ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Cyanokit 2.5 g powder for solution for infusion
2.
Each vial contains 2.5 g of hydroxocobalamin. After reconstitution with 100 ml of diluent, each ml of
the reconstituted solution contains 25 mg of hydroxocobalamin.
For a full list of excipients, see section 6.1.
3.
Powder for solution for infusion.
Dark red crystalline powder.
4.
Treatment of known or suspected cyanide poisoning.
Cyanokit is to be administered together with appropriate decontamination and supportive measures.
Initial dose
Cyanokit is administered as an intravenous infusion over 15 minutes.
Adults
: The initial dose of Cyanokit is 5 g.
Paediatric patients:
In infants to adolescents, the initial dose of Cyanokit is 70 mg/kg body weight not
exceeding 5 g.
Body weight
in kg
5
10
20
30
40
50
60
Initial dose
in g
in ml
0.35
14
0.70
28
1.40
56
2.10
84
2.80
112
3.50
140
4.20
168
Subsequent dose
Depending upon the severity of the poisoning and the clinical response (see section 4.4), a second
dose may be administered by intravenous infusion. The rate of infusion for the second dose ranges
from 15 minutes (for patients extremely unstable) to 2 hours based on patient condition.
Adults:
The subsequent dose of Cyanokit is 5 g.
Paediatric patients:
In infants to adolescents, the subsequent dose of Cyanokit is 70 mg/kg body
weight not exceeding 5 g.
2
Maximum dose
Adults
: The maximum recommended dose is 10 g.
Paediatric patients:
In infants to adolescents, the maximum recommended dose is 140 mg/kg not
exceeding 10 g.
Renal and hepatic impairments
Although the safety and efficacy of hydroxocobalamin have not been studied in renal and hepatic
impairments, Cyanokit is administered as emergency therapy in an acute, life-threatening situation
only and no dosage adjustment is required in these patients.
For instructions on preparation and handling, see section 6.6.
None.
Treatment of cyanide poisoning must include immediate attention to airway patency, adequacy of
oxygenation and hydration, cardiovascular support, and management of seizures. Consideration must
be given to decontamination measures based on the route of exposure.
Cyanokit does not substitute oxygen therapy
and must
not
delay the set up of the
above
measures.
The presence and extent of cyanide poisoning are often initially unknown. There is no widely
available, rapid, confirmatory cyanide blood test. Treatment decisions must be made on the basis of
clinical history and/or signs and symptoms of cyanide intoxication.
Cyanide poisoning may result from exposure to smoke from closed space fires, inhalation, ingestion,
or dermal exposure. Sources of cyanide poisoning include hydrogen cyanide and its salts, cyanogens,
including cyanogenic plants, aliphatic nitriles, or prolonged exposure to sodium nitroprusside.
Signs and symptoms of cyanide poisoning
Common signs and symptoms of cyanide poisoning include: nausea, vomiting, headache, altered
mental status (e.g. confusion, disorientation), chest tightness, dyspnoea, tachypnoea or hyperpnoea
(early), bradypnoea or apnoea (late), hypertension (early) or hypotension (late), cardiovascular
collapse, seizures or coma, mydriasis, and plasma lactate concentration > 8 mmol/l.
In the setting of multiple casualties such as terrorism or chemical disaster, panic symptoms including
tachypnoea and vomiting may mimic early cyanide poisoning signs. The presence of altered mental
status (confusion and disorientation) and/or mydriasis is suggestive of true cyanide poisoning.
Smoke inhalation
Not all smoke inhalation victims necessarily will have cyanide poisoning, but may present with burns,
trauma, and exposure to additional toxic substances aggravating the clinical picture. Before Cyanokit
is administered, it is recommended to check affected persons for the presence of the following:
•
exposure to fire smoke in an enclosed area
•
soot present around mouth, nose and/or oropharynx
•
altered mental status
In this setting hypotension and/or a plasma lactate concentration ≥ 10 mmol/l (higher than the one
mentioned under signs and symptoms due to the fact that carbon monoxide contributes to lactic
3
acidaemia) are highly suggestive of cyanide poisoning. In the presence of the above signs, treatment
with Cyanokit must not be delayed to obtain a plasma lactate concentration.
Hypersensitivity reactions
Known hypersensitivity to hydroxocobalamin or vitamin B
12
must be taken into benefit-risk
consideration before administration of Cyanokit, since hypersensitive reactions may occur in patients
receiving hydroxocobalamin (see section 4.8).
Increase in blood pressure
Transient, generally asymptomatic, increase in blood pressure may occur in patients receiving
hydroxocobalamin. The maximal increase in blood pressure has been observed toward the end of
infusion.
Effects on blood cyanide assay
Hydroxocobalamin will lower blood cyanide concentrations. While determination of blood cyanide
concentration is not required and must not delay treatment with hydroxocobalamin, it may be useful
for documenting cyanide poisoning. If a cyanide blood level determination is planned, it is
recommended to draw the blood sample before initiation of treatment with Cyanokit.
Interference with burn assessment
Because of its deep red colour, hydroxocobalamin has the potential to induce a red colouration of the
skin and therefore may interfere with burn assessment. However, skin lesions, oedema, and pain are
highly suggestive of burns.
Interference with laboratory tests
Because of its deep red colour, hydroxocobalamin has the potential to interfere with determination of
laboratory parameters (e.g. clinical chemistry, haematology, coagulation, and urine parameters).
In vitro
tests indicate that the extent and duration of the interference is dependant on numerous factors
such as the dose of hydroxocobalamin, analyte, analyte concentration, methodology, analyser,
concentrations of cobalamins-(III) including cyanocobalamin and partially the time between sampling
and measurement.
Based on
in vitro
studies and pharmacokinetic data obtained in healthy volunteers the following table
describes interference with laboratory tests that may be observed following a 5 g dose of
hydroxocobalamin. Interference following a 10 g dose can be expected to last up to an additional
24 hours. The extent and duration of interference in cyanide-poisoned patients may differ according to
the severity of intoxication. Results may vary considerably from one analyser to another, therefore,
caution is required when reporting and interpreting laboratory results.
Observed
in vitro
interferences of hydroxocobalamin with laboratory tests
Laboratory
parameter
No interference
observed
Artificially
increased*
Artificially
decreased*
Duration of
interference
after a 5 g dose
Unpredictable***
Clinical
chemistry
Calcium
Sodium
Potassium
Chloride
Urea
Gamma glutamyl
transferase (GGT)
Creatinine
Total and
conjugate
bilirubin**
Triglycerides
Cholesterol
Total protein
Glucose
Albumin
Alkaline
Alanine
aminotransferase
(ALT)
Amylase
Phosphate
Uric acid
Aspartate
aminotransferase
(AST)
Creatine kinase (CK)
Creatine kinase
isoenzym MB
(CKMB)
Lactate dehydrogenase
24 hours with the
exception of
bilirubin (up to
4 days)
4
Laboratory
parameter
No interference
observed
Artificially
increased*
Artificially
decreased*
Duration of
interference
after a 5 g dose
Unpredictable***
phosphatase
(LDH)
Haematology Erythrocytes
Haematocrit
Mean corpuscular
volume (MCV)
Leucocytes
Lymphocytes
Monocytes
Eosinophils
Neutrophils
Platelets
Haemoglobin
(Hb)
Mean
corpuscular
haemoglobin
(MCH)
Mean
corpuscular
haemoglobin
concentration
(MCHC)
12-16 hours
Coagulation
Activated partial
thromboplastin time
(aPTT)
Prothrombin time (PT)
Quick or INR
24 hours
* ≥ 10% interference observed on at least one analyser
** Artificially decreased using the diazo method
*** Inconsistent results
Analysers used: ACL Futura (Instrumentation Laboratory), Axsym/Architect (Abbott), BM Coasys
110
(Boehringer
Mannheim), CellDyn 3700 (Abbott), Clinitek 500 (Bayer), Cobas Integra 700, 400 (Roche), Gen-S Coultronics, Hitachi 917,
STA
®
Compact, Vitros 950 (Ortho Diagnostics)
Hydroxocobalamin may interfere with all urine colorimetric parameters. The effects on these tests
typically last 48 hours after a 5 g dose, but may persist for longer periods. Caution is required in the
interpretation of urinary colorimetric tests for as long as chromaturia is present.
Use with other cyanide antidotes
The safety of administering other cyanide antidotes simultaneously with Cyanokit has not been
established (see section 6.2). If the decision is made to administer another cyanide antidote with
Cyanokit, these medicinal products must not be administered concurrently in the same intravenous line
(see section 6.2).
No interaction studies have been performed.
Animal studies have shown teratogenic effects following daily exposure throughout organogenesis
(see section 5.3). There are no adequate data from the use of hydroxocobalamin in pregnant women
and the potential risk for humans is unknown.
However, taken into account:
-
that no more than two injections of hydroxocobalamin are to be administered,
-
the potentially life threatening condition,
-
the lack of alternative treatment,
hydroxocobalamin may be given to a pregnant woman.
In case of known pregnancy at the time of treatment with Cyanokit or in case that pregnancy becomes
known after treatment with Cyanokit, health care professionals are requested to promptly report the
exposure during pregnancy to the Marketing Authorisation Holder and to carefully follow-up on the
pregnancy and its outcome.
5
Because hydroxocobalamin will be administered in potentially life-threatening situations, breast-
feeding is not a contraindication to its use.
No studies on the effects on the ability to drive or to use machines have been performed.
A total of 347 subjects were exposed to hydroxocobalamin in clinical studies. Of these 347 subjects,
245 patients had suspected exposure to cyanide at the time of hydroxocobalamin administration. The
remaining 102 subjects were healthy volunteers who had not been exposed to cyanide at the time of
hydroxocobalamin administration.
Most patients will experience a reversible red colouration of the skin and mucous membranes that may
last up to 15 days after administration of Cyanokit. All patients will show a dark red colouration of the
urine quite marked during the three days following administration. Urine colouration may last up to
35 days after administration of Cyanokit.
The following undesirable effects have been reported in association with Cyanokit use. However,
because of the limitations of the available data, it is not possible to apply frequency estimations:
Investigations
Cyanokit may cause red discolouration of the plasma, which may cause artificial elevation or
reduction in the levels of certain laboratory parameters (see section 4.4).
Cardiac disorders
Ventricular extrasystoles. An increase in heart rate was observed in cyanide-poisoned patients.
Blood and lymphatic system disorders
Decrease in the percentage of lymphocytes.
Nervous system disorders
Memory impairment; dizziness.
Eye disorders
Swelling, irritation, redness.
Respiratory, thoracic and mediastinal disorders
Pleural effusion, dyspnoea, throat tightness, dry throat, chest discomfort.
Gastrointestinal disorders
Abdominal discomfort, dyspepsia, diarrhoea, vomiting, nausea, dysphagia.
Renal and urinary disorders
Chromaturia (see above).
Skin and subcutaneous tissue disorders
6
Reversible red colouration of the skin and mucous membranes (see above). Pustular rashes, which
may last for several weeks, affecting mainly the face and the neck.
Vascular disorders
Transient increase in blood pressure, usually resolving within several hours; hot flush. A decrease in
blood pressure was observed in cyanide-poisoned patients.
General disorders and administration site conditions
Headache; injection site reaction; peripheral oedema.
Immune system disorders
Allergic reactions including angioneurotic oedema, skin eruption, urticaria and pruritus.
Psychiatric disorders
Restlessness.
Doses as high as 15 g have been administered without reported specific dose related adverse reactions.
If overdose occurs, treatment is directed to the management of symptoms. Haemodialysis may be
effective in such a circumstance, but is only indicated in the event of significant hydroxocobalamin-
related toxicity.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antidotes, ATC code: V03AB33
Mechanism of action
The action of hydroxocobalamin in the treatment of cyanide poisoning is based on its ability to tightly
bind cyanide ions. Each hydroxocobalamin molecule can bind one cyanide ion by substituting the
hydroxo ligand linked to the trivalent cobalt ion to form cyanocobalamin. Cyanocobalamin is a stable,
non-toxic compound that is excreted in the urine.
Efficacy
Due to ethical considerations, no controlled human efficacy studies have been performed.
•
Animal pharmacology
The effectiveness of hydroxocobalamin was examined in a controlled study in cyanide-poisoned adult
dogs. Dogs were poisoned by intravenous administration of a lethal dose of potassium cyanide. Dogs
then received sodium chloride 9 mg/ml, 75 mg/kg or 150 mg/kg hydroxocobalamin, administered
intravenously over 7.5 minutes. The 75 mg/kg and 150 mg/kg doses are approximately equivalent to
5 g and 10 g of hydroxocobalamin, respectively, in humans, not only on a body weight basis but also
on C
max
basis of hydroxocobalamin [total cobalamins-(III), see section 5.2].
Survival at hour 4 and at day 14 was significantly greater in 75 mg/kg and 150 mg/kg
hydroxocobalamin dose groups compared with dogs receiving sodium chloride 9 mg/ml alone:
7
Survival of cyanide-poisoned dogs
Sodium chloride
9 mg/ml
(N=17)
Treatment
Hydroxocobalamin
Parameter
75 mg/kg
(N=19)
150 mg/kg
(N=18)
Survival at Hour 4, N (%)
7 (41)
18 (95)*
18 (100)*
Survival at Day 14, N (%)
3 (18)
15 (79)*
18 (100)*
* p< 0.025
Histopathology revealed brain lesions that were consistent with cyanide-induced hypoxia. The
incidence of brain lesions was markedly lower in dogs having received 150 mg/kg hydroxocobalamin
than in dogs having received 75 mg/kg hydroxocobalamin or sodium chloride 9 mg/ml.
The rapid and complete recovery of haemodynamics and subsequently of blood gases, pH, and lactate
after cyanide poisoning likely contributed to the better outcome of the hydroxocobalamin-treated
animals. Hydroxocobalamin reduced whole blood cyanide concentrations from about 120 nmol/ml to
30-40 nmol/ml by the end of the infusion compared with 70 nmol/ml in dogs receiving sodium
chloride 9 mg/ml alone.
•
Cyanide-poisoned patients
A total of 245 patients with suspected or known cyanide-poisoning were included in the clinical
studies of the efficacy of hydroxocobalamin as an antidote. Of the 213 patients in whom the outcome
was known the survival was 58%. Of the 89 patients who died, 63 were initially found in cardiac
arrest, suggesting that many of these patients had almost certainly suffered irreparable brain injury
prior to administration of hydroxocobalamin. Among 144 patients not in initial cardiac arrest whose
outcomes were known, 118 (82%) survived. Furthermore, in 34 patients with known cyanide
concentrations above the lethal threshold (≥ 100 µmol/l), 21 (62%) survived following treatment with
hydroxocobalamin.
Administration of hydroxocobalamin was generally associated with a normalisation of blood pressure
(systolic blood pressure > 90 mmHg) in 17 of 21 patients (81%) who had low blood pressure (systolic
blood pressure > 0 and ≤ 90 mmHg) after exposure to cyanide. Where neurological assessment over
time was possible, (96 patients of the 171 patients who presented with neurological symptoms prior to
hydroxocobalamin administration), 51 (53%) patients receiving hydroxocobalamin showed
improvement or a complete restoration.
•
Elderly
Approximately 50 known or suspected cyanide victims aged 65 or older received hydroxocobalamin
in clinical studies. In general, the effectiveness of hydroxocobalamin in these patients was similar to
that of younger patients.
•
Paediatric patients
Documentation on efficacy is availablefor 54 paediatric patients. The mean age of the paediatric
patients was about six years and the mean dose of hydroxocobalamin was about 120 mg/kg body
weight. The survival rate of 41% depended very much on the clinical situation. Out of the
20 paediatric patients without initial cardiac arrest, 18 (90%) survived, of whom 4 with sequelae. In
general, the effectiveness of hydroxocobalamin in paediatric patients was similar to that of adults.
5.2 Pharmacokinetic properties
Following intravenous administration of Cyanokit, significant binding to plasma proteins and low
molecular weight physiological compounds occurs, to form various cobalamin-(III) complexes by
replacing the hydroxo ligand. The low molecular weight cobalamins-(III) formed including
8
hydroxocobalamin are termed free cobalamins-(III); the sum of free and protein-bound cobalamins is
termed total cobalamins-(III). In order to reflect the exposure to the sum of all derivatives,
pharmacokinetics of cobalamins-(III) were investigated instead of hydroxocobalamin, requiring the
concentration unit µg eq/ml (i.e. cobalamin-(III) entity without specific ligand).
Dose-proportional pharmacokinetics were observed following single dose intravenous administration
of 2.5 to 10 g of Cyanokit in healthy volunteers. Mean free and total cobalamins-(III) C
max
values of
113 and 579 µg eq/ml, respectively, were determined following a dose of 5 g Cyanokit (the
recommended initial dose). Similarly, mean free and total cobalamins-(III) C
max
values of 197 and
995 µg eq/ml, respectively, were determined following the dose of 10 g Cyanokit. The predominant
mean half-life of free and total cobalamins-(III) was approximately 26 to 31 hours at the 5 and 10 g
dose level.
The mean total amount of cobalamins-(III) excreted in urine during the collection period of 72 hours
was approximately 60% of a 5 g dose and approximately 50% of a 10 g dose of Cyanokit. Overall, the
total urinary excretion was calculated to be at least 60 to 70% of the administered dose. The majority
of the urinary excretion occurred during the first 24 hours, but red coloured urine was observed for up
to 35 days following the intravenous infusion.
When normalized for body weight, male and female subjects revealed no major differences in plasma
and urinary pharmacokinetic parameters of free and total cobalamins-(III) following the administration
of 5 g or 10 g Cyanokit.
In cyanide-poisoned patients, hydroxocobalamin is expected to bind cyanide to form cyanocobalamin,
which is excreted in the urine. The pharmacokinetics of total cobalamins-(III) in this population may
be affected by the body's cyanide load, since cyanocobalamin was reported to exhibit a 2-3 times
lower half-life than total cobalamins-(III) in healthy volunteers.
5.3 Preclinical safety data
In anaesthetised rabbits, hydroxocobalamin exerted haemodynamic effects (increased mean arterial
blood pressure and total peripheral resistance, decreased cardiac output) related to its nitric oxide-
scavenging property.
No special hazard for humans was identified based on conventional studies of single and repeated dose
toxicity and genotoxicity. The liver and kidney were found to be the major target organs. However
findings were only seen at exposure levels considered being higher than the maximum human
exposure, indicating limited relevance to clinical use. In particular, liver fibrosis was observed in dogs
after administration of hydroxocobalamin for 4 weeks at 300 mg/kg. The relevance of this finding to
humans is unlikely since it was not reported in short-term studies conducted with hydroxocobalamin.
Developmental toxicity, including teratogenicity, was observed in rats and rabbits at dose levels of
150 mg/kg and higher administered daily throughout organogenesis. The dose of 150 mg/kg
approximately corresponds to the maximum recommended human dose.
No data are available on male and female fertility as well as on peri- and postnatal development.
Hydroxocobalamin
has not been evaluated for carcinogenic potential.
6.
6.1 List of excipients
Hydrochloric acid
9
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in
section
6.6.
Physical incompatibility (particle formation) was observed with the mixture of hydroxocobalamin in
solution and the following medicinal products: diazepam, dobutamine, dopamine, fentanyl,
nitroglycerin, pentobarbital, phenytoin sodium, propofol and thiopental. Chemical incompatibility was
observed with sodium thiosulfate, sodium nitrite, and has been reported with ascorbic acid.
Consequently, these medicinal products must not be administered simultaneously through the same
intravenous line as hydroxocobalamin.
Simultaneous administration of hydroxocobalamin and blood products (whole blood, packed red cells,
platelet concentrate and fresh frozen plasma) through the same intravenous line is not recommended
(see section 6.6).
6.3 Shelf life
3 years.
Chemical and physical in-use stability of the reconstituted solution has been demonstrated for 6 hours
at a temperature between 2°C and 40°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 and
would normally not be longer than 6 hours at 2°C to 8ºC.
6.4 Special precautions for storage
Do not store above 25°C.
For the purpose of ambulatory use, Cyanokit may be exposed during short periods to the temperature
variations of usual transport (15 days submitted to temperatures ranging from 5°C to 40°C), transport
in the desert (4 days submitted to temperatures ranging from 5°C to 60°C) and freezing/defrosting
cycles (15 days submitted to temperatures ranging from -20°C to 40°C).
For storage conditions of the reconstituted medicinal product, see section 6.3.
6.5 Nature and contents of container
Type II colourless 250 ml glass vial closed with bromobutyl rubber stopper and an aluminium cap
with a plastic lid. Each vial contains 2.5 g powder for solution for infusion.
Each carton contains two glass vials (each glass vial packed in one cardboard box), two sterile transfer
devices, one sterile intravenous infusion set and one sterile short catheter for administration to
children.
6.6 Special precautions for disposal and other handling
Each vial is to be reconstituted with 100 ml of diluent using the supplied sterile transfer device.
Sodium chloride 9 mg/ml (0.9%) solution for injection is the recommended diluent. Only when
sodium chloride 9 mg/ml (0.9%) solution for injection is not available, Lactated Ringer solution or 5%
glucose can also be used.
The Cyanokit vial is to be rocked or inverted for at least 30 seconds to mix the solution. It must not be
shaken as shaking the vial may cause foam and therefore may make checking reconstitution less easy.
Because the reconstituted solution is a dark red solution, some insoluble particles may not be seen.
The intravenous infusion set provided in the kit must then be used as it includes an appropriate filter
10
and is to be primed with the reconstituted solution. Repeat this procedure if necessary with the second
vial.
If blood products (whole blood, packed red cells, platelet concentrate and fresh frozen plasma) and
hydroxocobalamin are administered simultaneously, use of separate intravenous lines (preferably on
contralateral extremities) is recommended (see section 6.2).
7.
Merck Santé s.a.s.
37, rue Saint-Romain
69379 Lyon Cedex 08
France
8.
EU/1/07/420/001
9.
23/11/2007
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMEA)
0
http://www.emea.europa.eu/.
11
1.
Cyanokit 5 g powder for solution for infusion
2.
The vial contains 5 g of hydroxocobalamin.
After reconstitution with 200 ml of diluent, each ml of the reconstituted solution contains 25 mg of
hydroxocobalamin.
For a full list of excipients, see section 6.1.
3.
Powder for solution for infusion.
Dark red crystalline powder.
4.
Treatment of known or suspected cyanide poisoning in all age ranges.
Cyanokit is to be administered together with appropriate decontamination and supportive measures
(see section 4.4).
Posology
Initial dose
Adults
: The initial dose of Cyanokit is 5 g (200 ml, complete volume of reconstituted solution).
Paediatric population:
In infants to adolescents (0 to 18 years old), the initial dose of Cyanokit is
70 mg/kg body weight not exceeding 5 g.
Body weight
in kg
5
10
20
30
40
50
60
Initial dose
in g
in ml
0.35
14
0.70
28
1.40
56
2.10
84
2.80
112
3.50
140
4.20
168
Subsequent dose
Depending upon the severity of the poisoning and the clinical response (see section 4.4), a second
dose may be administered.
Adults:
The subsequent dose of Cyanokit is 5 g (200 ml, complete volume of reconstituted solution).
Paediatric population:
In infants to adolescents (0 to 18 years old), the subsequent dose of Cyanokit is
70 mg/kg body weight not exceeding 5 g.
12
Maximum dose
Adults
: The maximum total recommended dose is 10 g.
Paediatric population:
In infants to adolescents (0 to 18 years old), the maximum total recommended
dose is 140 mg/kg not exceeding 10 g.
Renal and hepatic impairment
Although the safety and efficacy of hydroxocobalamin have not been studied in renal and hepatic
impairments, Cyanokit is administered as emergency therapy in an acute, life-threatening situation
only and no dose adjustment is required in these patients.
Method of administration
Initial dose of Cyanokit is administered as an intravenous infusion over 15 minutes.
The rate of intravenous infusion for the second dose ranges from 15 minutes (for patients extremely
unstable) to 2 hours based on patient condition.
For instructions on preparation and handling, see section 6.6.
None.
Treatment of cyanide poisoning must include immediate attention to airway patency, adequacy of
oxygenation and hydration, cardiovascular support, and management of seizures. Consideration must
be given to decontamination measures based on the route of exposure.
Cyanokit does not substitute oxygen therapy and must not delay the set up of the above measures.
The presence and extent of cyanide poisoning are often initially unknown. There is no widely
available, rapid, confirmatory cyanide blood test. Treatment decisions must be made on the basis of
clinical history and/or signs and symptoms of cyanide intoxication.
Cyanide poisoning may result from exposure to smoke from closed space fires, inhalation, ingestion,
or dermal exposure. Sources of cyanide poisoning include hydrogen cyanide and its salts, cyanogens,
including cyanogenic plants, aliphatic nitriles, or prolonged exposure to sodium nitroprusside.
Signs and symptoms of cyanide poisoning
Common signs and symptoms of cyanide poisoning include: nausea, vomiting, headache, altered
mental status (e.g. confusion, disorientation), chest tightness, dyspnoea, tachypnoea or hyperpnoea
(early), bradypnoea or apnoea (late), hypertension (early) or hypotension (late), cardiovascular
collapse, seizures or coma, mydriasis, and plasma lactate concentration > 8 mmol/l.
In the setting of multiple casualties such as terrorism or chemical disaster, panic symptoms including
tachypnoea and vomiting may mimic early cyanide poisoning signs. The presence of altered mental
status (confusion and disorientation) and/or mydriasis is suggestive of true cyanide poisoning.
13
Smoke inhalation
Not all smoke inhalation victims necessarily will have cyanide poisoning, but may present with burns,
trauma, and exposure to additional toxic substances aggravating the clinical picture. Before Cyanokit
is administered, it is recommended to check affected persons for the presence of the following:
•
exposure to fire smoke in an enclosed area
•
soot present around mouth, nose and/or oropharynx
•
altered mental status
In this setting hypotension and/or a plasma lactate concentration ≥ 10 mmol/l (higher than the one
mentioned under signs and symptoms due to the fact that carbon monoxide contributes to lactic
acidaemia) are highly suggestive of cyanide poisoning. In the presence of the above signs, treatment
with Cyanokit must not be delayed to obtain a plasma lactate concentration.
Hypersensitivity reactions
Known hypersensitivity to hydroxocobalamin or vitamin B
12
must be taken into benefit-risk
consideration before administration of Cyanokit, since hypersensitive reactions may occur in patients
receiving hydroxocobalamin (see section 4.8).
Increase in blood pressure
Transient, generally asymptomatic, increase in blood pressure may occur in patients receiving
hydroxocobalamin. The maximal increase in blood pressure has been observed toward the end of
infusion (see section 4.8).
Effects on blood cyanide assay
Hydroxocobalamin will lower blood cyanide concentrations. While determination of blood cyanide
concentration is not required and must not delay treatment with hydroxocobalamin, it may be useful
for documenting cyanide poisoning. If a cyanide blood level determination is planned, it is
recommended to draw the blood sample before initiation of treatment with Cyanokit.
Interference with burn assessment
Because of its deep red colour, hydroxocobalamin has the potential to induce a red colouration of the
skin and therefore may interfere with burn assessment. However, skin lesions, oedema, and pain are
highly suggestive of burns.
Interference with laboratory tests
Because of its deep red colour, hydroxocobalamin has the potential to interfere with determination of
laboratory parameters (e.g. clinical chemistry, haematology, coagulation, and urine parameters).
In vitro
tests indicate that the extent and duration of the interference is dependant on numerous factors
such as the dose of hydroxocobalamin, analyte, analyte concentration, methodology, analyser,
concentrations of cobalamins-(III) including cyanocobalamin and partially the time between sampling
and measurement.
Based on
in vitro
studies and pharmacokinetic data obtained in healthy volunteers the following table
describes interference with laboratory tests that may be observed following a 5 g dose of
hydroxocobalamin. Interference following a 10 g dose can be expected to last up to an additional
24 hours. The extent and duration of interference in cyanide-poisoned patients may differ according to
the severity of intoxication. Results may vary considerably from one analyser to another, therefore,
caution is required when reporting and interpreting laboratory results.
14
Observed
in vitro
interferences of hydroxocobalamin with laboratory tests
Laboratory
parameter
No interference
observed
Artificially
increased*
Artificially
decreased*
Unpredictable***
Duration of
interference
after a 5 g dose
Clinical
chemistry
Calcium
Sodium
Potassium
Chloride
Urea
Gamma glutamyl
transferase (GGT)
Creatinine
Total and
conjugate
bilirubin**
Triglycerides
Cholesterol
Total protein
Glucose
Albumin
Alkaline
phosphatase
Alanine
aminotransferase
(ALT)
Amylase
Phosphate
Uric acid
Aspartate
aminotransferase
(AST)
Creatine kinase (CK)
Creatine kinase
isoenzym MB
(CKMB)
Lactate dehydrogenase
(LDH)
24 hours with the
exception of
bilirubin (up to
4 days)
Haematology Erythrocytes
Haematocrit
Mean corpuscular
volume (MCV)
Leucocytes
Lymphocytes
Monocytes
Eosinophils
Neutrophils
Platelets
Haemoglobin
(Hb)
Mean
corpuscular
haemoglobin
(MCH)
Mean
corpuscular
haemoglobin
concentration
(MCHC)
12-16 hours
Coagulation
Activated partial
thromboplastin time
(aPTT)
Prothrombin time (PT)
Quick or INR
24 hours
* ≥ 10% interference observed on at least one analyser
** Artificially decreased using the diazo method
*** Inconsistent results
Analysers used: ACL Futura (Instrumentation Laboratory), Axsym/Architect (Abbott), BM Coasys
110
(Boehringer
Mannheim), CellDyn 3700 (Abbott), Clinitek 500 (Bayer), Cobas Integra 700, 400 (Roche), Gen-S Coultronics, Hitachi 917,
STA
®
Compact, Vitros 950 (Ortho Diagnostics)
Hydroxocobalamin may interfere with all urine colorimetric parameters. The effects on these tests
typically last 48 hours after a 5 g dose, but may persist for longer periods. Caution is required in the
interpretation of urinary colorimetric tests for as long as chromaturia is present.
Interference with haemodialysis
Because of its deep red color, hydroxocobalamin may cause haemodialysis machines to shut down due
to an erroneous detection of a ‘blood leak’. This should be considered before haemodialysis is initiated
in patients treated with hydroxocobalamin.
Use with other cyanide antidotes
The safety of administering other cyanide antidotes simultaneously with Cyanokit has not been
established (see section 6.2). If the decision is made to administer another cyanide antidote with
Cyanokit, these medicinal products must not be administered concurrently in the same intravenous line
(see section 6.2).
No interaction studies have been performed.
15
Pregnancy
Animal studies have shown teratogenic effects following daily exposure throughout organogenesis
(see section 5.3). There are no adequate data from the use of hydroxocobalamin in pregnant women
and the potential risk for humans is unknown.
However, taken into account:
-
that no more than two injections of hydroxocobalamin are to be administered,
-
the potentially life threatening condition,
-
the lack of alternative treatment,
hydroxocobalamin may be given to a pregnant woman.
In case of known pregnancy at the time of treatment with Cyanokit or in case that pregnancy becomes
known after treatment with Cyanokit, health care professionals are requested to promptly report the
exposure during pregnancy to the Marketing Authorisation Holder and to carefully follow-up on the
pregnancy and its outcome.
Breast-feeding
Because hydroxocobalamin will be administered in potentially life-threatening situations, breast-
feeding is not a contraindication to its use. In the absence of data in breast-fed infants, breast-feeding
discontinuation is recommended after receiving Cyanokit.
Fertility
No studies on fertility have been performed (see section 5.3).
No studies on the effects on the ability to drive or to use machines have been performed.
A total of 347 subjects were exposed to hydroxocobalamin in clinical studies. Of these 347 subjects,
245 patients had suspected exposure to cyanide at the time of hydroxocobalamin administration. The
remaining 102 subjects were healthy volunteers who had not been exposed to cyanide at the time of
hydroxocobalamin administration.
Most patients will experience a reversible red colouration of the skin and mucous membranes that may
last up to 15 days after administration of Cyanokit. All patients will show a dark red colouration of the
urine quite marked during the three days following administration. Urine colouration may last up to
35 days after administration of Cyanokit.
The following adverse reactions have been reported in association with Cyanokit use. However,
because of the limitations of the available data, it is not possible to apply frequency estimations:
Blood and lymphatic system disorders
Decrease in the percentage of lymphocytes.
Immune system disorders
Allergic reactions including angioneurotic oedema, skin eruption, urticaria and pruritus.
Psychiatric disorders
Restlessness.
16
Nervous system disorders
Memory impairment; dizziness.
Eye disorders
Swelling, irritation, redness.
Cardiac disorders
Ventricular extrasystoles. An increase in heart rate was observed in cyanide-poisoned patients.
Vascular disorders
Transient increase in blood pressure, usually resolving within several hours; hot flush. A decrease in
blood pressure was observed in cyanide-poisoned patients.
Respiratory, thoracic and mediastinal disorders
Pleural effusion, dyspnoea, throat tightness, dry throat, chest discomfort.
Gastrointestinal disorders
Abdominal discomfort, dyspepsia, diarrhoea, vomiting, nausea, dysphagia.
Skin and subcutaneous tissue disorders
Reversible red colouration of the skin and mucous membranes (see above). Pustular rashes, which
may last for several weeks, affecting mainly the face and the neck.
Renal and urinary disorders
Chromaturia (see above).
General disorders and administration site conditions
Headache; injection site reaction; peripheral oedema.
Investigations
Cyanokit may cause red discolouration of the plasma, which may cause artificial elevation or
reduction in the levels of certain laboratory parameters (see section 4.4).
Paediatric population
Limited data on children (0 to 18 years old) treated with hydroxocobalamin did not show any
difference in the safety profile of hydroxocobalamin between adults and children.
Doses as high as 15 g have been administered without reported specific dose related adverse reactions.
If overdose occurs, treatment is directed to the management of symptoms. Haemodialysis may be
effective in such a circumstance, but is only indicated in the event of significant hydroxocobalamin-
related toxicity. However, hydroxocobalamin because of its deep red colour may interfere with the
performance of haemodialysis machines (see section 4.4).
17
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antidotes, ATC code: V03AB33
Mechanism of action
The action of hydroxocobalamin in the treatment of cyanide poisoning is based on its ability to tightly
bind cyanide ions. Each hydroxocobalamin molecule can bind one cyanide ion by substituting the
hydroxo ligand linked to the trivalent cobalt ion to form cyanocobalamin. Cyanocobalamin is a stable,
non-toxic compound that is excreted in the urine.
Efficacy
Due to ethical considerations, no controlled human efficacy studies have been performed.
•
Animal pharmacology
The effectiveness of hydroxocobalamin was examined in a controlled study in cyanide-poisoned adult
dogs. Dogs were poisoned by intravenous administration of a lethal dose of potassium cyanide. Dogs
then received sodium chloride 9 mg/ml, 75 mg/kg or 150 mg/kg hydroxocobalamin, administered
intravenously over 7.5 minutes. The 75 mg/kg and 150 mg/kg doses are approximately equivalent to
5 g and 10 g of hydroxocobalamin, respectively, in humans, not only on a body weight basis but also
on C
max
basis of hydroxocobalamin [total cobalamins-(III), see section 5.2].
Survival at hour 4 and at day 14 was significantly greater in 75 mg/kg and 150 mg/kg
hydroxocobalamin dose groups compared with dogs receiving sodium chloride 9 mg/ml alone:
Survival of cyanide-poisoned dogs
Sodium chloride
9 mg/ml
(N=17)
Treatment
Hydroxocobalamin
Parameter
75 mg/kg
(N=19)
150 mg/kg
(N=18)
Survival at Hour 4, N (%)
7 (41)
18 (95)*
18 (100)*
Survival at Day 14, N (%)
3 (18)
15 (79)*
18 (100)*
* p< 0.025
Histopathology revealed brain lesions that were consistent with cyanide-induced hypoxia. The
incidence of brain lesions was markedly lower in dogs having received 150 mg/kg hydroxocobalamin
than in dogs having received 75 mg/kg hydroxocobalamin or sodium chloride 9 mg/ml.
The rapid and complete recovery of haemodynamics and subsequently of blood gases, pH, and lactate
after cyanide poisoning likely contributed to the better outcome of the hydroxocobalamin-treated
animals. Hydroxocobalamin reduced whole blood cyanide concentrations from about 120 nmol/ml to
30-40 nmol/ml by the end of the infusion compared with 70 nmol/ml in dogs receiving sodium
chloride 9 mg/ml alone.
•
Cyanide-poisoned patients
A total of 245 patients with suspected or known cyanide-poisoning were included in the clinical
studies of the efficacy of hydroxocobalamin as an antidote. Of the 213 patients in whom the outcome
was known the survival was 58%. Of the 89 patients who died, 63 were initially found in cardiac
arrest, suggesting that many of these patients had almost certainly suffered irreparable brain injury
prior to administration of hydroxocobalamin. Among 144 patients not in initial cardiac arrest whose
18
outcomes were known, 118 (82%) survived. Furthermore, in 34 patients with known cyanide
concentrations above the lethal threshold (≥ 100 µmol/l), 21 (62%) survived following treatment with
hydroxocobalamin.
Administration of hydroxocobalamin was generally associated with a normalisation of blood pressure
(systolic blood pressure > 90 mmHg) in 17 of 21 patients (81%) who had low blood pressure (systolic
blood pressure > 0 and ≤ 90 mmHg) after exposure to cyanide. Where neurological assessment over
time was possible, (96 patients of the 171 patients who presented with neurological symptoms prior to
hydroxocobalamin administration), 51 (53%) patients receiving hydroxocobalamin showed
improvement or a complete restoration.
•
Elderly
Approximately 50 known or suspected cyanide victims aged 65 or older received hydroxocobalamin
in clinical studies. In general, the effectiveness of hydroxocobalamin in these patients was similar to
that of younger patients.
•
Paediatric population
Documentation on efficacy is available for 54 paediatric patients. The mean age of the paediatric
patients was about six years and the mean dose of hydroxocobalamin was about 120 mg/kg body
weight. The survival rate of 41% depended very much on the clinical situation. Out of the
20 paediatric patients without initial cardiac arrest, 18 (90%) survived, of whom 4 with sequelae. In
general, the effectiveness of hydroxocobalamin in paediatric patients was similar to that of adults.
5.2 Pharmacokinetic properties
Following intravenous administration of Cyanokit, significant binding to plasma proteins and low
molecular weight physiological compounds occurs, to form various cobalamin-(III) complexes by
replacing the hydroxo ligand. The low molecular weight cobalamins-(III) formed including
hydroxocobalamin are termed free cobalamins-(III); the sum of free and protein-bound cobalamins is
termed total cobalamins-(III). In order to reflect the exposure to the sum of all derivatives,
pharmacokinetics of cobalamins-(III) were investigated instead of hydroxocobalamin, requiring the
concentration unit µg eq/ml (i.e. cobalamin-(III) entity without specific ligand).
Dose-proportional pharmacokinetics were observed following single dose intravenous administration
of 2.5 to 10 g of Cyanokit in healthy volunteers. Mean free and total cobalamins-(III) C
max
values of
113 and 579 µg eq/ml, respectively, were determined following a dose of 5 g Cyanokit (the
recommended initial dose). Similarly, mean free and total cobalamins-(III) C
max
values of 197 and
995 µg eq/ml, respectively, were determined following the dose of 10 g Cyanokit. The predominant
mean half-life of free and total cobalamins-(III) was approximately 26 to 31 hours at the 5 and 10 g
dose level.
The mean total amount of cobalamins-(III) excreted in urine during the collection period of 72 hours
was approximately 60% of a 5 g dose and approximately 50% of a 10 g dose of Cyanokit. Overall, the
total urinary excretion was calculated to be at least 60 to 70% of the administered dose. The majority
of the urinary excretion occurred during the first 24 hours, but red coloured urine was observed for up
to 35 days following the intravenous infusion.
When normalized for body weight, male and female subjects revealed no major differences in plasma
and urinary pharmacokinetic parameters of free and total cobalamins-(III) following the administration
of 5 g or 10 g Cyanokit.
In cyanide-poisoned patients, hydroxocobalamin is expected to bind cyanide to form cyanocobalamin,
which is excreted in the urine. The pharmacokinetics of total cobalamins-(III) in this population may
be affected by the body's cyanide load, since cyanocobalamin was reported to exhibit a 2-3 times
lower half-life than total cobalamins-(III) in healthy volunteers.
19
5.3 Preclinical safety data
In anaesthetised rabbits, hydroxocobalamin exerted haemodynamic effects (increased mean arterial
blood pressure and total peripheral resistance, decreased cardiac output) related to its nitric oxide-
scavenging property.
No special hazard for humans was identified based on conventional studies of single and repeated dose
toxicity and genotoxicity. The liver and kidney were found to be the major target organs. However
findings were only seen at exposure levels considered being higher than the maximum human
exposure, indicating limited relevance to clinical use. In particular, liver fibrosis was observed in dogs
after administration of hydroxocobalamin for 4 weeks at 300 mg/kg. The relevance of this finding to
humans is unlikely since it was not reported in short-term studies conducted with hydroxocobalamin.
Developmental toxicity, including teratogenicity, was observed in rats and rabbits at dose levels of
150 mg/kg and higher administered daily throughout organogenesis. The dose of 150 mg/kg
approximately corresponds to the maximum recommended human dose.
No data are available on male and female fertility as well as on peri- and postnatal development.
Hydroxocobalamin
has not been evaluated for carcinogenic potential.
6.
6.1 List of excipients
Hydrochloric acid (for pH-adjustment)
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in
section
6.6.
Physical incompatibility (particle formation) was observed with the mixture of hydroxocobalamin
reconstituted solution and the following medicinal products: diazepam, dobutamine, dopamine,
fentanyl, nitroglycerin, pentobarbital, phenytoin sodium, propofol and thiopental.
Chemical incompatibility was observed with the mixture of hydroxocobalamin reconstituted solution
and the following medicinal products: epinephrine, lidocaine hydrochloride, adenosine, atropine,
midazolam, ketamin, succinylcholine chloride, amiodarone hydrochloride, sodium bicarbonate,
sodium thiosulfate, sodium nitrite, and has been reported with ascorbic acid.
Consequently, these and other medicinal products must not be administered simultaneously through
the same intravenous line as hydroxocobalamin.
Simultaneous administration of hydroxocobalamin and blood products (whole blood, packed red cells,
platelet concentrate and fresh frozen plasma) through the same intravenous line is not recommended.
6.3 Shelf life
3 years.
For the purpose of ambulatory use, Cyanokit may be exposed during short periods to the temperature
variations of usual transport (15 days submitted to temperatures ranging from 5°C to 40°C), transport
in the desert (4 days submitted to temperatures ranging from 5°C to 60°C) and freezing/defrosting
cycles (15 days submitted to temperatures ranging from -20°C to 40°C). If these temporary conditions
have been exceeded, the product should be discarded.
20
Chemical and physical in-use stability of the reconstituted solution with sodium chloride 9 mg/ml
(0.9%) has been demonstrated for 6 hours at a temperature between 2°C and 40°C.
From a microbiological point of view, the medicinal product should be used immediately. If not used
immediately, in-use storage times and conditions prior to use are the responsibility of the user and
would normally not be longer than 6 hours at 2°C to 8ºC.
6.4 Special precautions for storage
Do not store above 25°C.
For storage conditions of the reconstituted medicinal product, see section 6.3.
6.5 Nature and contents of container
Type I colourless 250 ml glass vial closed with bromobutyl rubber stopper and an aluminium cap with
a plastic lid.
Each pack contains one glass vial packed in one cardboard box, one sterile transfer device, one sterile
intravenous infusion set and one sterile short catheter for administration to children.
6.6 Special precautions for disposal and other handling
No special requirements for disposal.
The vial is to be reconstituted with 200 ml of diluent using the supplied sterile transfer device. Sodium
chloride 9 mg/ml (0.9%) solution for injection is the recommended diluent. Only when sodium
chloride 9 mg/ml (0.9%) solution for injection is not available, Lactated Ringer solution or glucose
50 mg/ml (5%) solution for injection can also be used.
The Cyanokit vial is to be rocked or inverted for at least 1 minute to mix the solution. It must not be
shaken as shaking the vial may cause foam and therefore may make checking reconstitution less easy.
Because the reconstituted solution is a dark red solution, some insoluble particles may not be seen.
The intravenous infusion set provided in the kit must then be used as it includes an appropriate filter
and is to be primed with the reconstituted solution.
7.
Merck Santé s.a.s.
37, rue Saint-Romain
69379 Lyon Cedex 08
France
8.
9.
23/11/2007
21
Detailed information on this product is available on the website of the European Medicines Agency
1 H
http://www.ema.europa.eu
22
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
23
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer(s) responsible for batch release
Merck Santé S.A.S.
Centre de Production de Semoy
2, rue du Pressoir Vert
F-45400 Semoy
France
The printed package leaflet of the medicinal product must state the name and address of the
manufacturer responsible for the release of the concerned batch.
B. CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to medical prescription.
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 9.0 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 8.0 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 European Medicines Agency
Periodic Safety Update Report (PSUR)
Following the addition of an additional strength (Cyanokit 5 g, powder for solution for infusion), the
Marketing Authorisation Holder will submit PSURs every six months for a period of two years then
yearly for two years and then every three years thereafter.
24
ANNEX III
LABELLING AND PACKAGE LEAFLET
25
A. LABELLING
26
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON
1.
Cyanokit 2.5 g powder for solution for infusion
Hydroxocobalamin
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each vial contains 2.5 g of hydroxocobalamin. After reconstitution with 100 ml of diluent, each ml of
the reconstituted solution contains 25 mg of hydroxocobalamin.
3.
LIST OF EXCIPIENTS
Excipient: Hydrochloric acid.
4.
Two vials, each containing 2.5 g of powder for solution for infusion.
Two transfer devices.
One intravenous infusion set.
One short catheter for administration to children.
This kit does not contain diluent.
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For 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
27
9.
SPECIAL STORAGE CONDITIONS
Do not store above 25°C.
Read the leaflet for storage conditions in ambulatory use.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Merck Santé s.a.s.
37, rue Saint-Romain
69379 Lyon Cedex 08
France
EU/1/07/420/001
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted
28
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARDBOARD BOX
1.
Cyanokit 2.5 g powder for solution for infusion
Hydroxocobalamin
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each vial contains 2.5 g of hydroxocobalamin. After reconstitution with 100 ml of diluent, each ml of
the reconstituted solution contains 25 mg of hydroxocobalamin.
3.
LIST OF EXCIPIENTS
Excipient: Hydrochloric acid.
4.
One vial containing 2.5 g of powder for solution for infusion.
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For 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
9.
SPECIAL STORAGE CONDITIONS
Do not store above 25°C.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
29
Merck Santé s.a.s.
37, rue Saint-Romain
69379 Lyon Cedex 08
France
EU/1/07/420/001
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted
30
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING
VIAL
1.
Cyanokit 2.5 g powder for solution for infusion
Hydroxocobalamin
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each vial contains 2.5 g of hydroxocobalamin. After reconstitution with 100 ml of diluent, each ml of
the reconstituted solution contains 25 mg of hydroxocobalamin.
3.
LIST OF EXCIPIENTS
Excipient: Hydrochloric acid.
4.
Powder for solution for infusion containing 2.5 g of hydroxocobalamin.
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For 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
9.
SPECIAL STORAGE CONDITIONS
Do not store above 25°C.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
31
Merck Santé s.a.s.
37, rue Saint-Romain
69379 Lyon Cedex 08
France
EU/1/07/420/001
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted
32
MEDICAL OR HEALTHCARE PROFESSIONALS EDUCATIONAL STICKER
“To be attached to the patient’s medical record:
Cyanokit has been administered to this patient.
Cyanokit may interfere with burn assessment (red coloration of the skin) and laboratory tests (see
SPC).”
33
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON
1.
Cyanokit 5 g powder for solution for infusion
Hydroxocobalamin
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
The vial contains 5 g of hydroxocobalamin. After reconstitution with 200 ml of diluent, each ml of the
reconstituted solution contains 25 mg of hydroxocobalamin.
3.
LIST OF EXCIPIENTS
Excipient: Hydrochloric acid (for pH adjustment).
4.
Powder for solution for infusion
One vial
One transfer device.
One intravenous infusion set.
One short catheter for administration to children.
This kit does not contain diluent.
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use.
Intravenous 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
Read the leaflet for storage conditions in ambulatory use
34
9.
SPECIAL STORAGE CONDITIONS
Do not store above 25°C.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Merck Santé s.a.s.
37, rue Saint-Romain
69379 Lyon Cedex 08
France
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted
35
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARDBOARD BOX
1.
Cyanokit 5 g powder for solution for infusion
Hydroxocobalamin
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
The vial contains 5 g of hydroxocobalamin. After reconstitution with 200 ml of diluent, each ml of the
reconstituted solution contains 25 mg of hydroxocobalamin.
3.
LIST OF EXCIPIENTS
Excipient: Hydrochloric acid (for pH adjustment).
4.
Powder for solution for infusion
One vial
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use.
Intravenous 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
9.
SPECIAL STORAGE CONDITIONS
Do not store above 25°C.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
36
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Merck Santé s.a.s.
37, rue Saint-Romain
69379 Lyon Cedex 08
France
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted
37
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING
VIAL
1.
Cyanokit 5 g powder for solution for infusion
Hydroxocobalamin
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
The vial contains 5 g of hydroxocobalamin. After reconstitution with 200 ml of diluent, each ml of the
reconstituted solution contains 25 mg of hydroxocobalamin.
3.
LIST OF EXCIPIENTS
Excipient: Hydrochloric acid (for pH adjustment).
4.
Powder for solution for infusion containing 5 g of hydroxocobalamin.
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use.
Intravenous 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
9.
SPECIAL STORAGE CONDITIONS
Do not store above 25°C.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
38
APPROPRIATE
Merck Santé s.a.s.
37, rue Saint-Romain
69379 Lyon Cedex 08
France
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted
39
MEDICAL OR HEALTHCARE PROFESSIONALS EDUCATIONAL STICKER
“To be attached to the patient’s medical record:
Cyanokit has been administered to this patient.
Cyanokit may interfere with burn assessment (red coloration of the skin) and laboratory tests and may
lead to shut down of haemodialysis machines (see SmPC).”
40
B. PACKAGE LEAFLET
41
PACKAGE LEAFLET: INFORMATION FOR THE USER
Cyanokit 2.5 g powder for solution for infusion
hydroxocobalamin
Read all of this leaflet carefully before you start using this medicine.
•
Keep this leaflet. You may need to read it again.
•
If you have any further questions, ask your doctor or pharmacist.
•
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 Cyanokit is and what it is used for
3.
How to use Cyanokit
4.
Possible side effects
5.
How to store Cyanokit
6.
Further information
1.
WHAT CYANOKIT
IS AND WHAT IT IS USED FOR
Cyanokit is an antidote for the treatment of known or suspected cyanide poisoning.
Cyanokit is to be administered together with appropriate decontamination and supportive measures.
Cyanide is a highly poisonous chemical. Cyanide poisoning may be caused by exposure to smoke
from household and industrial fires, breathing or swallowing cyanide, or contact with cyanide on skin.
2.
BEFORE YOU USE CYANOKIT
Take special care with Cyanokit
Tell your doctor or other health personnel
•
if you are allergic to hydroxocobalamin or vitamin B
12
. They will have to take it into account
before treating you with Cyanokit.
•
that you have been treated with Cyanokit if you need to have any blood or urine tests. Cyanokit
may modify the results of these tests.
Using other medicines
Please tell your doctor if you are taking or have recently taken any other medicines, including
medicines obtained without a prescription.
Detailed information for your doctor or other health personnel regarding simultaneous administration
of Cyanokit with other medicines can be found at the end of this package leaflet (see 'Handling
instructions').
Pregnancy and breast-feeding
This medicine is an emergency treatment. It can be administered during pregnancy and breast-feeding.
Tell your doctor as soon as possible if you were pregnant or think you may have been pregnant during
treatment with Cyanokit.
42
2.
Before you use Cyanokit
Driving and using machines
It is not known whether Cyanokit affects the ability to drive or use machines.
3.
HOW TO USE CYANOKIT
You will have Cyanokit by infusion into a vein. You may have one or two infusions.
You will have the first infusion of Cyanokit over 15 minutes. If you need a second infusion, you will
have it over 15 minutes to 2 hours. It depends on how serious the poisoning is.
Detailed instructions for your doctor or other health personnel on how to prepare the Cyanokit
infusion and how to determine the dose can be found at the end of this package leaflet (see 'Handling
instructions').
If you have any further questions on the use of this product, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Cyanokit
can cause side effects, although not everybody gets them.
The following
side effects may be expected:
Most patients will experience a reversible red colouration of the skin and membranes lining body
cavities (mucous membranes) that may last up to 15 days after administration of Cyanokit. All patients
will show a dark red colouration of the urine quite marked during the three days following
administration. Urine colouration may last up to 35 days after administration of Cyanokit.
Allergy (hypersensitivity)
Tell your doctor
immediately
if you have the following symptoms during or after this treatment:
•
swelling around the eyes, lips, tongue, throat or hands
•
breathing difficulties, hoarseness, difficulty in speaking
•
skin redness, nettle rash (urticaria) or itching.
Such side effects may be serious and need immediate attention.
Heart and blood pressure problems
•
symptoms such as headache or dizziness, as they may be due to a rise in blood pressure. This
rise in blood pressure especially occurs at the end of having this treatment and usually settles
down within several hours
•
irregular heart beat
•
redness of the face (flush).
A decrease in blood pressure and a faster heart beat have also been observed in patients who have
cyanide poisoning.
Breathing and chest problems
•
fluid in the chest (pleural effusion)
•
breathing difficulties
•
a feeling of tightness in the throat
•
dry throat
•
chest discomfort.
Gastrointestinal (digestive) problems
43
•
discomfort in your stomach
•
indigestion
•
diarrhoea
•
feeling sick (nausea)
•
being sick (vomiting)
•
difficulty in swallowing.
Eye problems
•
swelling, irritation, redness.
Skin reactions
•
blister-like lesions on the skin (pustular rashes). These may last for several weeks, and affect
mainly the face and the neck.
•
inflammation in the part of the body where the medicine was infused.
Other side effects
•
restlessness
•
problems with memory
•
dizziness
•
headache
•
swelling of ankles
•
changes in the results of blood tests for certain white blood cells (lymphocytes)
•
coloured plasma, which may cause artificial elevation or reduction in the levels of certain
laboratory parameters.
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 CYANOKIT
Keep out of the reach and sight of children.
Do not use Cyanokit
after the expiry date which is stated on the vial, the cardboard box and the carton
after EXP. The expiry date refers to the last day of that month.
Do not store above 25°C.
For the purpose of ambulatory use, Cyanokit may be exposed during short periods to the temperature
variations of
•
usual transport (15 days submitted to temperatures ranging from 5 to 40°C)
•
transport in the desert (4 days submitted to temperatures ranging from 5 to 60°C) and
•
freezing/defrosting cycles (15 days submitted to temperatures ranging from -20 to 40°C).
For storage conditions of the reconstituted medicine, see 'Handling instructions' at the end of this
package leaflet.
Medicines 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.
44
6.
FURTHER INFORMATION
What Cyanokit
contains
•
The active substance is hydroxocobalamin. Each vial contains 2.5 g of powder for solution for
infusion. After reconstitution with 100 ml of diluent, each ml of the reconstituted solution
contains 25 mg of hydroxocobalamin.
•
The other ingredient is hydrochloric acid.
What Cyanokit
looks like and contents of the pack
Cyanokit powder for solution for infusion is a dark red crystalline powder supplied in a glass vial
closed with bromobutyl rubber stopper and an aluminium cap with a plastic lid.
Each carton contains two glass vials (each glass vial packed in one cardboard box), two sterile transfer
devices, one sterile intravenous infusion set and one sterile short catheter for administration to
children.
Marketing Authorisation Holder
Merck Santé s.a.s.
37, rue Saint-Romain
69379 Lyon Cedex 08
France
Manufacturer
Merck Santé s.a.s. / SEMOY
2, rue du Pressoir Vert
45400 Semoy
France
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency (EMEA) web
site:
2 H
http://www.emea.europa.eu/
.
---------------------------------------------------------------------------------------------------------------------------
--
The following information is intended for medical or healthcare professionals only:
Handling Instructions
Treatment of cyanide poisoning must include immediate attention to airway patency, adequacy
of oxygenation and hydration, cardiovascular support, and management of seizures.
Consideration must be given to decontamination measures based on the route of exposure.
Cyanokit does not substitute oxygen therapy
and must
not
delay the set up of the
above
measures.
The presence and extent of cyanide poisoning are often initially unknown. There is no widely
available, rapid, confirmatory cyanide blood test. However, if a cyanide blood level
determination is planned, it is recommended to draw the blood sample before initiation of
treatment with Cyanokit. Treatment decisions must be made on the basis of clinical history
45
and/or signs and symptoms of cyanide intoxication. If there is clinical suspicion of cyanide
poisoning, it is strongly recommended that Cyanokit be administered without delay.
Preparation of Cyanokit
Each vial is to be reconstituted
with 100 ml of diluent
using the supplied sterile transfer device.
Sodium chloride 9 mg/ml (0.9%)
solution for injection
is the recommended diluent. Only when
sodium chloride 9 mg/ml (0.9%) solution for injection is not available, Lactated Ringer solution or 5%
glucose can also be used.
The Cyanokit vial is to be rocked or inverted for at least 30 seconds to mix the solution. It must not be
shaken as shaking the vial may cause foam and therefore may make checking reconstitution less easy.
Because the reconstituted solution is a dark red solution, some insoluble particles may not be seen.
The intravenous infusion set provided in the kit must then be used as it includes an appropriate filter
and is to be primed with the reconstituted solution. Repeat this procedure if necessary with the second
vial.
Initial dose
Cyanokit is administered as an intravenous infusion over 15 minutes.
Adults
: The initial dose of Cyanokit is 5 g.
Paediatric patients:
In infants to adolescents, the initial dose of Cyanokit is 70 mg/kg body weight not
exceeding 5 g.
Body weight
in kg
5
10
20
30
40
50
60
Initial dose
in g
in ml
0.35
14
0.70
28
1.40
56
2.10
84
2.80
112
3.50
140
4.20
168
Subsequent dose
Depending upon the severity of the poisoning and the clinical response, a second dose may be
administered by intravenous infusion. The rate of infusion for the second dose ranges from 15 minutes
(for patients extremely unstable) to 2 hours based on patient condition.
Adults:
The subsequent dose of Cyanokit is 5 g.
Paediatric patients:
In infants to adolescents, the subsequent dose of Cyanokit is 70 mg/kg body
weight not exceeding 5 g.
Maximum dose
Adults
: The maximum recommended dose is 10 g.
Paediatric patients:
In infants to adolescents, the maximum recommended dose is 140 mg/kg not
exceeding 10 g.
Renal and hepatic impairments
No dosage adjustment is required in these patients.
46
Simultaneous administration of Cyanokit and other products
Cyanokit must not be mixed with other medicinal products except sodium chloride 9 mg/ml (0.9%)
solution for injection or Lactated Ringer solution or 5% glucose.
If blood products (whole blood, packed red cells, platelet concentrate and fresh frozen plasma) and
hydroxocobalamin are administered simultaneously, use of separate intravenous lines (preferably on
contralateral extremities) is recommended.
Combination with another cyanide antidote:
Chemical incompatibility was observed with sodium
thiosulfate and sodium nitrite. If the decision is made to administer another cyanide antidote with
Cyanokit, these medicinal products must not be administered concurrently in the same intravenous
line.
In-use stability of the reconstituted solution
Chemical and physical in-use stability has been demonstrated for 6 hours at a temperature between
2°C to 40°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 and
would normally not be longer than 6 hours at 2°C to 8°C.
47
PACKAGE LEAFLET: INFORMATION FOR THE USER
Cyanokit 5 g powder for solution for infusion
hydroxocobalamin
Read all of this leaflet carefully before using this medicine.
•
Keep this leaflet. You may need to read it again.
•
If you have any further questions, ask your doctor or pharmacist.
•
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 Cyanokit is and what it is used for
3.
How Cyanokit is used
4.
Possible side effects
5.
How Cyanokit is stored
6.
Further information
1.
WHAT CYANOKIT
IS AND WHAT IT IS USED FOR
Cyanokit is an antidote for the treatment of known or suspected cyanide poisoning in all age ranges.
Cyanokit is to be administered together with appropriate decontamination and supportive measures.
Cyanide is a highly poisonous chemical. Cyanide poisoning may be caused by exposure to smoke
from household and industrial fires, breathing or swallowing cyanide, or contact with cyanide on skin.
2.
BEFORE CYANOKIT IS USED
Take special care with Cyanokit
Tell your doctor or other health personnel
•
if you are allergic to hydroxocobalamin or vitamin B
12
. They will have to take it into account
before treating you with Cyanokit.
•
that you have been treated with Cyanokit if you need to have any blood or urine tests. Cyanokit
may modify the results of these tests.
Using other medicines
Please tell your doctor if you are taking or have recently taken any other medicines, including
medicines obtained without a prescription.
Detailed information for your doctor or other health personnel regarding simultaneous administration
of Cyanokit with other medicines can be found at the end of this package leaflet (see 'Handling
instructions').
Pregnancy and breast-feeding
This medicine is an emergency treatment. It can be administered during pregnancy and breast-feeding.
Tell your doctor as soon as possible if you were pregnant or think you may have been pregnant during
treatment with Cyanokit.
Your doctor will recommend you to stop breast-feeding after treatment with Cyanokit.
48
2.
Before Cyanokit is used
Driving and using machines
It is not known whether Cyanokit affects the ability to drive or use machines.
3.
HOW CYANOKIT
IS USED
Your doctor or health care professional will give you Cyanokit by infusion into a vein. You may have
one or two infusions.
You will have the first infusion of Cyanokit over 15 minutes. If you need a second infusion, you will
have it over 15 minutes to 2 hours. It depends on how serious the poisoning is.
Detailed instructions for your doctor or other health care professional on how to prepare the Cyanokit
infusion and how to determine the dose can be found at the end of this package leaflet (see 'Handling
instructions').
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Cyanokit
can cause side effects, although not everybody gets them.
The following
side effects may be expected:
Most patients will experience a reversible red colouration of the skin and membranes lining body
cavities (mucous membranes) that may last up to 15 days after administration of Cyanokit. All patients
will show a dark red colouration of the urine quite marked during the three days following
administration. Urine colouration may last up to 35 days after administration of Cyanokit.
Allergy (hypersensitivity)
Tell your doctor
immediately
if you have the following symptoms during or after this treatment:
•
swelling around the eyes, lips, tongue, throat or hands
•
breathing difficulties, hoarseness, difficulty in speaking
•
skin redness, nettle rash (urticaria) or itching.
Such side effects may be serious and need immediate attention.
Heart and blood pressure problems
•
symptoms such as headache or dizziness, as they may be due to a rise in blood pressure. This
rise in blood pressure especially occurs at the end of having this treatment and usually settles
down within several hours
•
irregular heart beat
•
redness of the face (flush).
A decrease in blood pressure and a faster heart beat have also been observed in patients who have
cyanide poisoning.
Breathing and chest problems
•
fluid in the chest (pleural effusion)
•
breathing difficulties
•
a feeling of tightness in the throat
•
dry throat
•
chest discomfort.
49
Gastrointestinal (digestive) problems
•
discomfort in your stomach
•
indigestion
•
diarrhoea
•
feeling sick (nausea)
•
being sick (vomiting)
•
difficulty in swallowing.
Eye problems
•
swelling, irritation, redness.
Skin reactions
•
blister-like lesions on the skin (pustular rashes). These may last for several weeks, and affect
mainly the face and the neck.
•
inflammation in the part of the body where the medicine was infused.
Other side effects
•
restlessness
•
problems with memory
•
dizziness
•
headache
•
swelling of ankles
•
changes in the results of blood tests for certain white blood cells (lymphocytes)
•
coloured plasma, which may cause artificial elevation or reduction in the levels of certain
laboratory parameters.
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 CYANOKIT
IS STORED
Keep out of the reach and sight of children.
Do not use Cyanokit
after the expiry date which is stated on the vial, the cardboard box and the carton
after EXP. The expiry date refers to the last day of that month.
Do not store above 25°C.
For the purpose of ambulatory use, Cyanokit may be exposed during short periods to the temperature
variations of
•
usual transport (15 days submitted to temperatures ranging from 5 to 40°C)
•
transport in the desert (4 days submitted to temperatures ranging from 5 to 60°C) and
•
freezing/defrosting cycles (15 days submitted to temperatures ranging from -20 to 40°C).
For storage conditions of the reconstituted medicine, see 'Handling instructions' at the end of this
package leaflet.
Medicines 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.
50
6.
FURTHER INFORMATION
What Cyanokit
contains
•
The active substance is hydroxocobalamin. The vial contains 5 g of hydroxocobalamin. After
reconstitution with 200 ml of diluent, each ml of the reconstituted solution contains 25 mg of
hydroxocobalamin.
•
The other ingredient is hydrochloric acid (for pH adjustment).
What Cyanokit
looks like and contents of the pack
Cyanokit powder for solution for infusion is a dark red crystalline powder supplied in a glass vial
closed with bromobutyl rubber stopper and an aluminium cap with a plastic lid.
Each pack contains one glass vial packed in one cardboard box, one sterile transfer device, one sterile
intravenous infusion set and one sterile short catheter for administration to children.
Marketing Authorisation Holder
Merck Santé s.a.s.
37, rue Saint-Romain
69379 Lyon Cedex 08
France
Manufacturer
Merck Santé s.a.s. / SEMOY
2, rue du Pressoir Vert
45400 Semoy
France
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu/
---------------------------------------------------------------------------------------------------------------------------
--
The following information is intended for medical or healthcare professionals only:
Handling instructions
Treatment of cyanide poisoning must include immediate attention to airway patency, adequacy
of oxygenation and hydration, cardiovascular support, and management of seizures.
Consideration must be given to decontamination measures based on the route of exposure.
Cyanokit does not substitute oxygen therapy and must not delay the set up of the above
measures.
The presence and extent of cyanide poisoning are often initially unknown. There is no widely
available, rapid, confirmatory cyanide blood test. However, if a cyanide blood level
determination is planned, it is recommended to draw the blood sample before initiation of
treatment with Cyanokit. Treatment decisions must be made on the basis of clinical history
and/or signs and symptoms of cyanide intoxication. If there is clinical suspicion of cyanide
poisoning, it is strongly recommended that Cyanokit be administered without delay.
51
Preparation of Cyanokit
The vial is to be reconstituted
with 200 ml of diluent
using the supplied sterile transfer device.
Sodium chloride 9 mg/ml (0.9%)
solution for injection
is the recommended diluent. Only when
sodium chloride 9 mg/ml (0.9%) solution for injection is not available, Lactated Ringer solution or
glucose 50 mg/ml (5%) solution for injection can also be used.
The Cyanokit vial is to be rocked or inverted for at least 1 minute to mix the solution. It must not be
shaken as shaking the vial may cause foam and therefore may make checking reconstitution less easy.
Because the reconstituted solution is a dark red solution, some insoluble particles may not be seen.
The intravenous infusion set provided in the kit must then be used as it includes an appropriate filter
and is to be primed with the reconstituted solution.
Posology
Initial dos
e
Adults
: The initial dose of Cyanokit is 5 g (200 ml, complete volume of reconstituted solution).
Paediatric population:
In infants to adolescents (0 to 18 years old), the initial dose of Cyanokit is
70 mg/kg body weight not exceeding 5 g.
Body weight
in kg
5
10
20
30
40
50
60
Initial dose
in g
in ml
0.35
14
0.70
28
1.40
56
2.10
84
2.80
112
3.50
140
4.20
168
Subsequent dose
Depending upon the severity of the poisoning and the clinical response, a second dose may be
administered.
Adults:
The subsequent dose of Cyanokit is 5 g (200 ml, complete volume of reconstituted solution).
Paediatric population:
In infants to adolescents (0 to 18 years old), the subsequent dose of Cyanokit is
70 mg/kg body weight not exceeding 5 g.
Maximum dose
Adults
: The maximum total recommended dose is 10 g.
Paediatric population:
In infants to adolescents (0 to 18 years old), the maximum total recommended
dose is 140 mg/kg not exceeding 10 g.
Renal and hepatic impairment
No dose adjustment is required in these patients.
Method of administration
Initial dose of Cyanokit is administered as an intravenous infusion over 15 minutes.
The rate of intravenous infusion for the second dose ranges from 15 minutes (for patients extremely
unstable) to 2 hours based on patient condition.
52
Simultaneous administration of Cyanokit and other products
Cyanokit must not be mixed with diluents other than sodium chloride 9 mg/ml (0.9%) solution for
injection or Lactated Ringer solution or glucose 50 mg/ml (5%) solution for injection.
As physical and chemical incompatibilities were observed with a number of selected medicinal products
that are frequently used in resuscitation efforts, these and other medicinal products must not be
administered simultaneously in the same intravenous line as hydroxocobalamin.
If blood products (whole blood, packed red cells, platelet concentrate and fresh frozen plasma) and
hydroxocobalamin are administered simultaneously, use of separate intravenous lines (preferably on
contralateral extremities) is recommended.
Combination with another cyanide antidote:
Chemical incompatibility was observed with sodium
thiosulfate and sodium nitrite. If the decision is made to administer another cyanide antidote with
Cyanokit, these medicinal products must not be administered concurrently in the same intravenous
line.
In-use stability of the reconstituted solution
Chemical and physical in-use stability of the reconstituted solution with sodium chloride 9 mg/ml
(0.9%) has been demonstrated for 6 hours at a temperature between 2°C to 40°C.
From a microbiological point of view, the medicinal product should be used immediately. If not used
immediately, in-use storage times and conditions prior to use are the responsibility of the user and
would normally not be longer than 6 hours at 2°C to 8°C.
53
Source: European Medicines Agency
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