Hydroxyurea 500mg Capsules Hard
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Hydroxyurea 500 mg capsules, hard
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
One capsule contains 500 mg hydroxycarbamide.
For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Capsule, hard (capsule)
White capsule body with yellow cap
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Hydroxyurea is indicated for the treatment of patients with:
• chronic myeloid leukaemia (CML) in the chronic or accelerated phase of the disease.
• essential thrombocythaemia or polycythaemia vera with a high risk of thromboembolic complications.
4.2 Posology and method of administration
Treatment must only be administered by a doctor experienced in oncology or haematology. The doses are based on the patient’s actual or ideal bodyweight, whichever is the less.
Chronic myeloid leukaemia
For chronic myeloid leukaemia (CML), hydroxy carbamide is normally administered at an initial dose of 40 mg/kg daily, depending on the white blood cell count. The dose is reduced by 50 % (20 mg/kg daily) if the white blood cell count drops below 20 x 109/l. The dose is then adjusted individually in order to maintain a white blood cell count of 5 - 10 x 109/l. The dose of hydroxycarbamide should be reduced if the white blood cell count drops below 5 x 109/l and increased if a white blood cell count of >10 x 109/l is observed.
If the white blood cell count drops below 2.5 x 109/l, or the platelet count drops below 100 x 109/l, treatment should be discontinued until the counts significantly rise towards normal.
An adequate trial period to determine the antineoplastic effect of hydroxyurea is six weeks. The treatment should be discontinued, if there is a significant progress of the disease. If there is a significant clinical response therapy may be continued indefinitely.
Essential Thrombocythaemia
In cases of essential thrombocythaemia, hydroxycarbamide is normally administered at an initial dose of 15 mg/kg/day and the dose is adjusted to maintain a platelet count of below 600 x 109/l, without lowering the white blood cell count below 4 x 109/l.
Polycythaemia vera
In cases of polycythaemia vera, hydroxycarbamide should be administered at an initial dose of 15-20 mg/kg/day. The hydroxy carbamide dose should be individually adjusted to keep the haematocrit value below 45 % and the platelet count below 400 x 10 /l.
For most patients this can be achieved through continuous administration of hydroxy carbamide with an average daily dose of 500 to 1000 mg. If the haematocrit value and the platelet count can be sufficiently controlled, treatment should be continued indefinitly.
Children: Because of the rarity of these conditions in children, dosage regimens have not been established.
Dosages for elderly patients: Elderly patients can be more sensitive to the effects of hydroxycarbamide, and may require a lower dosage regimen.
Dosages in cases of impaired renal and/or hepatic function:
There are no data available. Dose recommendations cannot be given for patients with impaired renal and/or hepatic function (see 4.4).
The capsules must be swallowed whole and must not dissolve in the mouth.
4.3 Contraindications
Hydroxyurea is contraindicated in cases of severe bone marrow depression, leucocytopenia (< 2.5 x 109 leucocytes/l), thrombocytopenia (< 100 x 109 platelets/l) or severe anaemia.
Hydroxyurea is contraindicated for patients who are hypersensitive to hydroxycarbamide or any of the excipients. Treatment should be discontinued if hypersensitivity to hydroxyurea occurs.
Administration of hydroxyurea is contraindicated during lactation (see 4.6). Concomitant use with yellow fever vaccine (see section 4.5).
4.4 Special warnings and precautions for use
Hydroxycarbamide can cause bone marrow depression with leucopenia as the first and most common symptom. Thrombocytopenia and anaemia are less common and rare without prior leucopenia.
A complete blood status test, including determination of the patient’s haemoglobin count, total leucocyte (white blood cell) count and platelet count, should be performed regularly, even after the individual optimum dose has been established. The control interval should be indiviualised, but is normally once a week. If the white blood cell count drops below 2.5 x 109/l, or the platelet count drops below 100 x 109/l, treatment should be discontinued until the counts rise significantly towards normal (see 4.2).
In cases of anaemia before or during ongoing treatment, red blood cells can be transfused if necessary.
Self-limiting megaloblastic erythropoiesis is often observed early on in treatment with hydroxycarbamide. The morphological changes are similar to pernicious anaemia, but are not related to a vitamin Bi2 or folic acid deficiency.
During treatment with hydroxyurea, frequent monitoring of blood counts should be conducted as well as monitoring of hepatic and renal function.
There is limited experience of patients with impaired renal and/or hepatic function. Therefore, special care should be taken in the treatment of these patients, especially at the beginning of therapy.
Patients should be instructed to drink abundantly.
In patients who are receiving long-term treatment with hydroxycarbamide for myeloproliferative disorders, such as polycythaemia vera and thrombocythaemia, secondary leukaemia may develop. At present, the extent to which this is due to the underlying disorder or to treatment with hydroxycarbamide is not known.
It is recommended that patients check for dermatological changes during treatment with hydroxycarbamide, as squamous cell carcinoma has been reported in isolated instances.
Hydroxycarbamide can induce painful leg ulcers, which are usually difficult to treat and so require cessation of therapy. Discontinuation of hydroxycarbamide usually leads to slow resolution of the ulcers over some weeks.
Cutaneous vasculitis 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.
Hydroxycarbamide should be administered with caution to patients who are being or have previously been treated with another antineoplastic drug or radiation therapy, as side effects can occur more frequently and are more serious than those reported for the use of hydroxycarbamide, other antineoplastic drugs or radiation therapy alone. These effects primarily include bone marrow depression, gastric irritation and mucositis.
An exacerbation of erythema caused by previous or simultaneous irradiation may occur.
If hydroxycarbamide is combined with nucleoside reverse transcriptase inhibitors (NRTI), the risk of adverse reactions due to NRTI can be increased (see also 4.5).
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.
Concomitant use with live attenuated vaccines (excepted yellow fever vaccines see Contra indications) (see section 4.5).
Contraceptive measures
Hydroxycarbamide may be genotoxic. Therefore, men under therapy are advised not to father a child and to use safe contraceptive measures during and for at least 1 year after therapy. They should be informed about the possibility of sperm conservation before the start of therapy.
Women of childbearing potential should use an effective contraceptive measure during treatment (See 4.6 Pregnancy and lactation) with hydroxycarb amide.
4.5 Interaction with other medicinal products and other forms of interaction
Hydroxycarbamide should be administered with caution to patients who receive concomitant or have received previous treatment with other antineoplastic drugs or radiation therapy, as side effects can occur more often and be more serious than those reported for the use of hydroxycarbamide, other antineoplastic drugs or radiation therapy alone. These effects primarily include bone marrow depression, gastric irritation and mucositis.
An exacerbation of erythema caused by previous or concomitant radiation therapy may occur.
In vitro studies have demonstrated the ability of hydroxycarbamide to enhance the cytotoxicity in both cytarabine and fluoropyrimidines. It is unclear if this interaction clinically leads to cooperative toxicity or requires dose adjustment.
If hydroxycarbamide is combined with antiretroviral substances (nucleoside analogues) pancreatitis and liver damage, partly with lethal outcome, as well as peripheral neuropathy have been reported. A combination of hydroxyurea with nucleoside analogues is not recommended.
The risk of vasculitic toxicities is increased in patients who receive prior or concomitant interferon therapy. 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.
Concomitant use contraindicated (see section 4.3)
- Yellow fever vaccine: risk of generalised vaccinale disease mortal.
Concomitant use not recommended (see section 4.4)
- Live attenuated vaccines (except yellow fever): risk of systemic, possible fatal disease. This risk is increased in subjects who are already immunosuppressed by their underlying disease.
Use an inactivated vaccine where this exists (poliomyelitis)
Concomitant use to take into consideration
Ciclosporine, Tacrolimus: Excessive immunosuppression with risk of lymphoproliferation.
4.6 Pregnancy and lactation
Fertility
Reversible azoo or oligospermia have been rarely observed in men. Male patients should be informed about the possibility of sperm conservation before the start of therapy.
Hydroxycarbamide may be genotoxic. Therefore, if a patient intends to become pregnant after a therapy with hydroxycarbamide a specialized consultation is recommended. Men under therapy are advised to use safe contraceptive measures during and at least 1 year after therapy.
Pregnancy
Animal experiments with hydroxycarbamide indicated teratogenic effects (see 5.3). In the human, according to a retrospective analysis of a cohort of 123 adult patients treated with hydroxycarbamide, twenty-three pregnancies have been reported from 15 women treated with hydroxycarbamide and partners of 3 men treated with hydroxycarbamide. Most (61 %) had a normal outcome with regard to term and normal birth. In the other cases with known evolution, pregnancy had been interrupted either voluntarily or upon medical advice. Thus the data on a limited number of exposed pregnancies indicate no adverse effects on pregnancy or on the health of the foetus/newborn.
Nevertheless, based on the limited amount of information, hydroxycarbamide should not be used unless clearly necessary during pregnancy. The risk/benefit evaluation should be made on individual basis taking into account the other therapeutic options.
Women of child-bearing potential should take adequate birth-control measures during treatment with hydroxycarbamide.
If pregnancy still occurs during treatment, the possibility of specialized consultation should be used and a careful follow-up with adequate clinical and ultrasonographic examinations should be considered.
Lactation
As hydroxycarbamide is excreted into breast-milk, breast-feeding must be discontinued while taking the drug.
4.7 Effects on ability to drive and use machines
The patient’s ability to react may be impaired during treatment with hydroxyurea. This should be considered when heightened attention is required, e.g. when driving and using machines.
4.8 Undesirable effects
Bone marrow depression is the dose-limiting toxicity of hydroxycarbamide. Gastrointestinal side effects are common, but require rarely a dose reduction or cessation of treatment.
The evaluation of undesirable effects is based on the following information on frequency:
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)
Blood and lymphatic system disorders
Common: Bone marrow depression, leucopenia, megaloblastosis Uncommon: Thrombocytopenia, anaemia
During treatment with hydroxycarbamide, megaloblastosis can occur that does not respond to treatment with folic acid or B12.
The bone-marrow suppression subsides, however, when therapy is discontinued.
In patients receiving long-term treatment with hydroxycarbamide for myeloproliferative disorders, such as polycythaemia vera and
thrombocythaemia, secondary leukaemia may develop. At present, the extent to which this is due to the underlying disorder or to treatment with hydroxycarbamide is not known.
Hydroxycarbamide can reduce plasma clearance and utilisation of iron in red blood cells. However, it does not appear to alter the red blood cell survival time.
Nervous system disorders
Rare: Rare neurological disturbances including headache, dizziness, disorientation, hallucinations, convulsions
High doses may cause moderate drowsiness.
Respiratory, thoracic and mediastinal disorders
Rare: Acute pulmonary reactions consisting of diffuse pulmonary infiltrates, fever and dyspnoea, allergic alveolitis
Gastrointestinal disorders
Common: Diarrhoea, constipation
Uncommon: Nausea, vomiting, anorexia, stomatitis
Severe gastric stress (nausea, vomiting, anorexia) caused by a combination of hydroxycarbamide and radiation therapy can usually be controlled by temporarily interrupting treatment with hydroxycarbamide.
Renal and urinary disorders
Uncommon: Transient impairment of renal tubular function accompanied by elevation in serum uric acid, urea and creatinine Rare: Dysuria
Very rare: Renal impairment
Skin and subcutaneous tissue disorders
Uncommon: Maculopapular rash, facial erythema, acral erythema Rare: Alopecia
Very rare: Dermatomyositis-like skin changes, hyperpigmentation or atrophy of skin and nails, cutaneous ulcers (especially leg ulcers), pruritus, actinic keratosis, skin cancer (squamous cell cancer, basal cell carcinoma), violet papules, desquamation
Hydroxycarbamide may aggravate inflammation of the mucous membranes after exposure to radiation. It can cause a recall of erythema and hyperpigmentation in previously irradiated tissues. Erythema, atrophy of skin and nails, desquamation, violet papules, alopecia, dermatomyositis-like skin changes, actinic keratosis, skin cancer (squamous cell carcinoma, basal cell carcinoma), cutaneous ulcers (especially leg ulcers), pruritus and hyperpigmentation of skin and nails have been observed in isolated cases partly after years of long-term daily maintenance treatment with 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.
Metabolism and nutrition disorders
Rare: Tumour lysis syndrome
General disorders
Uncommon: Drug fever, shivering, malaise Rare: Hypersensitivity reactions
Hepatobiliary disorders
Uncommon: Increase in liver enzymes, bilirubin
4.9 Overdose
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.
Immediate treatment consists of gastric lavage followed by supportive care and monitoring of the haematopoietic system.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Other antineoplastic agents ATC code: L01X X05
The exact mechanism of action for hydroxycarbamide is unknown. The most important effect of hydroxycarbamide appears to be blocking of the ribonucleotide reductase system, which results in the inhibition of DNA synthesis. Cellular resistance is normally caused by increased ribonucleotide reductase levels as a result of gene amplification.
5.2 Pharmacokinetic properties
The pharmacokinetic information is limited. Hydroxycarbamide is well absorbed and oral bioavailability is complete. Following oral administration, peak plasma concentrations are achieved within approx. 0.5 to 2 hours. Hydroxycarbamide is partially eliminated via the kidneys. The contribution of this route of elimination to the total elimination of hydroxycarbamide is unclear since the fractions of the given dose recovered in urine ranged from 9 to 95 %. Metabolism of hydroxycarbamide has not been thoroughly studied in humans.
Hydroxycarbamide crosses the blood-brain barrier.
5.3 Preclinical safety data
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.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Capsule contents:
Citric acid anhydrous
Disodium hydrogen phosphate anhydrous
Magnesium stearate
Capsule shell:
Gelatine
Titanium dioxide (E171),
Ferric oxide, yellow (E172)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
6.4 Special precautions for storage
Do not store above 30 °C.
6.5 Nature and contents of container
PVC/PVDC/aluminium-blister
Packs containing 20, 25, 50, 100 and 120 capsules.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Procedures for proper handling and disposal of anticancer drugs should be considered.
Any unused product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
Hexal AG,
Industriestrasse 25,
83607 Holzkirchen,
Germany.
8 MARKETING AUTHORISATION NUMBER(S)
PL 10880/0128
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
02/09/2009
10 DATE OF REVISION OF THE TEXT
02/09/2009