Rydapt

This medication may be prescribed for other uses; ask your doctor or pharmacist for more information.

Midostaurin is a cancer medicine that interferes with the growth and spread of cancer cells in the body.

Midostaurin is used together with other cancer medicines to treat acute myeloid leukemia.

Midostaurin is also used to treat certain rare blood disorders, including systemic mastocytosis with mast cell leukemia or other cancers affecting the blood, bone marrow, or lymphatic tissue.

Midostaurin may be used only if your tumor has a specific genetic marker, for which your doctor will test.

Midostaurin may also be used for purposes not listed in this medication guide.

Use birth control to prevent pregnancy, whether you are a man or a woman. Midostaurin use by either parent may cause birth defects. Avoid pregnancy and breast-feeding for at least 4 months after you stop using this medicine.

You should not use midostaurin if you are allergic to it.

To make sure midostaurin is safe for you, tell your doctor if you have ever had:

• lung disease or breathing problems.

Midostaurin can harm an unborn baby or cause birth defects, whether the mother or father is taking this medicine.

• If you are a woman, do not use midostaurin if you are pregnant. You may need to have a negative pregnancy test before starting this treatment. Use effective birth control to prevent pregnancy while you are using this medicine and for at least 4 months after your last dose.
• If you are a man, use effective birth control if your sexual partner is able to get pregnant. An unborn baby can be harmed if a man fathers the child while he is using midostaurin. Keep using birth control for at least 4 months after your last dose.
• Tell your doctor right away if a pregnancy occurs while either the mother or the father is taking midostaurin.

You should not breast-feed while using this medicine and for at least 4 months after your last dose.

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Medicines used to treat cancer are very strong and can have many side effects. Before receiving this medicine, make sure you understand all the risks and benefits. It is important for you to work closely with your doctor during your treatment.

Take this medicine only as directed by your doctor. Do not use more of it, do not use it more often, and do not use it for a longer time than your doctor ordered.

This medicine should come with a patient information leaflet. Read and follow the instructions carefully. Ask your doctor if you have any questions.

Swallow the capsule whole. Do not crush, break, chew, or open it. Take this medicine with food.

You may also receive medicines to help prevent nausea and vomiting.

If you missed a dose or vomit after taking your medicine, do not take an extra dose. Take your next dose at your scheduled dose.

Do not eat grapefruit or drink grapefruit juice while you are using this medicine.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (capsules):
  • For treatment of acute myeloid leukemia:
    • Adults—50 milligrams (mg) two times a day 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.
    • Children—Use and dose must be determined by your doctor.
  • For treatment of ASM, SM-AHN, and MCL:
    • Adults—100 milligrams (mg) two times a day (about every 12 hours apart).
    • Children—Use and dose must be determined by your doctor.

Missed Dose

This medicine needs to be given on a fixed schedule. If you miss a dose, call your doctor, home health caregiver, or treatment clinic for instructions.

Storage

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Store the medicine in the original package to protect from moisture.

• It is used to treat a type of leukemia.
• It is used to treat mastocytosis.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Mouth irritation or mouth sores.
• Headache.
• Muscle or joint pain.
• Bone pain.
• Nosebleed.
• Signs of a common cold.
• Not able to sleep.
• Dry skin.
• Weight gain.
• Hard stools (constipation).
• Feeling tired or weak.
• Dizziness.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

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

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

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, 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.

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.

Other notable adverse reactions occurring in less than 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 infectiona (7%)
• Metabolism and nutrition disorders: Hyperuricemia (8%)
• Nervous system disorders: Tremor (4%)
• Eye disorders: Eyelid edema (3%)
• Cardiac disorders: Hypertensiona (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: Thrombosisa (5%)
• Investigations: Weight increased (7%), hypercalcemia (3%)

a based on grouping of individual PTs:

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

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 ECOG performance status of 0 or 1, and 75% had no hepatic impairment (bilirubin and AST ≤ 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.

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%), interstitial lung disease or pneumonitis (2%), pulmonary edema (3%) a

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%).

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.

Pregnancy

Risk Summary

Based on mechanism of action and findings in animal reproduction studies, Rydapt may cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on Rydapt use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. In animal reproduction studies, oral administration of midostaurin to pregnant rats and rabbits during organogenesis 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 [see Data]. Advise pregnant women of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated population are unknown. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

When midostaurin was administered to female rats prior to mating and through the first week of pregnancy at a dose of 60 mg/kg/day (approximately 0.1 times the human exposure at the recommended dose based on AUC), there were increases in pre- and post-implantation loss, including total litter loss, resulting in a reduction in the number of live embryos.

During organogenesis, midostaurin administered at oral doses greater than or equal to 3 mg/kg/day (approximately 0.004 times the human exposure at the recommended dose by AUC) to pregnant female rats caused late embryo-fetal death. Dilated lateral brain ventricles were observed in offspring of rats given doses greater than or equal to 3 mg/kg/day. Extra rib and reduced fetal birth weight with effects on fetal growth (severe renal pelvic cavitation and widened anterior fontanelle) were observed in the absence of maternal toxicity at the highest dose of 30 mg/kg/day (approximately 0.05 times the human exposure at the recommended dose by AUC). Midostaurin administered orally to pregnant rabbits during organogenesis led to maternal toxicity with spontaneous abortions and some delay in fetal growth (reduced fetal birth weight) at doses greater than or equal to 10 mg/kg/day (approximately 0.01 times the human exposure at the recommended dose by AUC).

In an oral pre- and postnatal development study in the rat, adverse effects upon maternal performance included dams with signs of dystocia and a lower live litter size at 30 mg/kg/day (approximately 0.05 times the human exposure at the recommended dose by AUC). For the F1 offspring, lower body weights, accelerated complete eye opening and delayed auricular startle ontogeny were noted at 30 mg/kg/day.

Lactation

Risk Summary

There are no data on the presence of midostaurin or its active metabolites in human milk, the effect on the breastfed infant, or the effect on milk production. Orally administered midostaurin and its active metabolites pass into the milk of lactating rats within 1 hour of a 30 mg/kg/day dose, with approximately 5 times more in the milk of lactating rats compared to plasma. Because of the potential for serious adverse reactions in breastfed infants from Rydapt advise women not to breastfeed during treatment with Rydapt and for at least 4 months after the last dose.

Females and Males of Reproductive Potential

Pregnancy Testing

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

Contraception

Females

Rydapt may cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with Rydapt and for 4 months after the last dose.

Males

Males with female sexual partners of reproductive potential should use effective contraception during Rydapt treatment and for at least 4 months after stopping treatment with Rydapt [see Nonclinical Toxicology (13.1)].

Infertility

Based on findings in animals, Rydapt may impair fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Nonclinical Toxicology (13.1)].

Pediatric Use

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

Geriatric Use

Of the 142 patients with advanced SM in clinical studies of Rydapt, 64 (45%) were aged 65 and over, and 16 (11%) were aged 75 years and over. No overall differences in safety or response rate were observed between the subjects aged 65 and over compared with younger subjects. Greater sensitivity of older individuals cannot be ruled out.

Clinical studies in AML with Rydapt did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

In general, administration for elderly patients should be cautious, based on patient’s eligibility for concomitant chemotherapy and reflecting the greater frequency of concomitant disease or other drug therapy.

Rydapt (midostaurin) is a multikinase inhibitor for oral use. The molecular formula for midostaurin is C35H30N4O4. The molecular weight is 570.65 g/mole. The chemical name of midostaurin is N-[(2S,3R,4R,6R)-3-Methoxy-2-methyl-16-oxo-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-4-yl]-N-methylbenzamide. The chemical structure of midostaurin is shown below:

Rydapt is supplied as a soft capsule containing 25 mg of midostaurin. The capsule contains polyoxyl 40 hydrogenated castor oil, gelatin, polyethylene glycol 400, glycerin 85%, dehydrated alcohol, corn oil mono-di-triglycerides, titanium dioxide, vitamin E, ferric oxide yellow, ferric oxide red, carmine, hypromellose 2910, propylene glycol, and purified water.

Take Rydapt exactly as prescribed by your doctor. Follow all directions on your prescription label. Do not use this medicine in larger or smaller amounts or for longer than recommended.

Rydapt is usually taken 2 times per day (once every 12 hours) with food.

Take your doses at regular intervals to keep a steady amount of the drug in your body at all times.

You may be given medication to prevent nausea or vomiting while you are taking Rydapt.

If you vomit shortly after taking Rydapt, do not take an extra dose. Wait until your next scheduled dose time to take the medicine again.

Do not crush or open a capsule.

While using Rydapt, you may need frequent blood tests (every 1 to 4 weeks). This medicine is usually given until your body no longer responds to the medication.

Use all medications as directed by your doctor. Read the instructions provided with each medication. Do not change your doses or medication schedule without your doctor's advice.

Store Rydapt in the original container at room temperature, away from moisture and heat.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of infection like fever, chills, very bad sore throat, ear or sinus pain, cough, more sputum or change in color of sputum, pain with passing urine, mouth sores, or wound that will not heal.
• Signs of skin infection like oozing, heat, swelling, redness, or pain.
• Signs of high blood sugar like confusion, feeling sleepy, more thirst, more hungry, passing urine more often, flushing, fast breathing, or breath that smells like fruit.
• Signs of kidney problems like unable to pass urine, change in how much urine is passed, blood in the urine, or a big weight gain.
• Signs of electrolyte problems like mood changes, confusion, muscle pain or weakness, a heartbeat that does not feel normal, seizures, not hungry, or very bad upset stomach or throwing up.
• Signs of bleeding like throwing up blood or throw up that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; vaginal bleeding that is not normal; bruises without a reason or that get bigger; or any bleeding that is very bad or that you cannot stop.
• Flushing.
• Chest pain.
• Pinpoint red spots on the skin.
• Sweating a lot.
• Swelling.
• A heartbeat that does not feel normal.
• Very bad dizziness or passing out.
• Not able to focus.
• Shakiness.
• Feeling very tired or weak.
• Very bad and sometimes deadly lung problems have happened with this drug. Call your doctor right away if you have lung or breathing problems like trouble breathing, shortness of breath, or a cough that is new or worse.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Mouth irritation or mouth sores.
• Headache.
• Muscle or joint pain.
• Bone pain.
• Nosebleed.
• Signs of a common cold.
• Not able to sleep.
• Dry skin.
• Weight gain.
• Hard stools (constipation).
• Feeling tired or weak.
• Dizziness.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.