Hydroxyurea

Hydroxyurea is an antineoplastic agent belonging to the pharmacological class of anti-metabolites.

The FDA has approved Hydroxyurea for treating resistant chronic myeloid leukaemia, melanoma, and sickle cell anaemia.

Hydroxyurea has more than 80% bioavailability when taken orally and quickly enters the peritoneal and cerebrospinal fluids. Intestinal bacteria break down a small amount, and the liver metabolizes 50–60%. There is excretion; 25–80% of it is eliminated in urine, of which 30% is urea and 50% is unchanged.

Hydroxyurea's most common side effects are haematological disorders, gastrointestinal symptoms, eating disorders, and weight loss.

Hydroxyurea is available as capsules and tablets.

The molecule is available in India, the United States, Canada, the United Kingdom, Australia, Germany, France, Japan, China, Brazil and South Africa.

Hydroxyurea is an antineoplastic agent belonging to the pharmacological class of anti-metabolites.

A hydroxylated form of urea called Hydroxyurea has been shown to disrupt DNA synthesis through several possible pathways. Still, it has little to no effect on the synthesis of RNA or proteins. Hydroxyurea prevents the conversion of DNA bases by inhibiting ribonucleotide reductase and delaying the conversion of ribonucleotides to deoxyribonucleotides.

In addition to potentially causing direct harm to DNA, Hydroxyurea also prevents thymidine from entering DNA. Specific to the S phase of the cell cycle, Hydroxyurea can retain cells in the G1 phase. Hydroxyurea promotes the synthesis of fetal haemoglobin and has antiviral properties.

Hydroxyurea reaches its peak plasma concentration within 1-4 hours.

Hydroxyurea is available as capsules and tablets.

Capsules/Tablets: To be swallowed whole with water/liquid. Do not chew, crush or break it.

As the physician recommends, take the medication once daily with or without food. Dosage and frequency depend on the specific medical condition.

• Chronic Myelocytic Leukemia, Resistant
• Solid Tumors
• Head & Neck Tumors
• Sickle Cell Disease

• Chronic Myelogenous Leukemia: Cancer of the bone marrow and blood cells is known as chronic myelogenous leukaemia (CML) or chronic myeloid leukaemia. Hydroxyurea suppresses the growth of rapidly dividing cancer cells by inhibiting DNA synthesis in rapidly dividing cancer cells. It helps manage elevated white blood cell counts, reducing symptoms and complications associated with leukocytosis.
• Head and neck cancer: Cancer of the mouth, nose, sinuses, or throat is called head and neck cancer. To make cancer cells more susceptible to the effects of radiation, Hydroxyurea is often used in conjunction with other treatments, such as chemotherapy and radiation therapy for head and neck cancer. Hydroxyurea increases the effectiveness of radiation treatment by preventing DNA synthesis, which increases the death of cancer cells.
• Sickle cell anaemia: A condition known as sickle cell anaemia causes red blood cells (RBCs) to lose their flexibility and round shape, eventually taking on a sickle shape and finally going extinct. Your red blood cells get more significant when you take Hydroxyurea. It prevents them from taking on the shape of a sickle and makes them rounder and more flexible. The drug increases fetal haemoglobin (HbF), a particular kind of haemoglobin, to achieve this. Since it is present in newborns, haemoglobin F is also known as fetal haemoglobin. This helps in the treatment of the illness and also prevents potentially fatal complications down later in life.

Hydroxyurea is indicated in the following conditions;

• Resistant chronic myeloid leukaemia.
• Locally advanced head and neck (excluding the lip) squamous cell carcinomas combined with concurrent chemoradiation therapy.
• For children with sickle cell anaemia who have experienced moderate-to-severe painful crises on a recurrent basis, to lessen the frequency of these episodes and the need for blood transfusions.

Orally: As Hydroxyurea is a cytotoxic medication, it is essential to swallow the capsules whole and not to open, break, or chew them. Administer folic acid as a preventative measure. When taking tablets, swallow the recommended daily dosage with water; avoid splitting the 100 mg tablets. Before using, immediately dissolve the tablets in a small amount of water if you cannot swallow them. Because Hydroxyurea is cytotoxic, always following precise handling and disposal instructions is essential.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

• Capsule: 200mg, 300mg , 400mg , 500mg
• Tablet:100mg,1000mg

Hydroxyurea is available as capsules and tablets.

Dose Adjustment in Adult Patients:

Solid Tumors: 20–30 mg/kg PO every day OR 80 mg/kg PO every three days as an intermittent treatment

Head & Neck Tumors

Concomitant radiation therapy: 80 mg/kg PO every three days

Start seven days before the radiation is expected to start.

Resistant Continuous Therapy for Chronic Myelocytic Leukemia: 20–30 mg/kg PO every day

Off-label treatment for sickle cell disease

Start with a 15 mg/kg dose daily while maintaining a watch on the patient's blood cell count every two weeks.

Every twelve weeks, titrate by five milligrams per kilogram per day.

If blood counts fall between the acceptable and toxic ranges, the dose is not increased.

Not more than 35 mg/kg per day

If blood counts appear toxic, stop treatment until hematologic recovery; treatment may be resumed after a 2.5 mg/kg/day reduction in the dose associated with haematological toxicity.

Adjusting the dosage based on blood counts

When a painful crisis arises, the dosage is 5 mg/kg/day every eight weeks.

Give a maximum of 35 mg/kg/day until mild myelosuppression (absolute neutrophil count [ANC] 2,000–4,000/mcL) is attained.

The dosage should be increased only if a painful crisis arises or if blood counts fall within an acceptable range.

If myelosuppression develops, do not increase.

Essential (off-label) thrombocytopenia, 15 mg/kg PO qDay

Titrate to preserve WBC count and regulate platelets

HIV Adjunct Treatment (Off-label): 500 mg PO BID

Add antiretrovirals

Off-label use of psoriasis: 1000–1500 mg/day PO qDay–BID

Follow essential dietary guidelines and precautions when using Hydroxyurea. Eat a balanced diet every day, either with or without meals. To avoid becoming dehydrated, maintain a daily water intake. Monitor blood cell counts and report any unusual bleeding or bruises immediately. Hydroxyurea can harm fetuses, so use accurate contraception. If there is a history of liver or renal problems, proceed with caution. Include sun protection before exposure to the sun for extended periods to prevent any skin reactions.

The dietary restriction should be individualized as per patient requirements.

• Hypersensitivity: Anyone who has previously experienced hypersensitivity to Hydroxyurea or any of its components.
• Bone marrow depression, i.e. leukopenia (<2500 WBC/mm3) or thrombocytopenia (<700,000/mm3).
• Severe anemia

The adverse reactions related to Hydroxyurea can be categorized as

•Common Adverse Effects: Infections, other infections, bacterial infections, gastrointestinal disorders, and neutropenia.

•Less Common Adverse Effects: Skin changes and oral ulcers.

•Rare Adverse Effects: Severe myelosuppression, acute mucocutaneous toxicity, and potentially serious infections.

Reports on Postmarketing

Infestations and infections: infection with parvovirus B19

Disorders of the blood and lymphatic system: anaemia (haemoglobin <4.5 g/dL); hemolytic anaemia; bone marrow depression, including neutropenia (<2 X 10^9/L), reticulocytopenia (<80 X 10Postmarketing Reports^9/L), macrocytosis, and thrombocytopenia (<80 X 10^9/L).

gastrointestinal disorders: stomatitis, severe hypomagnesemia, gastrointestinal ulcers, vomiting, nausea, and gastrointestinal disturbances

Hepatic enzyme elevation in hepatobiliary disorders

Skin and subcutaneous tissue disorders include leg ulcers, cutaneous dryness, nail hyperpigmentation, scaling, violet papules, cutaneous lupus erythematosus, oral mucositis, rash, melanonychia, alopecia, and skin reactions (oral, ungula, and cutaneous pigmentation).

Disorders of the kidneys and urinary system: dysuria, increases in blood urea nitrogen

Immune disorders: Erythematous systemic lupus

Nutritional disorders and metabolism: Anorexia

Disorders of the nervous system: feeling lightheaded, sleepiness, confusion, hallucinations, convulsions

Respiratory disorders include pneumonia, allergic alveolitis, cough, diffuse pulmonary infiltrates, dyspnea, and pulmonary fibrosis.

Disorders of the reproductive system and breasts: amenorrhea, azoospermia, and oligospermia

General disorders include asthenia, oedema, malaise, fever, and chills.

Studies: Increased weight

Hypersensitivity: Drug-induced fever (pyrexia) (>39°C, >102°F) that required hospitalization and was reported along with symptoms related to the gastrointestinal tract, lungs, musculoskeletal system, hepatobiliary system, dermatology, or cardiovascular system; fever usually started within 6 weeks of starting the medication and went away when the Hydroxyurea was stopped; fever usually returned within 24 hours of starting the drug again.

The clinically relevant drug interactions of Hydroxyurea are briefly summarized here.

• Drug-Drug Interaction: Hydroxyurea may have interactions with antiviral medications (didanosine, stavudine, and indinavir), antigout medications (allopurinol), antigout medicines (aspirin, ibuprofen), blood thinners (warfarin), antiallergic medications (diphenhydramine), and sleep aids (zolpidem).
• Individuals with reduced blood cell production, liver disease, kidney disease, and brain disorders are at risk for drug-disease interactions.

• Pregnancy

Pregnancy Category D (FDA): Use in cases where no safer medication is available and life is in danger. Positive evidence of prenatal risk in humans.

There are no studies on the use of this medication in pregnant women.

There is not enough data on drug use during pregnancy to understand the risks associated with it.

When pregnant patients or their partners become exposed to Hydroxyurea, it is essential to follow up carefully and get the necessary clinical, biological, and ultrasonographic testing.

Inform expectant mothers of the possible harm to their unborn child and make sure all women who are capable of reproducing are pregnant before starting treatment.

Fertility

Treatment may reduce male fertility, according to research on humans and animals. Men have been reported to exhibit either oligospermia or azoospermia. Men should be informed about the possibility of sperm conservation before beginning therapy.

Contraception

Use effective contraception during therapy and for at least six months following it if you are a female of reproductive potential.

Fertile males should use reliable contraception for at least a year, both during and after treatment.

Animal data

Certain drugs, such as Hydroxyurea that interfere with DNA synthesis could be mutagenic.

When pregnant rats and rabbits were given Hydroxyurea during organogenesis, the effects were teratogenic and embryotoxic at doses 0.8 and 0.3 times, respectively, the maximum daily dose advised for humans.

Fetal malformations have been seen in rats and rabbits, including partially ossified cranial bones, missing lumbar vertebrae, hydrocephaly, and absent eye sockets.

Developmental delays, smaller live litter sizes, and decreased fetal viability were the main symptoms of embryotoxicity.

• Nursing Mothers

Breastfeeding is not advised while receiving treatment.

It's unknown if Hydroxyurea is eliminated in human milk, how it affects breastfed children, or how it affects milk production.

• Pediatric Use

As per the FDA, the safety and efficacy of pediatric patients have not been established.

Dose adjustment

Sickle Cell Disease

<2 years: Safety and efficacy not established

2 to 18 years

initial dosage

20 mg/kg OR qDay Monitor blood levels every two weeks

Considerations for Dosing

Fetal haemoglobin (HbF) levels can be used to assess a treatment's effectiveness.

Measure HbF levels every three to four months while maintaining a watch for any increases of at least two times the baseline value.

Before beginning, confirm that any females capable of reproducing are pregnant.

Dose Adjustment in Kidney Impairment Patients:

For CrCl ≥60 mL/min, there is no need to modify the dosage.

CrCl less than 60 mL/min or end-stage renal disease (ESRD): Cut back to 7.5 mg/kg/day while closely monitoring the hematologic parameters.

ESRD patients receiving dialysis: Take the dose after hemodialysis on the days you have dialysis.

Dose Adjustment in Hepatic Impairment Patients:

Closely monitor all the hematologic parameters.

The physician should be vigilant about the knowledge pertaining to identifying and treating overdosage of Hydroxyurea.

Signs and Symptoms

Patients who received Hydroxyurea at a dosage that was multiple times higher than the usual recommended dosage have reported experiencing acute mucocutaneous toxicity. The following symptoms were noted: intense generalized hyperpigmentation of the skin, pain, violet erythema, oedema on the palms and soles of the feet, followed by scaling of the hands and feet, and severe acute stomatitis.

Management

Supportive care and symptom-specific interventions are essential in Hydroxyurea overdosage, as there is no specific antidote. Administer activated charcoal to reduce further absorption. Supportive care measures may include the administration of intravenous fluids, pain management, and topical treatments for skin manifestations. Close monitoring of vital signs and laboratory parameters is essential. In severe cases, hospitalization may be necessary for intensive monitoring and supportive care. Careful observation for intercurrent infection is critical, with timely initiation of appropriate antibiotic therapy if needed.

Pharmacodynamics:

It is unknown whether hydroxyurea concentrations, a decline in crisis rate, and an increase in HbF are correlated.

Pharmacokinetics:

• Absorption: When taken orally, Hydroxyurea enters the digestive system and exits the body with a bioavailability of more than 80%. Peak plasma concentrations are reached in one to four hours.
• Distribution: Hydroxyurea spreads quickly throughout the human body, getting into the ascites, peritoneal fluid, and cerebrospinal fluid. It is mainly concentrated in leukocytes and erythrocytes, and its estimated volume of distribution (Vd: 0.5 L/kg; protein binding: 75-80%) roughly corresponds to the body's total water content.
• Metabolism: Between 50 and 60 per cent of Hydroxyurea is metabolized by the liver, with the remaining small amount being broken down by intestinal bacterial urease. Acetate hydroxamic acid and urea are examples of inactive metabolites.
• Excretion: Hepatic metabolism is saturable, and renal excretion is nonlinear. Between 25 and 80 per cent of the drug is eliminated through urine, with 30 per cent of the drug being urea. The clearance rate varies between 4.3 and 5.5 L/h/m2, and the terminal half-life is 3–4 hours.

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• Dong M, McGann PT. Changing the Clinical Paradigm of Hydroxyurea Treatment for Sickle Cell Anemia Through Precision Medicine. Clin Pharmacol Ther. 2021 Jan;109(1):73-81. doi: 10.1002/cpt.2028. Epub 2020 Oct 8. PMID: 32869281; PMCID: PMC7902468.
• Pandey A, Kaur H, Borah S, Khargekar N, Karra VK, Adhikari T, Jain D, Madkaikar M. A systematic review on hydroxyurea therapy for sickle cell disease in India. Indian J Med Res. 2022 Aug;156(2):299-311. doi: 10.4103/ijmr.ijmr_3447_21. PMID: 36629190; PMCID: PMC10057355.

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