NSF) cases annually and for 3
consecutive years commencing one year after Commission Decision.
•
Submit protocols and timelines for studies evaluating the potential for long-term accumulation
of gadolinium in human bone within 3 months of the Commission Decision. Co-factors that
may increase the risk of NSF such as serum calcium and phosphate levels at the time of
administration of gadolinium-containing contrast agents (GdCAs) should be studied and
biomarkers evaluated. The testing of bone samples from patients undergoing hip and knee
replacement surgery is recommended.
•
Within 3 months of the
Commission Decision, send a proposal for an educational program
aimed to improve the traceability of Optimark and harmonisation of the traceability method
across Europe for the effective monitoring of the use of GdCAs. The proposal must include the
detachable (“sticky”) labels agreed for all GdCAs.
•
Submit a proposal for a Direct Healthcare Professional Communication in line with the key
message document for communication to healthcare professionals agreed by the CHMP to
inform prescribers of the measures to minimise the risk of NSF with Optimark.
22
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 2009/02
presented in Module 1.8.1. of the Marketing Authorisation Application, is in place and functioning
before and whilst the product is on the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version dated 22 May 2007 of the Risk Management Plan
(RMP) presented in Module 1.8.2. of the Marketing Authorisation Application and any subsequent
updates of the RMP agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the
updated RMP should be submitted at the same time as the next Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted
•
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
•
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
•
At the request of the EMEA
23
ANNEX III
LABELLING AND PACKAGE LEAFLET
24
A. LABELLING
25
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Text for the outer packaging of 10 ml, 15 ml, 20 ml and 30 ml pre-filled syringes
1.
Optimark 500 micromol/ml solution for injection in a pre-filled syringe
Gadoversetamide
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
1 ml contains 330.9 mg gadoversetamide, equivalent to 500 micromol.
3.
LIST OF EXCIPIENTS
Excipients: versetamide, calcium hydroxide, calcium chloride dihydrate, sodium hydroxide and/or
hydrochloric acid, water for injections.
4.
Solution for injection
10 ml (1, 10 syringes)
15 ml (1, 10 syringes)
20 ml (1, 10 syringes)
30 ml (1, 10 syringes)
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Intravenous use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
Contrast medium for magnetic resonance imaging
8.
EXPIRY DATE
EXP:
26
9.
SPECIAL STORAGE CONDITIONS
Keep the syringe in the outer carton in order to protect from light.
Do not refrigerate or freeze.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
For single use only. Discard any remaining solution after first use.
Covidien Deutschland GmbH, Gewerbepark 1, 93333 Neustadt/Donau, Germany
EU/1/07/398/007 (1 x 10 ml)
EU/1/07/398/008 (10 x 10 ml)
EU/1/07/398/009 (1 x 15 ml)
EU/1/07/398/010 (10 x 15 ml)
EU/1/07/398/011 (1 x 20 ml)
EU/1/07/398/012 (10 x 20 ml)
EU/1/07/398/013 (1 x 30 ml)
EU/1/07/398/014 (10 x 30 ml)
13. BATCH NUMBER
Lot:
14. GENERAL CLASSIFICATION FOR SUPPLY
Subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted
27
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING
Text for the immediate packaging of 15 ml, 20 ml and 30 ml pre-filled syringes
1.
Optimark 500 micromol/ml solution for injection in a pre-filled syringe
Gadoversetamide
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
1 ml contains 330.9 mg gadoversetamide, equivalent to 500 micromol.
3.
LIST OF EXCIPIENTS
Excipients: versetamide, calcium hydroxide, calcium chloride dihydrate, sodium hydroxide and/or
hydrochloric acid, water for injections.
4.
Solution for injection
15 ml
20 ml
30 ml
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Intravenous use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP:
28
9.
SPECIAL STORAGE CONDITIONS
Keep the syringe in the outer carton in order to protect from light.
Do not refrigerate or freeze.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
For single use only. Discard any remaining solution after first use.
Covidien Deutschland GmbH, Gewerbepark 1, 93333 Neustadt/Donau, Germany
EU/1/07/398/007 (1 x 10 ml)
EU/1/07/398/008 (10 x 10 ml)
EU/1/07/398/009 (1 x 15 ml)
EU/1/07/398/010 (10 x 15 ml)
EU/1/07/398/011 (1 x 20 ml)
EU/1/07/398/012 (10 x 20 ml)
EU/1/07/398/013 (1 x 30 ml)
EU/1/07/398/014 (10 x 30 ml)
13. BATCH NUMBER
Lot:
14. GENERAL CLASSIFICATION FOR SUPPLY
Subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted
29
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
Text for the immediate packaging of the 10 ml pre-filled syringe
1.
Optimark 500 micromol/ml solution for injection in a pre-filled syringe
Gadoversetamide
IV use.
2.
METHOD OF ADMINISTRATION
Read the package leaflet before use.
3.
EXPIRY DATE
EXP:
4.
BATCH NUMBER
Lot:
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
10 ml
6.
OTHER
Keep the syringe in the outer carton in order to protect from light.
Do not refrigerate or freeze.
30
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Text for the outer packaging of 10 ml, 15 ml and 20 ml vials
1.
Optimark 500 micromol/ml solution for injection in a vial
Gadoversetamide
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
1 ml contains 330.9 mg gadoversetamide, equivalent to 500 micromol.
3.
LIST OF EXCIPIENTS
Excipients: versetamide, calcium hydroxide, calcium chloride dihydrate, sodium hydroxide and/or
hydrochloric acid, water for injections.
4.
Solution for injection
10 ml (1, 10 vials)
15 ml (1, 10 vials)
20 ml (1, 10 vials)
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Intravenous use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
Contrast medium for magnetic resonance imaging
8.
EXPIRY DATE
EXP:
31
9.
SPECIAL STORAGE CONDITIONS
Keep the vial in the outer carton in order to protect from light.
Do not refrigerate or freeze.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
For single use only. Discard any remaining solution after first use.
Covidien Deutschland GmbH, Gewerbepark 1, 93333 Neustadt/Donau, Germany
EU/1/07/398/001 (1 x 10 ml)
EU/1/07/398/002 (10 x 10 ml)
EU/1/07/398/003 (1 x 15 ml)
EU/1/07/398/004 (10 x 15 ml)
EU/1/07/398/005 (1 x 20 ml)
EU/1/07/398/006 (10 x 20 ml)
13. BATCH NUMBER
Lot:
14. GENERAL CLASSIFICATION FOR SUPPLY
Subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted
32
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING
Text for the immediate packaging of 15 ml and 20 ml vials
1.
Optimark 500 micromol/ml solution for injection in a vial
Gadoversetamide
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
1 ml contains 330.9 mg gadoversetamide, equivalent to 500 micromol.
3.
LIST OF EXCIPIENTS
Excipients: versetamide, calcium hydroxide, calcium chloride dihydrate, sodium hydroxide and/or
hydrochloric acid, water for injections.
4.
Solution for injection
15 ml
20 ml
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Intravenous use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP:
33
9.
SPECIAL STORAGE CONDITIONS
Keep the vial in the outer carton in order to protect from light.
Do not refrigerate or freeze.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
For single use only. Discard any remaining solution after first use.
Covidien Deutschland GmbH, Gewerbepark 1, 93333 Neustadt/Donau, Germany
EU/1/07/398/001 (1 x 10 ml)
EU/1/07/398/002 (10 x 10 ml)
EU/1/07/398/003 (1 x 15 ml)
EU/1/07/398/004 (10 x 15 ml)
EU/1/07/398/005 (1 x 20 ml)
EU/1/07/398/006 (10 x 20 ml)
13. BATCH NUMBER
Lot:
14. GENERAL CLASSIFICATION FOR SUPPLY
Subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted
34
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
Text for the immediate packaging of the 10 ml vial
1.
Optimark 500 micromol/ml solution for injection in a vial
Gadoversetamide
IV use.
2.
METHOD OF ADMINISTRATION
Read the package leaflet before use.
3.
EXPIRY DATE
EXP:
4.
BATCH NUMBER
Lot:
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
10 ml
6.
OTHER
Keep the vial in the outer carton in order to protect from light.
Do not refrigerate or freeze.
35
B. PACKAGE LEAFLET
36
PACKAGE LEAFLET: INFORMATION FOR THE USER
Optimark 500 micromol/ml solution for injection in a pre-filled syringe
Gadoversetamide
Read all of this leaflet carefully before you are being given this medicine.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your doctor or pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet
:
1.
What Optimark is and what it is used for
2.
Before you are given Optimark
3.
How Optimark is given
4.
How to store Optimark
6.
Further information
1.
WHAT Optimark IS AND WHAT IT IS USED FOR
Optimark is an injectable contrast medium. It is used to make clearer diagnostic images of the brain,
spine and of the liver, in adults and children. As a result, it helps to clearly show abnormalities in the
brain and spine, and in the liver.
This medicine is for diagnostic use only.
2.
BEFORE YOU ARE GIVEN Optimark
Do not use Optimark
if you are allergic (hypersensitive)
•
to the
active substance
gadoversetamide or
•
to any of the
other ingredients
of Optimark, or
•
to other
gadolinium contrast agents
You should not be given Optimark if you suffer from severe kidney impairment, or if you are a patient
who is about to have or has had a liver transplant as use of Optimark in patients with these conditions
has been associated with a disease called Nephrogenic Systemic fibrosis (NSF). NSF is a disease
involving thickening of the skin and connective tissues. NSF may result in debilitating joint
immobility, muscle weakness or may affect the normal working of internal organs which may
potentially be life threatening.
Optimark should not be used in new born babies up to the age of 4 weeks.
Before you receive Optimark, you will need to have a blood test to check how well your kidneys are
working.
Take special care with Optimark
Diagnostic procedures involving the use of contrast agents should be conducted under supervision of
a physician with the prerequisite training and a thorough knowledge of the procedure to be performed.
Tell your doctor, if:
37
5.
Possible side effects
•
you suffer from allergies (e.g. medicinal products, seafood, hay fever, hives) or asthma
•
you had any reactions to previous injections of a contrast agent, including a previous history of
reaction to iodine-based contrast agents
•
your kidneys do not work properly
•
you have recently had, or soon expect to have, a liver transplant
•
Optimark is planned to be used in your child who is below the age of two years
Tell your doctor, if:
•
you are feeling thirsty and/or if you have only had small quantities or nothing to drink before
the examination
•
you have a cardiac pacemaker or any ferromagnetic implant (vascular clips, etc.) or a metallic
stent in your body
•
you are taking a special kind of antihypertensive medicine, i.e. a beta-blocker
•
you have heart disease
•
you suffer from epilepsy or brain lesions
you are or your child is on a controlled sodium diet
If any of these apply to you, your doctor will decide whether the intended examination is possible or
not.
Taking other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription.
Pregnancy and breast-feeding
Ask you doctor for advice before taking any medicine.
Pregancy
You must tell your doctor if you are or might become pregnant as Optimark should not be used
during pregnancy unless strictly necessary.
Breast-feeding
Tell your doctor if you are breast-feeding or about to start breast-feeding. Breast-feeding should be
discontinued for at least 24 hours after you receive Optimark.
Driving and using machines
If you are an ambulant patient and plan to drive or use tools or machines, take into acount that
dizziness may incidentally occur after you undergo a procedure involving the injection of Optimark.
Important information about some of the ingredients of Optimark
This medicine contains less than 1 mmol sodium (23 mg) per dose of up to 17 ml, i.e. essentially
‘sodium- free’. Higher doses contain 1 mmol of sodium or more, which have to be taken into
consideration if you are or your child is on a controlled sodium diet.
3.
HOW Optimark IS GIVEN
The usual dose
The usual dose is about 14 ml injected over about 7 -14 seconds into a vein, usually a vein in an arm.
The injection is then flushed through with a saline injection to make sure none is left in the needle or
tube used for the injection. A second dose may be given within 30 minutes of the first injection.
Certain questions regarding treatment of a brain disease may require the injection of three times the
usual dose in one injection. The doctor will decide how much Optimark is needed for your
examination. You must tell the doctor or nurse/technologist immediately if you feel pain around the
area where the needle is placed.
38
•
Dosage in special patient groups
You should not be given Optimark if you suffer from severe kidney problems or if you are a patient
who is about to have or has had a liver transplant. Optimark should also not be used in newborn
babies up to the age of 4 weeks.
In patients with moderate kidney problems, more than one dose of Optimark should not be used
during a scan. Optimark injections should not be repeated unless the interval between injections is at
least 7 days.
It is not necessary to adjust your dose if you are 65 years of age or older but you will have a blood test
to check how well your kidneys are working.
If you are given more Optimark than you should have been
If too much Optimark was injected it is unlikely that it will do you much harm, as much higher doses
did not lead to any problems when some people received them. If your kidneys are working normally
it is unlikely you will have any problems. Optimark can be removed using dialysis. If you think you
have been injected with too much Optimark, tell the doctor or nurse/technologist immediately.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicinal products, Optimark can cause side effects, although not everybody gets them.
Most of the undesirable effects observed after the use of Optimark were of mild to moderate intensity
and transient in nature. The most common undesirable effects were a strange taste in the mouth,
feeling hot, headache and dizziness.
Immediately tell the doctor or nurse/technologist who is giving you the injection, if you feel unwell,
especially if you feel any tightness, pain or discomfort in your chest, face or throat, or you have
difficulty breathing. Possible side effects are described in greater detail below.
The majority of adverse reactions observed after the use of Optimark were found to be adverse
reactions of the nervous system, followed by general adverse reactions, digestive tract disorders/skin
disorders.
The frequencies below and the following symptoms are based on clinical trials, and on the experience
in using Optimark after it was on the market:
very common:
In more than 1 of 10 treated patients
common:
In less than 1 of 10, but more than 1 of 100 treated patients
uncommon:
In less than 1 of 100, but more than 1 of 1,000 treated patients
rare:
In less than 1 of 1,000, but more than 1 of 10,000 treated patients
very rare:
In 1 case or less of 10,000 treated patients including isolated reports
Frequency Possible side effects
common dizziness, headache, strange taste in the mouth, feeling hot
uncommon allergic/hypersensitivity reaction, tingling sensation, numbness, reduced sense of
smell, skin red and warm, nasal congestion, sore throat, nausea, diarrhoea, hives,
itching, rash, chest discomfort, feeling cold, administration site reactions
rare
decreased appetite, feeling anxious, sleep disorder, fainting, shaking, drowsy feeling,
burning sensation, ringing in the ears, eyelid redness, eye pain, vision blurred, fast
heart beat, awareness of the heartbeat, irregular heartbeats, extra heartbeats, low blood
pressure, high blood pressure, shortness of breath, hoarseness, cough, runny nose,
throat constriction, mouth watering, vomiting, abdominal pain, constipation, dry
mouth, cold sweat, redness, sweating, higher blood level of a substance (creatinine)
usually eliminated by the kidneys, blood in urine, chest pain, face swollen, fatigue,
39
fever, swelling in limbs, pain, cold feeling in extremities, liver enzyme increased,
urine analysis abnormal, mineral values in urine increased, heart and muscle enzyme
increased, decreased haemoglobin, changes in blood calcium levels
very rare
Feeling confused, convulsion, bloodshot eyes, heart beat irregularities, tightening of
the airways, swollen throat or vocal cords, raw throat, itchy nose, sneezing, swelling
around the eyes, flu-like symptoms, feeling unwell, problems with the electrical
rhythm of the heart (long QT)
There have been reports of nephrogenic systemic fibrosis (which causes hardening of the skin and
may affect also soft tissue and internal organs).
When Optimark was used in children aged 2 or older they had similar side effects as in adults.
You must report any of the following symptoms immediately to the doctor or nurse/technologist, and
get immediate treatment as they can be or can become very serious: side effects affecting the heart
(fainting, extra heart beats, chest pain) or the respiratory system (shortness of breath, tightening of the
airways, swollen or tight throat, itchy or runny nose, sneezing).
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE Optimark
Keep out of the reach and sight of children.
Do not use Optimark after the expiry date which is stated on the label. Keep the syringe in the outer
carton in order to protect from light.
Do not refrigerate or freeze.
Medicinal products should not be disposed of via wastewater or household waste. Ask your
pharmacist how to dispose of medicines no longer required. These measures will help to protect the
environment.
6.
FURTHER INFORMATION
What Optimark contains
•
The
active substance
is gadoversetamide.
1 ml contains 330.9 mg gadoversetamide, equivalent to 500 micromol.
•
The
other ingredients
are: versetamide, calcium hydroxide, calcium chloride dihydrate, sodium
hydroxide and/or hydrochloric acid, water for injections.
What Optimark looks like and contents of the pack
Optimark syringes contain a clear, colourless to pale yellow solution.
Optimark is supplied in pre-filled syringes made of polypropylene. Syringe tip cap and piston are
made of bromobutyl rubber.
Optimark pre-filled syringes are supplied in the following package sizes:
1 x 10 ml 10 x 10 ml
1 x 15 ml 10 x 15 ml
1 x 20 ml 10 x 20 ml
1 x 30 ml 10 x 30 ml
Not all package sizes may be marketed.
Optimark is also available in glass vials of 10 ml, 15 ml and 20 ml.
40
Do not use the solution if it is discoloured or particulate matter is present.
Marketing Authorisation Holder
For any information about this medicine, please contact the Marketing Authorisation Holder:
Covidien Deutschland GmbH
Gewerbepark 1
93333 Neustadt/Donau
Germany
Manufacturer
Mallinckrodt Medical Imaging Ireland
Mulhuddart, Dublin 15
Ireland
This leaflet was last approved in:
Detailed information on this product is available on the European Medicines Agency (EMEA) web
site http://www.ema.europa.eu/
The following information is intended for medical or healthcare professionals only:
Optimark is indicated for use with magnetic resonance imaging (MRI) of the central nervous system
(CNS) and liver. It provides contrast enhancement and facilitates visualization and helps with
characterization of focal lesions and abnormal structures in the CNS and liver in patients with known
or highly suspected pathology.
Hypersensitivity
Allergoid and other idiosyncratic reactions may occur with all contrast media for intravenous
application, also with gadoversetamide, which could become manifest in form of cardiovascular,
respiratory and skin reactions. Most of these reactions occur within half an hour after administering
the contrast medium. As with all other contrast media of the same class, late reactions may occur
(after hours or days) in rare cases; however, none were reported in the completed clinical trials.
If hypersensitivity reactions occur, the administration of the contrast medium must be discontinued
immediately and intravenous treatment initiated, if necessary.
During the examination, supervision by a physician is necessary and insertion of a flexible in-
dwelling catheter is recommended. To enable immediate action in emergencies, the necessary
medicinal products (e.g. epinephrine/adrenaline, theophylline, antihistamines, corticosteroids and
atropines), endotracheal tube and ventilator must be immediately available.
The risk of hypersensitivity reactions is increased in the following cases:
-
patients with allergic predisposition
-
patients with bronchial asthma; in these patients it is especially the risk of bronchospasm which is
increased
-
patients with a history of reactions to contrast agents, including a previous history of reaction to
iodine-based contrast agents
41
Damastown
As with any paramagnetic contrast agent, enhancement of MRI with Optimark may impair the
visualization of existing lesions. Some of these lesions may be seen on unenhanced, non-contrast
MRI. Therefore, caution should be exercised when contrast enhanced scan interpretation is made in
the absence of a companion unenhanced MRI.
Before the examination, care must be taken that patients are sufficiently hydrated. The usual
contraindications of MR examinations must be applied, such as exclusion of patients with infusion
pumps, pacemakers, ferro-magnetic clips etc.
•
Before the injection of contrast media, patients should be asked whether they have any allergies (e.g.
allergies to seafood or medicinal products, hay fever, urticaria), whether they are hypersensitive to
contrast media and whether they have bronchial asthma. Premedication with antihistamines and/or
glucocorticoids may be considered.
•
Patients with cardiovascular disease
In this group of patients hypersensitivity reactions may be severe. Especially in patients with serious
heart diseases (e.g. severe heart failure, coronary artery disease) cardiovascular reactions may
deteriorate. However, these were not evident from clinical trials with Optimark.
•
Central nervous system disorders
In patients suffering from epilepsy or brain lesions the likelihood of convulsions during the
examination may be increased. Precautions are necessary when examining these patients (e.g.
monitoring of the patient) and the equipment and medicinal products needed for the rapid treatment of
possible convulsions should be available.
•
Renal impairment and liver transplant patients
Prior to administration of Optimark, all patients should be screened for renal dysfunction by obtaining
laboratory tests.
There have been reports of nephrogenic systemic fibrosis (NSF) associated with use of Optimark and
some other gadolinium-containing contrast agents in patients with acute or chronic severe renal
impairment (GFR <30ml/min/1.73m
2
). Patients who have had or are undergoing liver transplantation
are at particular risk since the incidence of acute renal failure is high in this group. Therefore,
Optimark must not be used in patients with severe renal impairment, in patients who have had or are
undergoing liver transplantation. The risk for development of NSF in patients with moderate renal
impairment (GFR 30–59 ml/min/1.73 m
2
) is unknown, therefore, Optimark should be only used after
careful risk-benefit evaluation in patients with moderate renal impairment at a dose not exceeding
100 micromol/kg body weight. More than one dose should not be used during a scan. Because of the
lack of information on repeated administration, Optimark injections should not be repeated unless the
interval between injections is at least 7 days.
Gadoversetamide is dialysable. Haemodialysis shortly after Optimark administration may be useful at
removing Optimark from the body. There is no evidence to support the initiation of haemodialysis for
prevention or treatment of NSF in patients not already undergoing haemodialysis.
•
Children
Optimark must not be administered with an autoinjector. The required dose should be administered by
hand to children to avoid overdosage by mistake.
•
Neonates and infants
Optimark should not be given to newborn babies up to the age of 4 weeks and to children below the
age of two years. Safety and efficacy have not been studied in this age group.
•
Elderly
As the renal clearance of gadoversetamide may be impaired in the elderly, it is particularly important
to screen patients aged 65 years and older for renal dysfunction.
•
Sodium
This medicinal product contains less than 1 mmol sodium (23 mg) per dose of up to 17 ml, i.e.
essentially ‘sodium- free’. Higher doses contain 1 mmol of sodium or more, which should be taken
into consideration for patients on a controlled sodium diet.
•
Serum iron and zinc
Caution should be exercised because transient decreases in serum iron and zinc parameters have been
observed in clinical trials. The clinical significance of this is unknown.
Pregnancy and Lactation
Optimark should not be used during pregnancy unless the clinical condition of the women requires the
use of gadoversetamide.
42
Patients taking beta-blockers
It should be noted that patients using beta-blockers do not necessarily respond to the beta-agonists
usually used for the treatment of hypersensitivity reactions.
•
Breast-feeding should be discontinued for at least 24 hours after administration of Optimark.
The agent should be administered as a bolus peripheral intravenous injection at a dose of 0.2 ml/kg
(0.1 mmol/kg) body weight. To ensure complete injection of the contrast medium, the injection should
be followed by a 5 ml flush of sodium chloride 9 mg/ml (0.9 %) injection. The imaging procedure
should be completed within 1 hour of administration of the contrast medium.
In cranial MRI, if a strong clinical suspicion of a lesion persists despite a single dose contrast-
enhanced MRI or when more accurate information on the number, size or extent of lesions might
influence management or therapy of the patient, in subjects with normal renal function, a second
bolus injection of 0.1 mmol/kg may be administered within 30 minutes of the first injection as it may
increase the diagnostic yield of the examination. The safety of repeat doses has not been established
in children and adolescents, in patients with impaired renal function, or the elderly.
Limited data with other gadolinium contrast agents suggests that for the exclusion of additional
cranial metastases in a patient with a known solitary resectable metastasis, an MR exam with the
injection of 0.3 mmol/kg body weight of Optimark may lead to higher diagnostic confidence.
Optimark is not recommended for use in children below the age of two years because the safety,
efficacy, and impact of immature kidney function have not been studied in this age group. Optimark
has been studied in children of 2 years and older with a similar safety profile as shown in the adult
population.
Insertion of a flexible in-dwelling venous catheter is recommended.
No formal interaction studies have been performed.
Gadoversetamide has been shown to cause interference in the measurement of serum calcium using
the ortho-cresolphthalein complexone (OCP) colorimetric method. However, the administration of
gadoversetamide does not cause a true decrease in serum calcium. In the presence of
gadoversetamide, the OCP technique produces an erroneous, low value for plasma calcium. The
magnitude of this measurement artefact is proportional to the concentration of gadoversetamide in the
blood, and in patients with normal renal clearance accurate values can be obtained approximately 90
minutes following injection. In patients with compromised renal function, clearance of
gadoversetamide will be slowed and the interference with calcium determination by OCP prolonged.
Gadoversetamide does not affect other methods of measuring serum calcium, such as the arsenazo III
colorimetric method, atomic absorption spectroscopy, and inductively coupled plasma mass
spectroscopy.
Special precautions for disposal and other handling
Optimark is intended for single use only; any unused portions should be discarded.
Optimark pre-filled syringes should be used immediately. Do not use the solution if it is discoloured
or particulate matter is present. If non-disposable equipment is used, scrupulous care should be taken
to prevent residual contamination with traces of cleansing agents.
Pre-filled syringes:
Assembly and Inspection
Inspect the syringe for signs of leakage. Do not use if leakage is observed.
After screwing the push rod into the syringe
piston, it is important to
turn the push rod an
additional ½ turn
so that the grey piston
rotates freely.
43
Prior to using the syringe, twist off grey tip
cap and discard. Syringe is now ready for
needle or infusion tubing attachment.
Discard syringe and unused portion of the solution after use.
Any unused product or waste material should be disposed of in accordance with local requirements.
The peel-off tracking label on the pre-filled syringes should be stuck onto the patients record to enable
accurate recording of the gadolinium contrast agent used. The dose used should also be recorded.
44
PACKAGE LEAFLET: INFORMATION FOR THE USER
Optimark 500 micromol/ml solution for injection in a vial
Gadoversetamide
Read all of this leaflet carefully before you are being given this medicine.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your doctor or pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet
:
1.
What Optimark is and what it is used for
2.
Before you are given Optimark
3.
How Optimark is given
4.
How to store Optimark
6.
Further information
1.
WHAT Optimark IS AND WHAT IT IS USED FOR
Optimark is an injectable contrast medium. It is used to make clearer diagnostic images of the brain,
spine and of the liver, in adults and children. As a result, it helps to clearly show abnormalities in the
brain and spine, and in the liver.
This medicine is for diagnostic use only.
2.
BEFORE YOU ARE GIVEN Optimark
Do not use Optimark
if you are allergic (hypersensitive)
•
to the
active substance
gadoversetamide or
•
to any of the
other ingredients
of Optimark, or
•
to other
gadolinium contrast agents
You should not be given Optimark if you suffer from severe kidney impairment, or if you are a patient
who is about to have or has had a liver transplant as use of Optimark in patients with these conditions
has been associated with a disease called Nephrogenic Systemic fibrosis (NSF). NSF is a disease
involving thickening of the skin and connective tissues. NSF may result in debilitating joint
immobility, muscle weakness or may affect the normal working of internal organs which may
potentially be life threatening.
Optimark should not be used in new born babies up to the age of 4 weeks.
Before you receive Optimark, you will need to have a blood test to check how well your kidneys are
working.
Take special care with Optimark
Diagnostic procedures involving the use of contrast agents should be conducted under supervision of
a physician with the prerequisite training and a thorough knowledge of the procedure to be performed.
Tell your doctor, if:
45
5.
Possible side effects
•
you suffer from allergies (e.g. medicinal products, seafood, hay fever, hives) or asthma
•
you had any reactions to previous injections of a contrast agent, including a previous history of
reaction to iodine-based contrast agents
•
your kidneys do not work properly
•
you have recently had, or soon expect to have, a liver transplant
•
Optimark is planned to be used in your child who is below the age of two years
Tell your doctor, if:
•
you are feeling thirsty and/or if you have only had small quantities or nothing to drink before
the examination
•
you have a cardiac pacemaker or any ferromagnetic implant (vascular clips, etc.) or a metallic
stent in your body
•
you are taking a special kind of antihypertensive medicine, i.e. a beta-blocker
•
you have heart disease
•
you suffer from epilepsy or brain lesions
you are or your child is on a controlled sodium diet
If any of these apply to you, your doctor will decide whether the intended examination is possible or
not.
Taking other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription.
Pregnancy and breast-feeding
Ask you doctor for advice before taking any medicine.
Pregancy
You must tell your doctor if you are or might become pregnant as Optimark should not be used during
pregnancy unless strictly necessary.
Breast-feeding
Tell your doctor if you are breast-feeding or about to start breast-feeding. Breast-feeding should be
discontinued for at least 24 hours after you receive Optimark.
Driving and using machines
If you are an ambulant patient and plan to drive or use tools or machines, take into acount that
dizziness may incidentally occur after you undergo a procedure involving the injection of Optimark.
Important information about some of the ingredients of Optimark
This medicine contains less than 1 mmol sodium (23 mg) per dose of up to 17 ml, i.e. essentially
‘sodium- free’. Higher doses contain 1 mmol of sodium or more, which have to be taken into
consideration if you are or your child is on a controlled sodium diet.
3.
HOW Optimark IS GIVEN
The usual dose
The usual dose is about 14 ml injected over about 7 -14 seconds into a vein, usually a vein in an arm.
The injection is then flushed through with a saline injection to make sure none is left in the needle or
tube used for the injection. A second dose may be given within 30 minutes of the first injection.
Certain questions regarding treatment of a brain disease may require the injection of three times the
usual dose in one injection. The doctor will decide how much Optimark is needed for your
examination. You must tell the doctor or nurse/technologist immediately if you feel pain around the
area where the needle is placed.
46
•
Dosage in special patient groups
You should not be given Optimark if you suffer from severe kidney problems or if you are a patient
who is about to have or has had a liver transplant. Optimark should also not be used in newborn
babies up to the age of 4 weeks.
In patients with moderate kidney problems, more than one dose of Optimark should not be used
during a scan. Optimark injections should not be repeated unless the interval between injections is at
least 7 days.
It is not necessary to adjust your dose if you are 65 years of age or older but you will have a blood test
to check how well your kidneys are working.
If you are given more Optimark than you should have been
If too much Optimark was injected it is unlikely that it will do you much harm, as much higher doses
did not lead to any problems when some people received them. If your kidneys are working normally
it is unlikely you will have any problems. Optimark can be removed using dialysis. If you think you
have been injected with too much Optimark, tell the doctor or nurse/technologist immediately.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicinal products, Optimark can cause side effects, although not everybody gets them.
Most of the undesirable effects observed after the use of Optimark were of mild to moderate intensity
and transient in nature. The most common undesirable effects were a strange taste in the mouth,
feeling hot, headache and dizziness.
Immediately tell the doctor or nurse/technologist who is giving you the injection, if you feel unwell,
especially if you feel any tightness, pain or discomfort in your chest, face or throat, or you have
difficulty breathing. Possible side effects are described in greater detail below.
The majority of adverse reactions observed after the use of Optimark were found to be adverse
reactions of the nervous system, followed by general adverse reactions, digestive tract disorders/skin
disorders.
The frequencies below and the following symptoms are based on clinical trials, and on the experience
in using Optimark after it was on the market:
very common:
In more than 1 of 10 treated patients
common:
In less than 1 of 10, but more than 1 of 100 treated patients
uncommon:
In less than 1 of 100, but more than 1 of 1,000 treated patients
rare:
In less than 1 of 1,000, but more than 1 of 10,000 treated patients
very rare:
In 1 case or less of 10,000 treated patients including isolated reports
Frequency Possible side effects
common dizziness, headache, strange taste in the mouth, feeling hot
uncommon allergic/hypersensitivity reaction, tingling sensation, numbness, reduced sense of
smell, skin red and warm, nasal congestion, sore throat, nausea, diarrhoea, hives,
itching, rash, chest discomfort, feeling cold, administration site reactions
rare
decreased appetite, feeling anxious, sleep disorder, fainting, shaking, drowsy feeling,
burning sensation, ringing in the ears, eyelid redness, eye pain, vision blurred, fast
heart beat, awareness of the heartbeat, irregular heartbeats, extra heartbeats, low blood
pressure, high blood pressure, shortness of breath, hoarseness, cough, runny nose,
throat constriction, mouth watering, vomiting, abdominal pain, constipation, dry
mouth, cold sweat, redness, sweating, higher blood level of a substance (creatinine)
usually eliminated by the kidneys, blood in urine, chest pain, face swollen, fatigue,
47
fever, swelling in limbs, pain, cold feeling in extremities, liver enzyme increased,
urine analysis abnormal, mineral values in urine increased, heart and muscle enzyme
increased, decreased haemoglobin, changes in blood calcium levels
very rare
Feeling confused, convulsion, bloodshot eyes, heart beat irregularities, tightening of
the airways, swollen throat or vocal cords, raw throat, itchy nose, sneezing, swelling
around the eyes, flu-like symptoms, feeling unwell, problems with the electrical
rhythm of the heart (long QT)
There have been reports of nephrogenic systemic fibrosis (which causes hardening of the skin and
may affect also soft tissue and internal organs).
When Optimark was used in children aged 2 or older they had similar side effects as in adults.
You must report any of the following symptoms immediately to the doctor or nurse/technologist, and
get immediate treatment as they can be or can become very serious: side effects affecting the heart
(fainting, extra heart beats, chest pain) or the respiratory system (shortness of breath, tightening of the
airways, swollen or tight throat, itchy or runny nose, sneezing).
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE Optimark
Keep out of the reach and sight of children.
Do not use Optimark after the expiry date which is stated on the label. Keep the vial in the outer
carton in order to protect from light.
Do not refrigerate or freeze.
Medicinal products should not be disposed of via wastewater or household waste. Ask your
pharmacist how to dispose of medicines no longer required. These measures will help to protect the
environment.
6.
FURTHER INFORMATION
What Optimark contains
•
The
active substance
is gadoversetamide.
1 ml contains 330.9 mg gadoversetamide, equivalent to 500 micromoles.
•
The
other ingredients
are: versetamide, calcium hydroxide, calcium chloride dihydrate, sodium
hydroxide and/or hydrochloric acid, water for injections.
What Optimark looks like and contents of the pack
Optimark vials contain a clear, colourless to pale yellow solution.
Optimark is supplied in vials, fitted with bromobutyl rubber closures and aluminium cap seals.
Optimark vials are supplied in the following package sizes:
1 x 10 ml 10 x 10 ml
1 x 15 ml 10 x 15 ml
1 x 20 ml 10 x 20 ml
Not all package sizes may be marketed.
Optimark is also available in pre-filled syringes of 10 ml, 15 ml, 20 ml and 30 ml.
48
Do not use the solution if it is discoloured or particulate matter is present.
Marketing Authorisation Holder
For any information about this medicine, please contact the Marketing Authorisation Holder:
Covidien Deutschland GmbH
Gewerbepark 1
93333 Neustadt/Donau
Germany
Manufacturer
Mallinckrodt Medical Imaging Ireland
Damastown
Mulhuddart, Dublin 15
This leaflet was last approved in:
Detailed information on this product is available on the European Medicines Agency (EMEA) web
site http://www.ema.europa.eu
The following information is intended for medical or healthcare professionals only:
Optimark is indicated for use with magnetic resonance imaging (MRI) of the central nervous system
(CNS) and liver. It provides contrast enhancement and facilitates visualization and helps with
characterization of focal lesions and abnormal structures in the CNS and liver in patients with known
or highly suspected pathology.
Hypersensitivity
Allergoid and other idiosyncratic reactions may occur with all contrast media for intravenous
application, also with gadoversetamide, which could become manifest in form of cardiovascular,
respiratory and skin reactions. Most of these reactions occur within half an hour after administering
the contrast medium. As with all other contrast media of the same class, late reactions may occur
(after hours or days) in rare cases; however, none were reported in the completed clinical trials.
If hypersensitivity reactions occur, the administration of the contrast medium must be discontinued
immediately and intravenous treatment initiated, if necessary.
During the examination, supervision by a physician is necessary and insertion of a flexible in-
dwelling catheter is recommended. To enable immediate action in emergencies, the necessary
medicinal products (e.g. epinephrine/adrenaline, theophylline, antihistamines, corticosteroids and
atropines), endotracheal tube and ventilator must be immediately available.
The risk of hypersensitivity reactions is increased in the following cases:
-
patients with allergic predisposition
-
patients with bronchial asthma; in these patients it is especially the risk of bronchospasm which is
increased
-
patients with a history of reactions to contrast agents, including a previous history of reaction to
iodine-based contrast agents
49
Ireland
As with any paramagnetic contrast agent, enhancement of MRI with Optimark may impair the
visualization of existing lesions. Some of these lesions may be seen on unenhanced, non-contrast
MRI. Therefore, caution should be exercised when contrast enhanced scan interpretation is made in
the absence of a companion unenhanced MRI.
Before the examination, care must be taken that patients are sufficiently hydrated. The usual
contraindications of MR examinations must be applied, such as exclusion of patients with infusion
pumps, pacemakers, ferro-magnetic clips etc.
•
Before the injection of contrast media, patients should be asked whether they have any allergies (e.g.
allergies to seafood or medicinal products, hay fever, urticaria), whether they are hypersensitive to
contrast media and whether they have bronchial asthma. Premedication with antihistamines and/or
glucocorticoids may be considered.
•
Patients with cardiovascular disease
In this group of patients hypersensitivity reactions may be severe. Especially in patients with serious
heart diseases (e.g. severe heart failure, coronary artery disease) cardiovascular reactions may
deteriorate. However, these were not evident from clinical trials with Optimark.
•
Central nervous system disorders
In patients suffering from epilepsy or brain lesions the likelihood of convulsions during the
examination may be increased. Precautions are necessary when examining these patients (e.g.
monitoring of the patient) and the equipment and medicinal products needed for the rapid treatment of
possible convulsions should be available.
•
Renal impairment and liver transplant patients
Prior to administration of Optimark, all patients should be screened for renal dysfunction by obtaining
laboratory tests.
There have been reports of nephrogenic systemic fibrosis (NSF) associated with use of Optimark and
some other gadolinium-containing contrast agents in patients with acute or chronic severe renal
impairment (GFR <30ml/min/1.73m
2
). Patients who have had or are undergoing liver transplantation
are at particular risk since the incidence of acute renal failure is high in this group. Therefore,
Optimark must not be used in patients with severe renal impairment, in patients who have had or are
undergoing liver transplantation. The risk for development of NSF in patients with moderate renal
impairment (GFR 30–59 ml/min/1.73 m
2
) is unknown, therefore, Optimark should be only used after
careful risk-benefit evaluation in patients with moderate renal impairment at a dose not exceeding
100 micromol/kg body weight. More than one dose should not be used during a scan. Because of the
lack of information on repeated administration, Optimark injections should not be repeated unless the
interval between injections is at least 7 days.
Gadoversetamide is dialysable. Haemodialysis shortly after Optimark administration may be useful at
removing Optimark from the body. There is no evidence to support the initiation of haemodialysis for
prevention or treatment of NSF in patients not already undergoing haemodialysis.
•
Children
Optimark must not be administered with an autoinjector. The required dose should be administered by
hand to children to avoid overdosage by mistake.
•
Neonates and infants
Optimark should not be given to newborn babies up to the age of 4 weeks and to children below the
age of two years. Safety and efficacy have not been studied in this age group.
•
Elderly
As the renal clearance of gadoversetamide may be impaired in the elderly, it is particularly important
to screen patients aged 65 years and older for renal dysfunction.
•
Sodium
This medicinal product contains less than 1 mmol sodium (23 mg) per dose of up to 17 ml, i.e.
essentially ‘sodium- free’. Higher doses contain 1 mmol of sodium or more, which should be taken
into consideration for patients on a controlled sodium diet.
•
Serum iron and zinc
Caution should be exercised because transient decreases in serum iron and zinc parameters have been
observed in clinical trials. The clinical significance of this is unknown.
Pregnancy and Lactation
Optimark should not be used during pregnancy unless the clinical condition of the women requires the
use of gadoversetamide.
Breast-feeding should be discontinued for at least 24 hours after administration of Optimark.
50
Patients taking beta-blockers
It should be noted that patients using beta-blockers do not necessarily respond to the beta-agonists
usually used for the treatment of hypersensitivity reactions.
•
The agent should be administered as a bolus peripheral intravenous injection at a dose of 0.2 ml/kg
(0.1 mmol/kg) body weight. To ensure complete injection of the contrast medium, the injection should
be followed by a 5 ml flush of sodium chloride 9 mg/ml (0.9 %) injection. The imaging procedure
should be completed within 1 hour of administration of the contrast medium.
In cranial MRI, if a strong clinical suspicion of a lesion persists despite a single dose contrast-
enhanced MRI or when more accurate information on the number, size or extent of lesions might
influence management or therapy of the patient, in subjects with normal renal function, a second
bolus injection of 0.1 mmol/kg may be administered within 30 minutes of the first injection as it may
increase the diagnostic yield of the examination. The safety of repeat doses has not been established
in children and adolescents, in patients with impaired renal function, or the elderly.
Limited data with other gadolinium contrast agents suggests that for the exclusion of additional
cranial metastases in a patient with a known solitary resectable metastasis, an MR exam with the
injection of 0.3 mmol/kg body weight of Optimark may lead to higher diagnostic confidence.
Optimark is not recommended for use in children below the age of two years because the safety,
efficacy, and impact of immature kidney function have not been studied in this age group. Optimark
has been studied in children of 2 years and older with a similar safety profile as shown in the adult
population.
Insertion of a flexible in-dwelling venous catheter is recommended.
No formal interaction studies have been performed.
Gadoversetamide has been shown to cause interference in the measurement of serum calcium using
the ortho-cresolphthalein complexone (OCP) colorimetric method. However, the administration of
gadoversetamide does not cause a true decrease in serum calcium. In the presence of
gadoversetamide, the OCP technique produces an erroneous, low value for plasma calcium. The
magnitude of this measurement artefact is proportional to the concentration of gadoversetamide in the
blood, and in patients with normal renal clearance accurate values can be obtained approximately 90
minutes following injection. In patients with compromised renal function, clearance of
gadoversetamide will be slowed and the interference with calcium determination by OCP prolonged.
Gadoversetamide does not affect other methods of measuring serum calcium, such as the arsenazo III
colorimetric method, atomic absorption spectroscopy, and inductively coupled plasma mass
spectroscopy.
Special precautions for disposal and other handling
Optimark is intended for single use only; any unused portions should be discarded.
Optimark should be drawn into the syringe and used immediately. Do not use the solution if it is
discoloured or particulate matter is present. If non-disposable equipment is used, scrupulous care
should be taken to prevent residual contamination with traces of cleansing agents.
The product must be examined before use to confirm that all solids are dissolved and that the
container and closure are un-damaged. If solids remain, the vial must be discarded.
Discard syringe and unused portion of the solution after use.
Any unused product or waste material should be disposed of in accordance with local requirements.
The peel-off tracking label on the vials should be stuck onto the patients record to enable accurate
recording of the gadolinium contrast agent used. The dose used should also be recorded.
51
Source: European Medicines Agency
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