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达沙替尼片使用说明书  

功能主治：

本品用于治疗对甲磺酸伊马替尼耐药，或不耐受的费城染色体阳性（Ph+）慢性髓细胞白血病（CML）慢性期、加速期和急变期（急粒变和急淋变）成年患者。

用法用量：

应当由具有白血病诊断和治疗经验的医师进行治疗。
Ph+慢性期CML的患者推荐起始剂量为达沙替尼100mg，每日1次，口服。服用时间应当一致，早上或晚上均可。
Ph+加速期、急变期(急粒变和急淋变)CML的患者推荐起始剂量为70mg，每日2次，分别于早晚口服(见【注意事项】)。
片剂不得压碎或切割，必须整片吞服。本品可与食物同服或空腹服用。
治疗持续时间：在临床试验中，本品治疗均持续至疾病进展或患者不再耐受该治疗。尚未对达到完全细胞遗传学缓解(CCyR)后停止治疗的影响进行研究。
为了达到所推荐的剂量，本品共有20mg、50mg、70mg和100mg薄膜衣片四种规格。推荐根据患者的反应和耐受性情况进行剂量的增加或降低。
剂量递增：
在成年Ph+ CML患者的临床试验中，如果患者在推荐的起始剂量治疗下未能达到血液学或细胞遗传学缓解，则慢性期CML患者可以将剂量增加至140mg，每日1次，对于进展期(加速期和急变期)CML患者，可以将剂量增加至90mg，每日2次。
不良反应发生时的剂量调整：
骨髓抑制：
在临床试验中，骨髓抑制可以通过下列手段来处理：中断给药、剂量降低或终止研究治疗。必要时给予血小板和红细胞输注。出现耐药性骨髓抑制(如嗜中性粒细胞减少症状持续超过7天)的可使用造血生长因子。非血液学不良反应：
如果在达沙替尼用药过程中发生了重度非血液学不良反应，那么必须停止治疗，直至事件解决。随后，治疗可以以适当降低后的剂量重新开始，剂量降低的程度根据最初事件的严重程度来定。
儿童患者：由于缺少安全性和疗效数据，不推荐本品用于儿童和18岁以下的青少年(见【药理毒理】“药效学特点”)。
老年患者：在老年患者中没有观察到具有临床意义的与年龄相关的药代动力学方面的差异。没有必要针对老年患者进行专门的剂量推荐。
肝功能损害：轻度、中度或重度肝功能损害的患者可以接受推荐的起始剂量。尽管如此，本品应慎用于肝功能损害的患者(见【注意事项】和【药代动力学】)。
肾功能损害：尚未在肾功能降低的患者中进行本品的临床试验(试验排除了血清肌酐浓度>1.5倍正常上限的患者)。由于达沙替尼及其代谢产物在肾脏的清除率<4%，因此，肾功能不全的患者预期不会出现全身清除率的降低。

· 不良反应：

· 国外安全性数据
下列数据为临床试验中2,182例患者对本品的暴露情况的总结(起始剂量为100mg每日1次，140mg每日1次，50mg每日2次或70mg每日2次，伴随至少24个月的随访期)。在接受本品治疗的2,182例患者中，25%患者的年龄≥65岁，5%患者的年龄≥75岁。中位的治疗持续时间为15个月(范围为0.03至36个月)。
大部分达沙替尼治疗组患者在某个时间出现了不良反应。大部分反应均为轻度至中度。慢性期CML患者中有15%，加速期CML患者中有16%，急粒变CML患者中有15%，急淋变CML患者中有8%，Ph+ ALL患者中有8%由于不良反应中止治疗。在慢性期CML患者的III期剂量优化研究中，接受100mg，每日1次治疗的患者中因药物不良反应而中止治疗的比例要低于接受70mg，每日2次治疗的患者(分别为10%和16%);接受100mg，每日1次治疗的患者中断给药和降低剂量的比例也低于接受70mg，每日2次治疗的患者。接受140mg，每日1次治疗的进展期CML和Ph+ ALL患者中降低剂量和中断给药的发生率也低于接受70mg，每日2次治疗的患者。
大部分伊马替尼不耐受的慢性期CML患者能够耐受达沙替尼治疗。在慢性期CML的临床研究中，215例对伊马替尼不耐受的患者中，有10例出现了与既往接受伊马替尼治疗时同等程度的3级或4级的非血液学毒性;这10例患者中的8例可通过降低药物剂量得到控制，并可以继续接受本品治疗。
最常见的不良反应包括体液潴留(包括胸腔积液)、腹泻、头痛、恶心、皮疹、呼吸困难、出血、疲劳、肌肉骨骼疼痛、感染、呕吐、咳嗽、腹痛和发热。与药物相关的发热性中性粒细胞减少症的发生率为5%。
不良反应例如胸腔积液、腹水、肺水肿和伴或不伴浅表性水肿的心包积液被统一描述为“体液潴留”。3级或4级的体液潴留的发生率为10%。3级或4级的胸腔和心包积液的发生率分别为7%和1%。3级或4级的腹水和全身水肿的发生率均<1%。1%患者出现了3级或4级的肺水肿。体液潴留的常规处理方法是支持治疗，包括利尿剂或短期的激素治疗。虽然本品在老年患者中的安全性特征与其在年轻人群中的安全性特征类似，但是年龄≥65岁的患者更有可能出现体液潴留和呼吸困难事件，应当对其进行密切的观察(见【注意事项】)。
服用本品的患者中报告了与药物相关的出血事件(从瘀斑和鼻衄到3级或4级的胃肠道出血和CNS出血)(见【注意事项】)。重度CNS出血的发生率<1%。有8例患者为致死性，其中6例与CTC 4级血小板减少症相关。3级或4级的胃肠道出血的发生率为4%，通常都需要中断治疗并输血。其它3级或4级出血的发生率为2%。大部分出血相关事件均伴随有3级或4级的血小板减少症。此外，体外和体内的血小板检测提示，本品的治疗对血小板活化作用具有可逆的影响(见【注意事项】)。
本品治疗会伴有贫血、中性粒细胞减少症和血小板减少症。上述事件在进展期CML或Ph+ ALL患者中要比慢性期CML患者更为常见(见【注意事项】)。
临床试验中推荐在开始本品治疗前，伊马替尼应停用至少7天。
在本品临床试验的患者中报告了下列不良反应(实验室检查结果异常除外)(见表2)。按系统器官分类和发生率列出了以下反应。频率的定义如下：非常常见(≥1/10);常见(≥1/100至<1/10);不常见(≥1/1,000至<1/100);罕见(≥1/10,000至<1/1,000)。在每个频率组内，不良反应按严重程度递减的顺序列出。  

 

 

Pronunciation

(da SA ti nib)

Index Terms

BMS-354825

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Sprycel: 20 mg, 50 mg, 70 mg, 80 mg, 100 mg, 140 mg

Brand Names: U.S.

Sprycel

Pharmacologic Category

Antineoplastic Agent, BCR-ABL Tyrosine Kinase InhibitorAntineoplastic Agent, Tyrosine Kinase Inhibitor

Pharmacology

BCR-ABL tyrosine kinase inhibitor; targets most imatinib-resistant BCR-ABL mutations (except the T315I and F317V mutants) by distinctly binding to active and inactive ABL-kinase. Kinase inhibition halts proliferation of leukemia cells. Also inhibits SRC family (including SRC, LKC, YES, FYN); c-KIT, EPHA2 and platelet derived growth factor receptor (PDGFRβ)

Distribution

2505 L

Metabolism

Hepatic (extensive); metabolized by CYP3A4 (primarily), flavin-containing mono-oxygenase-3 (FOM-3) and uridine diphosphate-glucuronosyltransferase (UGT) to an active metabolite and other inactive metabolites (the active metabolite plays only a minor role in the pharmacology of dasatinib)

Excretion

Feces (~85%, 19% as unchanged drug); urine (~4%, 0.1% as unchanged drug)

Time to Peak

0.5 to 6 hours

Half-Life Elimination

Terminal: 3 to 5 hours

Protein Binding

Dasatinib: 96%; metabolite (active): 93%

Special Populations: Renal Function Impairment

Only 4% of the drug and its metabolites are excreted by the kidney.

Special Populations: Hepatic Function Impairment

Patients with moderate hepatic impairment had decreases in dose-normalized Cmax and AUC by 47% and 8%, respectively. Patients with severe hepatic impairment had decreases in dose-normalized Cmaxand AUC of 43% and 28%, respectively, compared with healthy controls.

Use: Labeled Indications

Acute lymphoblastic leukemia: Treatment of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) with resistance or intolerance to prior therapy.

Chronic myeloid leukemia: Treatment of 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.

Off Label Uses

Gastrointestinal stromal tumor (GIST)

Data from two phase II studies support the use of dasatinib for the treatment of GIST [Montemurro 2012], [Trent 2011]. Additional trials may be necessary to further define the role of dasatinib in this condition.

Contraindications

There are no contraindications listed in the manufacturer's US labeling.

Canadian labeling: Hypersensitivity to dasatinib or any other component of the formulation; breast-feeding

Dosing: Adult

Note: The effect of discontinuation on long-term disease outcome after achieving cytogenetic response (including complete cytogenetic response) or major molecular response is not known.

Chronic myelogenous leukemia (CML), Philadelphia chromosome-positive (Ph+), newly diagnosed in chronic phase: Oral: 100 mg once daily until disease progression or unacceptable toxicity. In clinical studies, a dose escalation to 140 mg once daily was allowed in patients not achieving hematologic or cytogenetic response at recommended initial dosage.

CML, Ph+, resistant or intolerant: Oral:

Chronic phase: 100 mg once daily until disease progression or unacceptable toxicity. In clinical studies, a dose escalation to 140 mg once daily was allowed in patients not achieving hematologic or cytogenetic response at recommended initial dosage.

Accelerated or blast phase: 140 mg once daily until disease progression or unacceptable toxicity. In clinical studies, a dose escalation to 180 mg once daily was allowed in patients not achieving hematologic or cytogenetic response at recommended initial dosage.

Acute lymphoblastic leukemia (ALL), Ph+: Oral: 140 mg once daily until disease progression or unacceptable toxicity. In clinical studies, a dose escalation to 180 mg once daily was allowed in patients not achieving hematologic or cytogenetic response at recommended initial dosage.

Gastrointestinal stromal tumors (GIST; off-label use): Oral: 70 mg twice daily (Montemurro 2012; Trent 2011).

Missed doses: If a dose is missed, take the next regularly scheduled dose; 2 doses should not be taken at the same time.

Dosage adjustment for concomitant CYP3A4 inhibitors: Avoid concomitant administration with strong CYP3A4 inhibitors (eg, clarithromycin, itraconazole, ketoconazole, nefazodone, protease inhibitors, telithromycin, voriconazole, grapefruit juice); if concomitant administration with a strong CYP3A4 inhibitor cannot be avoided, consider reducing dasatinib from 100 mg once daily to 20 mg once daily or from 140 mg once daily to 40 mg once daily, with careful monitoring. If reduced dose is not tolerated, the strong CYP3A4 inhibitor must be discontinued or dasatinib therapy temporarily held until concomitant inhibitor use has ceased. When a strong CYP3A4 inhibitor is discontinued, allow a washout period (~1 week) prior to adjusting dasatinib dose upward.

Dosage adjustment for concomitant CYP3A4 inducers: Avoid concomitant administration with strong CYP3A4 inducers (eg, carbamazepine, dexamethasone, phenobarbital, phenytoin, rifabutin, rifampin, St John’s wort); if concomitant administration with a strong CYP3A4 inducer cannot be avoided, consider increasing the dasatinib dose with careful monitoring.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling. However, <4% of dasatinib and metabolites are renally excreted.

Dosing: Hepatic Impairment

No initial dosage adjustment is necessary; use with caution. Transaminase or bilirubin elevations during treatment may be managed with treatment interruption or dose reduction.

Dosing: Adjustment for Toxicity

Hematologic toxicity: Note: Growth factor support may be considered in patients with resistant myelosuppression.

Chronic phase CML (100 mg daily starting dose): For ANC <500/mm3 or platelets <50,000/mm3, withhold treatment until ANC ≥1000/mm3 and platelets ≥50,000/mm3; then resume treatment at the original starting dose if recovery occurs in ≤7 days. If platelets <25,000/mm3 or recurrence of ANC <500/mm3 for >7 days, withhold treatment until ANC ≥1000/mm3 and platelets ≥50,000/mm3; then resume treatment at 80 mg once daily (second episode). For third episode, further reduce dose to 50 mg once daily (for newly diagnosed patients) or discontinue (for patients resistant or intolerant to prior therapy)

Accelerated or blast phase CML and Ph+ ALL (140 mg once daily starting dose): For ANC <500/mm3 or platelets <10,000/mm3, if cytopenia unrelated to leukemia, withhold treatment until ANC ≥1000/mm3and platelets ≥20,000/mm3; then resume treatment at the original starting dose. If cytopenia recurs, withhold treatment until ANC ≥1000/mm3 and platelets ≥20,000/mm3; then resume treatment at 100 mg once daily (second episode) or 80 mg once daily (third episode). For cytopenias related to leukemia (confirm with marrow aspirate or biopsy), consider dose escalation to 180 mg once daily.

Nonhematologic toxicity: Withhold treatment until toxicity improvement or resolution; if appropriate, resume treatment at a reduced dose based on the event severity and recurrence.

Dermatologic toxicities: Manage rash with antihistamines or topical or systemic steroids (Khoury 2009), or treatment interruption, dose reduction, or discontinuation. Discontinue if dasatinib-related severe mucocutaneous reaction occurs.

Fluid retention: Manage with diuretics, short courses of corticosteroids, and/or supportive care. Severe pleural effusions may require thoracentesis and oxygen therapy; consider dose reduction or treatment interruption. For grade 3 pleural effusion, withhold treatment until resolves to grade 1 or lower and consider corticosteroids (eg, prednisone 20 to 40 mg/day for 3 to 4 days), diuretics, thoracentesis and/or pleurodesis; may resume dasatinib at a decreased dose when effusion resolves (Khoury 2009).

Pulmonary arterial hypertension: Discontinue with confirmed pulmonary arterial hypertension.

Extemporaneously Prepared

An oral suspension may be prepared by dissolving dasatinib tablet(s) for one dose in 30 mL chilled orange or apple juice (without preservatives). After 5 minutes, swirl the contents for 3 seconds and repeat the process every 5 minutes for a total of 20 minutes following addition of tablet(s). Minimize time between end of 20 minutes and administration since suspension will taste more bitter if allowed to stand longer. Swirl contents of container one last time, then administer immediately. To ensure the full dose is administered, rinse container with 15 mL juice and administer residue. May be administered orally (or by nasogastric tube). Discard any unused portion after 60 minutes.

Sprycel data on file, Bristol-Myers Squibb

Administration

Administer once daily (morning or evening). May be taken without regard to food. Swallow whole; do not break, crush, or chew tablets. Take with a meal if GI upset occurs (Khoury 2009).

Dietary Considerations

Avoid grapefruit juice.

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Drug Interactions

Acetaminophen: May enhance the hepatotoxic effect of Dasatinib. Dasatinib may increase the serum concentration of Acetaminophen. Consider therapy modification

Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): Dasatinib may enhance the anticoagulant effect of Agents with Antiplatelet Properties. Monitor therapy

Antacids: May decrease the absorption of Dasatinib. Consider therapy modification

Anticoagulants: Dasatinib may enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Aprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).Monitor therapy

ARIPiprazole: CYP3A4 Inhibitors (Weak) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations. Monitor therapy

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical).Avoid combination

Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).Monitor therapy

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Dasatinib. Management: Avoid when possible. If such a combination cannot be avoided, consider increasing dasatinib dose and monitor clinical response and toxicity closely. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Dasatinib. Management: Use of this combination should be avoided; consider reducing dasatinib dose if a strong CYP3A4 inhibitor must be used. If using dasatinib 100 mg/day, consider reduction to 20 mg/day; if using dasatinib 140 mg/day, consider reduction to 40 mg/day. Consider therapy modification

CYP3A4 Substrates (High risk with Inhibitors): Dasatinib may increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dexamethasone (Systemic): May decrease the serum concentration of Dasatinib. Management: Avoid when possible. If such a combination cannot be avoided, consider increasing dasatinib dose and monitoring clinical response and toxicity closely. Consider therapy modification

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Flibanserin: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Flibanserin. Monitor therapy

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Histamine H2 Receptor Antagonists: May decrease the absorption of Dasatinib. Management: Antacids (taken 2 hours before or after dasatinib administration) can be used in place of H2-antagonists if some acid-reducing therapy is needed. Avoid combination

HYDROcodone: CYP3A4 Inhibitors (Weak) may increase the serum concentration of HYDROcodone.Monitor therapy

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Lomitapide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lomitapide. Management: Patients on lomitapide 5 mg/day may continue that dose. Patients taking lomitapide 10 mg/day or more should decrease the lomitapide dose by half. The lomitapide dose may then be titrated up to a max adult dose of 30 mg/day. Consider therapy modification

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

MiFEPRIStone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying). Management: Though the drugs listed here have uncertain QT-prolonging effects, they all have some possible association with QT prolongation and should generally be avoided when possible. Consider therapy modification

Mitotane: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Netupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).Monitor therapy

NiMODipine: CYP3A4 Inhibitors (Weak) may increase the serum concentration of NiMODipine. Monitor therapy

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).Monitor therapy

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Pimozide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Pimozide. Avoid combination

Pitolisant: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Combined use of pitolisant with a CYP3A4 substrate that has a narrow therapeutic index should be avoided. Other CYP3A4 substrates should be monitored more closely when used with pitolisant. Consider therapy modification

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Propacetamol: Dasatinib may enhance the hepatotoxic effect of Propacetamol. Dasatinib may increase serum concentrations of the active metabolite(s) of Propacetamol. Specifically, acetaminophen concentrations may increase. Consider therapy modification

Proton Pump Inhibitors: May decrease the serum concentration of Dasatinib. Management: Antacids (taken 2 hours before or after dasatinib administration) can be used in place of the proton pump inhibitor if some acid-reducing therapy is needed. Avoid combination

QTc-Prolonging Agents (Highest Risk): QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of QTc-Prolonging Agents (Highest Risk). Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

QTc-Prolonging Agents (Moderate Risk): QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of QTc-Prolonging Agents (Moderate Risk). Monitor therapy

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

St John's Wort: May decrease the serum concentration of Dasatinib. Avoid combination

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Consider therapy modification

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation.Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

Voriconazole: May enhance the QTc-prolonging effect of Dasatinib. Voriconazole may increase the serum concentration of Dasatinib. Management: This combination should be avoided; consider reducing dasatinib dose if voriconazole must be used. If using dasatinib 100 mg/day, consider reduction to 20 mg/day; if using dasatinib 140 mg/day, consider reduction to 40 mg/day. Monitor ECG closely. Consider therapy modification

Adverse Reactions

≥10%:

Cardiovascular: Facial edema, peripheral edema

Central nervous system: Headache (12% to 33%), fatigue (8% to 26%), pain (11%)

Dermatologic: Skin rash (11% to 21%; includes drug eruption, erythema, erythema multiforme, erythematous rash, erythrosis, exfoliative rash, follicular rash, heat rash, macular rash, maculopapular rash, milia, papular rash, pruritic rash, pustular rash, skin exfoliation, skin irritation, urticaria vesiculosa, vesicular rash), pruritus (12%)

Endocrine & metabolic: Fluid retention (19% to 48%; grades 3/4: 1% to 8%; cardiac-related: 9%)

Gastrointestinal: Diarrhea (17% to 31%), nausea (8% to 24%), vomiting (5% to 16%), abdominal pain (7% to 12%)

Hematologic & oncologic: Thrombocytopenia (grades 3/4: 22% to 85%), neutropenia (grades 3/4: 29% to 79%), anemia (grades 3/4: 13% to 74%), hemorrhage (8% to 26%; grades 3/4: 1% to 9%), febrile neutropenia (4% to 12%; grades 3/4: 4% to 12%)

Infection: Infection (9% to 14%; includes bacterial, fungal, viral)

Local: Localized edema (3% to 22%; grades 3/4: ≤1%; superficial)

Neuromuscular & skeletal: Musculoskeletal pain (<22%), myalgia (7% to 13%), arthralgia (≤13%)

Respiratory: Pleural effusion (5% to 28%; grades 3/4: ≤7%), dyspnea (3% to 24%)

Miscellaneous: Fever (6% to 18%)

1% to <10%:

Cardiovascular: Cardiac conduction disturbance (7%), ischemic heart disease (4%), cardiac disease (≤4%; includes cardiac failure, cardiomyopathy, diastolic dysfunction, ejection fraction decreased, left ventricular dysfunction, ventricular failure), edema (≤4%; generalized), pericardial effusion (≤4%; grades 3/4: ≤1%), prolonged Q-T interval on ECG (≤1%), cardiac arrhythmia, chest pain, flushing, hypertension, palpitations, tachycardia

Central nervous system: Intracranial hemorrhage (≤3%; grades 3/4: ≤3%), chills, depression, dizziness, drowsiness, insomnia, myasthenia, neuropathy, peripheral neuropathy

Dermatologic: Acne vulgaris, alopecia, dermatitis, eczema, hyperhidrosis, urticaria, xeroderma

Endocrine & metabolic: Hyperuricemia, weight gain, weight loss

Gastrointestinal: Constipation (10%), gastrointestinal hemorrhage (2% to 9%; grades 3/4: 1% to 7%), abdominal distention, change in appetite, colitis (including neutropenic colitis), dysgeusia, dyspepsia, enterocolitis, gastritis, mucositis, stomatitis

Hematologic & oncologic: Bruise

Hepatic: Increased serum bilirubin (grades 3/4: ≤6%), increased serum ALT (grades 3/4: ≤5%), increased serum AST (grades 3/4: ≤4%), ascites (≤1%)

Infection: Herpes virus infection, sepsis

Neuromuscular & skeletal: Muscle spasm (5%), stiffness, weakness

Ophthalmic: Blurred vision, decreased visual acuity, dry eye syndrome, visual disturbance

Otic: Tinnitus

Renal: Increased serum creatinine (grades 3/4: ≤8%)

Respiratory: Pulmonary hypertension (≤5%; grades 3/4: ≤1%), pulmonary edema (≤4%; grades 3/4: ≤3%), cough, pneumonia (bacterial, viral, or fungal), pneumonitis, pulmonary infiltrates, upper respiratory tract infection

Miscellaneous: Soft tissue injury (oral)

<1% (Limited to important or life-threatening): Abnormal gait, abnormal platelet aggregation, abnormal T waves on ECG, acute coronary syndrome, acute pancreatitis, acute respiratory distress, amnesia, anal fissure, angina pectoris, anxiety, arthritis, asthma, ataxia, atrial fibrillation, atrial flutter, bronchospasm, bullous skin disease, cardiomegaly, cerebrovascular accident, cholecystitis, cholestasis, confusion, conjunctivitis, coronary artery disease, cor pulmonale, cranial nerve palsy (facial), decreased libido, deep vein thrombosis, dehydration, dementia, dermal ulcer, diabetes mellitus, dyschromia, dysphagia, embolism, emotional lability, epistaxis, equilibrium disturbance, erythema nodosum, esophagitis, fibrosis (dermal), fistula (anal), gastroesophageal reflux disease, gastrointestinal disease (protein wasting), gingival hemorrhage, gynecomastia, hearing loss, hematoma, hematuria, hemoptysis, hemorrhage (ocular), hepatitis, hypercholesterolemia, hypersensitivity reaction, hypersensitivity angiitis, hyperthyroidism, hypoalbuminemia, hypotension, hypothyroidism, increased creatine phosphokinase, increased gamma-glutamyl transferase, increased lacrimation, increased pulmonary artery pressure, increased troponin, inflammation (panniculitis), interstitial pulmonary disease, intestinal obstruction, livedo reticularis, lymphadenopathy, lymphocytopenia, malaise, menstrual disease, myocarditis, nail disease, nephrotic syndrome, optic neuritis, osteonecrosis, ototoxicity (hemorrhage), palmar-plantar erythrodysesthesia, pancreatitis, pericarditis, petechia, photophobia, pleuropericarditis, prolongation P-R interval on ECG, proteinuria, pulmonary embolism, pure red cell aplasia, reactivation of HBV, renal failure, renal insufficiency, rhabdomyolysis, seizure, skin photosensitivity, Stevens-Johnson syndrome, Sweet syndrome, syncope, tendonitis, thrombophlebitis, thrombosis, thyroiditis, transient ischemic attacks, tremor, tumor lysis syndrome, upper gastrointestinal tract ulcer, urinary frequency, uterine hemorrhage, vaginal hemorrhage, ventricular arrhythmia, ventricular tachycardia, vertigo, voice disorder

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Severe dose-related bone marrow suppression (thrombocytopenia, neutropenia, anemia) is associated with treatment (usually reversible); dosage adjustment and/or temporary interruption may be required for severe myelosuppression; the incidence of myelosuppression is higher in patients with advanced chronic myeloid leukemia (CML) and Ph+ acute lymphoblastic leukemia (ALL). Monitor blood counts every 2 weeks for 12 weeks and then every 3 months thereafter or as clinically indicated (for chronic phase CML) or weekly for the first 2 months, then monthly thereafter or as clinically necessary (for accelerated or blast phase CML or for ALL).

• Cardiovascular adverse events: Cardiac ischemic events, cardiac fluid retention-related events, and conduction abnormalities (arrhythmia and palpitations) have been reported. Monitor for signs and symptoms of cardiac dysfunction.

• Dermatologic toxicity: Cases of severe mucocutaneous dermatologic reactions (including Stevens-Johnson syndrome and erythema multiforme) have been reported with dasatinib. Discontinue dasatinib if severe mucocutaneous reaction occurs and other etiologies have been ruled out.

• Fluid retention: Dasatinib may cause fluid retention, including pleural and pericardial effusions, pulmonary hypertension, and generalized or superficial edema. A prompt chest x-ray (or other appropriate diagnostic imaging) is recommended for symptoms suggestive of effusion (new or worsening dyspnea on exertion or at rest, pleuritic chest pain, or dry cough). Fluid retention may be managed with supportive care (diuretics or corticosteroids); thoracentesis and oxygen therapy may be necessary for severe fluid retention; consider dose reduction or treatment interruption. Utilizing once-daily dosing is associated with a decreased frequency of fluid retention. The risk for pleural effusion is increased in patients with hypertension, prior cardiac history and a twice a day administration schedule; interrupt treatment for grade ≥2 effusion; may consider reinitiating at a reduced dose after resolution (Quintás-Cardama 2007). Use with caution in patients where fluid accumulation may be poorly tolerated, such as in cardiovascular disease (HF or hypertension) and pulmonary disease.

• Hemorrhage: Fatal intracranial and GI hemorrhage have been reported in association with dasatinib use; severe hemorrhage (including CNS, GI) may occur due to thrombocytopenia. In addition to thrombocytopenia, dasatinib may also cause platelet dysfunction. Concomitant medications that inhibit platelet function or anticoagulants may increase the risk of bleeding.

• Pulmonary arterial hypertension: Dasatinib may increase the risk for pulmonary arterial hypertension (PAH). PAH may occur at any time after starting treatment, including after >12 months of therapy. Evaluate for underlying cardiopulmonary disease prior to therapy initiation and during therapy; evaluate and rule out alternative etiologies in patients with symptoms suggestive of PAH (eg, dyspnea, fatigue, hypoxia, fluid retention) and interrupt therapy if symptoms are severe. Discontinue permanently with confirmed PAH diagnosis (may be reversible upon discontinuation).

• QT prolongation: May prolong QT interval; there are reports of patients with QTcF >500 msec. Use caution in patients at risk for QT prolongation, including patients with long QT syndrome, patients taking antiarrhythmic medications or other medications that lead to QT prolongation or potassium-wasting diuretics, patients with cumulative high-dose anthracycline therapy, and conditions which cause hypokalemia or hypomagnesemia. Correct hypokalemia and hypomagnesemia prior to and during dasatinib therapy.

• Tumor lysis syndrome: Tumor lysis syndrome (TLS) has been reported in patients with resistance to imatinib therapy, usually in patients with advanced phase disease. Risk for TLS is higher in patients with advanced stage disease and/or a high tumor burden; monitor patients at risk more frequently. Maintain adequate hydration and correct uric acid levels prior to treatment; monitor electrolyte levels.

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with hepatic impairment due to extensive hepatic metabolism.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Use with caution in patients taking anticoagulants or medications interfering with platelet function; not studied in clinical trials. Avoid concomitant use with CYP3A4 inducers and inhibitors; if concomitant use cannot be avoided, consider dasatinib dosage adjustments.

• Drugs that affect gastric pH: Elevated gastric pH may reduce dasatinib bioavailability; avoid concomitant use with proton pump inhibitors and H2 blockers. If needed, may consider antacid administration at least 2 hours before or 2 hours after the dasatinib dose.

Special populations:

• Elderly: Patients 65 years of age and older are more likely to experience toxicity (compared with younger patients).

Monitoring Parameters

CBC with differential every 2 weeks for 12 weeks and then every 3 months thereafter or as clinically indicated (for chronic phase chronic myeloid leukemia [CML]) or weekly for 2 months, then monthly or as clinically necessary (for accelerated or blast phase CML or for acute lymphoblastic leukemia [ALL]); bone marrow biopsy; liver function tests, electrolytes including calcium, phosphorus, magnesium; monitor for fluid retention; monitor for signs/symptoms of cardiac dysfunction; ECG monitoring if at risk for QTc prolongation; chest x-ray is recommended for symptoms suggestive of pleural effusion (eg, cough, dyspnea); signs/symptoms of tumor lysis syndrome and dermatologic reactions.

Thyroid function testing recommendations (Hamnvik 2011):

Preexisting levothyroxine therapy: Obtain baseline TSH levels, then monitor every 4 weeks until levels and levothyroxine dose are stable, then monitor every 2 months

Without preexisting thyroid hormone replacement: TSH at baseline, then monthly for 4 months, then every 2 to 3 months

Pregnancy Considerations

Dasatinib crosses the placenta, with fetal plasma and amniotic concentrations comparable to maternal concentrations. Adverse effects, including hydrops fetalis and fetal leukopenia and thrombocytopenia have been reported following maternal exposure to dasatinib. Women of reproductive potential should use effective contraception during and for 30 days after the final dose to avoid becoming pregnant. Pregnant women are advised to avoid contact with crushed or broken tablets.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience muscle pain, joint pain, constipation or headache. Have patient report immediately to prescriber signs of infection, signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; hematuria; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding); shortness of breath; excessive weight gain; swelling of arms or legs; cough; angina; tachycardia; passing out; abnormal heartbeat; severe dizziness; severe abdominal pain; severe nausea; vomiting; severe diarrhea; severe loss of strength and energy; signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes); or signs of tumor lysis syndrome (tachycardia or abnormal heartbeat; any passing out; urinary retention; muscle weakness or cramps; nausea, vomiting, diarrhea or lack of appetite; or feeling sluggish) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.