Sodium Thiosulfate Hope Pharmaceuticals 250 mg/ml solution for Injection

Ireland - English - HPRA (Health Products Regulatory Authority)

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Active ingredient:
Sodium thiosulfate
Available from:
Hope Pharmaceuticals Ltd
ATC code:
V03AB; V03AB06
INN (International Name):
Sodium thiosulfate
Dosage:
250 milligram(s)/millilitre
Pharmaceutical form:
Solution for injection
Therapeutic area:
Antidotes; thiosulfate
Authorization number:
PA22874/002/001
Authorization date:
2019-08-23

Sodium Thiosulfate Hope Pharmaceuticals 250 mg/ml Solution for Injection

sodium thiosulfate

Read all of this leaflet carefully

This leaflet contains information about sodium thiosulfate, which will have already been given to you by injection into one of

your veins.

Although you will not be taking this medicine yourself, this leaflet contains important information to help you

understand how Sodium Thiosulfate is used.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or nurse.

If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this

leaflet. See section 4.

In this leaflet

1. What is sodium thiosulfate and what it is used for

2. Before you are given sodium thiosulfate

3. How sodium thiosulfate is given

4. Possible side effects

5. How to store sodium thiosulfate

6. Contents of the pack and other information

1.

What sodium thiosulfate is and what it is used for

Sodium Thiosulfate Hope Pharmaceuticals 250 mg/ml Solution for Injection is used as an antidote for cyanide poisoning.

Cyanide poisoning is a condition that develops when you inhale, touch, or swallow cyanide. Cyanide is a poisonous

chemical that prevents your body from absorbing oxygen. The lack of oxygen can damage your organs and be life-

threatening.

2.

Before you are given sodium thiosulfate

Your doctor will take special care if you:

have had an allergic reaction to sulfites.

You will be monitored during use with sodium thiosulfate, and the dose of the medication will be adjusted if necessary.

This medicine contains approximately 3.6 g of sodium per vial, equivalent to 180% of the WHO recommended maximum

daily intake of 2g sodium for an adult.

This medicine contains 115 mg of potassium per 50ml vial.

This medicine also contains 140 mg of boric acid per 50ml vial. If you are pregnant, talk to your doctor as it contains boron,

which may be harmful to your baby.

Using other medicines

The following medicines have side effects that are similar to the side effects that may occur with sodium thiosulfate.

Other solutions for injection that contain sodium, such as sodium chloride.

It may be necessary for your doctor to adjust the dose of sodium thiosulfate or one of your other medications.

Do not take sodium thiosulfate concurrently with hydroxocobalamin.

Pregnancy and breast-feeding

Sodium thiosulfate should not be used during pregnancy or while breast-feeding. Tell your doctor right away if you are

pregnant or breast feeding.

3.

How sodium thiosulfate is given

Sodium thiosulfate will be given by injection into a vein by a doctor or nurse. Your doctor will choose the dose that is right

for you.

If signs of cyanide poisoning reappear, your doctor will decide if you should receive more sodium thiosulfate.

If you have any further questions on the use of sodium thiosulfate, ask your doctor or nurse.

4.

Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

The side effects of sodium thiosulfate include:

Heart: reduced blood pressure

Blood: cuts take longer to stop bleeding than normal

Head: headache, disorientation

Stomach and Gut: nausea, vomiting

Body as a whole: salty taste in mouth, warm sensation over body

The frequencies at which the above reactions occur are not known yet.

Reporting of side effects:

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this

leaflet. You can also report side effects directly to HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1

6764971; Fax: +353 1 6762517; Website: www.hpra.ie; e-mail: medsafety@hpra.ie. By reporting side effects you can help

provide more information on the safety of this medication.

5.

How to store sodium thiosulfate

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the vial label and carton. The expiry date refers to the last

day of that month.

Store below 25°C. For single use only. Use immediately after opening. Discard any unused portions.

Do not throw away any medicines via

wastewater or household waste. Ask your

pharmacist how to dispose of medicines no

longer required. These measures will help protect the environment.

6.

Contents of the pack and other information

What Sodium Thiosulfate Hope Pharmaceuticals 250 mg/ml Solution for Injection contains

The active substance is sodium thiosulfate. Each 50 ml vial contains 12.5 g

of sodium thiosulfate (250 mg/ml). The other

ingredients are boric acid, potassium chloride, sodium hydroxide and water for injections. Sodium hydroxide and boric acid may

also be used to adjust the pH of the solution.

What Sodium Thiosulfate Hope Pharmaceuticals 250 mg/ml Solution For Injection looks like and contents of the pack

Sodium Thiosulfate Hope Pharmaceuticals 250 mg/ml Solution for Injection must be clear and colourless. If

particulate

matter or discolouration is

present, the solution must not be used and should be discarded.

Each carton contains one 50 ml single use glass vial.

Marketing Authorisation Holder

Hope Pharmaceuticals, Ltd.

Kyletelogue House

9 Cherrywood Park

Tallanstown, County Louth

Ireland

Manufacturer Responsible for Batch Release

Mawdsleys Brooks & Company Limited

Doncaster DN2 4LT

United Kingdom

This medicinal product is authorised in the Member States of the EEA under the following names:

Ireland

Sodium Thiosulfate Hope

Pharmaceuticals 250 mg/ml

Solution for Injection

Netherlands

Natriumthiosulfaat Hope

250 mg/ml, Oplossing voor

Injectie

Spain

Tiosulfato de Sodio Hope

250 mg/ml Solución

Inyectable

Sweden

Natriumtiosulfat Hope

250 mg/ml Injektionsvätska,

Lösning

United Kingdom

Sodium Thiosulfate

250 mg/ml Solution for

Injection

This leaflet was last revised in August 2019.

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Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Sodium Thiosulfate Hope Pharmaceuticals 250 mg/ml solution for Injection

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 50 mL vial contains 12.5 g of sodium thiosulfate (250 mg/mL).

Excipients of known effect

3.6 g of sodium in 50 ml of solution for injection.

115 mg of potassium in 50 ml of solution for injection.

140 mg of boric acid in 50 mL of solution for injection.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Solution for Injection

The solution for injection is a clear and colourless solution.

4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

Sodium thiosulfate is indicated for sequential use withhydroxocobalamin or sodium nitrite for the treatment of acute cyanide

poisoning that is judged to be life-threatening.

When the diagnosis of cyanide poisoning is uncertain, the potentially life-threatening risks associated with sodium thiosulfate

should be carefully weighed against the potential benefits, especially if the patient is not in extremis.

Sodium thiosulfate is to be administered together with appropriate decontamination and supportive measures (see section 4.4).

4.2 Posology and method of administration

Posology

For intravenous use. For single use only.

Adults

Initial dose: 10 mL (300 mg) of sodium nitrite (rate of 2.5 to 5 mL/minute) should be administered intravenously, immediately

followed by 50 mL (12.5 g) of sodium thiosulfate (rate of 5 mL/minute).

Alternatively, an initial dose of 5 g hydroxocobalamin administered as an intravenous infusion over 15 minutes followed by 50

mL (12.5 g) of sodium thiosulfate (rate of 5 mL/minute).

Special populations

Older people

No specific dose adjustment is required in elderly patients (aged > 65 years).

Paediatric population

In infants to adolescents (0 to 18 years old), 0.2 mL/kg (6 mg/kg or 6-8 mL/m2 BSA) of sodium nitrite (rate of 2.5 to 5

mL/minute) not to exceed 10 mL should be administered intravenously, immediately followed by 1 mL/kg of body weight

(250 mg/kg or approximately 30-40 mL/m2 of BSA) (rate of 2.5 to 5 mL/minute) not to exceed 50 mL total dose of sodium

thiosulfate.

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Alternatively, in infants to adolescents (0 to 18 years old), the initial dose of hydroxocobalamin is 70 mg/kg body weight not

exceeding 5 g followed by 1 mL/kg of body weight (250 mg/kg or approximately 30-40 mL/m2 of BSA) (rate of 2.5 to 5

mL/minute) not to exceed 50 mL total dose of sodium thiosulfate.

NOTE: If no treatment response is observed within 30 to 60 minutes or if signs of poisoning reappear, repeat treatmentafter 30

minutes of initial administration using one-half the original dose of both sodium nitrite and sodium thiosulfate.

In adult and paediatric patients with known anaemia, it is recommended that the dosage of sodium nitrite should be reduced

proportionately to the hemoglobin concentration (see Sodium Nitrite SmPC section 4.4).

Renal and hepatic impairment

Although the safety and efficacy of sodium thiosulfate have not been studied in patients with renal and hepatic impairments,

sodium thiosulfate is administered as emergency therapy in an acute, life-threatening situation only and no dose adjustment is

required in these patients.

Method of administration

Comprehensive treatment of acute cyanide intoxication requires support of vital functions. Supportive care alonemay be

sufficient treatment without administration of antidotes for many cases of cyanide intoxication, particularly in conscious

patients without signs of severe toxicity. Administration ofcyanide antidotes should be considered adjunctive to appropriate

supportive therapies such as airway, ventilatory, and circulatory support. Supportive therapies, including oxygen

administration, should not be delayed to administer cyanide antidotes.

Sodium nitrite injection and sodium thiosulfate injection are administered by slow intravenous injection. Cyanide antidotes

should be given as early as possible after a diagnosis of acute life-threatening cyanide poisoning has been established. Sodium

thiosulfate may be administered soon after prior treatment with a fast-acting cyanide antidote such as sodium nitrite or

hydroxocobalamin. Blood pressure must be monitored during infusion in both adults and children. The rate of infusion should

be decreased if significant hypotension is noted.

All parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration,

whenever solution and container permit.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

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.

Sodium thiosulfate 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.

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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 Sodium thiosulfate 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 sodium thiosulfate must not be delayed to obtain a plasma

lactate concentration.

Sodium thiosulfate drug product may contain trace impurities of sodium sulfite. The presence of a trace amount of sulfites in

this product should not deter administration of the drug for treatment of emergency situations, even if the patient is

sulfite-sensitive.

Each 12.5 g dose of sodium thiosulfate contains approximately 3.6 g of sodium which is equivalent to 180% of the WHO

recommended maximal daily intake of 2 g sodium for an adult.

Each 12.5 g dose of sodium thiosulfate also contains 115 mg of potassium and 140 mg of boric acid.

4.5 Interaction with other medicinal products and other forms of interactions

No interaction studies have been performed. Possible interaction may occur with hydroxocobalamin. Sodium thiosulfate

should not be co-administered with hydroxocobalamin in the same injection line.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of sodium thiosulfate in pregnant

women. Animals studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).

As a precautionary measure, it is preferable to avoid the use of sodium thiosulfate during pregnancy.

Breastfeeding

It is unknown whether sodium thiosulfate is excreted in human milk. A risk to the suckling child cannot be excluded.

Breast-feeding should be discontinued during treatment with sodium thiosulfate.

Fertility

There are no fertility data from the use of sodium thiosulfate in animals.

4.7 Effects on ability to drive and use machines

Not relevant.

4.8 Undesirable effects

There have been no controlled clinical trials conducted to systematically assess the adverse events profile of sodium thiosulfate.

The medical literature has reported the following adverse events in association with sodium thiosulfate administration. These

adverse events were not reported in the context of controlled trials or with consistent monitoring and reporting

methodologies for adverse events. Therefore, frequency of occurrence of these adverse events cannot be assessed.

System organ class

Frequency

Undesirable effect

Cardiac and vascular disorders

Not known

Hypotension

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Nervous system disorders

Not known

Headache, disorientation

Gastrointestinal disorders

Not known

Nausea*, vomiting*

Blood and lymphatic system disorders

Not known

Prolonged bleeding time*

General disorders and administration site

conditions

Not known

Salty taste in mouth, warm sensation over body

*Description of selected adverse reactions

Nausea and vomiting

In humans, rapid administration of concentrated solutions or solutions not freshly prepared, and administration of large doses

of sodium thiosulfate have been associated with a higher incidence of nausea and vomiting. However, administration of

0.045 g sodium thiosulfate per kilogram up to a maximum of 15 g in a 10-15% solution over 10-15 minutes was associated

with nausea and vomiting in 7 of 26 patients without concomitant cyanide intoxication.

Prolonged bleeding time

In a series of 11 human subjects, a single intravenous infusion of 50 mL of 50% sodium thiosulfate was associated with

increases in clotting time 1-3 days after administration. However, no significant changes were observed in other

hematological parameters.

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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 676497; Fax: +353 1 6762517.

Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

4.9 Overdose

There is limited information about the effects oflarge doses of sodium thiosulfate in humans. Oral administration of 3 g

sodium thiosulfate per day for 1-2 weeks in humans resulted in reductions in room air arterial oxygen saturation to as low

as 75%, which was due to a rightward shift in the oxygen hemoglobin dissociation curve. The subjects returned to baseline

oxygen saturations 1 week after discontinuation of sodium thiosulfate. A single intravenous administration of 20 mL of

10%sodium thiosulfate reportedly did not change oxygen saturations.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: antidotes, ATC code: V03AB06 (sodium thiosulfate)

Mechanism of action

Exposure to a high dose of cyanide can result in death within minutes due to the inhibition of cytochrome oxidase resulting in

arrest of cellular respiration.

Specifically, cyanide binds rapidly with cytochrome a3, a component of the cytochrome c oxidase complex in mitochondria.

Inhibition of cytochrome a3 prevents the cell from using oxygen and forces anaerobic metabolism, resulting in lactate

production, cellular hypoxia and metabolic acidosis. In massive acute cyanide poisoning, the mechanism of toxicity may

involve other enzyme systems as well.

The synergy resulting from treatment of cyanide poisoning with the combination of sodium nitrite and sodium thiosulfate is

the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.

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Pharmacodynamic effects

Sodium Nitrite

Sodium nitrite is thought to exert its therapeutic effect by reacting with hemoglobin to form methemoglobin, an oxidized form

of hemoglobin incapable of oxygen transport but with high affinity for cyanide. Cyanide preferentially binds to

methemoglobin over cytochrome a3, forming the nontoxic cyanomethemoglobin. Methemoglobin displaces cyanide from

cytochrome oxidase, allowing resumption of aerobic metabolism. The chemical reaction is as follows:

NaNO

+ Hemoglobin → Methemoglobin

HCN + Methemoglobin → Cyanomethemoglobin

Vasodilation has also been cited to account for at least part of the therapeutic effect of sodium nitrite. It has been suggested

that sodium nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of

methemoglobinemia induced by other oxidants. Also, sodium nitrite appears to retain some efficacy even when the formation

of methemoglobin is inhibited by methylene blue.

Sodium Thiosulfate

The primary route of endogenous cyanide detoxification is by enzymatic transulfuration to thiocyanate (SCN-), which is

relatively nontoxic and readily excreted in the urine. Sodium thiosulfate is thought to serve as a sulfur donor in the reaction

catalyzed by the enzyme rhodanese, thus enhancing the endogenous detoxification of cyanide in the following chemical

reaction:

Rhodanese

+ CN

→ SCN

+ Na

Clinical efficacy and safety

There have been no controlled clinical trials conducted to systematically assess the clinical efficacy and safety of sodium

thiosulfate.

5.2 Pharmacokinetic properties

Absorption

Sodium thiosulfate taken orally is not systemically absorbed. Intravenous injection of sodium thiosulfate is 100% bioavailability.

Distribution

Sodium thiosulfate is rapidly distributed throughout extracellular fluid after IV administration. The volume of distribution of

sodium thiosulfate is 150 mL/kg.

Biotransformation and elimination

Most of the thiosulfate is oxidized to sulfate or is incorporated into endogenous sulphur compounds; a small proportion is

excretedthrough the kidneys.

Approximately 20-50% of exogenously administered thiosulfate is eliminated unchanged via the kidneys. After an intravenous

injection of 1 g sodium thiosulfate in patients, the reported serum thiosulfate half-life was approximately 20 minutes. However,

after an intravenous injection of a substantially higher dose of sodium thiosulfate (150 mg/kg, that is, 9 g for 60 kg body

weight) in normal healthy men, the reported elimination half-life was 182 minutes.

5.3 Preclinical safety data

Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human

exposure indicating little relevance to clinical use.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Boric Acid

Potassium Chloride

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Water for Injections

Sodium Hydroxide and/or boric acid for pH Adjustment

6.2 Incompatibilities

Chemical incompatibility has been reported between sodium thiosulfate and hydroxocobalamin and these drugs should not be

administered simultaneously through the same IV line. No chemical incompatibility has been reported between sodium

thiosulfate and sodium nitrite, when administered sequentially through the same IV line.

6.3 Shelf life

5 years

From a microbiological point of view, Sodium Thiosulfate Hope Pharmaceuticals 250 mg/ml solution for injection should be

used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.

6.4 Special precautions for storage

Do not store above 25 °C.

For storage conditions after first opening of the medicinal product, see section 6.3.

6.5 Nature and contents of container

Each carton of Sodium Thiosulfate Hope Pharmaceuticals 250 mg/ml solution for injection contains one 50 mL single use

glass vial of sodium thiosulfate 250 mg/mL solution for injection (containing 12.5 g of sodium thiosulfate).

Each glass vial includes a chlorobutyl stopper and an aluminum cap with a plastic lid.

6.6 Special precautions for disposal

No special requirements for disposal. Any unused medicinal product or waste material should be disposed of in accordance

with local requirements.

7 MARKETING AUTHORISATION HOLDER

Hope Pharmaceuticals Ltd

Kyletelogue House

9 Cherrywood Park

Tallanstown

Co Louth

Ireland

8 MARKETING AUTHORISATION NUMBER

PA22874/002/001

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 23

August 2019

10 DATE OF REVISION OF THE TEXT

September 2019

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