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Midostaurin

Pronunciation

(mye doe STAW rin)

Index Terms

  • CGP 41251
  • N-benzoyl-staurosporine
  • PKC 412

Dosage Forms

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

Capsule, Oral:

Rydapt: 25 mg [contains cremophor rh40]

Brand Names: U.S.

  • Rydapt

Pharmacologic Category

  • Antineoplastic Agent, FLT3 Inhibitor
  • Antineoplastic Agent, Tyrosine Kinase Inhibitor

Pharmacology

Midostaurin is a tyrosine kinase inhibitor which inhibits multiple receptors, such as wild type FLT3, FLT3 mutant kinases ITD and TKD, KIT (wild type and D816V mutant), PDGFRα/β, VEGFR2, and members of the serine/threonine protein kinase C (PKC) family.

Midostaurin inhibits FLT3 receptor signaling and cell proliferation, and induces apoptosis in ITD- and TKD- mutant expressing leukemic cells, as well as in cells overexpressing wild type FLT3 and PDGFR. It also may inhibit KIT signaling, cell proliferation, and histamine release (and induces apoptosis) in mast cells.

Absorption

Exposure was increased 1.2- or 1.6-fold when administered with a standard or high-fat meal, respectively, compared to the fasted state. Midostaurin Cmax was reduced 20% and 27%, respectively, when administered with a standard or high-fat meal compared to a fasted state.

Distribution

95.2 L

Metabolism

Primarily hepatic via CYP3A4 to active metabolites CGP62221 and CGP52421

Excretion

Feces (95%; 91% as metabolites and 4% as unchanged drug); urine (5%)

Time to Peak

1 to 3 hours (fasted state); 2.5 to 3 hours (with standard or high-fat meal)

Half-Life Elimination

21 hours (midostaurin); 32 hours (CGP62221); 482 hours (CGP52421)

Protein Binding

>99.8% bound to plasma proteins (parent drug, CGP62221, and CGP52421); midostaurin is mainly bound to α1-acid glycoprotein

Use: Labeled Indications

Acute myeloid leukemia, FLT3-positive: Treatment of adult patients with newly diagnosed FLT3 mutation-positive (as detected by an approved test) acute myeloid leukemia (AML), in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation chemotherapy

Limitations of use: Not indicated as single-agent induction therapy for the treatment of patients with AML.

Mast cell leukemia: Treatment of adult patients with mast cell leukemia (MCL)

Systemic mastocytosis: Treatment of adult patients with aggressive systemic mastocytosis (ASM) or systemic mastocytosis with associated hematological neoplasm (SM-AHN)

Contraindications

Hypersensitivity to midostaurin or any component of the formulation

Dosing: Adult

Note: Administer prophylactic antiemetics prior to midostaurin therapy.

Acute myeloid leukemia (AML), FLT3-positive: Oral: 50 mg twice daily on days 8 to 21 of each induction cycle (in combination with daunorubicin and cytarabine) and on days 8 to 21 of each consolidation cycle (in combination with high-dose cytarabine)

Mast cell leukemia: Oral: 100 mg twice daily until disease progression or unacceptable toxicity (Gotlib 2016)

Systemic mastocytosis (aggressive systemic mastocytosis or systemic mastocytosis with associated hematological neoplasm): Oral: 100 mg twice daily until disease progression or unacceptable toxicity (Gotlib 2016)

Missed doses: If a dose is missed or vomited, do not make up the dose; take the next dose at the usually scheduled time.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

CrCl ≥30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling; however, the pharmacokinetics of midostaurin and active metabolites were not significantly altered.

CrCl 15 to 29 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Dosing: Hepatic Impairment

Mild (total bilirubin >1 to 1.5 times ULN or AST > ULN) or moderate (total bilirubin 1.5 to 3 times ULN and any AST) impairment: There are no dosage adjustments provided in the manufacturer's labeling; however, the pharmacokinetics of midostaurin and active metabolites were not significantly altered.

Severe impairment (total bilirubin >3 times ULN and any AST): There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Dosing: Adjustment for Toxicity

Systemic mastocytosis (aggressive systemic mastocytosis, systemic mastocytosis with associated hematological neoplasm, or mast cell leukemia):

Hematologic toxicity (attributed to midostaurin):

ANC <1,000/mm3 (in patients without mast cell leukemia) or ANC <500/mm3 (in patients with baseline ANC of 500 to 1,500/mm3): Interrupt midostaurin; when ANC has improved to ≥1,000/mm3, resume therapy at a reduced dose of 50 mg twice daily and if tolerated, may increase dose to 100 mg twice daily.

Persistently low ANC for >21 days (associated with midostaurin): Discontinue midostaurin

Platelets <50,000/mm3 (in patients without mast cell leukemia) or platelets <25,000/mm3 (in patients with baseline platelet count of 25,000 to 75,000/mm3): Interrupt midostaurin; when platelets have improved to ≥50,000/mm3, resume therapy at a reduced dose of 50 mg twice daily and if tolerated, may increase dose to 100 mg twice daily.

Persistently low platelet count for >21 days (associated with midostaurin): Discontinue midostaurin

Hemoglobin <8 g/L (in patients without mast cell leukemia) or life-threatening anemia in patients with baseline hemoglobin of 8 to 10 g/L: Interrupt midostaurin; when hemoglobin has improved to ≥8 g/L, resume therapy at a reduced dose of 50 mg twice daily and if tolerated, may increase dose to 100 mg twice daily.

Persistently low hemoglobin for >21 days (associated with midostaurin): Discontinue midostaurin

Nonhematologic toxicity:

Nausea/vomiting, grade 3 or 4 (despite optimal antiemetic prophylaxis): Interrupt midostaurin for 3 days (6 doses), then resume therapy at a reduced dose of 50 mg twice daily. If tolerated, increase dose to 100 mg twice daily.

Other grade 3 or 4 toxicities: Interrupt midostaurin until improvement to ≤ grade 2, then resume therapy at a reduced dose of 50 mg twice daily. If tolerated, increase dose to 100 mg twice daily.

All indications: Pulmonary toxicity: Signs/symptoms of interstitial lung disease or pneumonitis without infectious etiology): Discontinue midostaurin.

Administration

Administer with food at approximately 12-hour intervals. Do not open or crush the capsules. Administer prophylactic antiemetics prior to midostaurin therapy.

Storage

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Store in the original package to protect from moisture.

Drug Interactions

Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Aprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

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

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Conivaptan: May increase the serum concentration of Midostaurin. Management: Seek alternatives to the concomitant use of midostaurin and conivaptan if possible. If concomitant use cannot be avoided, monitor patients for increased risk of adverse reactions. Consider therapy modification

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

CYP3A4 Inducers (Strong): May decrease the serum concentration of Midostaurin. Avoid combination

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

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Midostaurin. Management: Seek alternatives to the concomitant use of midostaurin and strong CYP3A4 inhibitors if possible. If concomitant use cannot be avoided, monitor patients for increased risk of adverse reactions. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. 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

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

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

DilTIAZem: May increase the serum concentration of Midostaurin. Management: Seek alternatives to the concomitant use of midostaurin and diltiazem if possible. If concomitant use cannot be avoided, monitor patients for increased risk of adverse reactions. 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

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

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

Grapefruit Juice: May increase the serum concentration of Midostaurin. Management: Seek alternatives to the concomitant use of midostaurin and grapefruit juice if possible. If concomitant use cannot be avoided, monitor patients for increased risk of adverse reactions Consider therapy modification

Highest Risk QTc-Prolonging Agents: Moderate Risk QTc-Prolonging Agents may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Hydroxychloroquine: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Avoid combination

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Ivabradine: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Avoid combination

MiFEPRIStone: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Avoid combination

Moderate Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of other Moderate Risk QTc-Prolonging Agents. 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

Netupitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Probucol: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Avoid combination

Promazine: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Avoid combination

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

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

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

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. 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

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Vinflunine: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Avoid combination

Xipamide: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Monitor therapy

Adverse Reactions

>10%:

Cardiovascular: Edema (40%), prolonged Q-T interval on ECG (11%)

Central nervous system: Headache (26% to 46%), fatigue (34%), dizziness (13%), insomnia (11% to 12%)

Dermatologic: Hyperhidrosis (14%), skin rash (14%)

Endocrine & metabolic: Hyperglycemia (20% to 80%), hypocalcemia (39% to 74%), hyperuricemia (8% to 37%), increased gamma-glutamyl transferase (35%), hyponatremia (34%), hypoalbuminemia (27%), hypokalemia (25%), hyperkalemia (23%), hypophosphatemia (22%), hypernatremia (21%), hypomagnesemia (20%)

Gastrointestinal: Nausea (47% to 83%), vomiting (19% to 68%), mucositis (66%), diarrhea (54%), increased serum lipase (37%), abdominal pain (34%), constipation (29%), increased serum amylase (20%), hemorrhoids (15%), gastrointestinal hemorrhage (14%)

Genitourinary: Urinary tract infection (16%)

Hematologic & oncologic: Febrile neutropenia (8% to 83%; grades ≥3: 84%), lymphocytopenia (66%; grades ≥3: 42%), leukopenia (61%; grades ≥3: 19%), anemia (60%; grades ≥3: 38%), thrombocytopenia (50%; grades ≥3: 27%), neutropenia (49%; grades ≥3: 22%), petechia (36%), prolonged partial thromboplastin time (13%; grades ≥3: 3%)

Hepatic: Increased serum ALT (31 % to 71%), increased serum alkaline phosphatase (39%), increased serum AST (32%), hyperbilirubinemia (29%)

Infection: Localized infection (24%; device related)

Neuromuscular & skeletal: Musculoskeletal pain (33% to 35%), arthralgia (14% to 19%)

Renal: Increased serum creatinine (25%), renal insufficiency (11% to 12%)

Respiratory: Upper respiratory tract infection (20% to 30%), epistaxis (12% to 28%), dyspnea (23%), cough (18%), pleural effusion (6% to 13%)

Miscellaneous: Fever (27%)

1% to 10%:

Cardiovascular: Hypotension (9%), hypertension (8%), cardiac failure (6%), thrombosis (5%), pericardial effusion (4%), ischemia (≤4%), myocardial infarction (≤4%)

Central nervous system: Disturbance in attention (7%), chills (5%), vertigo (5%), mental status changes (4%)

Dermatologic: Xeroderma (7%), cellulitis (≤7%), erysipelas (≤5%)

Endocrine & metabolic: Weight gain (6% to 7%), hypercalcemia (3%)

Gastrointestinal: Dyspepsia (6%), gastritis (3%)

Hematologic & oncologic: Bruise (6%), hematoma (6%)

Hypersensitivity: Hypersensitivity (4%)

Infection: Herpes virus infection (10%), sepsis (9%), fungal infection (7%)

Neuromuscular & skeletal: Tremor (4% to 6%)

Ophthalmic: Eyelid edema (3%)

Respiratory: Pneumonia (10%), bronchitis (6%), oropharyngeal pain (4%), pulmonary edema (3%), interstitial pulmonary disease (≤2%), pneumonitis (≤2%)

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Lymphopenia, leukopenia, neutropenia, thrombocytopenia and anemia have been commonly observed in patients with systemic mastocytosis. Although the incidence of hematologic toxicity in acute myeloid leukemia (AML) may be confounded by concomitant chemotherapy, febrile neutropenia was reported at a slightly higher incidence in patients with AML receiving chemotherapy plus midostaurin (compared to chemotherapy plus placebo). Monitor blood counts.

• GI toxicity: Nausea and vomiting commonly occur; premedicate with antiemetics prior to administration. Diarrhea, abdominal pain, and constipation also occur frequently. Mucositis has also been reported. · ·

• Hypersensitivity: Hypersensitivity reactions, including anaphylactic shock, angioedema, dyspnea, chest pain and flushing have been observed.

• Pulmonary toxicity: Interstitial lung disease and pneumonitis have been reported with midostaurin (either as monotherapy or in combination with other chemotherapy), some cases have been fatal. Monitor for pulmonary symptoms; discontinue in patients who develop signs/symptoms of interstitial lung disease or pneumonitis (without an infectious etiology).

Concurrent drug therapy issues:

• Drug-drug/drug-food 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.

Other warnings/precautions:

• FLT3 mutation positivity: In the treatment of acute myeloid leukemia, midostaurin is approved for use only in patients who are FLT3 mutation-positive (as detected by an approved test).

Monitoring Parameters

FLT3 mutation status (in AML); CBC with differential (in patients with systemic mastocytosis: at least weekly for the first 4 weeks, every other week for the next 8 weeks, and monthly thereafter or as clinically indicated); pregnancy status within 7 days of therapy initiation in women of reproductive potential; signs/symptoms of pulmonary toxicity (interstitial lung disease and pneumonitis); consider ECG for QT interval assessment in patients on concurrent medications that may prolong the QT interval.

Pregnancy Considerations

Adverse events were observed in animal reproduction studies with doses providing less than the human exposure at the recommended dose based on AUC. Based on the mechanism of action, midostaurin may cause fetal harm if used in pregnant women.

Pregnancy status should be verified within 7 days prior to therapy initiation. Females of reproductive potential and males with female partners of reproductive potential should use effective contraception during therapy and for at least 4 months after the last dose. Based on animal data, treatment with midostaurin may impair fertility in males and females.

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