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Selumetinib Sulfate – Uses, Dosage, Side Effects, Interaction

Dr. Harun Ar Rashid, MD - Arthritis, Bones, Joints Pain, Trauma, and Internal Medicine Specialist Dr. Harun Ar Rashid, MD - Arthritis, Bones, Joints Pain, Trauma, and Internal Medicine Specialist
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Drugs (A - Z)

Selumetinib is an orally active, small molecule with potential antineoplastic activity. Selumetinib is an ATP-independent inhibitor of mitogen-activated protein kinase kinase (MEK or MAPK/ERK kinase) 1 and 2. MEK 1 and 2 are dual specificity kinases that are essential mediators in the activation of the RAS/RAF/MEK/ERK pathway, are often upregulated in various cancer cells, and are drivers of diverse cellular responses, including proliferation. Inhibition of both MEK1 and 2 by selumetinib prevents the activation of MEK1/2 dependent effector proteins and transcription factors, thereby leading to an inhibition of cellular proliferation in various cancers.

Selumetinib is an oral, small-molecule inhibitor of the mitogen-activated protein kinase 1 and 2 (MEK1/2) that is used to treat symptomatic, refractory fibromas in neurofibromatosis type 1. Selumetinib is associated with transient and usually mild elevations in serum aminotransferase levels during therapy but has not been linked to cases of clinically apparent acute liver injury.

Selumetinib is a member of the class of benzimidazoles that is 1-methyl-1H-benzimidazole which is substituted at positions 4, 5, and 6 by fluorine, (4-bromo-2-chlorophenyl)amino, and N-(2-hydroxyethoxy)aminocarbonyl groups, respectively. It is a MEK1 and MEK2 inhibitor. It has a role as an EC 2.7.11.24 (mitogen-activated protein kinase) inhibitor, an antineoplastic agent and an anticoronaviral agent. It is a member of benzimidazoles, a hydroxamic acid ester, a member of monochlorobenzenes, a member of bromobenzenes, an organofluorine compound and a secondary amino compound.

Selumetinib Sulfate is the sulfate salt of selumetinib, an orally active, small molecule with potential antineoplastic activity. Selumetinib is an ATP-independent inhibitor of mitogen-activated protein kinase kinase (MEK or MAPK/ERK kinase) 1 and 2. MEK 1 and 2 are dual specificity kinases that are essential mediators in the activation of the RAS/RAF/MEK/ERK pathway, are often upregulated in various cancer cells, and are drivers of diverse cellular responses, including proliferation. Inhibition of both MEK1 and 2 by selumetinib prevents the activation of MEK1/2 dependent effector proteins and transcription factors, thereby leading to an inhibition of cellular proliferation in various cancers.

Mechanism of Action

The Ras-Raf-MEK-ERK signaling cascade is known to be activated in several types of cancer, and regulates the transcription of proteins involved in apoptosis. In addition, studies have shown that mutations of the Raf component of the pathway can contribute to chemotherapy drug resistance. Ras as well as several kinases and phosphatases are responsible for regulating the Raf-MEK-ERK pathway. Often in cancers, Ras (a G-protein coupled receptor) is deregulated, allowing downstream signalling to proceed unchecked. Through several complex steps, Raf phosphorylates and activates MEK, which then phosphorylates and activates ERK. ERK is then able to exert its effects on several downstream targets. As such, therapies inhibiting upstream components of this pathway have become attractive targets for cancer treatment. Selumetinib exerts its effects by selectively inhibiting MEK1 and MEK2 which can effectively blunt the pleiotropic effects of the Ras-Raf-MEK-ERK cascade. By inhibiting this oncogenic pathway, selumetinib reduces cell proliferation, and promotes pro-apoptotic signal transduction.

Selumetinib is a non-ATP-competitive mitogen-activated protein kinase kinase 1 and 2 (MEK1 and MEK2) inhibitor. By selectively targeting MEK1 and MEK2, selumetinib is able to inhibit oncogenic downstream effects of the Raf-MEK-ERK signaling pathway, which is often overactive in certain types of cancer. Indeed, a study investigating the effects of selumetinib in children with NF-1 found that treatment with the anti-neoplastic resulted in reduced tumor size. Decreases in tumor-associated pain and improvements in overall function were also subjectively reported. Selumetinib has minimal off-target activity, contributing to its impressive safety profile.

Activation of the Raf-MEK-ERK signaling pathway is known to be implemented in several types of malignancies, thus, mitogen-activated protein kinase kinase (MEK) inhibitors such as selumetinib are important tools that can target the problematic overactivity of this pathway.[rx] Results from clinical trials investigating earlier developed MEK inhibitors were underwhelming.[rx] However, selumetinib demonstrated impressive efficacy and tolerability in Phase I trials, leading to its continued investigation for the treatment of various types of tumors in Phase II trials.[rx]

Currently, the novel MEK 1 / 2 inhibitor, selumetinib, is approved solely for the treatment of Neurofibromatosis type 1 (NF-1) in a limited age group. NF-1 is considered rare with an estimated incidence of 1/3000 individuals.[rx] It is a genetic, autosomal dominant condition resulting from mutations of the NF1 gene, which can lead to various complications including the development of multiple tumors in the nervous system. Some patients with this disorder develop plexiform neurofibromas (PN); however, this is considered to be relatively uncommon compared to other variants of NF-1.[rx] Luckily, the use of selumetinib in patients with NF-1 has shown efficacy in shrinking associated tumors and is linked to other positive clinical outcomes.[rx]

Indications

  • Although selumetinib has been investigated for the treatment of several types of cancer, it is currently only indicated for the treatment of neurofibromatosis type 1 (NF1) in patients ≥2 years who have symptomatic, inoperable plexiform neurofibromas (PN).
  • Koselugo as monotherapy is indicated for the treatment of symptomatic, inoperable plexiform neurofibromas (PN) in paediatric patients with neurofibromatosis type 1 (NF1) aged 3 years and above.
  • Selumetinib is an oral, small-molecule inhibitor of the mitogen-activated protein kinase 1 and 2 (MEK1/2) that is used to treat symptomatic, refractory fibromas in neurofibromatosis type 1.

Use in Cancer

Selumetinib sulfate is approved to treat:

Selumetinib sulfate is also being studied in the treatment of other types of cancer.

Contraindications

  • decreased blood-clotting from low vitamin K
  • increased risk of bleeding due to clotting disorder
  • chronic heart failure
  • inflammation of the large intestine
  • a condition with muscle tissue breakdown called rhabdomyolysis
  • diarrhea
  • pregnancy
  • a patient who is producing milk and breastfeeding
  • increased creatine kinase levels
  • detachment of retinal pigment epithelium
  • Child-Pugh class B liver impairment
  • Child-Pugh class C liver impairment

Dosage

Strengths: 10 mg; 25 mg

Fibromatosis

2 years and older:

  • 25 mg/m2 orally 2 times a day (approximately every 12 hours) until disease progression or unacceptable toxicity

RECOMMENDED DOSE BASED ON BODY SURFACE AREA (BSA):

  • BSA less than 0.55 mg/m2: No dose recommendation.
  • BSA 0.55 to 0.69 m2: 20 mg/m2 orally in the morning and 10 mg/m2 in the evening
  • BSA 0.7 to 0.89 m2: 20 mg/m2 orally in the morning and 20 mg/m2 in the evening
  • BSA 0.9 to 1.09 m2: 25 mg/m2 orally in the morning and 25 mg/m2 in the evening
  • BSA 1.1 to 1.29 m2: 30 mg/m2 orally in the morning and 30 mg/m2 in the evening
  • BSA 1.3 to 1.49 m2: 35 mg/m2 orally in the morning and 35 mg/m2 in the evening
  • BSA 1.5 to 1.69 m2: 40 mg/m2 orally in the morning and 40 mg/m2 in the evening
  • BSA 1.7 to 1.89 m2: 45 mg/m2 orally in the morning and 45 mg/m2 in the evening
  • BSA 1.9 mg/m2 or greater: 50 mg orally in the morning and 50 mg/m2 in the evening

Treatment of pediatric patients 2 years and older with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas (PN)

Liver Dose Adjustments

DOSE ADJUSTMENTS FOR HEPATIC IMPAIRMENT:

  • MILD HEPATIC IMPAIRMENT (Child-Pugh A): No adjustment recommended.

MODERATE HEPATIC IMPAIRMENT (Child-Pugh B):

  • Body surface area (BSA) 0.55 to 0.69 m2: 10 mg/m2 orally in the morning and 10 mg/m2 in the evening
  • BSA 0.7 to 0.89 m2: 20 mg/m2 orally in the morning and 10 mg/m2 in the evening
  • BSA 0.9 to 1.09 m2: 20 mg/m2 orally in the morning and 20 mg/m2 in the evening
  • BSA 1.1 to 1.29 m2: 25 mg/m2 orally in the morning and 25 mg/m2 in the evening
  • BSA 1.3 to 1.49 m2: 30 mg/m2 orally in the morning and 25 mg/m2 in the evening
  • BSA 1.5 to 1.69 m2: 35 mg/m2 orally in the morning and 30 mg/m2 in the evening
  • BSA 1.7 to 1.89 m2: 35 mg/m2 orally in the morning and 35 mg/m2 in the evening
  • BSA 1.9 mg/m2 or greater: 40 mg orally in the morning and 40 mg/m2 in the evening

SEVERE HEPATIC IMPAIRMENT (Child-Pugh C): Not recommended.

Dose Adjustments

RECOMMENDED DOSE REDUCTIONS FOR ADVERSE REACTIONS:
BSA 0.55 to 0.69 m2:

  • First dose reduction: Reduce dose to 10 mg/m2 orally in the morning and 10 mg/m2 in the evening
  • Second dose reduction: Reduce dose to 10 mg/m2 orally once a day

BSA 0.7 to 0.89 m2:

  • First dose reduction: Reduce dose to 20 mg/m2 orally in the morning and 10 mg/m2 in the evening
  • Second dose reduction: Reduce dose to 10 mg/m2 orally in the morning and 10 mg/m2 in the evening

BSA 0.9 to 1.09 m2:

  • First dose reduction: Reduce dose to 25 mg/m2 orally in the morning and 10 mg/m2 in the evening
  • Second dose reduction: Reduce dose to 10 mg/m2 orally in the morning and 10 mg/m2 in the evening

BSA 1.1 to 1.29 m2:

  • First dose reduction: Reduce dose to 25 mg/m2 orally in the morning and 20 mg/m2 in the evening
  • Second dose reduction: Reduce dose to 20 mg/m2 orally in the morning and 10 mg/m2 in the evening

BSA 1.3 to 1.49 m2:

  • First dose reduction: Reduce dose to 25 mg/m2 orally in the morning and 25 mg/m2 in the evening
  • Second dose reduction: Reduce dose to 25 mg/m2 orally in the morning and 10 mg/m2 in the evening

BSA 1.5 to 1.69 m2:

  • First dose reduction: Reduce dose to 30 mg/m2 orally in the morning and 30 mg/m2 in the evening
  • Second dose reduction: Reduce dose to 25 mg/m2 orally in the morning and 20 mg/m2 in the evening

BSA 1.7 to 1.89 m2:

  • First dose reduction: Reduce dose to 35 mg/m2 orally in the morning and 30 mg/m2 in the evening
  • Second dose reduction: Reduce dose to 25 mg/m2 orally in the morning and 20 mg/m2 in the evening

BSA 1.9 m2 or greater:

  • First dose reduction: Reduce dose to 35 mg/m2 orally in the morning and 35 mg/m2 in the evening
  • Second dose reduction: Reduce dose to 25 mg/m2 orally in the morning and 25 mg/m2 in the evening

*Permanently discontinue this drug in patients unable to tolerate it after 2 dose reductions.

CARDIOMYOPATHY:

  • Asymptomatic decrease in left ventricular ejection (LVEF) of 10% or greater from baseline and less than lower level of normal: Withhold therapy until resolution; resume at reduced dose.
  • Symptomatic decreased LVEF: Permanently discontinue therapy.
  • Grade 3 or 4 decreased LVEF: Permanently discontinue therapy.

OCULAR TOXICITY:

  • Retinal pigment epithelial detachment (RPED): Withhold therapy until resolution; resume at reduced dose.
  • Retinal vein occlusion (RVO): Permanently discontinue therapy.

GASTROINTESTINAL TOXICITY:

  • Grade 3 diarrhea: Withhold until improved to Grade 0 or 1; resume at same dose; permanently discontinue if no improvement within 3 days.
  • Grade 4 diarrhea: Permanently discontinue therapy.
  • Grade 3 or 4 colitis: Permanently discontinue therapy.

SKIN TOXICITY:

  • Grade 3 or 4: Withhold therapy until improvement; resume at reduced dose.

INCREASED CREATININE PHOSPHOKINASE (CPK):

  • Grade 4 Increased CPK: Withhold therapy until improved to Grade 0 or 1; resume at reduced dose; permanently discontinue therapy if no improvement within 3 weeks.
  • Any Increased CPK and myalgia: Withhold therapy until improved to Grade 0 or 1; resume at reduced dose; permanently discontinue therapy if no improvement within 3 weeks.
  • Rhabdomyolysis: Permanently discontinue therapy.

OTHER ADVERSE REACTIONS:

  • Intolerable Grade 2: Withhold therapy until improved to Grade 0 or 1; resume at reduced dose.
  • Grade 3: Withhold therapy until improved to Grade 0 or 1; resume at reduced dose.
  • Grade 4: Withhold therapy until improved to Grade 0 or 1; resume at reduced dose; consider discontinuation of therapy.

DOSE MODIFICATIONS FOR DRUG INTERACTIONS:
STRONG OR MODERATE CYP450 3A4 INHIBITORS OR FLUCONAZOLE:

  • Avoid coadministration of strong or moderate CYP450 3A4 inhibitors or fluconazole with this drug.
  • If coadministration with strong or moderate CYP450 3A4 inhibitors or fluconazole cannot be avoided, reduce the dose of this drug as recommended below. After discontinuation of the strong or moderate CYP450 3A4 inhibitor or fluconazole for 3 elimination half-lives, resume the selumetinib dose that was taken prior to initiating the inhibitor or fluconazole:

RECOMMENDED DOSE OF SELUMETINIB FOR COADMINISTRATION WITH STRONG OR MODERATE CYP450 3A4 INHIBITORS OR FLUCONAZOLE:
IF THE CURRENT DOSE IS 25 MG/M2 TWICE DAILY, REDUCE TO 20 MG/M2 TWICE DAILY:
Daily doses for 20 mg/m2 twice daily:

  • BSA 0.55 to 0.69 m2: 10 mg/m2 orally in the morning and 10 mg/m2 in the evening
  • BSA 0.7 to 0.89 m2: 20 mg/m2 orally in the morning and 10 mg/m2 in the evening
  • BSA 0.9 to 1.09 m2: 20 mg/m2 orally in the morning and 20 mg/m2 in the evening
  • BSA 1.1 to 1.29 m2: 25 mg/m2 orally in the morning and 25 mg/m2 in the evening
  • BSA 1.3 to 1.49 m2: 30 mg/m2 orally in the morning and 25 mg/m2 in the evening
  • BSA 1.5 to 1.69 m2: 35 mg/m2 orally in the morning and 30 mg/m2 in the evening
  • BSA 1.7 to 1.89 m2: 35 mg/m2 orally in the morning and 35 mg/m2 in the evening
  • BSA 1.9 m2 or greater: 40 mg/m2 orally in the morning and 40 mg/m2 in the evening

IF THE CURRENT DOSE IS 20 MG/M2 TWICE DAILY, REDUCE TO 15 MG/M2 TWICE DAILY:
Daily doses for 15 mg/m2 twice daily:

  • BSA 0.55 to 0.69 m2: 10 mg/m2 orally once daily
  • BSA 0.7 to 0.89 m2: 10 mg/m2 orally in the morning and 10 mg/m2 in the evening
  • BSA 0.9 to 1.09 m2: 20 mg/m2 orally in the morning and 10 mg/m2 in the evening
  • BSA 1.1 to 1.29 m2: 25 mg/m2 orally in the morning and 10 mg/m2 in the evening
  • BSA 1.3 to 1.49 m2: 25 mg/m2 orally in the morning and 20 mg/m2 in the evening
  • BSA 1.5 to 1.69 m2: 25 mg/m2 orally in the morning and 25 mg/m2 in the evening
  • BSA 1.7 to 1.89 m2: 30 mg/m2 orally in the morning and 25 mg/m2 in the evening
  • BSA 1.9 m2 or greater: 30 mg/m2 orally in the morning and 30 mg/m2 in the evening

Administration advice:

  • This drug should be taken on an empty stomach 2 hours before or 1 hour after eating.
  • Swallow capsules whole with water; do not chew, dissolve or open capsule.
  • Do not administer to patients who are unable to swallow a whole capsule.
  • Do not take a missed dose unless it is more than 6 hours until the next scheduled dose.
  • If vomiting occurs after administration, do not take an additional dose, but continue with the next scheduled dose.

Side Effects

The Most Common 

  • vomiting
  • constipation
  • stomach pain
  • nausea
  • dry skin
  • headache
  • mouth ulcers
  • itching
  • redness around the fingernails
  • nose bleeding
  • fatigue
  • loss of appetite
  • hair loss or hair color changes
  • fever
  • unusual bleeding
  • pale skin or tiredness
  • blurred vision; loss of vision; dark spots in your vision; or other vision changes
  • diarrhea
  • rash, skin blisters or peeling
  • muscle pain, aches, or weakness; or dark urine
  • coughing or wheezing; shortness of breath; swelling of ankles and feet; or extreme tiredness

More common

  • Blistering, crusting, irritation, itching, or reddening of the skin
  • blood in urine
  • cracked, dry scaly skin
  • diarrhea
  • fast heartbeat
  • itching, pain, redness, swelling, tenderness, warmth on the skin
  • loosening of the fingernails
  • muscle or bone pain
  • nosebleeds
  • redness or soreness around the fingernails
  • swelling
  • Constipation
  • fever
  • hair loss, thinning of the hair
  • loss of appetite
  • nausea
  • stomach pain
  • swelling or inflammation of the mouth
  • unusual tiredness or weakness
  • vomiting

Rare

  • Blurred vision
  • change in vision
  • difficult or labored breathing
  • dizziness
  • headache
  • nervousness
  • overbright appearance of lights
  • pounding in the ears
  • rapid weight gain
  • seeing flashes or sparks of light
  • seeing floating spots before the eyes, or a veil or curtain across part of your vision
  • slow or fast heartbeat
  • tightness in the chest

Drug Interaction

Pregnancy and Lactation

US FDA pregnancy category: Not assigned.

Pregnancy

Based on findings from animal studies and its mechanism of action, KOSELUGO can cause fetal harm when administered to a pregnant woman. There are no available data on the use of KOSELUGO in pregnant women to evaluate drug-associated risk. In animal reproduction
studies, administration of selumetinib to mice during organogenesis caused reduced fetal weight, adverse structural defects, and effects on embryo-fetal survival at exposures approximately > 5 times the human exposure at the clinical dose of 25 mg/m2 twice daily (see Data). Advise pregnant women of the potential risk to the fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Lactation

There are no data on the presence of selumetinib or its active metabolite in human milk or their effects on the breastfed child or milk production. Selumetinib and its active metabolite were present in the milk of lactating mice (see Data). Due to the potential for adverse reactions in a breastfed child, advise women not to breastfeed during treatment with KOSELUGO and for 1 week after the last dose.

Why is this medication prescribed?

Selumetinib is used to treat neurofibromatosis type 1 (NF1; a nervous system disorder that causes tumors to grow on nerves) in children 2 years of age and older who have plexiform neurofibromas (PN; soft tumors) that cannot be completely removed by surgery. Selumetinib is in a class of medications called kinase inhibitors. It works by blocking the action of the abnormal protein that signals the tumors to grow. This helps to stop or slow tumor growth.

How should this medicine be used?

Selumetinib comes as a capsule to take by mouth. It is usually taken twice a day on an empty stomach. Do not eat any food 2 hours before or for 1 hour after each dose. Take selumetinib at around the same time(s) every day, approximately 12 hours apart. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take selumetinib exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Swallow the capsules whole with water; do not open, chew, or crush them.

If you vomit after taking selumetinib, do not take another dose. Continue your regular dosing schedule.

Your doctor may decrease your dose or temporarily or permanently stop your treatment if you experience certain side effects. Be sure to tell your doctor how you are feeling during your treatment with selumetinib. Ask your pharmacist or doctor for a copy of the manufacturer’s information for the patient. This medication may be prescribed for other uses; ask your doctor or pharmacist for more information.

What special precautions should I follow?

Before taking selumetinib,

  • tell your doctor and pharmacist if you are allergic to selumetinib, any other medications, or any of the ingredients in selumetinib capsules. Ask your pharmacist for a list of the ingredients.
  • tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: anticoagulants (‘blood thinners’) such as warfarin (Coumadin, Jantoven); antifungals such as fluconazole (Diflucan), itraconazole (Sporanox), ketoconazole (Nizoral), and voriconazole (Vfend); aprepitant (Emend); clarithromycin (Biaxin, in Prevpac); clopidogrel (Plavix); corticosteroids such as betamethasone (Celestone), budesonide (Entocort), cortisone (Cortone), dexamethasone (Decadron, Dexpak, Dexasone, others), hydrocortisone (Cortef, Hydrocortone), methylprednisolone (Medrol, Meprolone, others), prednisolone (Prelone, others), and prednisone (Rayos); diltiazem (Cardizem, Dilacor, Tiazac, others); erythromycin (E.E.S., E-Mycin, Erythrocin); certain medications for HIV including indinavir (Crixivan), nelfinavir (Viracept), ritonavir (Norvir, in Kaletra), and saquinavir (Fortovase, Invirase); idelalisib (Zydelig); nefazodone; phenobarbital; rifabutin (Mycobutin); rifampin (Rifadin, Rimactane, in Rifamate, in Rifater); verapamil (Calan, Covera); and vitamin E supplements. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
  • tell your doctor what herbal products you are taking, especially St. John’s wort.
  • tell your doctor if you have or have ever had vision problems, difficulty swallowing, or heart or liver disease.
  • tell your doctor if you are pregnant, plan to become pregnant, or if you plan on fathering a child. If you are female, you will need to take a pregnancy test before you start treatment and use birth control to prevent pregnancy during your treatment and for at least 1 week after your final dose. If you are a male, you and your partner should use birth control during your treatment with selumetinib and for 1 week after your final dose. Talk to your doctor about birth control methods that you can use during your treatment. If you or your partner become pregnant while taking selumetinib, call your doctor immediately. Selumetinib may harm the fetus.
  • tell your doctor if you are breastfeeding. You should not breastfeed while you are taking selumetinib and for 1 week after the final dose.

What special dietary instructions should I follow?

Avoid eating grapefruit or drinking grapefruit juice while taking this medication.

What should I do if I forget a dose?

Take the missed dose as soon as you remember it. However, if it is within 6 hours of the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

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  41. https://pubchem.ncbi.nlm.nih.gov
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  42. https://www.rcsb.org/pages/policies
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  43. Springer Nature
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  44. https://creativecommons.org/licenses/by-nc-nd/4.0/
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  45. https://www.whocc.no/copyright_disclaimer/
    https://www.whocc.no/atc/
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  46. https://creativecommons.org/publicdomain/zero/1.0/
    https://www.wikidata.org/wiki/Q7448840
  47. https://www.nlm.nih.gov/copyright.html
    https://www.ncbi.nlm.nih.gov/mesh/67517975
    http://www.nlm.nih.gov/mesh/meshhome.html
  48. https://www.kegg.jp/kegg/legal.html
    http://www.genome.jp/kegg-bin/get_htext?br08303.keg
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  49. http://www.unece.org/trans/danger/publi/ghs/ghs_welcome_e.html
  50. https://creativecommons.org/licenses/by/4.0/
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  51. https://pubchem.ncbi.nlm.nih.gov/substance/404180194

References

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