Hydroxycarbamide medac 500 mg capsule, hard

One capsule contains 500 mg hydroxycarbamide.

For excipients, see 6.1.

Capsule, hard

White capsules.

Treatment of patients with chronic myeloid leukaemia (CML) in the chronic or accelerated phase of the disease.

Treatment of patients with essential thrombocythemia or polycythemia vera with a high risk for thrombo-embolic complications.

Therapy should only be conducted by a physician experienced in oncology or haematology. Doses are based on real or ideal bodyweight of the patient, whichever is the less.

In CML hydroxycarbamide is usually given at an initial dose of 40 mg/kg daily dependent on the white cell count. The dose is reduced by 50% (20 mg/kg daily) when the white cell count is dropped below 20 x 10⁹/l. The dose is then adjusted individually to keep the white cell count at 5-10 x 10⁹/l. Hydroxycarbamide dose should be reduced if white cell counts fall below 5 x 10⁹/l and increased if white cell counts >10 x 10⁹/l are observed.

If white cell count falls below 2.5 x 10⁹/l, or the platelet count below 100 x 10⁹/l, therapy should be interrupted until the counts rise significantly towards normal.

An adequate trial period for determining the antineoplastic effect of Hydroxycarbamide medac is six weeks. Therapy should be interrupted indefinitely, if there is a significant progress of the disease. If there is a significant clinical response therapy may be continued indefinitely.

In essential thrombocythemia hydroxycarbamide is usually given at starting doses of 15 mg/kg/day with dose adjustment to maintain a platelet count below 600 x 10⁹ /l without lowering the white blood cell count below 4 x 10⁹/l.

In polycythemia vera hydroxycarbamide should be started at a dosage of 15-20 mg/kg/day. Hydroxycarbamide dose should be adjusted individually to maintain the hematocrit below 45% and platelet count below 400 x 10⁹/l. In most patients this can be achieved with hydroxycarbamide given continuously at average daily doses of 500 to 1000 mg.

If hematocrit and platelet count can be sufficiently controlled therapy should be continued indefinitely.

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.

Dosage in conditions of impaired renal and/or liver function:

There are no data available. Dose recommendation cannot be given to patients with impaired renal and/or liver function (see 4.4 Special warnings and precautions for use).

The capsules should be swallowed whole and not allowed to disintegrate within the mouth.

Hydroxycarbamide medac is contraindicated in severe bone marrow depression, leucocytopenia (<2,5 x 10⁹ leukocytes/l), thrombocytopenia (< 100 x 10⁹ platelets/l) or severe anaemia.

Hydroxycarbamide medac is contraindicated in patients with hypersensitivity to hydroxycarbamide or to any of the excipients. Therapy should be discontinued if hypersensitivity to Hydroxycarbamide medac occurs.

Hydroxycarbamide can cause bone marrow depression with leucopenia as first and most often occurring sign of this depression. Thrombocytopenia and anaemia occur less frequently and are rare without preceding leucopenia. Complete blood counts including determination of haemoglobin level, total leukocyte differentiation counts, and platelet counts should be performed regularly also after the individual optimal dose has been established. The control interval should be individualised, but is normally once a week. If white cell count falls below 2.5 x 10⁹/l, or the platelet count below 100 x 10⁹/l, therapy should be interrupted until the counts rise significantly towards normal. (See 4.2 Posology and method of administration).

In case of anaemia before or during ongoing treatment red blood cells may be replaced when needed. Megaloblastic erythropoesis, 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.

During therapy with Hydroxycarbamide medac frequent monitoring of blood counts should be conducted as well as monitoring of hepatic and renal function. In patients with impaired renal and/or liver function the experience is limited. 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 receiving long-term treatment with hydroxycarbamide for myeloproliferative disorders, such as polycythemia vera and thrombocythemia, secondary leukemia may develop. To what extent this relates to the underlying disease or to treatment with hydroxycarbamide is presently unknown.

The monitoring of skin changes is advisable during hydroxycarbamide treatment as in single cases squamous cell carcinoma of the skin was reported.

Hydroxycarbamide can induce painful leg ulcers which are usually difficult to treat and require cessation of therapy. Discontinuation of hydroxycarbamide usually leads to slow resolution of the ulcers over some weeks.

Hydroxycarbamide should be administered with caution to patients who receive concomitant or have received previous therapy with other antineoplastic drugs or irradiation, since adverse reactions can occur more frequently and more severe than those reported with the use of hydroxycarbamide, other antineoplastic drugs or irradiation alone. These effects primarily include bone marrow depression, gastric irritation, and mucositis.

An exacerbation of erythema caused by previous or simultaneous irradiation may occur.

The combination of hydroxycarbamide and nucleoside reverse transcriptase inhibitors (NRTI) may enhance the risk of side effects of NRTI, see also section 4.5, Interaction with other medicinal products and other forms of interaction.

Hydroxycarbamide may be genotoxic. Therefore, men under therapy are advised to use safe contraceptive measures during and for at least 3 months after therapy. They should be informed about the possibility of sperm conservation before the start of therapy.

Hydroxycarbamide medac should not be administered to patients who are pregnant or to mothers who are breast feeding, unless the benefits outweigh the possible hazards (see 4.6 Pregnancy and lactation).

Hydroxycarbamide medac should not be administered to patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.

Hydroxycarbamide should be administered with caution to patients who receive concomitant or have received previous therapy with other antineoplastic drugs or irradiation, since adverse reactions can occur more frequently and more severe than those reported with the use of hydroxycarbamide, other antineoplastic drugs or irradiation alone. These effects primarily include bone marrow depression, gastric irritation, and mucositis.

An exacerbation of erythema caused by previous or simultaneous irradiation may occur.

In-vitro studies have demonstrated hydroxycarbamide´s ability to enhance the cytotoxicity of both ara-C and the fluoropyrimidines. Whether this interaction leads clinically to a co-operative toxicity or to the necessity of adjusting the doses is unclear.

Hydroxycarbamide may enhance the antiretroviral activity of nucleoside reverse transcriptase inhibitors like didanosine and stavudine. Hydroxycarbamide inhibits HIV DNA synthesis and HIV replication by decreasing the amount of intracellular deoxynucleotides. Hydroxycarbamide may also enhance the potential side effects of nucleoside reverse transcriptase inhibitors such as pancreatitis and peripheral neuropathy.

Pregnancy

Hydroxycarbamide may be a potent mutagenic agent. Animal experiments with hydroxycarbamide indicated an increased incidence of congenital defects (see 5.3 Preclinical safety data). Hydroxycarbamide should not be administered to patients who are pregnant unless the benefits outweigh the possible hazards. Women of child-bearing potential have to take contraceptive precautions before the start of and during treatment with hydroxycarbamide.

If pregnancy still occurs during treatment the possibility of genetic consultation should be used. Hydroxycarbamide crosses the placenta.

Lactation:

As hydroxycarbamide passes into breast-milk, breast-feeding has to be interrupted before the start of treatment.

Fertility:

Hydroxycarbamide may be genotoxic, therefore, if a patient intends to become pregnant after a therapy with hydroxycarbamide a genetic consultation is recommended.

Men under therapy are advised to use safe contraceptive measures during and for at least 3 months after therapy. They should be informed about the possibility of sperm conservation before the start of therapy.

Ability to react may be impaired during treatment with Hydroxycarbamide medac. This should be borne in mind when heightened attention is required, e.g for driving and using machines.

Bone marrow depression is the dose limiting toxicity. Gastrointestinal side effects are common but require rarely dose reduction or cessation of treatment.

Common ( >1/100,<1/10)

Blood: Bone marrow depression, leucopenia, megaloblastosis.

Gastrointestinal: Diarrhoea, constipation.

Uncommon (>1/1,000, <1/100)

Blood: Thrombocytopenia, anaemia

Body as a whole: Nausea, vomiting, anorexia, stomatitis. Drug fever, chills, malaise.

Skin: Maculopapular rash, facial erythema, acral erythema.

Liver: Elevation of liver enzymes, bilirubin.

Urogenital: Transient impairment of the renal tubular function accompanied by elevation in serum uric acid, urea and creatinine.

Rare: (>1/10,000, <1/1,000)

Body as a whole: Hypersensitive reactions

Skin: Alopecia.

Respiratory: Acute pulmonary reactions consisting of diffuse pulmonary infiltrates, fever and dyspnoe, allergic alveolitits.

Urogenital: Dysuria.

Neurological: Rare neurological disturbances including headache, dizziness, disorientation, hallucinations.

Very rare: ( < 1/10,000)

Skin: 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.

Urogenital: renal impairment.

In the therapy with hydroxycarbamide megaloblastosis may occur which does not respond to treatment with folic acid or B₁₂.

The bone-marrow suppression subsides, however, when therapy is discontinued.

Severe gastric distress (nausea, emesis, anorexia) resulting from combined hydroxycarbamide and irradiation therapy may usually be controlled by temporarily discontinuing hydroxycarbamide administration.

Hydroxycarbamide may aggravate the inflammation of mucous membranes secondary to irradiation. 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 cancer, 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 therapy with hydroxycarbamide.

High doses may cause moderate drowsiness.

Rare neurological disturbances including headache, dizziness, disorientation, hallucinations, and convulsions have been reported.

In rare cases dysuria or renal impairment, hypersensitive reactions.

In individual cases allergic alveolitis.

In patients receiving long-term treatment with hydroxycarbamide for myeloproliferative disorders, such as polycythemia vera and thrombocythemia, secondary leukemia may develop. To what extent this relates to the underlying disease or to treatment with hydroxycarbamide is presently unknown.

Hydroxycarbamide can reduce plasma iron clearance and iron utilisation by erythrocytes. However, it does not appear to alter the red blood cell survival time.

Acute mucocutaneous symptoms have been observed in patients receiving hydroxycarbamide dosages several times the recommended dose. Soreness, violet erythema, oedema on palms and soles followed by scaling of hands and feet, severe generalised hyperpigmentation of the skin, and stomatitis have also been observed.

Immediate treatment consists of gastric lavage, followed by supportive care and monitoring of the haematopoetic system.

Pharmacotherapeutic group: Other antineoplastic agents

ATC-code: L01XX05

The exact mechanism of action of hydroxycarbamide is unknown. The most important effect of hydroxycarbamide appears to be blocking of the ribonucleotide reductase system resulting in inhibition of DNA synthesis. Cellular resistance is usually caused by increased ribonucleotide reductase levels as a result of gene amplification.

The pharmacokinetic information is limited. Hydroxycarbamide is well absorbed and the oral bioavailability is complete. After oral administration maximum plasma concentrations are reached within 0.5 to 2 hours. Hydroxycarbamide is eliminated partly via renal excretion. 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.

Repeated dose toxicity

Bone marrow damages, lymphoid atrophy in the spleen and degenerative changes in the epithelium of the small and large intestines are toxic effects which have been observed in animal studies. The potential risk for similar effects in humans must be considered.

Reproduction toxicity

Teratogenicity of hydroxycarbamide was demonstrated in many species, including rat, mouse and rabbit. The large variety of teratogenic effects were ranging from death of a large proportion of embryos to limb deformities, neural defects and even behavioural effects.

Additionally, hydroxycarbamide affected spermatogenesis and sperm motility of mice after repeated administration.

Genotoxicity

Hydroxycarbamide showed genotoxic properties in conventional testing systems.

Carcinogenicity

The preclinical information on the carcinogenic potential of hydroxycarbamide is meagre. A 12 months study on mice where the occurrence of lung tumours was studied did not show any carcinogenic potential in hydroxycarbamide.

Capsule content:

calcium citrate, disodium citrate, magnesium stearate, lactose monohydrate

Capsule shell:

titanium dioxide (E 171), gelatin

Not applicable.

4 years

No special precautions for storage.

The capsules are packed in blisters made of Al/PVDC and PVC/PVDC opacified with titanium dioxide.

Available pack sizes: 50 and 100 capsules.

Procedures for proper handling and disposal of anticancer drugs should be considered.

medac

Gesellschaft für klinische Spezialpräparate mbH

Fehlandtstraße 3

20354 Hamburg

Germany

PL 11587/0019

23 May 2001/9 January 2004

24 March 2005