Last updated March 1, 2022, by Marta Figueiredo, PhD
Fact-checked by Joana Carvalho, PhD
Hydroxyurea is an oral therapy initially approved for several types of cancer and later developed and used for sickle cell disease (SCD).
The therapy, marketed as Droxia by Bristol-Myers Squibb, was approved by the U.S. Food and Drug Administration (FDA) in 1998 to help reduce the frequency of vaso-occlusive crises (VOCs) and the need for blood transfusions in adults with SCD.
In June 2007, the European Commission granted approval to hydroxyurea, developed and sold by Addmedica under the brand name Siklos, for the same indication, but covering both adult and pediatric patients, 2 years and older.
Ten years later, in December 2017, the FDA approved Siklos to reduce VOCs and lower the need for blood transfusions in children ages 2 and older with SCD and recurrent, moderate-to-severe VOCs. The therapy’s use was extended to adult patients in February 2022. In the U.S., Siklos is marketed by Medunik USA through an agreement with Addmedica.
How does hydroxyurea work?
People with SCD produce an abnormal form of hemoglobin, the protein inside red blood cells that is responsible for oxygen transport. This faulty protein clumps together into long, rigid rods that deform red blood cells into a sickle or crescent-like shape.
Besides being targeted for destruction, leading to anemia, sickled cells often stick to blood vessel walls, blocking or slowing blood flow and triggering VOCs — when blood flow is blocked to the point that tissues become deprived of oxygen, provoking sudden episodes of pain.
Hydroxyurea is an orally available small molecule that works by increasing the levels of fetal hemoglobin, a form of hemoglobin produced during fetal development that is more effective at transporting oxygen throughout the body than its adult counterpart.
By increasing fetal hemoglobin, the therapy is expected to reduce red blood cell sickling and destruction, and improve oxygen transport throughout the body, thereby lowering the frequency of VOCs and the need for blood transfusions.
In addition, it also reduces the number of neutrophils, a type of immune cell that interacts with sickled red blood cells to clog blood vessels, resulting in VOCs.
Hydroxyurea in clinical trials
Several clinical trials tested hydroxyurea as a treatment for SCD, and ample evidence suggests the therapy benefits people living with the disease.
Specifically, the therapy was shown to consistently increase fetal hemoglobin levels, and reduce the frequency of VOCs and blood transfusions in both children and adults with SCD. It also lowered the number of acute chest syndrome (ACS) episodes and hospitalizations in both age groups, while improving survival. ACS, a leading cause of hospitalization and death in SCD patients, is characterized by chest pain, fever, and difficulty breathing. It results from reduced oxygen levels in the lungs due to the blockage of small blood vessels.
Notably, an Addmedica-sponsored Phase 4 observational trial, called ESCORT-HU (NCT02516579), evaluated the long-term safety and effectiveness of Siklos in 1,906 SCD patients, ages 2 and older, in a real-world setting. More than half of the participants were adults.
Results from the 141 children who had not been treated with hydroxyurea prior to enrollment showed that one year of treatment with Siklos significantly reduced the proportion of patients with at least one VOC, one ACS, one hospitalization due to SCD, or one blood transfusion. In addition, these benefits were associated with an increase in the levels of fetal hemoglobin.
Similar findings were reported for the 370 adults who were treated with Siklos for at least one year, and showed a significant drop in the number of VOCs lasting more than two days, as well as in ACS episodes, hospitalizations, and in the percentage of patients requiring blood transfusions relative to the year before enrollment.
The therapy was generally well-tolerated, with a safety profile consistent with that reported in previous trials, and with no new safety concerns identified.
Siklos is available in the form of scored 100 mg tablets and triple-scored 1,000 mg tablets, designed so they can be cut into smaller pieces and also dissolved in water, making administration easier for patients who have trouble swallowing tablets.
The medication should be given once daily at a recommended initial dose of 15 milligrams per kilogram of body (mg/kg) for adults and 20 mg/kg for children. Dosing may be increased by 5 mg/kg every eight weeks, or as soon as a VOC episode occurs, up to 35 mg/kg or until a maximum tolerated daily dose is reached.
Lower doses are recommended for SCD patients with kidney impairment.
Because it reduces the levels of certain blood cells, Siklos carries the risk of making patients more prone to infections and certain cancers. As such, the therapy’s label contains a boxed warning highlighting the risk of severely low blood cell counts and cancer. Such a warning is the most stringent imposed by the FDA.
Blood cell counts should be monitored before treatment and every other week thereafter. If blood counts are too low, Siklos should be discontinued until blood cell recovery is achieved and subsequently resumed at a lower dose.
Patients also are advised to protect their skin from the sun using sunblock, hats, and sun-protective clothing and to be regularly monitored for cancer.
It also is contraindicated, meaning it should not be prescribed, for patients with a history of allergic reactions to its active substance, hydroxyurea, or any of its ingredients.
The therapy’s most common side effects include infections and low white blood cell counts in children, and infections, headache, and dry skin in adults.
Siklos is associated with fertility problems in males, and females who become pregnant while taking it should consult their physician, as the therapy can cause fetal harm. Effective contraception during Siklos treatment and for at least six months after the last dose is recommended.
Complications of cutaneous vasculitis, or inflamed blood vessels in the skin, including leg ulcers, have also been reported in certain blood cancer patients given hydroxyurea. The label also includes warnings regarding the simultaneous use of Siklos and certain anti-viral medications and live virus vaccines.
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