Litalir

The treatment of chronic myeloid leukaemia.

The treatment of cancer of the cervix in conjunction with radiotherapy.

Litalir is indicated for the prevention of recurrent painful vaso-occlusive crises including acute chest syndrome in adults, adolescents and children older than 2 years suffering from symptomatic Sickle Cell Syndrome.

Posology

Adults

Treatment regimens can be continuous or intermittent. The continuous regimen is particularly suitable for chronic myeloid leukaemia, while the intermittent regimen, with its diminished effect on the bone marrow, is more satisfactory for the management of cancer of the cervix.

Litalir should be started 7 days before concurrent irradiation therapy. If Litalir is used concomitantly with radiotherapy, adjustment of radiation dosage is not usually necessary.

An adequate trial period for determining the antineoplastic effect of Litalir is six weeks. Where there is a significant clinical response therapy may be continued indefinitely, provided that the patient is kept under adequate observation and shows no unusual or severe reactions. Therapy should be interrupted if the white cell count drops below 2.5x10⁹L or the platelet count below 100x10⁹/L.

In these cases, the counts should be reevaluated after three days and therapy resumed when the counts return to acceptable levels. Hematopoietic rebound is usually rapid. If rapid rebound has not occurred during combined Litalir and irradiation therapy, irradiation may also be interrupted. Anemia, even if severe, can be managed without interrupting Litalir therapy.

Severe gastric distress, such as nausea, vomiting, and anorexia, resulting from combined therapy may usually be controlled by interruption of Litalir administration.

Pain or discomfort from inflammation of the mucous membranes at the irradiated site (mucositis) is usually controlled by measures such as topical anesthetics and orally administered analgesics. If the reaction is severe, Litalir therapy may be temporarily interrupted; if it is extremely severe, irradiation dosage may, in addition, be temporarily postponed.

Continuous therapy

Litalir 20-30 mg/kg should be given daily in single doses. Dosage should be based on the patient's actual or ideal weight, whichever is the less. Therapy should be monitored by repeat blood counts.

Intermittent therapy

Litalir 80 mg/kg in single doses should be given every third day. Using the intermittent regimes the likelihood of WBC depression is diminished, but if low counts are produced, 1 or more doses of Litalir should be omitted.

Concurrent use of Litalir with other myelosuppressive agents may require adjustments of dosages.

Special Populations

Children

Because of the rarity of these conditions in children, dosage regimens have not been established.

Elderly

Elderly patients may be more sensitive to the effects of hydroxycarbamide, and may require a lower dosage regimen.

Renal Impairment

Since renal excretion is a pathway of elimination, consideration should be given to decreasing the dosage of Litalir in this population.

Method of administration

For oral use.

NB: If the patient prefers, or is unable to swallow capsules, the contents of the capsules may be emptied into a glass of water and taken immediately. The contents of capsules should not be inhaled or allowed to come into contact with the skin or mucous membranes. Spillages must be wiped immediately.

Treatment with Litalir should be initiated by a physician experienced in the management of Sickle Cell Syndrome.

Posology

In adults, adolescents and children older than 2 years

The posology should be based on the patient's body weight (b.w.).

The starting dose of hydroxycarbamide is 15 mg/kg b.w. and the usual dose is between 15 and 30 mg/kg b.w./day.

As long as the patient responds to therapy either clinically or haematologically (e.g. increase of haemoglobin F (HbF), Mean Corpuscular Volume (MCV), neutrophil count) the dose of Litalir should be maintained.

In case of non-response (re-occurrence of crises or no decrease in crisis rate) the daily dose may be increased by steps of 2.5 to 5 mg/kg b.w./day using the most appropriate strength.

Under exceptional circumstances a maximum dose of 35 mg/kg b.w./day might be justified under close haematological monitoring.

In the event a patient does still not respond when treated with the maximum dose of hydroxycarbamide (35 mg/kg b.w./day) over three to six months, permanent discontinuation of Litalir should be considered.

If blood counts are within the toxic range Litalir should be temporarily discontinued until blood counts recover. Haematologic recovery usually occurs within two weeks. Treatment may then be reinstituted at a reduced dose. The dose of Litalir may then be increased again under close haematological monitoring. A dose producing haematological toxicity should not be tried more than two times.

The toxic range may be characterised by the following results of blood tests:

Long-term data on the continued use of hydroxycarbamide in patients with Sickle Cell Syndrome are available in children and adolescents, with a follow-up of 12 years in children and adolescents and over 13 years in adults. It is currently unknown how long patients should be treated with Litalir. The duration of treatment is the responsibility of the treating physician and should be based on the clinical and haematological status of the individual patient.

Special populations

Children less than 2 years of age

Because of the rarity of long term data on treatment with hydroxycarbamide in children less than 2 years of age, dose regimens have not been established and thus, in this population, the treatment with hydroxycarbamide is not recommended.

Renal impairment

As renal excretion is a main pathway of elimination, dose reduction of Litalir should be considered in patients with renal impairment. In patients with a creatinine clearance ≤ 60 ml/min the initial Litalir dose should be decreased by 50%. Close monitoring of blood parameters is advised in these patients. Litalir must not be administered to patients with severe renal impairment (creatinine clearance < 30 ml/min).

Hepatic impairment

There are no data that support specific dose adjustments in patients with hepatic impairment. Close monitoring of blood parameters is advised in these patients. Due to safety considerations, Litalir is contraindicated in patients with severe hepatic impairment.

Method of administration

Conforming to the individual dose, the tablet or the half or quarter of the tablet should be taken once daily, preferably in the morning before breakfast and, where necessary, with a glass of water or a very small amount of food.

For patients who are not able to swallow the tablets, these can be disintegrated immediately before use in a small quantity of water in a teaspoon. Adding a drop of syrup or mixing with food can mask a possible bitter taste.

Marked leucopenia (<2.5wbcx10⁹/L), thrombocytopenia (< 100x10⁹/L), or severe anaemia.

Hypersensitivity to the active substance or to any of the excipients.

Severe hepatic impairment (Child-Pugh classification C).

Severe renal impairment (creatinine clearance < 30 ml/min).

Breast-feeding.

The complete status of the blood, including bone marrow examination, if indicated, as well as kidney function and liver function should be determined prior to, and repeatedly during, treatment. If bone marrow function is depressed, treatment with Litalir should not be initiated. The determination of haemoglobin level, total leukocyte counts, and platelet counts should be performed at least once a week throughout the course of hydroxycarbamide therapy. If WBC falls below 2.5x10⁹/L or platelet count to <100x10⁹/L, therapy should be interrupted. Counts should be rechecked after 3 days and treatment resumed when they rise significantly towards normal.

Litalir may produce bone marrow suppression; leukopenia is generally its first and most common manifestation. Thrombocytopenia and anaemia occur less often and are seldom seen without a preceding leukopenia. Bone marrow depression is more likely in patients who have previously received radiotherapy or cytotoxic cancer chemotherapeutic agents; Litalir should be used cautiously in such patients. The recovery from myelosuppression is rapid when Litalir therapy is interrupted.

Severe anaemia must be corrected with whole blood replacement before initiating therapy with hydroxycarbamide. If, during treatment, anaemia occurs, correct without interrupting Litalir therapy. Erythrocytic abnormalities; megaloblastic erythropoeisis, which is self-limiting, is often seen early in the course of hydroxycarbamide therapy. The morphologic change resembles pernicious anaemia, but is not related to vitamin B₁₂ or folic acid deficiency. The macrocytosis may mask the incidental development of folic acid deficiency; regular determinations of serum folic acid are recommended. Hydroxycarbamide may also delay plasma iron clearance and reduce the rate of iron utilisation by erythrocytes but it does not appear to alter the red blood cell survival time.

Patients who have received irradiation therapy in the past may have an exacerbation of postirradiation erythema when Litalir is given.

Hydroxycarbamide should be used with caution in patients with marked renal dysfunction.

Hydroxycarbamide is not licensed for use in combination with antiretroviral agents for HIV disease and it may cause treatment failure and toxicities (in some cases fatal) in HIV patients.

In patients receiving long-term therapy with hydroxycarbamide for myeloproliferative disorders, such as polycythemia, secondary leukaemia has been reported. It is unknown whether this leukaemogenic effect is secondary to hydroxycarbamide or associated with the patient's underlying disease. Skin cancer has also been reported in patients receiving long-term hydroxycarbamide. Patients should be advised to protect skin from sun exposure, conduct self-inspection of the skin and be screened for secondary malignancies during routine follow-up visits.

Cutaneous vasculitic toxicities including vasculitic ulcerations and gangrene have occurred in patients with myeloproliferative disorders during therapy with hydroxycarbamide. The risk of vasculitic toxicities is increased in patients who receive prior or concomitant interferon therapy. The digital distribution of these vasculitic ulcerations and progressive clinical behaviour of peripheral vasculitic insufficiency leading to digital infarct or gangrene were distinctly different than the typical skin ulcers generally described with Hydroxycarbamide. Due to potentially severe clinical outcomes for the cutaneous vasculitic ulcers reported in patients with myeloproliferative disease, hydroxycarbamide should be discontinued if cutaneous vasculitic ulcerations develop and alternative cytoreductive agents should be initiated as indicated.

The possibility of an increase in serum uric acid, resulting in the development of gout or, at worst, uric acid nephropathy, should be borne in mind in patients treated with hydroxycarbamide, especially when used with other cytotoxic agents. It is therefore important to monitor uric acid levels regularly and maintain a high fluid intake during treatment.

This product contains lactose, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Vaccinations

Concomitant use of Litalir with a live virus vaccine may potentiate the replication of the vaccine virus and/or may increase some of the adverse reactions of the vaccine virus because normal defence mechanisms may be suppressed by hydroxycarbamide. Vaccination with a live vaccine in a patient taking Litalir may result in severe infection. The patient's antibody response to vaccines may be decreased. The use of live vaccines should be avoided during treatment and for at least six months after treatment has finished and individual specialist advice sought.

Treatment with Litalir requires close clinical monitoring. The haematological status of the patient, as well as renal and hepatic functions should be determined prior to, and repeatedly during treatment. During treatment with Litalir, blood counts must be monitored every two weeks at treatment initiation (i.e. for the first two months) and if the daily dose of hydroxycarbamide is up to 35 mg/kg b.w. Patients who are stable on lower doses should be monitored every 2 months.

Treatment with Litalir should be discontinued if bone marrow function is markedly depressed. Neutropenia is generally the first and most common manifestation of haematological suppression. Thrombocytopenia and anaemia occur less frequently, and are rarely seen without a preceding neutropenia. Recovery from myelosuppression is usually rapid when therapy is discontinued. Litalir therapy can then be re-initiated at a lower dose.

Litalir should be used with caution in patients with mild to moderate renal impairment.

Since there is no available data in patients with mild to moderate liver impairment, Litalir should be used with caution.

In patients with leg ulcers, Litalir should be used with caution. Leg ulcers are a common complication of Sickle Cell Syndrome, but have also been reported in patients treated with hydroxycarbamide. Cutaneous vasculitic toxicities, including vasculitic ulcerations and gangrene, have occurred in patients with myeloproliferative disorders during therapy with hydroxycarbamide. These vasculitic toxicities were reported most often in patients with a history of, or currently receiving, interferon therapy. Due to potentially severe clinical outcomes for the cutaneous vasculitic ulcers reported in patients with myeloproliferative disease, hydroxycarbamide should be discontinued and/or its dose reduced if cutaneous vasculitic ulcerations develop. Rarely, ulcers are caused by leukocytoclastic vasculitis.

Continuous follow-up of the growth of treated children and adolescents is recommended.

Hydroxycarbamide causes macrocytosis, which may mask the incidental development of folic acid and vitamin B₁₂ deficiency. Prophylactic administration of folic acid is recommended.

Hydroxycarbamide is unequivocally genotoxic in a wide range of test systems. Hydroxycarbamide is presumed to be a transspecies carcinogen. In patients receiving long-term hydroxycarbamide for myeloproliferative disorders, secondary leukaemia has been reported. It is unknown whether this leukemogenic effect is secondary to hydroxycarbamide or is associated with the patient's underlying disease. Skin cancer has also been reported in patients receiving long-term hydroxycarbamide.

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.

Hydroxycarbamide may cause drowsiness. Patients receiving it should not drive or operate machinery unless it has been shown not to affect physical or mental ability.

Litalir has minor influence on the ability to drive and use machines. Patients should be advised not to drive or operate machines, if dizziness is experienced while taking Litalir.

Bone-marrow suppression is the major toxic effect of hydroxycarbamide

Cutaneous vasculitic toxicities including vasculitic ulcerations and gangrene have occurred in patients with myeloproliferative disorders during therapy with hydroxycarbamide. The risk of vasculitic toxicities is increased in patients who receive prior or concomitant interferon therapy.

In some patients, hyperpigmentation, atrophy of skin and nails, scaling, violet papules and alopecia have been observed following several years of long-term daily maintenance therapy with hydroxycarbamide.

Cases of fatal and non-fatal pancreatitis and hepatotoxicity and severe peripheral neuropathy have been observed in HIV patients when hydroxycarbamide was administered with antiretroviral agents, in particular didanosine plus stavudine. Patients treated with hydroxycarbamide in combination with didanosine, stavudine and indinavir showed a median decline in CD4 cells of approximately 100/mm³.

Adverse reactions observed with combined Litalir and irradiation therapy were similar to those reported with the use of Litalir alone, primarily bone marrow depression (leukopenia and anaemia) and gastric irritation. Nearly all patients receiving an adequate course of combined Litalir and irradiation therapy will develop leukopenia. Decreased platelet counts (<100,000/mm³) have occurred rarely and usually in the presence of marked leukopenia. Litalir may potentiate some adverse reactions usually seen with irradiation alone, such as gastric distress and mucositis.

The list is presented by system organ class, MedDRA preferred term, and frequency using the following frequency categories: very common (>1/10), common (>1/100, < 1/10), uncommon (>1/1000, <1/100), rare (>1/10000, <1/1000), very rare (< 1/10000), and not known (cannot be estimated from the available data).

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

Summary of the safety profile

Specifically, the safety of hydroxycarbamide had been examined retroactively from cohorts of 123 adults over 13 years and 352 children older than 2 years and adolescents up to 12 years.

The most frequently reported adverse reaction is myelosuppression with neutropenia as the most common manifestation. Bone marrow depression is the dose-limiting toxic effect of hydroxycarbamide. When the maximum tolerated dose is not reached transient myelotoxicity usually occurs in less than 10% of patients, while under the maximum tolerated dose more than 50% can experience reversible bone marrow suppression. These adverse reactions are expected based on the pharmacology of hydroxycarbamide. Gradual dose titration may help to diminish these effects.

The clinical data obtained in patients with Sickle Cell Syndrome have not shown evidence of adverse reactions of hydroxycarbamide on hepatic and renal function.

Tabulated list of adverse reactions

The adverse reactions are listed below by system organ class and absolute frequency. Frequencies are defined as very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1,000 to <1/100), rare (>1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness:

¹ Haematological recovery usually occurs within two weeks of withdrawal of hydroxycarbamide.

² The macrocytosis caused by hydroxycarbamide is not vitamin B₁₂ or folic acid dependent.

³ Mainly due to an infection with Parvovirus or a splenic sequestration.

⁴ Oligospermia and azoospermia are in general reversible, but have to be taken into account when fatherhood is desired. These disorders are also associated with the underlying disease.

⁵ Weight gain may be an effect of improved general conditions.

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:

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: [email protected]

Immediate treatment consists of gastric lavage, followed by supportive therapy for the cardiorespiratory systems if required. In the long term, careful monitoring of the haemopoietic system is essential and, if necessary, blood should be transfused.

Acute mucocutaneous toxicity has been reported in patients receiving hydroxycarbamide at a dosage several times greater than that recommended. Soreness, violet erythema, oedema on palms and foot soles followed by scaling of hands and feet, intense generalised hyperpigmentation of skin, and severe acute stomatitis were observed.

Acute mucocutaneous toxicity has been reported in patients receiving hydroxycarbamide at doses several times above the therapeutic dose. Soreness, violet erythema, oedema on palms and soles followed by scaling of hand and feet, severe generalised hyperpigmentation of the skin and stomatitis have been observed.

In patients with Sickle Cell Syndrome, neutropenia was reported in isolated cases of hydroxycarbamide overdose (1.43 times and 8.57 times of the maximum recommended dose of 35 mg/kg b.w./day). It is recommended that blood counts are monitored for several weeks after overdose since recovery may be delayed.

Treatment of overdose consists of gastric lavage, followed by symptomatic treatment and control of bone marrow function.

Pharmacotherapeutic group: other antineoplastic agents

ATC Code: L01XX05

Hydroxycarbamide is an orally active antineoplastic agent. Although the mechanism of action has not yet been clearly defined, hydroxycarbamide appears to act by interfering with synthesis of DNA.

Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents, ATC code: L01XX05.

Mechanism of action

The specific mechanism of action of hydroxycarbamide is not fully understood. One of the mechanisms by which hydroxycarbamide acts is the elevation of foetal haemoglobin (HbF) concentrations in sickle cell patients. HbF interferes with the polymerisation of HbS and thus impedes the sickling of red blood cell. In all clinical studies, there was a significant increase in HbF from baseline after hydroxycarbamide use.

Recently, hydroxycarbamide has shown to be associated with the generation of nitric oxide suggesting that nitric oxide stimulates cyclic guanosine monophosphatase (cGMP) production, which then activates a protein kinase and increases the production of HbF. Other known pharmacological effects of hydroxycarbamide which may contribute to its beneficial effects in Sickle Cell Syndrome include decrease of neutrophils, increase of the water content of erythrocytes, increase of the deformability of sickled cells, and altered adhesion of red blood cells to the endothelium.

In addition hydroxycarbamide causes an immediate inhibition of DNA synthesis by acting as a ribonucleotide reductase inhibitor, without interfering with the synthesis of ribonucleic acid or protein.

Pharmacodynamic effects

Beside the inconstant correlation between reduction of crisis rate and the increase in HbF, the cytoreductive effect of hydroxycarbamide, particularly the drop of neutrophils, was the factor with the strongest correlation to a reduced crisis rate.

Clinical efficacy and safety

In nearly all clinical studies conducted in Sickle Cell Syndrome, hydroxycarbamide reduced the frequency of vaso-occlusive episodes by 66% to 80%, in children and in adults. The same decrease was observed for the number of hospital admissions and the number of days of hospitalisation in the treated groups. The yearly frequency of acute chest syndrome was also reduced by 25 to 33% under hydroxycarbamide in several studies. Acute chest syndrome is a frequent life-threatening complication of Sickle Cell Syndrome and is characterised by chest pain or fever or dyspnoea with recent infiltrate on chest X-ray.

A sustained clinical benefit was demonstrated in patients remaining on hydroxycarbamide treatment for up to 8 years.

After oral administration hydroxycarbamide is readily absorbed from the gastrointestinal tract. Peak plasma concentrations are reached in 2 hours; by 24 hours the serum concentrations are virtually zero. Approximately 80% of an oral or intravenous dose of 7 to 30 mg/kg may be recovered from the urine within 12 hours. Hydroxycarbamide crosses the blood-brain barrier. Hydroxycarbamide is well distributed throughout the body.

Absorption

After oral administration of 20 mg/kg of hydroxycarbamide, a rapid absorption is observed with peak plasma levels of about 30 mg/L occurring after 0.75 and 1.2 h in children and adult patients with Sickle Cell Syndrome, respectively. The total exposure up to 24 h post-dose is 124 mg*h/L in children and adolescents and 135 mg*h/L in adult patients. The oral bioavailability of hydroxycarbamide is almost complete as assessed in indications other than Sickle Cell Syndrome.

Distribution

Hydroxycarbamide distributes rapidly throughout the human body, enters the cerebrospinal fluid, appears in peritoneal fluid and ascites, and concentrates in leukocytes and erythrocytes. The estimated volume of distribution of hydroxycarbamide approximates total body water. The volume of distribution at steady state adjusted for bioavailability is 0.57 L/kg in patients with Sickle Cell Syndrome (amounting to approximately 72 and 90 L in children and adults, respectively). The extent of protein binding of hydroxycarbamide is unknown.

Biotransformation

The biotransformation pathways as well as the metabolites are not fully characterised. Urea is one metabolite of hydroxycarbamide.

Hydroxycarbamide at 30, 100 and 300 µM is not metabolised in vitro by cytochrome P450s of human liver microsomes. At concentrations ranging from 10 to 300 µM, hydroxycarbamide does not stimulate the in vitro ATPase activity of recombinant human P glycoprotein (PGP), indicating that hydroxycarbamide is not a PGP substrate. Hence, no interaction is to be expected in case of concomitant administration with substances being substrates of cytochromes P450 or P-glycoprotein.

Elimination

In a repeated dose study in adult patients with Sickle Cell Syndrome approximately 60% of the hydroxycarbamide dose was detected in urine at steady state. In adults, the total clearance adjusted for bioavailability was 9.89 L/h (0.16 L/h/kg) thereof 5.64 and 4.25 L/h by renal and non-renal clearance, respectively. The respective value for total clearance in children was 7.25 L/h (0.20 L/h/kg) with 2.91 and 4.34 L/h by renal and non-renal pathways.

In adults with Sickle Cell Syndrome, mean cumulative urinary hydroxycarbamide excretion was 62% of the administered dose at 8 hours, and thus higher than in cancer patients (35-40%). In patients with Sickle Cell Syndrome hydroxycarbamide was eliminated with a half-life of approximately six to seven hours, which is longer than reported in other indications.

Geriatric, gender, race

No information is available regarding pharmacokinetic differences due to age (except paediatric patients), gender or race.

Paediatric population

In paediatric and adult patients with Sickle Cell Syndrome the systemic exposure to hydroxycarbamide at steady state was similar by means of the area under the curve. The maximum plasma levels and the apparent volume of distribution related to body weight were well comparable between age groups. The time to reach maximum plasma concentration and the percentage of the dose excreted in urine were increased in children compared to adults. In paediatric patients, the half-life was slightly longer and the total clearance related to body weight slightly higher than in adult patients.

Renal impairment

As renal excretion is a pathway of elimination, consideration should be given to decreasing the dose of Litalir in patients with renal impairment. In an open single-dose study in adult patients with Sickle Cell Syndrome (Yan JH et al, 2005) the influence of renal function on pharmacokinetics of hydroxycarbamide was assessed. Patients with normal (creatinine clearance CrCl>80 ml/min), mild (CrCl 60-80 ml/min), moderate (CrCl 30 - 60 ml/min), or severe (<30 ml/min) renal impairment received hydroxycarbamide as a single dose of 15 mg/kg b.w. by using 200 mg, 300 mg, or 400 mg capsules. In patients, whose CrCl was below 60 ml/min or patients with end-stage renal disease the mean exposure to hydroxycarbamide was approximately 64% higher than in patients with normal renal function. As evaluated in a further study, in patients with a CrCl<60 ml/min the area under the curve was approximately 51% higher than in patients with a CrCl >60 ml/min, which suggests that a dose reduction of hydroxycarbamide by 50% may be appropriate in patients with a CrCl ≤ 60 ml/min. Haemodialysis reduced the exposure to hydroxycarbamide by 33%.

Close monitoring of blood parameters is advised in these patients.

Hepatic impairment

There are no data that support specific guidance for dose adjustment in patients with hepatic impairment, but, due to safety considerations, Litalir is contraindicated in patients with severe hepatic impairment. Close monitoring of blood parameters is advised in patients with hepatic impairment.

Hydroxycarbamide is unequivocally genotoxic and a presumed transpecies carcinogen which implies a carcinogenic risk to humans.

In preclinical toxicity studies the most common effects noted included bone marrow depression, lymphoid atrophy and degenerative changes in the epithelium of the small and large intestines. Cardiovascular effects and haematological changes were observed in some species. Also, in rats testicular atrophy with decreased spermatogenesis occurred, while in dogs reversible spermatogenic arrest was noted.

Hydroxycarbamide is unequivocally genotoxic in a wide range of test systems.

Conventional long-term studies to evaluate the carcinogenic potential of hydroxycarbamide have not been performed. However, hydroxycarbamide is presumed to be a transspecies carcinogen.

Hydroxycarbamide crosses the placenta barrier and has been demonstrated to be a potent teratogen and embryotoxic in a wide variety of animal models at or below the human therapeutic dose. Teratogenicity was characterised by partially ossified cranial bones, absence of eye sockets, hydrocephaly, bipartite sternebrae, missing lumbar vertebrae. Embryotoxicity was characterized by decreased foetal viability, reduced live litter sizes, and developmental delays.

Hydroxycarbamide administered to male rats at 60 mg/kg b.w./day (about double the recommended usual maximum dose in humans) produced testicular atrophy, decreased spermatogenesis and significantly reduced their ability to impregnate females.

Not applicable

Not applicable.

People who are not taking Litalir should not be exposed to it. To decrease the risk of exposure, wear disposable gloves when handling Litalir. Anyone handling Litalir should wash their hands before and after contact with the capsules. If the powder is spilled, it should be immediately wiped with a damp disposable towel and discarded in a closed container, such as a plastic bag, as should the empty capsules. Litalir should be kept away from children. Pregnant women should not handle Litalir.

To minimise the risk of dermal exposure, always wear impervious gloves when handling capsules containing Litalir. This includes all handling activities in clinical settings, pharmacies, storerooms and home healthcare settings, including during unpacking and inspection, transport within a facility, and dose preparation and administration. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Litalir is a medicinal product that must be handled with care. People who are not taking Litalir and in particular pregnant women should avoid being in contact with hydroxycarbamide.

Anyone handling Litalir should wash their hands before and after contact with the tablets.

Any unused product or waste material should be disposed of in accordance with local requirements.

In case the prescribed dose requires breaking the tablet in halves or quarters, this should be done out of the reach of food. Powder eventually spilled from the broken tablet should be wiped up with a damp disposable towel, which must be discarded.