Dasatinib is a medication that belongs to a class of drugs known as tyrosine kinase inhibitors (TKIs). It is primarily used in the treatment of certain types of cancer, particularly chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).

Dasatinib works by blocking the activity of specific tyrosine kinases, which are enzymes involved in the growth and division of cells. By inhibiting these kinases, dasatinib helps to slow down or stop the growth of cancer cells, ultimately leading to their destruction.

Dasatinib (Sprycel) is a second-generation tyrosine kinase inhibitor that selectively inhibits BCR/ABL, SRC, Ephrins, and GFR. It is indicated for the treatment of chronic myeloid leukemia in patients resistant or intolerant to first-line therapies and Philadelphia chromosome-positive acute lymphoblastic leukemia.

Indications of Dasatinib (Sprycel):

• Acute lymphoblastic leukemia:
  • Adult:
    • It is indicated for the treatment of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia in adult patients with resistance or intolerance to prior therapy.
  • Pediatric:
    • It is indicated for the treatment of newly diagnosed Ph+ acute lymphoblastic leukemia in combination with chemotherapy in pediatric patients ≥1 year of age.
• Chronic myeloid leukemia:
  • Adult:
    • It is indicated for treating newly diagnosed Ph+ chronic myeloid leukemia (CML) in chronic phase;
    • treatment of chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML with resistance or intolerance to prior therapy, including imatinib.
  • Pediatric:
    • It is used for treating Ph+ CML in chronic phase in pediatric patients ≥1 year of age.
• Off Label Use of Dasatinib in Adults:
  • Gastrointestinal stromal tumor (GIST)

Note: It is not known what happens if you stop taking dasatinib after achieving a good response in treating your cancer. More specifically, if you have seen improvements in your blood cell counts or molecular tests, like achieving a complete response or major response, it is uncertain how stopping the medication might affect your long-term outcome.

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Dasatinib (Sprycel) dose in Adults:

Dasatinib (Sprycel) Treatment dose of Philadelphia chromosome-positive (Ph+) Acute lymphoblastic leukemia:

• In the treatment of Philadelphia chromosome-positive (Ph+) Acute Lymphoblastic Leukemia (ALL), the recommended oral dose of dasatinib is 140 mg taken once daily.
• This dosage should be continued until there is disease progression or unacceptable side effects occur.
• If a patient does not achieve a hematologic or cytogenetic response at the recommended initial dosage, a dose escalation to 180 mg once daily may be considered.
• This higher dosage can be used to potentially improve the treatment response.

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Dasatinib (Sprycel) Treatment dose of Ph+ Chronic myelogenous leukemia, newly diagnosed in chronic phase: 

• In the treatment of newly diagnosed chronic phase Philadelphia chromosome-positive (Ph+) Chronic Myelogenous Leukemia (CML), the recommended oral dose of dasatinib is 100 mg taken once daily.
• This dosage should be continued until there is disease progression or unacceptable side effects occur.
• If a patient does not achieve a hematologic or cytogenetic response at the recommended initial dosage, a dose escalation to 140 mg once daily may be considered.
• This higher dosage can be used to potentially improve the treatment response.

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Dasatinib (Sprycel) Treatment dose of Ph+ CML, (resistant or intolerant): 

• Chronic phase:
  • The initial dose is 100 mg of dasatinib taken once daily.
  • This dosage should be continued until there is disease progression or unacceptable side effects occur.
  • If a patient does not achieve a hematologic or cytogenetic response at the recommended initial dosage, a dose escalation to 140 mg once daily may be considered to improve the treatment response.
• Accelerated or blast phase:
  • The initial dose is 140 mg of dasatinib taken once daily.
  • This dosage should be continued until there is disease progression or unacceptable side effects occur.
  • If a patient does not achieve a hematologic or cytogenetic response at the recommended initial dosage, a dose escalation to 180 mg once daily may be considered to improve the treatment response.

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Dasatinib (Sprycel) Treatment dose of Gastrointestinal stromal tumors (GIST): 

• In the off-label treatment of Gastrointestinal Stromal Tumors (GIST) using dasatinib, the recommended oral dose is 70 mg taken twice daily.

Missed doses:

• If a dose of dasatinib is missed, it is important to take the next regularly scheduled dose. Two doses should not be taken at the same time to make up for the missed dose.

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Dasatinib (Sprycel) Dosage adjustment for concomitant strong CYP3A4 inhibitors:

• Concomitant strong CYP3A4 inhibitors:
  • Avoid administering dasatinib with strong CYP3A4 inhibitors and grapefruit juice if possible.
  • If concomitant administration with a strong CYP3A4 inhibitor cannot be avoided, consider reducing the dasatinib dose as follows:
    • From 140 mg once daily to 40 mg once daily
    • From 100 mg once daily to 20 mg once daily
    • From 70 mg once daily to 20 mg once daily
  • Close monitoring is necessary when using reduced dasatinib doses.
  • If the reduced dasatinib dose is not well tolerated, options include discontinuing the strong CYP3A4 inhibitor or temporarily interrupting dasatinib therapy until the concomitant inhibitor use is discontinued.
  • Once the strong CYP3A4 inhibitor is discontinued, wait for approximately 1 week before adjusting the dasatinib dose upward.

Dasatinib (Sprycel) Dosage adjustment for concomitant strong CYP3A4 inducers:

• Concomitant strong CYP3A4 inducers:
  • Avoid administering dasatinib with strong CYP3A4 inducers, including St. John's wort, if possible.
  • If concomitant administration with a strong CYP3A4 inducer cannot be avoided, consider increasing the dasatinib dose with careful monitoring.
  • Close monitoring is necessary when using an increased dasatinib dose.

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Dasatinib (Sprycel) dose in children:

Dasatinib (Sprycel) Treatment dose of newly diagnosed Philadelphia chromosome-positive (Ph+) Acute lymphoblastic leukemia:

Note:

• When using dasatinib with chemotherapy, start the dasatinib treatment on or before day 15 of the induction chemotherapy.
• Take dasatinib for 2 years without increasing the dose during this time.
• Every 3 months or as needed, the dose may be adjusted based on changes in body weight.
• It's important to follow these instructions and consult with your healthcare provider for personalized guidance.

In the treatment of newly diagnosed Philadelphia chromosome-positive (Ph+) Acute Lymphoblastic Leukemia (ALL) in children weighing 10 kg or more and adolescents, the oral dose of dasatinib is determined based on body weight.

The recommended dosages are as follows:

• Children weighing 10 to less than 20 kg: Take 40 mg of dasatinib once daily.
• Children weighing 20 to less than 30 kg: Take 60 mg of dasatinib once daily.
• Children weighing 30 to less than 45 kg: Take 70 mg of dasatinib once daily.
• Adolescents weighing 45 kg or more: Take 100 mg of dasatinib once daily.

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Dasatinib (Sprycel) Treatment dose of Chronic myelogenous leukemia, Philadelphia chromosome-positive (Ph+), chronic phase:

Note:

• When using dasatinib in the treatment of any condition, it is typically recommended to continue taking the medication until there is disease progression or the occurrence of unacceptable side effects.
• During the course of treatment, the dose of dasatinib should be recalculated every 3 months or as clinically necessary, taking into account any changes in body weight.
• This helps ensure that the dosage remains appropriate and effective for the individual's specific condition.

In the treatment of Philadelphia chromosome-positive (Ph+) Chronic Myelogenous Leukemia (CML) in children weighing 10 kg or more and adolescents in the chronic phase, the oral dose of dasatinib is determined based on body weight.

The recommended initial dosages and possible dose escalation are as follows:

• Children weighing 10 to less than 20 kg: The initial dose is 40 mg of dasatinib once daily. If a hematologic or cytogenetic response is not achieved, the dose may be escalated to 50 mg once daily.
• Children weighing 20 to less than 30 kg: The initial dose is 60 mg of dasatinib once daily. If a hematologic or cytogenetic response is not achieved, the dose may be escalated to 70 mg once daily.
• Children weighing 30 to less than 45 kg: The initial dose is 70 mg of dasatinib once daily. If a hematologic or cytogenetic response is not achieved, the dose may be escalated to 90 mg once daily.
• Adolescents weighing 45 kg or more: The initial dose is 100 mg of dasatinib once daily. If a hematologic or cytogenetic response is not achieved, the dose may be escalated to 120 mg once daily.

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Using concomitant strong CYP3A4 inhibitors:

When taking dasatinib, it's best to avoid using strong CYP3A4 inhibitors and grapefruit juice at the same time. However, if it's not possible to avoid using a strong CYP3A4 inhibitor, there are some recommended dose adjustments to consider.

The dosage reduction depends on the current daily dose of dasatinib:

• If you are currently taking 40 mg or 60 mg of dasatinib, it may be necessary to stop the therapy until you can discontinue the strong CYP3A4 inhibitor. After the inhibitor is discontinued, wait for about 1 week before restarting dasatinib.
• If you are currently taking 70 mg or 100 mg of dasatinib, the dose should be decreased to 20 mg once daily.
• If you are currently taking 140 mg of dasatinib, the dose should be decreased to 40 mg once daily.

It's important to monitor patients closely during this time. If the reduced dose of dasatinib is not well tolerated, either stop using the strong CYP3A4 inhibitor or temporarily interrupt dasatinib therapy until the inhibitor is discontinued. Once the strong CYP3A4 inhibitor is discontinued, wait for about 1 week before adjusting the dasatinib dose upward.

Using concomitant strong CYP3A4 inducers:

When taking dasatinib, it is recommended to avoid using strong CYP3A4 inducers, including St. John's wort, at the same time. If it's not possible to avoid using a strong CYP3A4 inducer, there are some considerations to keep in mind:

• Strong CYP3A4 inducers should be avoided when taking dasatinib.
• If it is necessary to use a strong CYP3A4 inducer, the dasatinib dose may need to be increased.
• However, any dosage adjustment should be done with careful monitoring by a healthcare provider.
• It's crucial to work closely with your healthcare provider to determine the appropriate dosage adjustment based on your specific situation.

It's important to note that strong CYP3A4 inducers can affect the metabolism of dasatinib, potentially reducing its effectiveness. Therefore, avoiding concomitant administration with strong CYP3A4 inducers is generally recommended.

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Dasatinib (Sprycel) Dosing adjustment for toxicity:

Hematologic toxicity:

• In acute lymphoblastic leukemia, Philadelphia chromosome-positive (Ph+ ALL):
  • If neutropenia and/or thrombocytopenia cause a treatment delay of more than 14 days, pause dasatinib and resume at the same level when the next block of treatment begins.
  • If the blood cell counts remain low and the next block of treatment is delayed for another 7 days, a bone marrow assessment is recommended.
  • If the marrow cellularity is less than 10%, interrupt dasatinib until the absolute neutrophil count (ANC) is above 500/mm and then resume dasatinib at the full dose.
  • If the marrow cellularity is above 10%, consider resuming dasatinib.
• In chronic myelogenous leukemia, Philadelphia chromosome-positive (Ph+ CML):
  • If cytopenia (low blood cell counts) such as neutropenia or thrombocytopenia persists for more than 3 weeks, a marrow aspirate or biopsy should be performed to determine if it's due to leukemia.
  • If the cytopenia is unrelated to leukemia, dasatinib should be withheld until the ANC is equal to or above 1,000/mm and platelets are equal to or above 75,000/mm.
  • Afterward, dasatinib can be resumed at the original starting dose or at a reduced dose.
  • If the cytopenia recurs, another marrow aspirate/biopsy should be done, and dasatinib can be resumed at a reduced dose.
  • Temporary dose reductions may also be used for intermediate degrees of cytopenia and disease response, as needed.

Recommended dose reductions for neutropenia and thrombocytopenia in Ph+ CML:

• Original starting dose: 40 mg daily → May reduce dose to 20 mg once daily (one-level dose reduction).
• Original starting dose: 60 mg once daily → May reduce dose to 40 mg once daily (one-level dose reduction), and then to 20 mg once daily (two-level dose reduction).
• Original starting dose: 70 mg once daily → May reduce dose to 60 mg once daily (one-level dose reduction), and then to 50 mg once daily (two-level dose reduction).
• Original starting dose: 100 mg once daily → May reduce dose to 80 mg once daily (one-level dose reduction), and then to 70 mg once daily (two-level dose reduction).

Nonhematologic toxicity:

• For Ph+ ALL:
  • Grade 2 toxicity: If there is no recovery despite symptomatic management, consider interrupting dasatinib therapy.
  • Once the toxicity improves to grade 1 or lower, dasatinib can be resumed at the original starting dose. If the event recurs, resume dasatinib at a reduced dose (see dose reductions).
  • Grade ≥3 toxicity: Withhold dasatinib until the toxicity improves to grade 1 or lower, and then resume at a reduced dose (see dose reductions).

Recommended dose reductions for non-hematologic toxicities in Ph+ ALL:

• Original starting dose: 40 mg daily → May reduce dose to 20 mg once daily (one-level dose reduction).
• Original starting dose: 60 mg once daily → May reduce dose to 40 mg once daily (one-level dose reduction), and then to 20 mg once daily (two-level dose reduction).
• Original starting dose: 70 mg once daily → May reduce dose to 60 mg once daily (one-level dose reduction), and then to 50 mg once daily (two-level dose reduction).
• Original starting dose: 100 mg once daily → May reduce dose to 80 mg once daily (one-level dose reduction), and then to 70 mg once daily (two-level dose reduction).

For severe nonhematologic toxicity in Ph+ CML, treatment should be withheld until there is an improvement or resolution of the toxicity. If appropriate, dasatinib can be resumed at a reduced dose based on the severity and recurrence of the event.

Management strategies for specific toxicities such as dermatologic toxicities, fluid retention, pleural effusion, and pulmonary arterial hypertension are also mentioned. Discontinuation of dasatinib is recommended for confirmed pulmonary arterial hypertension.

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Dasatinib (Sprycel) Pregnancy Risk Category: X

• Dasatinib can pass from the mother to the fetus during pregnancy, and the levels of dasatinib in the fetal plasma and amniotic fluid are similar to those in the mother.
• There have been reports of negative effects on the fetus, such as hydrops fetalis (excessive fluid buildup) and reduced white blood cell and platelet counts, when pregnant women were exposed to dasatinib.
• It is important for females who can become pregnant to use reliable contraception while receiving dasatinib treatment and for 30 days after the final dose.
• Pregnant women should avoid handling crushed or broken dasatinib tablets to minimize the risk of exposure.

Use of dasatinib while breastfeeding

• The presence of dasatinib in breast milk is not known.
• The manufacturer does not recommend breastfeeding during dasatinib treatment and for 2 weeks after the final dose due to the potential for serious adverse reactions in the nursing infant.
• It is important to consult with a healthcare professional for personalized advice regarding breastfeeding and the use of dasatinib.

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Dasatinib (Sprycel) Dose adjustment in renal impairment:

• According to the manufacturer's labeling, no specific dosage adjustments are provided for dasatinib based on renal function.
• This is because only a small percentage (less than 4%) of dasatinib and its metabolites are eliminated through the kidneys.
• Therefore, dose modifications based on renal impairment are not typically necessary.

Dasatinib (Sprycel) Dose adjustment in liver disease:

• No initial dosage adjustment is required for dasatinib.
• However, caution should be exercised when using the medication.
• If there are elevations in transaminase (liver enzyme) or bilirubin levels during treatment, they can be managed by temporarily interrupting the treatment or reducing the dose.
• This approach helps to mitigate the potential liver-related side effects of dasatinib.

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Common Side Effects of Dasatinib (Sprycel):

• Cardiovascular:
  • Facial Edema
  • Peripheral Edema
• Central Nervous System:
  • Headache
  • Fatigue
  • Pain
• Dermatologic:
  • Skin Rash
  • Pruritus
• Endocrine & Metabolic:
  • Fluid Retention
• Gastrointestinal:
  • Diarrhea
  • Nausea
  • Vomiting
  • Abdominal Pain
• Hematologic & Oncologic:
  • Thrombocytopenia
  • Neutropenia
  • Anemia
  • Hemorrhage
  • Febrile Neutropenia
• Infection:
  • Infection
• Local:
  • Localized Edema
• Neuromuscular & Skeletal:
  • Musculoskeletal Pain
  • Limb Pain
  • Myalgia
  • Arthralgia
• Respiratory:
  • Pleural Effusion
  • Dyspnea
• Miscellaneous:
  • Fever

Rare Side Effects Of Dasatinib (Sprycel):

• Cardiovascular:
  • Cardiac Conduction problems and QT-interval prolongation
  • Ischemic Heart Disease, Cardiac Arrhythmias, and Pericardial effusion
  • Swelling of feet, Chest Pain, and palpitations
  • Flushing
  • Hypertension
  • Tachycardia
• Central Nervous System:
  • Intracranial bleeding
  • Chills
  • Depression
  • Dizziness
  • Drowsiness or Insomnia
  • Myasthenia-like symptoms and Neuropathy
• Dermatologic:
  • Acne 
  • Alopecia
  • Eczema (Dermatitis)
  • Hyperhidrosis (excessive sweating)
  • Urticaria
  • Xeroderma
• Endocrine & Metabolic:
  • Stunted Growth and growth Suppression
  • Hyperuricemia
  • Weight Gain or weight loss
• Gastrointestinal:
  • Constipation, abdominal distension
  • GI bleeding
  • Change In Appetite
  • Colitis, Gastritis, Mucositis, and Stomatitis
  • Abnormal taste
  • Dyspepsia
• Hematologic & Oncologic:
  • Bruise
• Hepatic:
  • Increased levels of Bilirubin, ALT, and AST
  • Ascites
• Infection:
  • Herpes Virus Infection
  • Sepsis
• Neuromuscular & Skeletal:
  • Muscle Spasm and stiffness
  • Abnormal Bone Growth
  • Asthenia
• Ophthalmic:
  • Blurred Vision or visual disturbances
  • Decreased Visual Acuity
  • Dry Eye Syndrome
• Otic:
  • Tinnitus
• Renal:
  • Increased Serum Creatinine
• Respiratory:
  • Pulmonary Hypertension
  • Pulmonary Edema
  • Cough
  • Pneumonia, Pneumonitis
  • Pulmonary Infiltrates or chest radiograph
  • Upper Respiratory Tract Infection
• Miscellaneous:
  • Soft Tissue Injury

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Contraindications to Dasatinib (Sprycel):

• In the US labeling of dasatinib, there are no specific situations where the use of dasatinib is completely prohibited.

• In the Canadian labeling, dasatinib is contraindicated in individuals who have a known hypersensitivity or allergy to dasatinib or any other component of the medication. Additionally, breastfeeding is contraindicated while taking dasatinib in Canada due to potential risks to the nursing infant.

Warnings and precautions

Suppression of bone marrow

• Dasatinib treatment is associated with a significant risk of bone marrow suppression, which can lead to low platelet count, low white blood cell count (neutropenia), and low red blood cell count (anemia).
• However, this bone marrow suppression is usually reversible by adjusting the dosage of dasatinib or temporarily interrupting the treatment.
• The incidence of myelosuppression is higher in patients with advanced chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL).
• To monitor for this side effect, blood counts should be checked every 2 weeks for the first 12 weeks and then every 3 months thereafter for patients with chronic phase CML.
• For patients with accelerated or blast phase CML or ALL, blood counts should be checked weekly for the first 2 months and then monthly or as needed.
• In pediatric patients with Philadelphia chromosome-positive ALL, blood counts should be monitored before each block of chemotherapy and as clinically indicated, with more frequent monitoring during the consolidation blocks of chemotherapy until recovery.

Cardiovascular adverse events

• Dasatinib can potentially affect the heart and may lead to cardiac dysfunction, including events like cardiac ischemia (reduced blood flow to the heart), fluid retention-related issues, and abnormalities in heart conduction (which can cause irregular heartbeat or palpitations).
• It is important to be vigilant for any signs or symptoms of cardiac dysfunction while undergoing dasatinib treatment.
• Regular monitoring of blood pressure is also recommended during treatment.
• If necessary, appropriate antihypertensive treatment may be initiated to help reduce the risk of heart-related complications.

Dermatologic toxicities:

• Dasatinib has been associated with severe mucocutaneous dermatologic reactions, such as Stevens-Johnson syndrome and erythema multiforme.
• If you experience a severe mucocutaneous reaction while taking dasatinib, and other possible causes have been ruled out, it is important to discontinue the medication.
• These reactions can be serious, and it is crucial to seek medical attention promptly for appropriate evaluation and management.

Fluid retention

• Dasatinib can cause fluid retention, which may manifest as pleural and pericardial effusions, pulmonary hypertension, and swelling in different parts of the body.
• If you experience symptoms such as difficulty breathing (especially during physical activity or at rest), chest pain when breathing deeply, or a dry cough, it is important to seek medical attention promptly.
• Diagnostic imaging, such as a chest X-ray, may be recommended to assess for the presence of fluid accumulation.
• Treatment for fluid retention may involve supportive care, such as the use of diuretics or corticosteroids.
• In severe cases, thoracentesis (fluid removal from the chest) and oxygen therapy may be necessary.
• Adjusting the dose or temporarily interrupting treatment may also be considered.
• Taking dasatinib once daily instead of twice daily has been associated with a lower risk of fluid retention.
• It is important to note that the risk of pleural effusion (fluid accumulation around the lungs) is higher in patients with a history of high blood pressure, previous heart problems, or when dasatinib is administered twice daily.
• If a pleural effusion of grade 2 or higher is observed, treatment may be interrupted, and it may be possible to resume at a lower dose after the effusion resolves.
• Grade 3 or 4 fluid retention/pleural effusion has been observed in adults, while grade 1 or 2 fluid retention has been seen in pediatric patients.
• Use dasatinib with caution in patients with conditions such as cardiovascular disease (heart failure or hypertension) or pulmonary disease, as fluid accumulation may be poorly tolerated in these individuals.
• Regular monitoring and close medical supervision are important to manage fluid retention effectively.

Hemorrhage

• Dasatinib carries a risk of serious and potentially fatal bleeding, including bleeding in the central nervous system (CNS).
• The most common site of bleeding is the gastrointestinal tract.
• Hemorrhage of grades 3 or 4 often necessitates treatment interruptions and blood transfusions.
• In clinical studies, most bleeding incidents were observed in patients with severe thrombocytopenia (low platelet count), although dasatinib can also affect platelet function.
• It is important to note that taking medications that inhibit platelet function or anticoagulants concurrently with dasatinib may further increase the risk of bleeding.
• It is crucial to closely monitor for signs of bleeding and promptly report any unusual bleeding, including persistent or excessive bleeding.

Hypertension in the pulmonary arterial system:

• Dasatinib has been associated with an increased risk of pulmonary arterial hypertension (PAH) in both adults and pediatric patients.
• PAH can occur at any time during treatment, even after more than a year of therapy.
• Before starting dasatinib and throughout the treatment, it is important to assess and evaluate patients for underlying cardiopulmonary conditions.
• If patients experience symptoms suggestive of PAH, such as shortness of breath, fatigue, low oxygen levels, or fluid retention, further evaluation should be conducted to rule out other potential causes.
• In severe cases, treatment with dasatinib may need to be interrupted.
• If a confirmed diagnosis of PAH is made, dasatinib should be discontinued permanently.
• It is worth noting that PAH may be reversible upon discontinuation of dasatinib.
• Close monitoring and early intervention are essential to ensure the timely management of this potential complication.

QT-Interval prolongation

• Dasatinib has the potential to increase the risk of QT interval prolongation, which may pose a risk for cardiac arrhythmias.
• Some patients treated with dasatinib have experienced a QTc (corrected QT interval) exceeding 500 milliseconds.
• Therefore, caution should be exercised when prescribing dasatinib to patients who are already at risk for QT prolongation.
• This includes patients with a history of long QT syndrome, those taking antiarrhythmic medications or other drugs known to prolong the QT interval, individuals receiving potassium-wasting diuretics, patients with a history of high-dose anthracycline therapy, and those with conditions that can cause low levels of potassium or magnesium in the body.
• It is important to correct any existing hypokalemia (low potassium levels) and hypomagnesemia (low magnesium levels) before initiating dasatinib therapy and monitor these electrolyte levels during treatment.
• By addressing these factors, healthcare providers can help mitigate the risk of QT prolongation and its potential complications.

Tumor lysis syndrome

• In some cases, dasatinib treatment has been associated with a condition called tumor lysis syndrome (TLS).
• TLS can occur in patients who have not responded well to imatinib therapy, particularly those with advanced-stage disease.
• The risk of developing TLS is higher in patients with advanced disease and a large tumor burden.
• To minimize the risk of TLS, it is important to closely monitor patients who are at higher risk.
• Adequate hydration should be maintained, and levels of uric acid and electrolytes should be corrected before initiating dasatinib treatment.
• Regular monitoring of electrolyte levels is also recommended.
• By closely monitoring and managing these factors, healthcare providers can help reduce the risk of tumor lysis syndrome in patients receiving dasatinib.

Hepatic impairment

• Caution should be exercised when using dasatinib in patients with hepatic impairment.
• Dasatinib is extensively metabolized in the liver, so patients with compromised liver function may have altered drug metabolism.
• Close monitoring and appropriate dose adjustments may be necessary in these patients to ensure the drug is used safely and effectively.

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Dasatinib: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Drug Interactions: Risk Category C Drugs (Need to be Cautious)
Increased risk of bleeding	Antiplatelets, NSAIDs, SSRIs, Anticoagulants
Increased levels of Dasatinib	Moderate CYP3A4 inhibitors Aprepitant Clofazimine Denosumab Duvelisib Fosaprepitant Fosnetupitant Larotrectinib Netupitant Palbociclib Simeprevir
Decreased levels of Dasatinib	Moderate CYP3A4 Inducers Bosentan Deferasirox Erdafitinib Sarilumab Siltuximab Tocilizumab
Increased risk of Bone Marrow Suppression	Chloramphenicol Ophthalmic Ocrelizumab Promazine Siponimod Trastuzumab
Skin testing may be falsely normal	Coccidioides immitis skin test
Increased risk of QT interval	Haloperidol Ondansetron Pentamidine Systemic Antidepressants Antipsychotics Class 1C antiarrhythmic drugs Kinase inhibitors CYP3A4 Inhibitors Quinolones
The therapeutic effects of these drugs is reduced	Pidotimod Sipuleucel - T Tertomotide

Drug Interactions: Risk Category D Drugs (Avoid these drugs if possible, may need dose adjustment if given together with Dasatinib)
Increased risk of Hepatotoxicity	Paracetamol (Acetaminophen)
Increased levels of Dasatinib	Strong CYP3A4 inhibitors Mifepristone Mitotane Stiripentol Tofacitinib
Decreased levels of Dasatinib	Antacids Strong CYP3A4 Inducers Dabrafenib Dexamethasone  Enzalutamide Lorlatinib Pitolisant
Increased risk of Immunosuppression and/or Bone Marrow Suppression	Baricitinib Fingolimod Leflunomide Roflumilast
Reduced efficacy of Vaccines	Inactivated Vaccines
Increased risk of QT interval	Domperidone
The therapeutic effects of these drugs is reduced	Echinacea Nivolumab

Drug Interactions: Risk Category X Drugs (Avoid these drugs)
Increased levels of Dasatinib	Conivaptan Fusidic Acid (Systemic) Grapefruit Juice Idelalisib
Decreased levels of Dasatinib	H2 Blockers PPIs St John's Wort
Increased risk of Immunosuppression and/or Bone Marrow Suppression	Cladribine Deferiprone Dipyrone Natalizumab Pimecrolimus Tacrolimus
Reduced efficacy of Vaccines	Live vaccines
Increased risk of QT interval	Pimozide Saquinavir
The therapeutic effects of these drugs is reduced	Intravesical BCG

Monitoring parameters:

• Complete Blood Count (CBC) with differential:
  • Chronic Phase Chronic Myeloid Leukemia (CML): Every 2 weeks for 12 weeks, then every 3 months or as clinically indicated.
  • Accelerated or Blast Phase CML or Acute Lymphoblastic Leukemia (ALL): Weekly for 2 months, then monthly or as clinically necessary.
  • Pediatric Patients with Ph+ ALL: Prior to each block of chemotherapy and as clinically indicated, and every 2 days until recovery during consolidation blocks of chemotherapy.
• Bone marrow biopsy.
• LFTs, RFTs, and electrolytes (including calcium, phosphorus, magnesium).
• Monitor for fluid retention and symptoms of cardiac dysfunction.
• Electrocardiogram (ECG) monitoring if at risk for QT prolongation.
• A chest x-ray is recommended for symptoms suggestive of pleural effusion (such as cough or dyspnea).
• Monitor for signs and symptoms of tumor lysis syndrome and dermatologic reactions.
• Monitor bone growth and development in children
• Routine BP and compliance with the treatment.

Thyroid Function Testing Recommendations (Hamnvik 2011):

• For patients with preexisting levothyroxine therapy:
  • Obtain baseline thyroid-stimulating hormone (TSH) levels.
  • Monitor TSH levels every 4 weeks until levels and levothyroxine dose are stable.
  • Once stable, monitor TSH levels every 2 months.
• For patients without preexisting thyroid hormone replacement:
  • Baseline TSH testing.
  • Monthly TSH monitoring for 4 months.
  • After 4 months, monitor TSH levels every 2 to 3 months.

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How to administer Dasatinib (Sprycel)?

Oral Administration of Dasatinib:

• Frequency: Take once daily, either in the morning or evening.
• Food: Can be taken with or without food. If gastrointestinal upset occurs, it can be taken with a meal.
• Swallowing: Take the tablets whole. Do not break, cut, crush, or chew them.
• Proton Pump Inhibitors and H Blockers: Do not take proton pump inhibitors and H blockers (medications that reduce stomach acid) at the same time as dasatinib. If needed, antacids can be considered, but they should be taken at least 2 hours before or 2 hours after the dasatinib dose.

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Mechanism of action of Dasatinib (Sprycel):

Dasatinib is a medication classified as a BCR-ABL tyrosine kinase inhibitor. It is primarily used to treat certain types of leukemia, particularly chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Here are some key points about dasatinib's mechanism of action:

• Target: Dasatinib specifically targets the BCR-ABL protein, which is an abnormal tyrosine kinase produced by the Philadelphia chromosome genetic mutation.
• Inhibition of BCR-ABL: Dasatinib binds to both active and inactive forms of the ABL kinase, which is part of the BCR-ABL fusion protein. By inhibiting this kinase, dasatinib effectively blocks the proliferation of leukemia cells.
• Imatinib Resistance: Dasatinib is particularly effective against BCR-ABL mutations that have become resistant to imatinib, another commonly used tyrosine kinase inhibitor. However, it is not effective against certain specific mutations, such as T315I and F317V.
• Additional Targets: In addition to BCR-ABL, dasatinib also inhibits other tyrosine kinases, including members of the SRC family (such as SRC, LCK, YES, and FYN), c-KIT, EPHA2, and platelet-derived growth factor receptor beta (PDGFRβ).

By targeting these various kinases, dasatinib helps to interrupt the abnormal signaling pathways that drive the growth and survival of leukemia cells. This inhibition plays a crucial role in the treatment of certain types of leukemia.

Distribution:

• The volume of distribution of dasatinib is approximately 2,505 liters, indicating that it is widely distributed throughout the body.

Protein Binding:

• Dasatinib has a high protein binding capacity, with approximately 96% of the drug binding to plasma proteins.
• The active metabolite also exhibits significant protein binding, with about 93% bound to plasma proteins.

Bioavailability:

• The bioavailability of dasatinib can be affected when the tablets are dispersed in juice.
• In a study conducted in healthy adults, the adjusted geometric mean ratio for the area under the concentration-time curve (AUC) was 0.84 when dasatinib tablets were dispersed in juice compared to intact tablets.

Metabolism:

• Dasatinib undergoes extensive hepatic metabolism primarily mediated by the enzyme CYP3A4.
• It is also metabolized by flavin-containing monooxygenase-3 (FOM-3) and uridine diphosphate-glucuronosyltransferase (UGT).
• These metabolic processes result in the formation of an active metabolite as well as other inactive metabolites.
• However, the active metabolite has a minor role in the pharmacology of dasatinib.

Elimination Half-life:

• The elimination half-life of dasatinib is approximately 3 to 5 hours in adults and 2 to 5 hours in pediatric patients.
• The terminal elimination half-life refers to the time it takes for the drug to decrease by half during the elimination phase.

Time to Peak Plasma Concentration:

• Dasatinib reaches its peak plasma concentration within a range of 0.5 to 6 hours after administration.

Excretion:

• The majority of dasatinib and its metabolites are excreted in the feces, accounting for approximately 85% of the administered dose.
• Only a small percentage, around 4% of the dose, is excreted in the urine, with a minimal amount being excreted unchanged.

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International Brand Names of Dasatinib:

• Sprycel
• Dasanix
• Etersa
• Liteda
• Rembre

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Dasatinib Brand Names in Pakistan:

Not available.