RYDAPT

RYDAPT- midostaurin capsule, liquid filled
Novartis Pharmaceuticals Corporation

1 INDICATIONS AND USAGE

1.1 Acute Myeloid Leukemia

RYDAPT is indicated in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation chemotherapy, for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) who are FLT3 mutation-positive, as detected by an FDA approved test [see Dosage and Administration (2.1), Clinical Studies (14.1)].

Limitations of Use

RYDAPT is not indicated as a single-agent induction therapy for the treatment of patients with AML.

1.2 Systemic Mastocytosis

RYDAPT is indicated for the treatment of adult patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN), or mast cell leukemia (MCL).

2 DOSAGE AND ADMINISTRATION

2.1 Patient Selection

Select patients for the treatment of AML with RYDAPT based on the presence of FLT3 mutation positivity [see Clinical Studies (14)]. Information on FDA-approved tests for the detection of FLT3 mutation in AML is available at: http://www.fda.gov/CompanionDiagnostics.

2.2 Recommended Dosage in Acute Myeloid Leukemia

The recommended dose of RYDAPT for patients with AML is 50 mg orally twice daily with food on Days 8 to 21 of each cycle of induction with cytarabine and daunorubicin and on Days 8 to 21 of each cycle of consolidation with high-dose cytarabine. For a description of the experience with single-agent treatment with RYDAPT beyond induction and consolidation [see Clinical Studies (14.1)].

2.3 Recommended Dosage in ASM, SM-AHN, and MCL

The recommended dose of RYDAPT for patients with ASM, SM-AHN, and MCL is 100 mg orally twice daily with food. Continue treatment until disease progression or unacceptable toxicity occurs. Table 1 provides recommendations for dose modifications of RYDAPT in patients with ASM, SM-AHN, and MCL. Monitor patients for toxicity at least weekly for the first 4 weeks, every other week for the next 8 weeks, and monthly thereafter while on treatment.

Table 1: RYDAPT Dose Modifications for Patients with Systemic Mastocytosis

Criteria	RYDAPT Dosing
ANC less than 1 x 109 /L attributed to RYDAPT in patients without MCL, or ANC less than 0.5 x 109 /L attributed to RYDAPT in patients with baseline ANC value of 0.5-1.5 x 109 /L	Interrupt RYDAPT until ANC greater than or equal to 1 x 109 /L, then resume RYDAPT at 50 mg twice daily, and if tolerated, increase to 100 mg twice daily. Discontinue RYDAPT if low ANC persists for greater than 21 days and is suspected to be related to RYDAPT.
Platelet count less than 50 x 109 /L attributed to RYDAPT in patients without MCL, or platelet count less than 25 x 109 /L attributed to RYDAPT in patients with baseline platelet count of 25-75 x 109 /L	Interrupt RYDAPT until platelet count greater than or equal to 50 x 109 /L, then resume RYDAPT at 50 mg twice daily, and if tolerated, increase to 100 mg twice daily. Discontinue if low platelet count persists for greater than 21 days and is suspected to be related to RYDAPT.
Hemoglobin less than 8 g/dL attributed to RYDAPT in patients without MCL, or life-threatening anemia attributed to RYDAPT in patients with baseline hemoglobin value of 8 to 10 g/dL	Interrupt RYDAPT until hemoglobin greater than or equal to 8 g/dL, then resume RYDAPT at 50 mg twice daily, and if tolerated, increase to 100 mg twice daily. Discontinue if low hemoglobin persists for greater than 21 days and is suspected to be related to RYDAPT.
Grade 3/4 nausea and/or vomiting despite optimal anti-emetic therapy	Interrupt RYDAPT for 3 days (6 doses), then resume RYDAPT at 50 mg twice daily, and if tolerated, increase to 100 mg twice daily.
Other Grade 3/4 non-hematological toxicities	Interrupt RYDAPT until event has resolved to less than or equal to Grade 2, then resume RYDAPT at 50 mg twice daily, and if tolerated, increase to 100 mg twice daily.
Abbreviations: ANC, absolute neutrophil count.National Cancer Institute Common Terminology for Adverse Events (NCI CTCAE) severity: Grade 1 = mild symptoms; 2 = moderate symptoms; 3 = severe symptoms; 4 = life-threatening symptoms.

2.4 Recommended Administration

• Administer prophylactic anti-emetics before treatment with RYDAPT to reduce the risk of nausea and vomiting.
• Administer RYDAPT orally with food, twice daily at approximately 12-hour intervals [see Clinical Pharmacology (12.3)]. Do not open or crush RYDAPT capsules.
• If a dose of RYDAPT is missed or vomited, do not make up the dose; take the next dose at the usual scheduled time.
• Consider interval assessments of QT by electrocardiogram (ECG) if RYDAPT is taken concurrently with medications that can prolong the QT interval.

3 DOSAGE FORMS AND STRENGTHS

25 mg capsules: pale orange oblong soft capsule with red ink imprint ‘PKC NVR’.

4 CONTRAINDICATIONS

RYDAPT is contraindicated in patients with hypersensitivity to midostaurin or to any of the excipients [see Description (11)]. Hypersensitivity reactions have included anaphylactic shock, dyspnea, flushing, chest pain, and angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) [see Adverse Reactions (6.1)].

5 WARNINGS AND PRECAUTIONS

5.1 Embryo-Fetal Toxicity

Based on its mechanism of action and findings from animal reproduction studies, RYDAPT may cause fetal harm when administered to pregnant women. In animal studies, midostaurin caused embryo-fetal toxicities, including late embryo-fetal death and reduced fetal birth weight, with delays in fetal growth at doses lower than the recommended human dose. Advise pregnant women of the potential risk to the fetus. Verify the pregnancy status of females of reproductive potential within 7 days prior to initiating RYDAPT therapy. Advise females of reproductive potential to use effective contraception during treatment with RYDAPT and for 4 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with RYDAPT and for 4 months after the last dose [see Use in Specific Populations (8.1, 8.3), Clinical Pharmacology (12.1)].

5.2 Pulmonary Toxicity

Cases of interstitial lung disease and pneumonitis, some fatal, have occurred in patients treated with RYDAPT as monotherapy or with chemotherapy.

Monitor patients for pulmonary symptoms. Discontinue RYDAPT in patients who experience signs or symptoms of interstitial lung disease or pneumonitis without an infectious etiology.

5.3 Risk of Prolonged Severe Neutropenia and Thrombocytopenia in Pediatric Patients Treated With Combination Chemotherapy

Prolonged Grade 4 neutropenia and thrombocytopenia occurred in two pediatric patients with AML who received an unapproved formulation of midostaurin in combination with chemotherapy, including anthracyclines, fludarabine, and cytarabine; these two patients were coadministered an azole antifungal (a strong CYP3A4 inhibitor), which may increase midostaurin concentrations and subsequently, the risk of toxicity [see Drug Interactions (7.1), Use in Specific Populations (8.4)]. The safety and effectiveness of RYDAPT in pediatric patients have not been established.

6 ADVERSE REACTIONS

The following serious adverse reactions are described elsewhere in the labeling:

• Pulmonary Toxicity [see Warnings and Precautions (5.2)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Acute Myeloid Leukemia

The safety evaluation of RYDAPT (50 mg twice daily with food) in patients with newly diagnosed FLT3 mutated AML is based on a randomized, double-blind, trial of RYDAPT (n = 345) or placebo (n = 335) with chemotherapy [see Clinical Studies (14.1)]. The overall median duration of exposure was 42 days (range, 2 to 576 days) for patients in the RYDAPT plus chemotherapy arm versus 34 days (range, 1 to 465 days) for patients in the placebo plus chemotherapy arm. On the RYDAPT plus chemotherapy arm, 35% of patients completed induction and consolidation therapy, compared to 25% of patients on the placebo plus chemotherapy arm.

The most frequent (incidence greater than or equal to 20%) adverse drug reactions (ADRs) in the RYDAPT plus chemotherapy arm were febrile neutropenia, nausea, mucositis, vomiting, headache, petechiae, musculoskeletal pain, epistaxis, device-related infection, hyperglycemia, ECG QT prolonged, and upper respiratory tract infections. The most frequent Grade 3/4 adverse reactions (incidence ≥ 10%) were febrile neutropenia, device-related infection, and mucositis.

The most frequent serious adverse reaction (≥ 10%) in patients in the RYDAPT plus chemotherapy arm was febrile neutropenia (16%), which occurred at a similar rate in the placebo arm (16%).

Discontinuation due to any adverse reaction occurred in 9% of patients in the RYDAPT arm versus 6% in the placebo arm. The most frequent (> 1%) Grade 3/4 adverse reactions leading to discontinuation in the RYDAPT arm was renal insufficiency (1%).

Excluding deaths due to disease progression, no fatal adverse reactions occurred in the study. Overall, the most frequent non-treatment related cause of death in the RYDAPT plus chemotherapy arm was sepsis (2%) and occurred at a similar rate in the placebo arm (2%).

Table 2 presents the frequency category of adverse reactions reported in the randomized trial in patients with newly diagnosed FLT3 mutated AML. Adverse reactions are listed according to body system. Within each body system, the adverse reactions are ranked by frequency, with the most frequent reactions first. Table 3 presents the key laboratory abnormalities from the same randomized trial in patients with newly diagnosed FLT3 mutated AML.

Table 2: Common Adverse Reactions (≥ 10% Incidence and ≥ 2% More Frequent on the Midostaurin Arm) of Patients with Acute Myeloid Leukemia in Study 1

	All Grades		Grades ≥ 3
Adverse Reaction	RYDAPT +chemo n = 2291 %	Placebo +chemo n = 2261 %	RYDAPT +chemo n = 3451 %	Placebo +chemo n = 3351 %
Gastrointestinal disorders
Nausea	83	70	6	10
Mucositisa	66	62	11	13
Vomiting	61	53	3	5
Hemorrhoids	15	11	1	0
Blood and lymphatic system disorders
Febrile neutropenia	83	81	84	83
Petechiae	36	27	1	1
Nervous system disorders
Headachea	46	38	3	3
Musculoskeletal and connective tissue disorders
Musculoskeletal paina	33	31	5	2
Arthralgia	14	8	< 1	< 1
Respiratory, thoracic, and mediastinal disorders
Epistaxis	28	24	3	1
Infections and infestations
Device-related infection	24	17	16	10
Upper respiratory tract infectiona	20	15	4	3
Investigations
Hyperglycemiaa	20	17	7	6
Electrocardiogram QT prolonged	20	17	6	5
Activated partial thromboplastin time prolonged	13	8	3	2
Skin and subcutaneous tissue disorders
Hyperhidrosis	14	8	0	0
Renal and urinary disorders
Renal insufficiencya	12	9	5	3
Psychiatric disorders
Insomnia	12	8	0	< 1
1 For trial sites in North America, only Grades 3 and 4 were collected.a Grouped terms: • Upper respiratory tract infections: e.g., nasopharyngitis, upper respiratory tract infections, sinusitis. • Mucositis: e.g., radiation mucositis, stomatitis, laryngeal pain. • Musculoskeletal pain: e.g., back pain, bone pain, pain in extremity. • Renal insufficiency: e.g., blood creatinine increased, renal failure, acute kidney injury. • Hyperglycemia: mainly hyperglycemia.

Other notable adverse reactions occurring in < 10% of patients treated with RYDAPT but at least 2% more frequently than in the placebo group included:

• Infections and infestations: Cellulitis^a (7%), fungal infection^a (7%)
• Metabolism and nutrition disorders: Hyperuricemia (8%)
• Nervous system disorders: Tremor (4%)
• Eye disorders: Eyelid edema (3%)
• Cardiac disorders: Hypertension^a (8%), pericardial effusion (4%)
• Respiratory, thoracic, and mediastinal disorders: Pleural effusion (6%)
• Skin and subcutaneous tissue disorders: Dry skin (7%)
• General disorders and administration-site conditions: Thrombosis^a (5%)
• Investigations: Weight increased (7%), hypercalcemia (3%)

^a Grouped terms:

• Thrombosis: e.g., thrombosis in device, thrombosis.
• Cellulitis: e.g., cellulitis, erysipelas.
• Fungal infection: e.g., bronchopulmonary aspergillosis, pneumonia fungal, splenic infection fungal, hepatic candidiasis.

Other clinically important adverse reactions (All Grades) at ≥ 10% that did not meet criteria for Table 2:

• Respiratory, thoracic, and mediastinal disorders: Pneumonitis (11%)

Table 3: New or Worsening Laboratory Abnormalities (≥ 10% Incidence and ≥ 2% More Frequent on the Midostaurin Arm) Reported in Patients with Acute Myeloid Leukemia on Study 1

Laboratory Abnormality	RYDAPT(50 mg twice daily)N = 345 All Grades %	RYDAPT(50 mg twice daily)N = 345Grade 3/4 %	PlaceboN = 335 All Grades %	PlaceboN = 335 Grade 3/4 %
Alanine aminotransferase increased	71	20	69	16
Hypernatremia	21	1	15	2
Hypocalcemia	74	7	70	8

In Study 1, 205 patients (120 in RYDAPT arm and 85 in placebo arm) who remained in remission following completion of consolidation continued to receive either single agent RYDAPT or placebo for a median of 11 months (range, 0.5 to 17 months) with 69 in the RYDAPT arm and 51 in the placebo completing 12 treatment cycles. Common adverse reactions (greater than or equal to 5% difference between the RYDAPT and placebo arms) reported for these patients included nausea (47% vs 18%), hyperglycemia (20% vs 13%) and vomiting (19% vs 5%).

Systemic Mastocytosis

Two single-arm, open-label multicenter trials (Study 2 and Study 3) evaluated the safety of RYDAPT (100 mg twice daily with food) as a single agent in 142 adult patients total with ASM, SM-AHN, or MCL. The median age was 63 (range, 24 to 82), 63% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and 75% had no hepatic impairment (bilirubin and AST ≤ upper limit of normal (ULN)] at baseline. The median duration of exposure to RYDAPT was 11.4 months (range, 0 to 81 months), with 34% treated for ≥ 24 months.

The most frequent adverse reactions (≥ 20%), excluding laboratory terms, were nausea, vomiting, diarrhea, edema, musculoskeletal pain, abdominal pain, fatigue, upper respiratory tract infection, constipation, pyrexia, headache, and dyspnea (Table 4). Grade ≥ 3 adverse reactions reported in ≥ 5%, excluding laboratory terms, were fatigue, sepsis, gastrointestinal hemorrhage, pneumonia, diarrhea, febrile neutropenia, edema, dyspnea, nausea, vomiting, abdominal pain, and renal insufficiency (Table 4).

Adverse reactions led to dose modifications (interruption or reduction) in 56% of patients. Among these, the most frequent adverse reactions (> 5%) were gastrointestinal symptoms, QT prolongation, neutropenia, pyrexia, thrombocytopenia, gastrointestinal hemorrhage, lipase increase, and fatigue. The median time to first dose modification for toxicity was 1.6 months, with 75% of dose modifications first occurring within 5 months of starting treatment.

Treatment discontinuation due to adverse reactions occurred in 21% of patients. The most frequent adverse reactions causing treatment discontinuation included infection, nausea or vomiting, QT prolongation, and gastrointestinal hemorrhage.

Serious adverse reactions were reported in 68% of patients, most commonly (≥ 20%) due to infections and gastrointestinal disorders.

On-treatment deaths unrelated to the underlying malignancy occurred in 16 patients (11%), most commonly from infection (sepsis or pneumonia), followed by cardiac events. Of the on-treatment deaths from disease progression, 4 were also attributable to infection.

Table 4 summarizes the adverse reactions reported in ≥ 10% of the patients with advanced SM.

Table 4: Adverse Reactions Reported in ≥ 10% of Patients with Advanced Systemic Mastocytosis (Study 2 and Study 3)

	RYDAPT (100 mg twice daily) N = 142
Adverse Reactiona	All Grades%	Grade ≥ 3%
Gastrointestinal disorders
Nausea	82	6
Vomiting	68	6
Diarrheaa	54	8
Abdominal paina	34	6
Constipation	29	< 1
Gastrointestinal hemorrhagea	14	9
General disorders and administration-site conditions
Edemaa	40	7
Fatiguea	34	9
Pyrexia	27	4
Infections and infestations
Upper respiratory tract infectiona	30	1
Urinary tract infectiona	16	3
Pneumoniaa	10	8
Herpesvirus infectiona	10	1
Musculoskeletal and connective tissue disorders
Musculoskeletal paina	35	4
Arthralgia	19	2
Nervous system disorders
Headachea	26	1
Dizziness	13	0
Respiratory, thoracic, and mediastinal disorders
Dyspneaa	23	7
Cougha	18	< 1
Pleural effusion	13	4
Epistaxis	12	3
Skin and subcutaneous disorders
Rasha	14	3
Investigations
QT prolonged	11	< 1
Psychiatric disorders
Insomnia	11	0
Renal disorders
Renal insufficiencya	11	5
Toxicity was graded per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3. Represents adverse reactions, excluding laboratory terms, occurring up to 28 days after last midostaurin dose, regardless of baseline grade. a Grouped terms: Upper respiratory tract infection: e.g., nasopharyngitis, upper respiratory tract infections. Urinary tract infection: e.g., urinary tract infection, cystitis. Pneumonia: e.g., pneumonia, lung infection. Herpesvirus infection: e.g., oral herpes, herpes zoster. Headache: e.g., headache, sinus headache. Dyspnea: e.g., dyspnea, bronchospasm, respiratory failure. Cough: e.g., cough, productive cough. Diarrhea: e.g., diarrhea, gastroenteritis, colitis. Abdominal pain: e.g., abdominal pain, abdominal pain upper. Gastrointestinal hemorrhage: e.g., gastrointestinal hemorrhage, hemorrhoidal hemorrhage, duodenal ulcer hemorrhage. Fatigue: e.g., fatigue, asthenia. Rash: e.g., rash, rash maculo-papular, erythema multiforme. Musculoskeletal pain: e.g., back pain, musculoskeletal pain, pain in extremity. Renal insufficiency: e.g., blood creatinine increased, renal failure, acute kidney injury. Edema: e.g., edema, edema peripheral.

Gastrointestinal Toxicities Leading to Treatment Modification: In patients with advanced SM, the median time to onset of nausea was 9 days, with 75% of cases beginning within the first 3 months. The median time to onset of vomiting was 1 month.

Other clinically significant adverse reactions occurring in ≤ 10% of patients included:

Infections and infestations: Sepsis (9%)^a , bronchitis (6%), cellulitis or erysipelas (5%)

Blood and lymphatic system disorders: Febrile neutropenia (8%)

Cardiac disorders: Cardiac failure (6%), myocardial infarction, or ischemia (4%)^a

Immune system disorders: Hypersensitivity (4%)^a

Nervous system disorders: Disturbance in attention (7%), tremor (6%), mental status changes (4%)

Ear and labyrinth disorders: Vertigo (5%)

Vascular disorders: Hypotension (9%), hematoma (6%)

Respiratory, thoracic, and mediastinal disorders: Oropharyngeal pain (4%), pulmonary edema (3%)^a , interstitial lung disease (1%), pneumonitis (<1%)

Gastrointestinal disorders: Dyspepsia (6%), gastritis (3%)^a

General disorders and administration site conditions: Chills (5%)

Investigations: Weight increased (6%)

Injury, poisoning, and procedural complications: Contusion (6%)

^a Grouped terms:

• Sepsis: e.g., sepsis, staphylococcal/Enterobacter/Escherichia sepsis
• Hypersensitivity: includes one report of anaphylactic shock
• Myocardial infarction or ischemia: e.g., myocardial infarction and acute myocardial infarction, angina pectoris
• Gastritis: gastritis, gastritis erosive, gastritis hemorrhagic
• Pulmonary edema: pulmonary edema, pulmonary congestion

Table 5 summarizes new or worsening laboratory abnormalities. Common (≥ 10%) Grade 3 or higher non-hematologic laboratory abnormalities were hyperglycemia (non-fasting), lipase increase, and hyperuricemia. The most common (≥ 20%) Grade 3 or higher hematologic laboratory abnormalities were lymphopenia, anemia, thrombocytopenia, and neutropenia. Grade 4 hematologic abnormalities occurring in ≥ 5% were thrombocytopenia (13%), neutropenia (8%), anemia (6%), and lymphopenia (6%).

Table 5: Most Common (≥ 20%) New or Worsening Laboratory Abnormalities Reported in Patients with Advanced Systemic Mastocytosis (Study 2 and Study 3)

	RYDAPT (100 mg twice daily) N = 142
Abbreviations: Alk phos, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma glutamyltransferase.Includes abnormalities occurring up to 28 days after last midostaurin dose, if new or worsened from baseline or if baseline was unknown. a Non-fasting.b Among 116 evaluable patients.
Test	All Grades%	Grade ≥ 3%
Hematology
Lymphopenia	66	42
Leukopenia	61	19
Anemia	60	38
Thrombocytopenia	50	27
Neutropenia	49	22
Chemistry
Hyperglycemiaa	80	18
Alk phos increase	39	9
Hypocalcemia	39	2
Lipase increase	37	18
Hyperuricemia	37	11
GGT increaseb	35	9
Hyponatremia	34	5
AST increase	32	3
ALT increase	31	4
Hyperbilirubinemia	29	4
Hypoalbuminemia	27	1
Hypokalemia	25	6
Creatinine increase	25	< 1
Hyperkalemia	23	4
Hypophosphatemia	22	1
Amylase increase	20	7
Hypomagnesemia	20	0