CYANOKIT Powder for solution for infusion Ref.[116063] Active ingredients: Vitamin B12a

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 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.

Renal disorders

Oxalate crystals have been observed in the urine of healthy volunteers given hydroxocobalamin. Cases of acute renal failure with acute tubular necrosis, renal impairment and urine calcium oxalate crystals present have been reported in patients treated with hydroxocobalamin following known or suspected cyanide poisoning. In some situations, hemodialysis was required to achieve recovery (see section 4.8).

Therefore, as a precaution, after Cyanokit administration, regular monitoring of renal function (including blood urea nitrogen and serum creatinine) should be performed until 7 days after drug onset.

Hypersensitivity reactions

Known hypersensitivity to hydroxocobalamin or vitamin B12 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.

Observed in vitro interferences of hydroxocobalamin with laboratory tests:

^* ≥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 Coasys¹¹⁰ (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.

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/or Health Authorities 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).

Not relevant.

Summary of the safety profile

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.

List of adverse reactions

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.

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: most patients will experience it up to 15 days after administration of Cyanokit. Pustular rashes, which may last for several weeks, affecting mainly the face and the neck.

Renal and urinary disorders:

• Acute renal failure with acute tubular necrosis, renal impairment, urine calcium oxalate crystals present (see section 4.4).
• Chromaturia: all patients will show a dark red colouration of the urine quite marked during the first three days following administration. Urine colouration may last up to 35 days after administration of Cyanokit (see section 4.4).

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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

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.