Drugs List

Therapeutic Indications

Uses

Prevention of recurrent vaso-occlusive crises in sickle cell syndrome

Prevention of recurrent painful vaso-occlusive crises including acute chest syndrome in paediatric and adult patients suffering from symptomatic Sickle Cell Syndrome

Administration

The tablets should be taken in the morning before breakfast with water or a very small amount of food.

The 1000 mg may be broken into halves or quarters. This should be done out of the reach of food and any spilled powder wiped up with a damp disposable towel and discarded in accordance with local requirements.

For patients unable to swallow, the 100 mg tablets can be disintegrated immediately before use in a small quantity of water in a teaspoon. Adding a few drops of syrup or mixing with food can mask a possible bitter taste.

Hands should be washed before and after contact with the tablets.

Contraindications

Children under 2 years
Breastfeeding
Pregnancy
Renal impairment - creatinine clearance below 30 ml/minute
Severe hepatic impairment
Severe myelosuppression

Precautions and Warnings

History of radiotherapy
Hepatic impairment
Myelosuppression secondary to chemotherapy
Positive HIV status
Renal impairment - creatinine clearance 30-60ml/minute
Skin ulcer

Live virus vaccine should not be given for 6 months after treatment
May exacerbate previously existing erythema
Talimogene laherparepvec should not be given for 6 months after treatment
Advise patient ability to drive or operate machinery may be impaired
Give pre-treatment counselling and consideration of sperm cryopreservation
May be increased risk of skin cancer
Treatment to be prescribed under the supervision of a specialist
Ensure patient has adequate fluid intake
Monitor hepatic function before treatment and regularly during treatment
Monitor renal function before treatment and regularly during treatment
Monitor blood counts in stable and in low dose patients every 2 months
Monitor blood counts monthly for first 2 months, & if on max. dose
Monitor skin changes
Monitor uric acid levels
Suspend if reticulocytes fall below 80,000 cubic mm & Hb below 9g/dl
Suspend treatment if haemoglobin falls below 4.5g/dl
Suspend treatment if neutrophil count is less than 1,500/cubic mm
Suspend treatment if platelet count falls below 80,000 per cubic mm
Discontinue/review treatment if cutaneous vasculitic ulcers develop
Female: Ensure adequate contraception during treatment
Male: Contraception required during and for 3 months after treatment
Advise patient on appropriate sun protection methods

Macrocytosis may mask the incidental development of folic acid or vitamin B12 deficiency. Prophylactic supplementation with folic acid is recommended. Hydroxycarbamide may delay plasma iron clearance and reduce the rate of iron utilisation by erythrocytes. It does not appear to alter the red blood cell survival time

Secondary leukaemia has been reported in patients receiving long term treatment for myeloproliferative disorders such as polycythemia vera, thrombocythemia and vaso-occlusive crises in sickle cell syndrome. It is unknown whether this leukaemogenic effect is related to hydroxycarbamide or associated with the patients underlying disease. Cases of squamous cell carcinomas have been reported during long term treatment, therefore it is advisable to monitor any skin changes. Patients should also be advised to protect their skin from excessive sun exposure.

Cutaneous vasculitic toxicities including vasculitic ulcerations and gangrene have occurred in patients with myeloproliferative disorders during therapy. The risk is increased in patients who have received prior or concomitant interferon therapy. Due to the potentially severe clinical outcomes hydroxycarbamide should be reviewed and the dose reduced or discontinued if cutaneous vasculitic ulcerations develop. Discontinuation of hydroxycarbamide usually leads to a slow resolution of the ulcers.

Erythema caused by previous irradiation may be exacerbated by hydroxycarbamide therapy.

Patients and or parents or the legal responsible person must be able to follow directions regarding the administration of this medicinal product, their monitoring and care.

Pregnancy and Lactation

Pregnancy

Hydroxycarbamide is contraindicated in pregnancy.

Hydroxycarbamide crosses the placenta and is a potent teratogenic and embryotoxic agent.
There have been a few reported cases of apparently healthy children born after exposure to hydroxycarbamide in-utero. However, the data is too limited to draw conclusions about safety during pregnancy or the long-term growth and development of children exposed in-utero.

Animal experiments indicate an increased incidence of congenital defects including the CNS system, palate and skeleton, when hydroxycarbamide is administered during pregnancy.

The effect of concurrent therapies must also be considered.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14-17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

Hydroxycarbamide is contraindicated in pregnancy.

Hydroxycarbamide crosses the placenta and is a potent teratogenic and embryotoxic agent.
There have been a few reported cases of apparently healthy children born after exposure to hydroxycarbamide in-utero. However, the data is too limited to draw conclusions about safety during pregnancy or the long-term growth and development of children exposed in-utero.

Animal experiments indicate an increased incidence of congenital defects including the CNS system, palate and skeleton, when hydroxycarbamide is administered during pregnancy.

The effect of concurrent therapies must also be considered.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Side Effects

Abdominal pain
Allergic alveolitis
Alopecia
Amenorrhoea
Anaemia
Anorexia
Asthenia
Azoospermia
Bleeding
Bone marrow depression
Chills
Constipation
Convulsions
Cutaneous atrophy
Dermatomyositis
Desquamation
Diarrhoea
Disorientation
Dizziness
Drowsiness
Dry skin
Dyspnoea
Dysuria
Elevation of liver enzymes
Erythema
Fever
Gangrene
Gastro-intestinal ulceration
Hallucinations
Headache
Hepatitis
Hepatotoxicity
Hyperpigmentation
Hypersensitivity reactions
Hypomagnesaemia
Impaired renal tubular function
Increased risk of skin cancer
Increased uric acid level
Keratosis
Leg ulcers
Leucopenia
Leukaemia
Macrocytosis
Malaise
Megaloblastosis
Melaena
Mucositis
Nail disorders
Nausea
Neurological disorders
Neutropenia
Oligospermia
Pancreatitis
Peripheral neuropathy
Pruritus
Pulmonary fibrosis
Pulmonary infiltrates
Pulmonary oedema
Rash
Reduction in reticulocytes
Renal impairment
Scaling of skin
Secondary leukaemia
Serum bilirubin increased
Serum creatinine increased
Serum urea increased
Skin carcinoma
Skin ulcer
Stomatitis
Thrombocytopenia
Tumour lysis syndrome
Violet papules
Vomiting
Weight gain

Presentation

Tablets containing hydroxycarbamide.

Drugs List

Therapeutic Indications

Uses

Prevention of recurrent vaso-occlusive crises in sickle cell syndrome

Prevention of recurrent painful vaso-occlusive crises including acute chest syndrome in paediatric and adult patients suffering from symptomatic Sickle Cell Syndrome

Dosage

Adults

Children

Patients with Renal Impairment

Administration

The tablets should be taken in the morning before breakfast with water or a very small amount of food.

The 1000 mg may be broken into halves or quarters. This should be done out of the reach of food and any spilled powder wiped up with a damp disposable towel and discarded in accordance with local requirements.

For patients unable to swallow, the 100 mg tablets can be disintegrated immediately before use in a small quantity of water in a teaspoon. Adding a few drops of syrup or mixing with food can mask a possible bitter taste.

Hands should be washed before and after contact with the tablets.

Contraindications

Children under 2 years
Breastfeeding
Pregnancy
Renal impairment - creatinine clearance below 30 ml/minute
Severe hepatic impairment
Severe myelosuppression

Precautions and Warnings

History of radiotherapy
Hepatic impairment
Myelosuppression secondary to chemotherapy
Positive HIV status
Renal impairment - creatinine clearance 30-60ml/minute
Skin ulcer

Live virus vaccine should not be given for 6 months after treatment
May exacerbate previously existing erythema
Talimogene laherparepvec should not be given for 6 months after treatment
Advise patient ability to drive or operate machinery may be impaired
Give pre-treatment counselling and consideration of sperm cryopreservation
May be increased risk of skin cancer
Treatment to be prescribed under the supervision of a specialist
Ensure patient has adequate fluid intake
Monitor hepatic function before treatment and regularly during treatment
Monitor renal function before treatment and regularly during treatment
Monitor blood counts in stable and in low dose patients every 2 months
Monitor blood counts monthly for first 2 months, & if on max. dose
Monitor skin changes
Monitor uric acid levels
Suspend if reticulocytes fall below 80,000 cubic mm & Hb below 9g/dl
Suspend treatment if haemoglobin falls below 4.5g/dl
Suspend treatment if neutrophil count is less than 1,500/cubic mm
Suspend treatment if platelet count falls below 80,000 per cubic mm
Discontinue/review treatment if cutaneous vasculitic ulcers develop
Female: Ensure adequate contraception during treatment
Male: Contraception required during and for 3 months after treatment
Advise patient on appropriate sun protection methods

Macrocytosis may mask the incidental development of folic acid or vitamin B12 deficiency. Prophylactic supplementation with folic acid is recommended. Hydroxycarbamide may delay plasma iron clearance and reduce the rate of iron utilisation by erythrocytes. It does not appear to alter the red blood cell survival time

Secondary leukaemia has been reported in patients receiving long term treatment for myeloproliferative disorders such as polycythemia vera, thrombocythemia and vaso-occlusive crises in sickle cell syndrome. It is unknown whether this leukaemogenic effect is related to hydroxycarbamide or associated with the patients underlying disease. Cases of squamous cell carcinomas have been reported during long term treatment, therefore it is advisable to monitor any skin changes. Patients should also be advised to protect their skin from excessive sun exposure.

Cutaneous vasculitic toxicities including vasculitic ulcerations and gangrene have occurred in patients with myeloproliferative disorders during therapy. The risk is increased in patients who have received prior or concomitant interferon therapy. Due to the potentially severe clinical outcomes hydroxycarbamide should be reviewed and the dose reduced or discontinued if cutaneous vasculitic ulcerations develop. Discontinuation of hydroxycarbamide usually leads to a slow resolution of the ulcers.

Erythema caused by previous irradiation may be exacerbated by hydroxycarbamide therapy.

Patients and or parents or the legal responsible person must be able to follow directions regarding the administration of this medicinal product, their monitoring and care.

Pregnancy and Lactation

Pregnancy

Hydroxycarbamide is contraindicated in pregnancy.

Hydroxycarbamide crosses the placenta and is a potent teratogenic and embryotoxic agent.
There have been a few reported cases of apparently healthy children born after exposure to hydroxycarbamide in-utero. However, the data is too limited to draw conclusions about safety during pregnancy or the long-term growth and development of children exposed in-utero.

Animal experiments indicate an increased incidence of congenital defects including the CNS system, palate and skeleton, when hydroxycarbamide is administered during pregnancy.

The effect of concurrent therapies must also be considered.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14-17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

Hydroxycarbamide is contraindicated in pregnancy.

Hydroxycarbamide crosses the placenta and is a potent teratogenic and embryotoxic agent.
There have been a few reported cases of apparently healthy children born after exposure to hydroxycarbamide in-utero. However, the data is too limited to draw conclusions about safety during pregnancy or the long-term growth and development of children exposed in-utero.

Animal experiments indicate an increased incidence of congenital defects including the CNS system, palate and skeleton, when hydroxycarbamide is administered during pregnancy.

The effect of concurrent therapies must also be considered.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Counselling

Advise patient to take in the morning before breakfast with water or a very small amount of food.

Advise patient hands should be washed before and after contact with tablets.

Advise patient to ensure breaking tablets into halves or quarters should be done out of the reach of food. Advise patient to wipe up any spilled powder with a damp disposable cloth in accordance with local guidance.

Advise patient about responsibility for understanding and following directions with regards to administration, monitoring and care.

Advise patient on appropriate sun protection methods.

Advise patient on contraception required. If appropriate, advise patient to consider sperm cyropreservation.

Advise patient ability to drive or operate machinery may be impaired.

Side Effects

Abdominal pain
Allergic alveolitis
Alopecia
Amenorrhoea
Anaemia
Anorexia
Asthenia
Azoospermia
Bleeding
Bone marrow depression
Chills
Constipation
Convulsions
Cutaneous atrophy
Dermatomyositis
Desquamation
Diarrhoea
Disorientation
Dizziness
Drowsiness
Dry skin
Dyspnoea
Dysuria
Elevation of liver enzymes
Erythema
Fever
Gangrene
Gastro-intestinal ulceration
Hallucinations
Headache
Hepatitis
Hepatotoxicity
Hyperpigmentation
Hypersensitivity reactions
Hypomagnesaemia
Impaired renal tubular function
Increased risk of skin cancer
Increased uric acid level
Keratosis
Leg ulcers
Leucopenia
Leukaemia
Macrocytosis
Malaise
Megaloblastosis
Melaena
Mucositis
Nail disorders
Nausea
Neurological disorders
Neutropenia
Oligospermia
Pancreatitis
Peripheral neuropathy
Pruritus
Pulmonary fibrosis
Pulmonary infiltrates
Pulmonary oedema
Rash
Reduction in reticulocytes
Renal impairment
Scaling of skin
Secondary leukaemia
Serum bilirubin increased
Serum creatinine increased
Serum urea increased
Skin carcinoma
Skin ulcer
Stomatitis
Thrombocytopenia
Tumour lysis syndrome
Violet papules
Vomiting
Weight gain

Overdosage

It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.

The following number will direct the caller to the relevant local centre (0844) 892 0111

Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Further Information

Last Full Review Date: December 2015

Reference Sources

Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment, 2nd edition (2007) ed. Schaefer, C., Peters, P. and Miller, R. Elsevier, London.

Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 9th edition (2011) ed. Briggs, G., Freeman, R. and Yaffe, S. Lippincott Williams & Wilkins, Philadelphia.

The Renal Drug Handbook. Fourth Edition (2014) ed. Ashley, C and Dunleavy, A, Radcliffe Publishing Ltd, London.

Summary of Product Characteristics: Siklos Tablets 100mg and Siklos Tablets 1000mg. Nordic Pharma UK Ltd. Revised August 2021.

NICE Evidence Services Available at: www.nice.org.uk Last accessed: 07 September 2017

US National Library of Medicine. Toxicology Data Network. Drugs and Lactation Database (LactMed).
Available at: https://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT
Hydroxyurea Last revised: 3 March 2014
Last accessed: 19 November 2015