Sickle Cell Disease Products

Last Updated

Medications listed in the tables and non-FDA approved indications included in these retrospective criteria are not indicative of Texas Vendor Drug Program formulary coverage.

  • Revision history
    • July 22, 2022
  • Initially developed
    • April 2020

1.1. Adults

Current therapeutic options available for the outpatient management of sickle cell disease include hydroxyurea (Droxia®, Siklos®), L-glutamine (Endari®), and voxelotor (Oxbryta®). Hydroxyurea is a chemotherapeutic agent used to stimulate red blood cell (RBC) fetal hemoglobin (HbF) production, which is associated with a lower risk of acute sickle cell complications. Although the exact mechanism of action for sickle cell disease is unknown, hydroxyurea is FDA approved for patients with recurrent moderate-to-severe painful crises to reduce the frequency of painful crises and the need for blood transfusions. However, hydroxyurea cannot be used to treat crises1-7. L-glutamine is an essential amino acid thought to decrease oxidative damage to sickled RBCs by increasing nicotinamide adenine dinucleotide (NAD+) synthesis, thereby reducing the complications of sickle cell disease such as chronic hemolysis and vasoocclusive events.1-5,8 Voxelotor is a first-in-class hemoglobin S (HbS) polymerization inhibitor which increases the affinity of HbS for oxygen by stabilizing the oxygenated hemoglobin state2-5,9.

Maximum recommended adult dosages are summarized in Table 1. Medication profiles identifying patients prescribed dosages exceeding these recommendations will be reviewed.

Table 1: Maximum Daily Adult Dosages for Sickle Cell Disease Products2-9
Drug Name Dosage Form/Strength Treatment Indication Maximum Recommended Dosage
hydroxyurea (Droxia®) 200 mg, 300 mg, 400 mg capsules Reduction in frequency of painful crises and to reduce the need for blood transfusions in patients with moderate to severe painful crises 35 mg/kg/day as long as blood counts are within acceptable range
hydroxyurea (Siklos®) 100 mg, 1000 mg tablets Reduction in frequency of painful crises and to reduce the need for blood transfusions in patients with moderate to severe painful crises 35 mg/kg/day as long as blood counts are within acceptable range
L-glutamine (Endari®) 5 gram powder packets Reduction in acute complications of sickle cell disease

Based on patient weight:

Less than 30 kg 5 g twice daily 30-65 kg 10 g twice daily

Greater than 65 kb 15 g twice daily
voxelotor (Oxbryta®) 500 mg tablets Treatment of sickle cell disease 1500 mg once daily+

Legend:

  • + voxelotor dose should be increased to 2000 mg once daily if prescribed with a moderate CYP3A4 inducer and 2500 mg once daily if prescribed concurrently with strong CYP3A4 inducers or reduced to 1000 mg once daily in patients with severe hepatic impairment

1.2. Pediatrics

L-glutamine (Endari®), voxelotor (Oxbryta®), and hydroxyurea as Siklos® have been approved for use in pediatric patients, but the safety and efficacy of hydroxyurea (Droxia®) has not been established in pediatric patients6-10. Hydroxyurea (Siklos®) is approved for patients 2 years of age and older to reduce the frequency of recurrent moderate-to-severe painful crises7. Growth should be continuously monitored in pediatric patients prescribed hydroxyurea; additionally, pediatric patients 2-16 years of age are at greater risk of developing neutropenia compared to patients older than 16 years7. L-glutamine is approved for pediatric patients 5 years and older, while voxelotor is approved for patients 4 years of age and older2,8,9 .

The maximum recommended pediatric dose for individual agents is summarized in Table 2. Table 3 provides dosing recommendations for patients 4 years of age to less than 12 years of age while taking concomitant strong or moderate CYP3A4 inducers while taking voxelotor therapy. Table 4 provides dosing recommendations for patients 4 years of age to less than 12 years of age with severe hepatic impairment (Child-Pugh Class C) while taking voxelotor therapy. Prescribed dosages exceeding these recommendations will be reviewed.

Table 2: Maximum Daily Pediatric Dosages for Sickle Cell Disease Products2-9
Drug Name Dosage Form/Strength Treatment Indication Maximum Recommended Dosage 
hydroxyurea (Siklos®) 100 mg, 1000 mg tablets Reduction in frequency of painful crises and to reduce the need for blood transfusions in patients with moderate to severe painful crises 2-17 years of age: 35 mg/kg/day as long as blood counts are within acceptable range
L-glutamine (Endari®) 5 gram powder packets Reduction in acute complications of sickle cell disease

5 – 17 years of age: Based on patient weight:

Less than 30 kg 5 g twice daily

30-65 kg 10 g twice daily

Greater than 65 kb 15 g twice daily
voxelotor (Oxbryta®) 500 mg tablets, 300 mg tablet for suspension Treatment of sickle cell disease
  • 4 – 11 years of age:
    • 40 kg or greater: 1,500 mg
    • 2 – 39 kg: 900 mg
    • 10 – 19 kg: 600 mg+
  • 12 years of age and older:
    • 1500 mg+

Legend:

  • +Voxelotor for those 12 years of age and older: dose should be increased to 2000mg once daily if prescribed with a moderate CYP3A4 inducer and 2500 mg once daily if prescribed concurrently with strong CYP3A4 inducers or reduced to 1000 mg once daily in patients with severe hepatic impairment.9 Further recommendations can be found for children less than 12 years of age in Table 3 and Table 4.
Table 3: Recommended Daily Dosage of Voxelotor (Oxbryta®) for Patients 4 Years to Less Than 12 Years When Used with Concomitant Strong or Moderate CYP3A4 Inducers9
Body Weight Concomitant Use of Strong CYP3A4 Inducers Concomitant Use of Moderate CYP3A4 Inducers
40 kg or greater 2500 mg (five 500 mg tablets) or 2400 mg (eight 300 mg tablets for oral suspension) 2000 mg (four 500 mg tablets) OR 2100 mg (seven 300 mg tablets for oral suspension)
20 kg to less than 40 kg 1500 mg    1200 mg
10 kg to less than 20 kg 900 mg 900 mg
Table 4: Recommended Daily Dosage of Voxelotor (Oxbryta®) for Patients 4 Years to Less Than 12 Years with Severe Hepatic Impairment (Child-Pugh C)9
Body Weight Recommended Dose (once daily)
40 kg or greater 1000 mg (two 500 mg tablets) OR 900 mg (three 300 mg tablets for oral suspension)
20 kg to less than 40 kg 600 mg
10 kg to less than 20 kg 300 mg

2. Duration of Therapy

There is no basis for limiting long-term therapy of sickle cell disease; however, treatment with hydroxyurea requires monitoring of blood counts every 2 weeks due to the risk of myelosuppression. Hydroxyurea should be discontinued until hematologic recovery if blood counts reach toxic ranges defined as: neutrophils less than 2,000/mm3, platelets less than 80,000/mm3, hemoglobin less than 4.5 g/dL, or reticulocytes less than 80,000/mm3 if hemoglobin is less than 9 g/dL2,5-9.

3. Duplicative Therapy

Sickle cell disease treatment is complex and may require combination therapy. Both L-glutamine and voxelotor can be used alone or in combination with hydroxyurea1. In a phase 3 clinical trial, investigators found L-glutamine was effective in preventing vasoocclusive pain in patients with frequent episodes (greater than or equal to 2 in the prior year), regardless of hydroxyurea use; therefore, it can serve as an alternative to hydroxyurea or be used as an adjunctive therapy5,11. Similarly, voxelotor may be administered with or without hydroxyurea to reduce sickle cell anemia2-5,9,12.

4. Drug-Drug Interactions

Patient profiles will be assessed to identify those drug regimens, which may result in clinically significant drug-drug interactions. Major drug-drug interactions considered clinically significant for sickle cell disease products are summarized in Table 3. Only those drug-drug interactions classified as clinical significance level 1/contraindicated or those considered life threatening which have not yet been classified will be reviewed.

Table 4. Sickle Cell Disease Product Drug-Drug Interactions2,3,6-9
Target Drug Interacting Drug Interaction Recommendation Clinical Significance Level
Hydroxyurea (Droxia®, Siklos®) Live Vaccines (MMR*, Varicella, Zoster, Smallpox, Typhoid, Yellow fever, Rotavirus+) May increase risk of infection by live vaccine Avoid use until at least 3 months after discontinuation of immunosuppressive drugs unless benefits clearly outweigh potential risks Contraindicated (DrugReax) 1 – severe (CP)
Hydroxyurea (Droxia®, Siklos®) Stavudine May increase risk of severe peripheral neuropathy, fatal pancreatitis, and hepatotoxicity Avoid concurrent use Major (DrugReax)  2 – major (CP)
Hydroxyurea (Droxia®, Siklos®) Didanosine May result in fatal pancreatitis and hepatotoxicity Avoid concurrent use Major (DrugReax) 2 – major (CP)
Voxelotor (Oxbryta®) Strong or moderate CYP3A4 inducers (e.g. phenytoin, nafcillin, carbamazepine) May reduce voxelotor plasma concentration and result in reduced efficacy Avoid concurrent use or increase voxelotor dosage to 2000-2500 mg daily Major (DrugReax) 2 – major (CP)
Voxelotor (Oxbryta®) Fluconazole May increase voxelotor plasma concentration and result in increased toxicity Avoid concurrent use, replace with alternative drugs, or decrease voxelotor dosage to 1000 mg daily Major (DrugReax) 2 – major (CP)
Voxelotor (Oxbryta®) Strong CYP3A4 inhibitors (e.g. ketoconazole, clarithromycin, itraconazole) May increase voxelotor plasma concentration and result in increased toxicity Avoid concurrent use, replace with alternative drug, or Decrease voxelotor dosage to 1000 mg daily Major (DrugReax) 2 – major (CP)
Voxelotor (Oxbryta®) CYP 3A4 substrates with narrow therapeutic indices (e.g. oxycodone, cyclosporine, fentanyl, tacrolimus) May result in increased concentration of sensitive CYP3A4 substrates Avoid concurrent use or consider dose reduction of sensitive CYP3A4 substrates with narrow therapeutic index Major (DrugReax) 3 – moderate (CP)

Legend:

  • * MMR-Measles, mumps, rubella
  • + Rotavirus vaccination is indicated up to 24 months of age; because hydroxyurea (Siklos®) is indicated for use in pediatric patients 2 years and older, there is a small chance that a patient might be considered for both treatments; this combination should be avoided.

5. References

  1. Chan C, Frei-Jones M. Sickle Cell Disease. In: DiPiro JT, Yee GC, Posey L, Haines ST, Nolin TD, Ellingrod V. eds. Pharmacotherapy: a pathophysiologic approach, 11e New York, NY: McGraw-Hill. Available from: http://accesspharmacy.mhmedical.com.ezproxy.lib.utexas.edu/content.aspx?bookid=2577&sectionid=228902837. Accessed June 6, 2022.
  2. DRUGDEX® System (electronic version). Truven Health Analytics, Greenwood Village, Colorado, USA. Available at: http://www.micromedexsolutions.com.libproxy.uthscsa.edu/. Accessed June 6, 2022.
  3. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2022. Available at: http://www.clinicalpharmacology-ip.com.ezproxy.lib.utexas.edu/. Accessed June 6, 2022.
  4. Facts and Comparisons eAnswers [database online]. Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2022. Available at:  https://fco-factsandcomparisons-com.ezproxy.lib.utexas.edu. Accessed June 9, 2022.
  5. Lexicomp Online, Lexi-Drugs Online, Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2022. Available at: https://online-lexi-com.ezproxy.lib.utexas.edu/lco/action/home. Accessed June 6, 2022.
  6. Hydroxyurea (Droxia®) package insert. E.R. Squibb & Sons, L.L.C., August 2021.
  7. Hydroxyurea (Siklos®) package insert. Medunik. December 2021.
  8. L-glutamine (Endari®) package insert. Emmaus Medical, Inc., October 2020.
  9. Voxelotor (Oxbryta®) package insert. Global Blood Therapeutics Inc., December 2021.
  10. Lexicomp Online, Pediatric and Neonatal Lexi-Drugs Online, Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2022. Available at:  https://online-lexi-com.ezproxy.lib.utexas.edu/lco/action/home. Accessed June 7, 2022.
  11. Niihara Y, Miller ST, Kanter J, et al. Investigators of the phase 3 trial of l-glutamine in sickle cell disease. A phase 3 trial of l-glutamine in sickle cell disease. N Engl J Med. 2018;379(3):226-235. [PubMed 30021096] 10.1056/NEJMoa1715971
  12. Vichinsky E, Hoppe CC, Ataga KI, et al. A phase 3 randomized trial of voxelotor in sickle cell disease. N Engl J Med. 2019;381:509-19. doi: 10.1056/NEJMoa1903212