Midostaurin is a multi-target kinase inhibitor that was approved by the FDA in 2017 for the treatment of certain types of acute myeloid leukemia (AML) and aggressive systemic mastocytosis (including systemic mastocytosis with associated hematological neoplasm and mast cell leukemia).

Midostaurin (Rydapt) is a multi-targeted tyrosine kinase inhibitor that is used in the treatment of various hematological diseases such as acute myeloid leukemia and mast cell leukemia.

Midostaurin (Rydapt) Uses:

• Acute myeloid leukemia, FLT3-positive:
  • It is used in the treatment of adult patients with newly diagnosed FLT3 mutation-positive (as detected by a standard test) acute myeloid leukemia (AML), in addition to standard cytarabine and daunorubicin induction and cytarabine consolidation chemotherapy.
  • Limitations of use: It should Notbe used as single-agent induction therapy for the treatment of patients with AML.
• Mast cell leukemia:
  • It is also used in the management  of adult patients with mast cell leukemia (MCL)
• Systemic mastocytosis:
  • It is used to treat aggressive systemic mastocytosis (ASM) or systemic mastocytosis associated with hematological neoplasm (SM-AHN)

Midostaurin Dose in Adults:

Note:

• Midostaurin is a medicine used to treat certain types of leukemia and a condition called mastocytosis.
• When you take Midostaurin, there's a chance you might feel nauseous and vomit.
• To help prevent this, your doctor might give you anti-nausea medication before you start taking Midostaurin.
• This should make it less likely for you to feel sick to your stomach and throw upTop of Form

Midostaurin (Rydapt) Dose in the treatment of Acute myeloid leukemia (AML), FLT3-positive: Oral:

For treating a type of cancer called FLT3-positive Acute myeloid leukemia (AML) with Midostaurin:

Start Phase (Induction):

• Take 50 mg of Midostaurin two times a day from the 8th to the 21st day. This is done alongside two other medicines (daunorubicin and cytarabine).
• If the leukemia is still there after this, you might need to do this phase again.

Next Phase (Consolidation):

• Take 50 mg of Midostaurin two times a day from the 8th to the 21st day. This is repeated every 28 days for 4 times total. During this phase, another medicine called high-dose cytarabine is also used.

Follow-up (Maintenance, but this is not a standard treatment):

• Take 50 mg of Midostaurin two times a day every day. This is done for a total of 12 cycles (each cycle is 28 days). You stop earlier if the leukemia comes back.

Midostaurin (Rydapt) Dose in the treatment of Mast cell leukemia:

For treating Mast cell leukemia with Midostaurin:

• Take 100 mg of Midostaurin by mouth two times a day.
• Continue taking it until either the disease gets worse or the side effects become too hard to handle.

Midostaurin (Rydapt) Dose in the treatment of Systemic mastocytosis (aggressive systemic mastocytosis or systemic mastocytosis with associated hematological neoplasm):

For treating Systemic mastocytosis (either the aggressive kind or the type with another blood disease):

• Take 100 mg of Midostaurin by mouth two times a day.
• Keep taking it until the disease worsens or the side effects are too much to handle.

If you forget a dose or throw it up:

• Don't take an extra pill to make up for it.
• Just take your next pill when you're supposed to.

Use in Children:

Not indicated.

Midostaurin (Rydapt) Pregnancy Category: N

• Because of how Midostaurin works and findings from animal studies, it's possible that taking this medicine while pregnant could harm the unborn baby.
• If you're about to start taking Midostaurin, doctors need to make sure you're not pregnant within 7 days before you begin.
• If you can get pregnant or if you're a guy with a partner who can get pregnant, you need to use reliable birth control during the treatment and for at least 4 months after the last dose of Midostaurin.
• If you're a woman and you think you might have been exposed to Midostaurin during pregnancy, either by taking it yourself or through a partner who's taking it, contact Novartis Pharmaceuticals Corporation for more information at 1-888-669-6682 or on their website https://psi.novartis.com.

Use of midostaurin during breastfeeding

• We don't know if Midostaurin gets into breast milk.
• Since there's a chance that it could harm a baby who is breastfed, the company that makes the medicine recommends:
  • Not breastfeeding while taking Midostaurin.
  • And continuing not to breastfeed for at least 4 months after the last dose.

Midostaurin (Rydapt) Dose in Kidney Disease:

• If your kidneys can clear 30 mL/minute or more of blood (CrCl ≥30 mL/minute):
  • The company that makes Midostaurin doesn't give any special dose instructions. The drug seems to work the same way as usual.
• If your kidneys clear between 15 to 29 mL/minute (CrCl 15 to 29 mL/minute):
  • The company doesn't have any specific dosage guidelines because they haven't studied it in people with this kidney function level.

Midostaurin (Rydapt) Dose in Liver disease:

• For mild liver issues (when your bilirubin level is a bit high, or your AST enzyme is high):
  • The company that makes Midostaurin doesn’t give any special dose instructions. The drug seems to work the same way as usual.
• For moderate liver issues (when your bilirubin level is moderately high):
  • Same as above. No special dose guidelines and the medicine appears to act normally.
• For severe liver issues (when your bilirubin level is very high):
  • The company hasn't provided specific dosing guidelines because they haven't studied it in people with this level of liver problem.

"Bilirubin" and "AST" are markers of liver function.

Common Side Effects of Midostaurin (Rydapt):

• Cardiovascular:
  • Edema
  • Prolonged Q-T Interval On ECG
• Central Nervous System:
  • Headache
  • Fatigue
  • Dizziness
  • Insomnia
• Dermatologic:
  • Hyperhidrosis
  • Skin Rash
• Endocrine & Metabolic:
  • Hyperglycemia
  • Hypocalcemia
  • Hyperuricemia
  • Increased Gamma-Glutamyl Transferase
  • Hyponatremia
  • Hypoalbuminemia
  • Hypokalemia
  • Hyperkalemia
  • Hypophosphatemia
  • Hypernatremia
  • Hypomagnesemia
• Gastrointestinal:
  • Nausea
  • Vomiting
  • Mucositis
  • Diarrhea
  • Increased Serum Lipase
  • Abdominal Pain
  • Constipation
  • Increased Serum Amylase
  • Hemorrhoids
  • Gastrointestinal Hemorrhage
• Genitourinary:
  • Urinary Tract Infection
• Hematologic & Oncologic:
  • Febrile Neutropenia
  • Lymphocytopenia
  • Leukopenia
  • Anemia
  • Thrombocytopenia
  • Neutropenia
  • Petechia
  • Prolonged Partial Thromboplastin Time
• Hepatic:
  • Increased Serum ALT
  • Increased Serum Alkaline Phosphatase
  • Increased Serum AST
  • Hyperbilirubinemia
• Infection:
  • Localized Infection
• Neuromuscular & Skeletal:
  • Musculoskeletal Pain
  • Arthralgia
• Renal:
  • Increased Serum Creatinine
  • Renal Insufficiency
• Respiratory:
  • Upper Respiratory Tract Infection
  • Epistaxis
  • Dyspnea
  • Cough
  • Pleural Effusion
• Miscellaneous:
  • Fever

Less Common Side Effects of Midostaurin (Rydapt):

• Cardiovascular:
  • Hypotension
  • Hypertension
  • Cardiac Failure
  • Thrombosis
  • Pericardial Effusion
  • Ischemia
  • Myocardial Infarction
• Central Nervous System:
  • Disturbance In Attention
  • Chills
  • Vertigo
  • Mental Status Changes
• Dermatologic:
  • Xeroderma
  • Cellulitis
  • Erysipelas
• Endocrine & Metabolic:
  • Weight Gain
  • Hypercalcemia
• Gastrointestinal:
  • Dyspepsia
  • Gastritis
• Hematologic & Oncologic:
  • Bruise
  • Hematoma
• Hypersensitivity:
  • Hypersensitivity
• Infection:
  • Herpes Virus Infection
  • Sepsis
  • Fungal Infection
• Neuromuscular & Skeletal:
  • Tremor
• Ophthalmic:
  • Eyelid Edema
• Respiratory:
  • Pneumonia
  • Bronchitis
  • Oropharyngeal Pain
  • Pulmonary Edema
  • Interstitial Pulmonary Disease
  • Pneumonitis

Contraindications to Midostaurin (Rydapt):

If you're allergic to Midostaurin or any part of the medicine, you shouldn't take it.

Warnings and precautions

Suppression of bone marrow

• People often see lower numbers of certain blood cells. This can include fewer lymphocytes, white blood cells, neutrophils (a type of white blood cell), platelets, and red blood cells.
• In patients with a type of cancer called AML, there might be a mix-up in understanding if these lower blood counts are because of the cancer, the Midostaurin, or the other cancer drugs they're taking. But, it seems like people with AML who take Midostaurin with their chemotherapy are slightly more likely to get a condition where they have a fever and too few neutrophils (febrile neutropenia) compared to those who take chemotherapy with a placebo (a pill with no medicine in it).
• Because of this, it's important to regularly check blood counts if someone is on Midostaurin.

Toxicity to the GI:

• Midostaurin can cause stomach and gut problems.
• It might make you feel nauseous or throw up, so doctors recommend taking anti-nausea medication before using it to prevent this.
• Diarrhea, tummy ache, and constipation are also common issues.
• Some people might develop sore areas in their mouth and digestive tract (mucositis) due to this medicine.

Hypersensitivity

• Some people can have allergic reactions to Midostaurin.
• This can include severe reactions like anaphylactic shock, which is a life-threatening allergic reaction.
• Other allergic signs include swelling (often of the face), difficulty breathing, chest pain, and redness or warmth of the skin.

Extension of QT

• Midostaurin can affect the heart's electrical activity, causing a longer time for the heart to recharge between beats. This is called QT prolongation.
• If someone is taking other medicines that can also affect the heart in this way, it's a good idea to get an ECG. An ECG is a test that checks the heart's electrical activity and can measure this QT interval.

Toxicity in the lungs:

• Midostaurin can cause lung problems.
• There are reports of people getting lung diseases like interstitial lung disease and pneumonitis when using Midostaurin, either alone or with other cancer drugs. Sadly, some of these cases led to death.
• If someone taking Midostaurin starts having lung issues, and it's not because of an infection, they should stop taking the medicine.

Midostaurin: Drug Interaction

Monitoring parameters:

FLT3 Mutation (in AML patients)

• Check if the patient has the FLT3 mutation, which is relevant for AML treatment.

Blood Counts (for systemic mastocytosis patients)

• Weekly checks for the first month.
• Every other week for the next 2 months.
• Monthly after that, or more often if needed.

Pregnancy Check

• Make sure the patient is not pregnant by testing within 7 days before starting the treatment, especially for women who could become pregnant.

Lung Health

• Look out for signs of lung problems, specifically interstitial lung disease and pneumonitis.

Heart Health

• Consider an ECG test if the patient is on other medicines that might affect the heart's rhythm (QT interval).

Medication Adherence

• Make sure the patient is taking their medicine as prescribed.

How to administer Midostaurin (Rydapt)?

Nausea & Vomiting

• Midostaurin might make you feel nauseous or throw up.
• To prevent this, take anti-nausea medicine before starting your treatment.

How to Take It

• Take Midostaurin with food.
• Take it around every 12 hours.
• Don't open or crush the capsules.

Mechanism of action of Midostaurin (Rydapt):

Midostaurin is a kind of medicine that blocks specific proteins called tyrosine kinases. These proteins play a role in cell growth and signaling. Midostaurin targets multiple receptors:

FLT3 Receptors:

• Wild type FLT3 (normal version).
• FLT3 mutants ITD and TKD, which are linked to certain leukemias.
• It stops FLT3 signaling, cell growth, and encourages cell death in leukemic cells with these mutations.

KIT Receptors:

• Both wild type and D816V mutant versions.
• Midostaurin interferes with KIT signaling, cell growth, and prompts cell death.

PDGFRα/β Receptors:

• Midostaurin affects these receptors too, slowing down cell growth.

VEGFR2:

• It influences this receptor, which is involved in the growth of new blood vessels (angiogenesis).

Protein Kinase C (PKC) Family:

• Midostaurin affects members of this family of proteins, which are involved in many cell processes.

This medicine:

• Stops the signaling and growth of FLT3 receptors.
• Leads to cell death in leukemia cells with certain mutations.
• Could also impact KIT signaling, growth, and histamine release in mast cells (cells involved in allergic reactions).

This complex process helps fight leukemia and other conditions Midostaurin is used for.

Absorption:

• If taken with a regular meal, the amount your body absorbs increases by 1.2 times. With a high-fat meal, it's 1.6 times more compared to when you haven't eaten.
• However, its highest concentration (Cmax) in the body decreases by 20% with a regular meal and 27% with a high-fat meal compared to an empty stomach.

Distribution:

• Once absorbed, it spreads throughout the body in a volume of about 95.2 liters.

Binding:

• Midostaurin and its main metabolites, CGP62221 and CGP52421, are mostly bound to blood proteins (over 99.8%). The main protein it binds to is called α1-acid glycoprotein.

Metabolism:

• The liver mainly breaks down Midostaurin. The enzyme responsible is CYP3A4, turning Midostaurin into its active forms CGP62221 and CGP52421.

Half-life:

• Midostaurin: 19 hours
• CGP62221 (a metabolite): 32 hours
• CGP52421 (another metabolite): 482 hours

Peak Time:

• 1 to 3 hours on an empty stomach.
• 2.5 to 3 hours if taken with a meal.

Excretion:

• Mainly through feces (95%), with 91% as broken-down products and 4% unchanged.
• A small amount (5%) is removed through urine.

International Brand Names of Midostaurin:

• Rydapt

Midostaurin Brand Names in Pakistan:

Not Available.