Liquid Hydroxyurea (Xromi) for Children With Sickle Cell Anemia: A New Solution Compounding Existing Problems

Hydroxyurea has transformed the care of people with sickle cell anemia (SCA), providing a simple, once-daily, safe, and effective disease-modifying therapy [1]. By increasing fetal hemoglobin and improving red cell rheology, hydroxyurea prevents overt and covert complications of SCA [2, 3]. When started early in life, before substantial organ damage occurs, it interrupts and averts the natural history of this severe and unforgiving disease [4-7]. Despite well-established benefits, hydroxyurea remains underused across the United States [8, 9]. Prescription rates are low, adherence may be inconsistent, and many children who should receive early treatment never do [10-12]. Some providers are hesitant about its use for outwardly well-appearing infants; health systems often impose administrative obstacles; and families may have concerns about side effects and experience difficulties with cost, coverage, and logistics of long-term therapy. For many years, one practical obstacle was the formulation of the medication itself. Hydroxyurea was commercially available only as capsules, which infants and many children could not swallow. Although the World Health Organization advocates for “child-sized” formulations of essential medicines [13], no commercial liquid hydroxyurea existed. To address this need, many hospitals and health systems prepared extemporaneously compounded, liquid formulations. These compounding programs required dedicated infrastructure to comply with safety regulations for handling a nominally antineoplastic agent, and because hydroxyurea was only FDA-approved as capsules, pharmacies often needed to open the capsules manually to compound the liquid solution. Despite these barriers, these compounding programs provided an inexpensive solution that was remarkably successful. For example, the hospital-based compounding program at Boston Medical Center provided at-home delivery of compounded hydroxyurea for pediatric patients and achieved excellent adherence, with measurable reductions in hospitalizations and acute chest syndrome [14]. Such efforts by several pediatric centers demonstrated the feasibility and effectiveness of compounded liquid hydroxyurea. In 2024, the FDA approved Xromi, a ready-to-use, liquid formulation of hydroxyurea developed by Nova Laboratories Ltd., for children as young as 6 months of age. On the surface, this approval solves a long-standing problem. However, due to obstacles in the US healthcare system, it also creates new limitations to hydroxyurea access. Although Xromi's price is lower than other recently approved SCA treatments, it is far more expensive than generic hydroxyurea, with which it shares its active ingredient, safety profile, and efficacy [15]. At an average retail price of around $900 per 148 mL bottle (100 mg/mL), Xromi costs 30–90 times more than hydroxyurea capsules (GoodRx, September 2025). This price differential directly impacts payers, including any family that pays for their own medications. At this higher price, it is critical to avoid wasting the product because it is only available in the 148 mL bottle size. Pharmacies must either divide the bottles to achieve a full fill or provide a partial supply to the patient, which increases the burden of care. Xromi must remain refrigerated and expires 12 weeks after a bottle is opened, adding complexity for families and pharmacies. High retail prices for new medications are common in the United States, where prescription drugs cost on average 2.8 times more than in other countries [16]. Research and development costs are cited as one justification for these prices. In the case of Xromi, however, hydroxyurea was first synthesized in the late 19th century, has been used to treat SCA since the end of the 20th century, and was proven efficacious for children in the early 21st century [2, 17, 18]. Upon this background of research on hydroxyurea's safety and effectiveness, Nova Laboratories only needed to determine the stability, palatability, and pharmacokinetics of their product [19]. This should be commended as it fills an important need, but is unlikely to be sufficient to explain the high cost. Xromi was granted FDA orphan drug exclusivity to fill the need for a liquid formulation for children with SCA. This provides 7 years of market exclusivity in accordance with the Orphan Drug Act (ODA). The ODA incentivizes companies to develop drugs for conditions that affect under 200,000 Americans, which may otherwise be an insufficient market to recover investment costs [20, 21]. Sickle cell disease affects approximately 100,000 Americans of predominantly Black race and historically receives less research funding than comparable diseases that affect primarily White populations [22-24]. Although most drugs have not reached FDA approval, the ODA has successfully stimulated increased research and development into SCA treatment options [20]. A downside of approval under the ODA for SCA and other rare diseases is the increased price that pharmaceutical companies can charge due to the monopoly created by the exclusivity clause [21]. This exclusivity, combined with the favorable clinical benefits and safety profile of hydroxyurea, generally a likely factor heavily into the high pricing of Xromi. Further exacerbating barriers to access, the FDA approval of Xromi means that health systems that had developed successful compounding programs are no longer permitted to supply liquid hydroxyurea. Section 503A of the Federal Food, Drug, and Cosmetic Act prohibits compounding pharmacies from selling “products that are essentially copies” of a commercially available, FDA-approved drug [25]. The regulation also prohibits attempts to bypass this rule through minor modifications without valid medical needs, and explicitly mentions that compounding a drug solely to provide a cheaper alternative is not acceptable. Insurance companies implement utilization strategies to contain costs [26]. Cost-sharing approaches include copayments and coinsurance. Anecdotally, the copayments for Xromi are often between $10 and $100, but may exceed $500 per month. Utilization management strategies include step therapy, quantity limits, and prior authorizations (PA), often in combination. PAs are cost-control processes requiring advanced approval by the payer to authorize a service or prescription [26]. Unfortunately, clinicians report that PA processes are often opaque, unpredictable, frustrating, and time-consuming, leading to worse outcomes, delayed care, treatment abandonment, patient harm, and provider burnout [27, 28]. The PA process has been described as a “medical injustice disguised as paperwork” [27], enabling insurers to create a tangled, bureaucratic web of roadblocks in order to deny care that healthcare providers recommend to their patients. To contain the costs of treatment with Xromi, many payers now require PAs with limitations that vary widely, but generally rely on restrictive indications and illogical recommendations for stepwise therapy. For example, one private insurance company based in Ohio requires patients to meet all of five criteria, which include recurrent painful crises and frequent blood transfusions; these criteria are aligned with the FDA indications, but national guidelines recommend offering hydroxyurea to all infants with SCA regardless of disease severity due to the clinical benefits even in apparently asymptomatic children with the disease [29-31]. A plan in Louisiana states that members older than 2 years must take a stepwise approach and start with generic hydroxyurea capsules, despite it not being developmentally appropriate for a 2-year-old to swallow pills [32]. Medicaid coverage of Xromi varies, but anecdotally requires a PA in the majority of states. For the plans that require stepwise therapy, due to the regulations barring hospital and pharmacy-based compounding of hydroxyurea, there are no reasonable alternative treatment options with the same clinical benefits. The alternative becomes no treatment at all. PAs are not only burdensome to obtain initially, but they also require renewal. If renewal requirements are stringent, they may create additional barriers. For example, to continue Xromi Arkansas Medicaid requires that the patient is adherent with over 75% utilization, and the frequency of pain or transfusions improves [33]. These requirements are not otherwise indications to discontinue treatment. PAs negatively impact medical decision-making and dissuade optimal care. In a survey of physicians, 75% report avoiding new medications despite safety and benefit because of PA requirements [28]. Considering the large number of clinicians who already view hydroxyurea as burdensome [10], this additional barrier will almost certainly further decrease the prescription rate for children with SCA. Most Medicaid plans approve 12 months of treatment at a time, but whether or not a new PA will be required with each dose change depends on the insurance plan. For most pediatric medications, doses are increased with weight gain; furthermore, in children with SCA, maximal clinical benefits are seen with dose individualization to achieve the maximum tolerated dose [31, 34]. With either approach, the hydroxyurea dose will change at least once, but likely several times, within those 12 months. A new PA with each dose change is not reasonable. To ensure this new solution is widely available, several components of the current system need to be adapted. Pediatric hematologists have a role in advocating at all levels of the healthcare system. Considering the majority of children with SCA are insured through Medicaid, direct advocacy with state programs may have a high impact. In Ohio, we alerted the medical directors of the Ohio Department of Medicaid (ODM) of the aforementioned challenges introduced by Xromi. With a greater understanding of the health and financial benefits of treating young children with SCA, ODM agreed to approve Xromi for all children with SCA under 12 years of age without a PA. Additionally, as a result of our prior advocacy and the stable shelf-life of Xromi, a 3-month supply can be filled with each dispensation rather than a 1-month supply. This decreases the number of visits a family must make to the pharmacy from 12 to four times per year. Other states may follow this lead if brought to them by local clinicians. Where the PA requirements remain, the medical necessity of hydroxyurea for children must be unequivocally stated. Reference to the BABY HUG trial with improved outcomes in those on hydroxyurea versus placebo, even among apparently “asymptomatic” patients, may strengthen this argument. Stepwise therapy to start with hydroxyurea capsules does not make sense for those who cannot swallow pills, and the allowance of dose titration will facilitate optimal dosing. SCA clinics need adequate staffing to complete the required PA paperwork. Pharmacy-led PA programs may be an effective way to spread the burden across staff [35]. Artificial intelligence has also been proposed as a tool to decrease the PA burden [36]. Ultimately, the shift to Xromi will be an acceptable change only if patients can access their medication. We have implemented a hydroxyurea monitoring system as a quality improvement tool to track hydroxyurea dispensation, proportion of days covered, fetal hemoglobin, and healthcare utilization. With this, if our hydroxyurea use falters, we hope to identify and mitigate it early. Other sickle cell centers may consider a similar system. In summary, Xromi fills the long-standing need for commercially available liquid hydroxyurea, but access to it is limited by challenges built into the current healthcare system. Federal law now prohibits health systems from compounding liquid hydroxyurea, so for children with SCA who cannot swallow pills, this essential treatment depends on a branded medication that costs significantly more than generic capsules with identical efficacy and safety. For families, prescribers, and payers, the consequences are immediate and tangible: higher prices and restrictive insurance policies that delay or deny care. Paradoxically, a development intended to expand access to treatment has actually made it harder for many children with SCA to receive the very medication that can change their lives; changes at all levels are necessary to ensure access to this new solution. Alexandra Power-Hays and Charles T. Quinn contributed equally to the conceptualization and writing of this manuscript. Alexandra Power-Hays was previously on a health equity advisory board for Novo Nordisk. Charles T. Quinn has consulted for Novo Nordisk and Disc Medicine. These relationships did not influence the writing of this manuscript.