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• Respiratory, thoracic, and mediastinal disorders: Interstitial lung disease

• Skin and subcutaneous tissue disorders: Acute febrile neutrophilic dermatosis (Sweet syndrome)

5.1 Embryo-Fetal Toxicity

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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)].

7.2 Effect of RYDAPT on Other Drugs

Newly added section: 

CYP2B6 Substrates

RYDAPT decreased the systemic exposure of a sensitive CYP2B6 substrate [see Clinical Pharmacology (12.3)]. Dose adjustments for the coadministered CYP2B6 substrate may be necessary with RYDAPT.

Substrates of Transporters

Coadministration of RYDAPT increased the exposure of a breast cancer resistance protein (BCRP) and organic anion transporter polypeptide (OATP)1B1 substrate [see Clinical Pharmacology (12.3)]. Dose adjustments for the coadministered BCRP or OATP1B1 substrates may be necessary with RYDAPT.

8.1 Pregnancy

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Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to RYDAPT during pregnancy. Females who may have been exposed to RYDAPT during pregnancy directly or through a male partner receiving RYDAPT therapy should contact the Novartis Pharmaceuticals Corporation at 1-888-669-6682 and/or at https://report.novartis.com/.

8.3 Females and Males of Reproductive Potential

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RYDAPT may cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Pregnancy Testing

Pregnancy testing is recommended for females of reproductive potential within seven days prior to initiating RYDAPT.

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with RYDAPT and for 4 months after the last dose.

Males

Advise males with female partners of reproductive potential to use effective contraception during RYDAPT treatment and for 4 months after stopping treatment with RYDAPT [see Nonclinical Toxicology (13.1)].

17 PATIENT COUNSELING INFORMATION

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Advise the patient to read the FDA-approved patient labeling (Patient Information).

Pulmonary Adverse Reactions

Inform patients to seek medical attention for new cough, chest discomfort, or shortness of breath [see Warnings and Precautions (5.2)].

Gastrointestinal Adverse Reactions

Inform patients that RYDAPT can cause nausea, vomiting, and diarrhea. Advise patients to contact their healthcare provider if these symptoms occur or are persisting despite supportive medications [see Adverse Reactions (6.1)].

Embryo-Fetal Toxicity

• Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with RYDAPT and for 4 months after the last dose. Advise females to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.1), Use in Specific Populations (8.1, 8.3)].

• Advise male patients 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 (8.3)].

• Advise females who may have been exposed to RYDAPT during pregnancy directly or through male partner receiving RYDAPT therapy to contact the Novartis Pharmaceuticals Corporation at 1-888-669-6682 and/or at https://report.novartis.[see Use in Specific Populations (8.1)].

  Lactation

Advise women not to breastfeed during treatment with RYDAPT and for 4 months after the last dose [see Use in Specific Populations (8.2)].

6.1 Clinical Trials Experience

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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, electrocardiogram QT prolonged, and upper respiratory tract infections. The most frequent Grade 3/4 adverse reactions (incidence greater than or equal to 10%) were febrile neutropenia, device-related infection and mucositis.

Other clinically important adverse reactions (All Grades) at greater than or equal to 10% that did not meet criteria for Table 2:

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

Other clinically significant adverse reactions occurring in less than or equal to 10% of patients included:

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

 6.2 Postmarketing Experience

(Newly Added Subsection)

The following adverse drug reactions have been derived from post-marketing experience with RYDAPT via spontaneous case reports and literature cases. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Respiratory, thoracic and mediastinal disorders: Interstitial lung disease

NEW subsection added

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.

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Safety and effectiveness of RYDAPT have not been established in pediatric patients.

The safety and effectiveness of an unapproved midostaurin formulation was investigated, but not established in two open-label studies: a study in 22 pediatric patients aged 6 months to 17 years who received midostaurin as a single agent for relapsed or refractory leukemia [NCT00866281] and a study in 4 patients aged 8 to 14 years who received midostaurin in combination with       chemotherapy for newly diagnosed FLT3-mutated AML [NCT03591510]. Prolonged Grade 4 neutropenia and thrombocytopenia occurred in 2 of the 4 pediatric patients with AML who received midostaurin in combination with chemotherapy, including anthracyclines, fludarabine, and cytarabine [see Warnings and Precautions (5.3)]. Grade 4 thrombocytopenia lasted for 44 days in one patient and Grade 4 thrombocytopenia and Grade 4 neutropenia lasted for 51 days and 46 days, respectively, in the other patient.

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)].

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RYDAPT is not safe when given to children in combination with chemotherapy. It is not known if RYDAPT is effective in children.

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• Embryo-Fetal Toxicity

  • Advise females who may have been exposed to RYDAPT during pregnancy directly or through male partner receiving RYDAPT therapy to contact the Novartis Pharmaceuticals Corporation at 1-888-669-6682 and /or at https://psi.novartis.com/