DROXIGET 25OMG

Indications

• Chronic myeloid leukaemia (specialist use only)
• Essential thrombocythaemia (specialist use only)
• Sickle-cell disease (prevention of recurrent vaso-occlusive crises)

Dosage

Adults: Chronic myeloid leukaemia: Initially 40 mg/kg daily, then reduced to 20 mg/kg daily. Essential thrombocyth

Mechanism of action

Hydroxycarbamide exerts its effects by inhibiting ribonucleotide reductase, which is crucial for DNA synthesis. This inhibition leads to a decrease in the conversion of ribonucleotides to deoxyribonucleotides, effectively halting DNA replication in rapidly dividing cells. Additionally, hydroxycarbamide may enhance the effects of radiation therapy on certain cancers by holding cells in the G1 phase of the cell cycle, making them more susceptible to radiation damage.

Pharmacodynamics

Hydroxycarbamide has a complex pharmacodynamic profile. It is known to increase fetal hemoglobin (HbF) levels in patients with sickle-cell disease, which can reduce the frequency of vaso-occlusive crises. The exact correlation between hydroxycarbamide concentrations and clinical outcomes, such as crisis rates and HbF increases, is not fully understood. Its effects are particularly pronounced in cells with high replication rates.

Pharmacokinetics

Hydroxycarbamide is well absorbed following oral administration, with peak plasma concentrations reached within 1 to 4 hours. It has a half-life ranging from 3 to 12 hours. The drug is primarily metabolized in the liver and excreted renally. Due to its renal clearance, dosage adjustments may be necessary in patients with impaired renal function to avoid increased toxicity.

Adverse effects

• Alopecia
• Anaemia
• Appetite decrease
• Asthenia
• Bone marrow disorders
• Chills
• Constipation
• Cutaneous vasculitis
• Dermatomyositis
• Diarrhoea
• Disorientation
• Dizziness
• Drowsiness
• Dyspnoea
• Dysuria
• Fever
• Gastrointestinal discomfort
• Thrombocytopenia
• Tinnitus
• Vertigo
• Vomiting
• Weight decrease
• Hepatotoxicity
• Interstitial lung disease
• Pancreatitis
• Proteinuria
• Renal failure
• Sepsis
• Disseminated intravascular coagulation
• QT interval prolongation
• Severe cutaneous adverse reactions

Interactions

• Live vaccines: Increased risk of generalized infection, possibly life-threatening

Precautions

• Use with caution in patients with hepatic impairment (increased risk of neutropenia)
• Use with caution in renal impairment (consider dose reduction if creatinine clearance <50 mL/min)
• Monitor for signs of peripheral neuropathy
• Review treatment if cutaneous vasculitic ulcerations develop
• ECG monitoring recommended in patients prescribed concomitant drugs that prolong the QT-interval

Pregnancy

Avoid unless essential as it is teratogenic in animal studies.

Breast-feeding

Discontinue breastfeeding.

Storage

Store in a cool, dry place, protected from light.

Formulations

• Hydroxycarbamide 100 mg tablets
• Hydroxycarbamide 500 mg tablets
• Hydroxycarbamide 1000 mg tablets

Mechanism of action

The precise mechanism by which hydroxyurea produces its antineoplastic effects cannot, at present, be described. However, the reports of various studies in rat and human tissue cultures lend support to the hypothesis that hydroxyurea causes an immediate inhibition of DNA synthesis, by acting as a ribonucleotide reductase inhibitor, without interfering with the synthesis of ribonucleic acid or of protein. Hydroxyurea probably acts by decreasing the rate of conversion of ribonucleotides and deoxyribonucleotides. This effect is particularly apparent in cells with a high rate of proliferation. Particularly, hydroxyurea reduces the tyrosyl free radical at the active site of the M2 via a one-electron transfer reaction through the –NH2-OH moiety. Three mechanisms have been postulated for the potentiation of the therapeutic effects of irradiation by hydroxyurea on squamous cell (epidermoid) carcinomas of the head and neck. In vitro studies utilizing Chinese hamster cells suggest that hydroxyurea is lethal to normally radioresistant S-stage cells and holds other cells of the cell cycle in the G1 or pre-DNA synthesis stage where they are most susceptible to the effects of irradiation. The third mechanism of action has been theorized on the basis of in vitro studies of HeLa cells: it appears that hydroxyurea, by inhibition of DNA synthesis, hinders the normal repair process of cells damaged but not killed by irradiation, thereby decreasing their survival rate; there is no alteration of RNA and protein syntheses. Another proposed mechanism of action of hydroxyurea is the elevation of HbF concentrations in Sickle Cell Disease patients. HbF interferes with the polymerization of HbS (sickle haemoglobin) and thus impedes the sickling of red blood cell. Recently, hydroxyurea has shown to be associated with the generation of nitric oxide, suggesting that nitric oxide stimulates cyclic guanosine monophosphates (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 Disease include decrease of neutrophils, improved deformability of sickled cells, and altered adhesion of red blood cells to the endothelium. The exact mechanism of antineoplastic activity of hydroxyurea has not been fully determined. Some studies indicate that hydroxyurea interferes with the synthesis of DNA without interfering with the synthesis of RNA or protein. Although hydroxyurea may have multiple sites of action, it appears likely that the drug inhibits the incorporation of thymidine into DNA; in addition, it may directly damage DNA. Hydroxyurea can destroy the tyrosyl free radical that is formed as the catalytic center of ribonucleoside diphosphate reductase, the enzyme that catalyzes the reductive conversion of ribonucleotides to deoxyribonucleotides; this conversion is a critical and probably rate-limiting step in the synthesis of DNA. The drug is an S-phase inhibitor and may cause cells to arrest at the G1-S border, decrease the rate of cell progression into the S phase, and/or cause cells to accumulate in the S phase as a result of inhibiting DNA synthesis. Animal studies indicate that the cytotoxic effects of hydroxyurea are limited to those tissues with high rates of cellular proliferation and the effects are evident only in those cells that are actively synthesizing DNA. Hydroxyurea, a drug widely used in therapy of several human diseases, inhibits deoxynucleotide synthesis and, consequently, DNA synthesis by blocking the cellular enzyme ribonucleotide reductase. Hydroxyurea inhibits human immunodeficiency virus type 1 (HIV-1) DNA synthesis in activated peripheral blood lymphocytes by decreasing the amount of intracellular deoxynucleotides, thus suggesting that this drug has an antiviral effect. Hydroxyurea has now been shown to block HIV-1 replication in acutely infected primary human lymphocytes (quiescent and a

Pharmacodynamics

The correlation between hydroxyurea concentrations, reduction of crisis rate, and increase in HbF, is not known.