Source: European Medicines Agency (EU) Revision Year: 2021 Publisher: Nova Laboratories Ireland Limited, 3rd Floor, Ulysses House, Foley Street, Dublin 1, D01 W2T2, Ireland
Pharmacotherapeutic group: Antineoplastic agents, 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 by acting as a ribonucleotide reductase inhibitor, without interfering with the synthesis of ribonucleic acid or protein.
One of the mechanisms by which hydroxycarbamide acts is the elevation of HbF concentrations in Sickle Cell Disease patients. HbF interferes with the polymerisation of HbS (sickle haemoglobin) 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 Disease include decrease of neutrophils, improved deformability of sickled cells, and altered adhesion of red blood cells to the endothelium.
Evidence for the efficacy of hydroxycarbamide in reducing the vaso-occlusive complications of Sickle Cell Disease in patients older than 2 years comes from four randomised controlled trials (Charache et al 1995 [MSH Study]; Jain et al 2012, Ferster et al 1996; Ware et al 2015 [TWiTCH]). Furthermore, findings from these pivotal studies are supported by observational studies including some long-term follow up.
The MSH study was a multicentre, randomised, and double-blind study, which compared hydroxycarbamide with placebo in adults with Sickle Cell Anaemia (HbSS genotype only) with the objective of reducing the frequency of pain crises. A total of 299 participants were randomised; 152 to hydroxycarbamide and 147 to matching placebo. Hydroxycarbamide was started at low dose (15 mg/kg per day) and increased at 12-weekly intervals by 5 mg/kg per day until mild bone marrow depression was achieved, as judged by either neutropenia or thrombocytopenia. Once the blood count had recovered, treatment was restarted at 2.5 mg/kg per day less than the toxic dose. There was a statistically significant difference between the hydroxycarbamide group and placebo group in the mean annual crisis rate (all crises), mean difference -2.80 (95% CI -4.74 to -0.86) (p=0.005), and for crises requiring hospitalisation, mean difference -1.50 (95% CI -2.58 to -0.42) (p=0.007).
The study also showed an increase in median time from the initiation of treatment to first painful crisis (2.76 months in the hydroxycarbamide arm compared with 1.35 months on placebo (p=0.014), second painful crisis (6.58 months in the hydroxycarbamide group compared with 4.13 months on placebo (p<0.0024), and third painful crisis (11.9 months in the hydroxycarbamide group compared with 7.04 months on placebo (p=0.0002).
Also rates of acute chest syndrome were decreased in those taking hydroxycarbamide when compared with those taking placebo; RR 0.44 (95% CI 0.28 to 0.68) (p<0.001). Similar decreases were seen in blood transfusion rates, a surrogate for life-threatening illness. Hydroxycarbamide did not reduce rates of hepatic or splenic sequestration when compared with placebo.
In keeping with the mechanism of action of hydroxycarbamide, the MSH study also showed a statistically significant increase in HbF (mean difference 3.9% (95% CI 2.69 to 5.11 (p<0.0001)) and haemoglobin levels (mean difference 0.6 g/dL (95% CI 0.28 to 0.92, p<0.0014) and a decrease in haemolytic markers in the groups treated with hydroxycarbamide. The MSH study showed increased haematological toxicity resulting in a dose reduction in the hydroxycarbamide group as compared with placebo, but there were no infections related to neutropenia or bleeding episodes due to thrombocytopenia.
A randomized cross-over study was conducted in 25 children and young adults (age range: 2 to 22 years) with homozygous sickle cell anaemia and severe clinical manifestations (defined as >3 vasoocclusive crises in the year before study entry and/or with previous history of stroke, acute chest syndrome, recurrent crises without a free interval, or splenic sequestration). The primary outcome measure of the study was the number and duration of hospitalisations. Patients were randomly assigned to receive either hydroxycarbamide first for 6 months, followed by placebo for 6 months, or placebo first, followed by hydroxycarbamide for 6 months. Hydroxycarbamide was administered at an initial dose of 20 mg/kg/day. The dose was increased to 25 mg/kg per day if change in HbF was <2% after 2 months. Dose was reduced by 50% for bone marrow toxicity.
The study reported 16 patients out of 22 (73%) did not require any hospitalisation for painful episodes when treated with hydroxycarbamide as compared with only 3 of 22 (14%) when treated with placebo. In addition, there was a reduction in mean hospital stay; 5.3 days in the hydroxycarbamide group and 15.2 days in the placebo group. There were no deaths reported in the study. An increase in HbF and a decrease in absolute neutrophil count were reported in the hydroxycarbamide group. Similarly after six months of treatment, haemoglobin and MCV increased significantly whilst platelet count and white blood cells (WBC) decreased significantly in the hydroxycarbamide group. Results of this study are presented in Tables 2 and 3 below.
Table 2. Number of Hospitalisations and Number of Days in Hospital by Treatment (Both Periods Combined) (Ferster et al, 1996):
| Hydroxycarbamide (n=22) | Placebo (n=22) | |
|---|---|---|
| Number of hospitalisations | ||
| 0 | 16 | 3 |
| 1 | 2 | 13 |
| 2 | 3 | 2 |
| 3 | 0 | 3 |
| 4 | 1 | 0 |
| 5 | 0 | 1 |
| Number of days in hospital | ||
| 0 | 16 | 3 |
| 1–10 | 2 | 13 |
| >10 | 4 | 6 |
| Range | 0-19 | 0-104 |
Table 3. Mean Haematologic Values Before and After 6 Months of Treatment with hydroxycarbamide (Ferster et al, 1996):
| Before Hydroxycarbamide Therapy (mean ± SD) | After Hydroxycarbamide Therapy (mean ± SD) | P value | |
|---|---|---|---|
| Haemoglobin (Hb) (g/dL) | 8.1 ± 0.75 | 8.5 ± 0.83 | Not significant |
| MCV (fL) | 85.2 ± 9.74 | 95.5 ± 11.57 | <0.001 |
| Mean corpuscular haemoglobin concentration (MCHC) (%) | 33.0 ± 2.08 | 32.3 ± 1.12 | Not significant |
| Platelets (×109/L) | 443.2 ± 189.1 | 386.7 ± 144.6 | Not significant |
| WBC (×109/L) | 12.47 ± 4.58 | 8.9 ± 2.51 | <0.001 |
| HbF (%) | 4.65 ± 4.81 | 15.34 ± 11.3 | <0.001 |
| Reticulocytes (%) | 148.6 ± 53.8 | 102.7 ± 48.5 | <0.001 |
In a randomised, double-blind, placebo controlled study conducted in a tertiary hospital in India, 60 children (aged 5-18 years) with three or more blood transfusions or vaso-occlusive crises requiring hospitalisation per year, were randomised to fixed dose 10 mg/mg per day hydroxycarbamide (n=30) or to a matched placebo (n=30). The primary outcome was the decrease in the frequency of vaso-occlusive crises per patient per year. Secondary outcomes included the decrease in frequency of blood transfusions and hospitalizations, and increase in HbF levels.
After 18 months of treatment, there was a significant difference in the number of vaso-occlusive crises between the hydroxycarbamide group and placebo group, mean difference -9.60 (95% CI -10.86 to -8.34) (p<0.00001). There was also significant difference between the hydroxycarbamide group and placebo groups in the number of blood transfusions, mean difference -1.85 (95% CI -2.18 to -1.52) (p<0.00001), in the number of hospitalisations, mean difference -8.89 (95% CI -10.04 to -7.74) (p<0.00001), and the duration of hospitalisation, mean difference -4.00 days (95% CI -4.87 to -3.13) (p<0.00001). Results are presented in Table 4.
The study also showed a statistically significant increase in HbF and Hb levels and a decrease in haemolytic markers in the groups treated with hydroxycarbamide.
Table 4. Comparison of the Number of Clinical Events before and after Intervention in the Hydroxycarbamide and Placebo Groups:
| Hydroxycarbamide | Placebo | |||||
|---|---|---|---|---|---|---|
| Number of events / patient / year | Before | After 18 months | Before | After 18 months | P value1 | P value2 |
| Vaso-occlusive crises | 12.13 ± 8.56 | 0.6 ± 1.37 | 11.46 ± 3.01 | 10.2 ± 3.24 | 0.10 | <0.001 |
| Blood transfusions | 2.43 ± 0.69 | 0.13 ± 0.43 | 2.13 ± 0.98 | 1.98 ± 0.82 | 0.25 | <0.001 |
| Hospitalisations | 10.13 ± 6.56 | 0.70 ± 1.28 | 9.56 ± 2.91 | 9.59 ± 2.94 | <0.001 | |
1 P value is for comparison between hydroxycarbamide and placebo groups at baseline
2 P value is for comparison between hydroxycarbamide and placebo groups at 18 months
Transcranial Doppler (TCD) with Transfusions Changing to Hydroxycarbamide (TWiTCH) was an NHLBI-funded Phase III multicenter, randomized clinical trial comparing 24 months of standard treatment (monthly blood transfusions) to alternative treatment (hydroxycarbamide) in 121 children aged 4-16 years with Sickle Cell Disease and abnormal TCD velocities (≥ 200 cm/s) who had received at least 12 months of chronic transfusions and did not have severe vasculopathy, documented clinical stroke, or transient ischaemic attack.. The primary objective of this study was to examine if hydroxycarbamide could maintain TCD velocities after an initial period of transfusions as effectively as chronic blood transfusions.
Subjects assigned to standard treatment (n=61) continued to receive monthly blood transfusions to maintain 30% HbS or lower, while those assigned to the alternative treatment (n=60), after having received blood transfusions for a mean duration of 4.5 years (±2.8), started oral hydroxycarbamide at 20 mg/kg/day, which was escalated to each participant’s maximum tolerated dose. This study used a non-inferiority trial design with a primary endpoint of TCD velocity at 24 months, controlling for baseline (enrollment) values. The non-inferiority margin was 15 cm/s. At the first scheduled interim analysis, non-inferiority was shown and the sponsor terminated the study. Final model-based TCD velocities were 143 cm/s (95% CI 140-146) in children who received standard transfusions and 138 cm/s (95% CI 135-142) in those who received hydroxycarbamide, with a difference of 4.54 cm/s (95% CI 0.10-8.98). Non-inferiority (p=8.82×10-16) and post-hoc superiority (p=0.023) were met. There was no difference in life-threatening neurological events between the treatment groups. Iron overload improved more in the hydroxycarbamide than the transfusion arm, with a greater average change in serum ferritin (–1805 versus –38 ng/mL; p<0.0001) and liver iron concentration (average = –1.9 mg/g versus +2.4 mg/g dry weight liver; p=0.0011).
After oral administration hydroxycarbamide is readily absorbed from the gastrointestinal tract. Peak plasma concentrations are reached within 2 hours and by 24 hours the serum concentrations are virtually zero. Bioavailability is complete or nearly complete in cancer patients.
In a comparative bioavailability study in healthy adult volunteers (n=28), 500 mg of hydroxycarbamide oral solution was demonstrated to be bioequivalent to the reference 500 mg capsule, with respect to both the peak concentration and area under the curve. There was a statistically significant reduction in time to peak concentration with hydroxycarbamide oral solution compared to the reference 500 mg capsule (0.5 versus 0.75 hours, p=0.0467), indicating a faster rate of absorption.
In a study of children with Sickle Cell Disease, liquid and capsule formulations resulted in similar area under the curve, peak concentrations, and half-life. The largest difference in the pharmacokinetic profile was a trend towards a shorter time to peak concentration following ingestion of the liquid compared with the capsule, but that difference did not reach statistical significance (0.74 versus 0.97 hours, p=0.14).
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 following oral dosing of hydroxycarbamide is approximately equal to total body water: adult values of 0.48 – 0.90 L/kg have been reported, whilst in children a population estimate of 0.7 L/kg has been reported. The extent of protein binding of hydroxycarbamide is unknown.
It appears that nitroxyl, the corresponding carboxylic acid and nitric oxide are metabolites: Urea has also been shown to be a 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 (P-gp), indicating that hydroxycarbamide is not a P-gp substrate. Hence, no interaction is to be expected in case of concomitant administration with substances being substrates of cytochromes P450 or P-gp.
The total body clearance of hydroxycarbamide in adult patients with Sickle Cell Disease is 0.17 L/h/kg.
The respective value in children was similar, 0.22 L/h/kg.
A significant fraction of hydroxycarbamide is eliminated by nonrenal (mainly hepatic) mechanisms. In adults, the urinary recovery of unchanged drug is reported to be approximately 37% of the oral dose when renal function is normal. In children, the fraction of hydroxycarbamide excreted unchanged into the urine comprised about 50%.
In adult cancer patients, hydroxycarbamide was eliminated with a half-life of approximately 2-3 hours.
In a single dose study in children with Sickle Cell Disease, the mean half-life was reported to be 1.7 hours.
Although there is no evidence of an age effect on the pharmacokinetic-pharmacodynamic relationship, elderly patients may be more sensitive to the effects of hydroxycarbamide and therefore consideration should be given to starting with a lower initial dose and more cautious dose escalation. Close monitoring of blood parameters is advised (see section 4.2).
As renal excretion is a pathway of elimination, consideration should be given to decreasing the dose of hydroxycarbamide in patients with renal impairment. In an open single-dose study in adult patients with Sickle Cell Disease the influence of renal function on pharmacokinetics of hydroxycarbamide was assessed. Patients with normal (CrCl>90 ml/min), mild (CrCl 60-89 ml/min), moderate (CrCl 30-59 ml/min), severe (CrCl 15-29 ml/min) renal impairment, and End Stage Renal Disease (CrCL <15 ml/min) received hydroxycarbamide as a single dose of 15 mg/kg body weight. 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.
It is recommended that the starting dose is reduced by 50% in patients with CrCl <60 ml/min (see sections 4.2 and 4.3).
Close monitoring of blood parameters is advised in these patients.
There are no data that support specific guidance for dose adjustment in patients with hepatic impairment, but, due to safety considerations, hydroxycarbamide is contraindicated in patients with severe hepatic impairment (see section 4.3). Close monitoring of blood parameters is advised in patients with hepatic impairment.
Preclinical toxicity studies have demonstrated the most commonly observed effects include bone marrow depression in rats, dogs and monkeys. In some species cardiovascular and haematological effects have also been observed. Observations in monkeys have also shown lymphoid atrophy and degeneration of the small and large intestine. Toxicology studies have also demonstrated testicular atrophy with decreased spermatogenesis and sperm count in rats and decreased testis weight and reduced sperm counts in mice as well. While in dogs reversible spermatogenic arrest was noted.
Hydroxycarbamide is unequivocally genotoxic and although conventional long-term carcinogenicity studies have not been conducted, hydroxycarbamide is presumed to be a transspecies carcinogen which implies a carcinogenic risk to humans.
Hydroxycarbamide crosses the placental barrier, demonstrated by dams exposed to hydroxycarbamide during gestation. Embryotoxicity manifesting as decreased foetal viability, reduced live litter sizes, and developmental delays has been reported in species including mice, hamsters, cats, dogs, and monkeys at doses comparable to human doses. Teratogenic effects manifested as partially ossified cranial bones, absence of eye sockets, hydrocephaly, bipartite sternebrae, and missing lumbar vertebrae.
Hydroxycarbamide administered to male rats at 60 mg/kg body weight/day (about double the recommended usual maximum dose in humans) produced testicular atrophy, decreased spermatogenesis and significantly reduced their ability to impregnate females.
Overall, exposure to hydroxycarbamide produces abnormalities in several experimental animal species and affects the reproductive capacity of male and female animals.
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