Consumer medicine information

Rydapt

Midostaurin

BRAND INFORMATION

Brand name

Rydapt

Active ingredient

Midostaurin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Rydapt.

What is in this leaflet

This leaflet answers some common questions about RYDAPT. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking RYDAPT against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What RYDAPT is used for

RYDAPT contains the active ingredient midostaurin.

RYDAPT belongs to a group of medicines called protein kinase inhibitors. It is used to treat certain types of white blood cell disorders.

RYDAPT is used to treat:

  • acute myeloid leukemia (AML) in adults who have a defect in a gene called FLT3. AML is a type of cancer of white blood cells. White blood cells usually help the body to fight infections, and in the case of AML, the body produces too many abnormal white blood cells (named "myeloid" cells).
  • a disease called advanced systemic mastocystosis in adults. This is a disorder in which the body produces too many mast cells, a type of white blood cell. Symptoms are caused when too many mast cells get into organs like the liver, bone marrow and spleen, or release substances like histamine into the blood.

RYDAPT works by blocking the action of some enzymes (kinases) of the abnormal cells and stops their division and growth. At the start of the treatment in AML, RYDAPT is always used together with other chemotherapies.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

This medicine is not addictive.

This medicine is available only with a doctor's prescription.

Before you take RYDAPT

When you must not take it

Do not take RYDAPT if you have an allergy to:

  • midostaurin
  • any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin

Do not take Rydapt if you are taking any of the following medicines:

  • rifampicin (used to treat tuberculosis)
  • carbamazepine or phenytoin (used to treat epilepsy)
  • enzalutamide (used to treat prostate cancer)
  • St. John's Wort (also known as Hypericum perforatum, a herbal medicine used to treat depression).

Do not take RYDAPT if you are you are pregnant, think you may be pregnant, or are planning to become pregnant during the course of treatment and for 4 months after your final dose of the medicine. It may affect your developing baby if you take it during pregnancy.

Do not take RYDAPT if you are breast-feeding or plan to breast-feed while on treatment with RYDAPT and for 4 months after your final dose of the medicine. It is not known if the active ingredient in RYDAPT can pass into breast milk and can cause harm to your baby.

Do not give this medicine to a child under the age of 18 years.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

  • any infection at the time of being prescribed RYDAPT
  • heart disorders
  • problems with your lungs or problems breathing

If you have not told your doctor about any of the above, tell him/her before you start taking RYDAPT.

Fertility preservation

Talk to your doctor about fertility preservation if you plan to have children in the future. RYDAPT may have an impact on fertility in men and women. Discuss with your doctor fertility preservation before starting treatment with RYDAPT.

Women with the potential to become pregnant

Discuss with your doctor if you are able to become pregnant. Even if your periods have stopped (menopause), it is important to check with your doctor whether there is a risk that you could become pregnant. If you are able to become pregnant you must:

  • use a highly effective method of birth control (contraception) so that you do not become pregnant while on treatment with RYDAPT
  • continue to use a highly effective method of birth control (contraception) for 4 months after your final dose of the medicine.

Talk to your doctor about the most suitable method of birth control (contraception) for you.

Talk to your doctor about a pregnancy test before starting treatment with RYDAPT. During treatment and 4 months after treatment, tell your doctor immediately if:

  • you believe your contraception has failed for any reason
  • your periods stop
  • you stop using contraception
  • you need to change your contraception.

Men taking RYDAPT

Always use a condom when you have sex with a female partner, even if you have had a vasectomy. Do this during treatment and for 4 months after your final dose of the medicine.

Do not donate semen while on treatment with RYDAPT and for 4 months after your final dose of the medicine.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and RYDAPT may interfere with each other. These include:

  • some medicines used to treat infections, such as ketoconazole or clarithromycin
  • some medicines used to treat epilepsy, such as carbamazepine
  • rifampicin, a medicine used to treat tuberculosis
  • some medicines used to treat depression such as nefazodone or the herbal medicine St. John's Wort (also known as hypericum perforatum)
  • some medicines used to treat high blood cholesterol, such as rosuvastatin
  • bupropion, a medicine used to quit smoking
  • medicines used to treat HIV, such as ritonavir.

These medicines may be affected by RYDAPT or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

How to take RYDAPT

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions on the box, ask your doctor or pharmacist for help.

How much to take

Your doctor will tell you exactly how many soft capsules of Rydapt to take.

Treatment of Acute Myeloid Leukemia
The usual daily dose is 50 mg (2 capsules) twice daily (4 capsules per day.

Treatment of Advanced Systemic Mastocytosis
The usual daily dose is 100 mg (4 capsules) twice daily (8 capsules per day).

Depending on how you respond to Rydapt, your doctor may prescribe you a lower dose or interrupt temporarily the treatment.

How to take it

Swallow the capsules whole with a full glass of water. RYDAPT capsules should be swallowed whole with a glass of water. RYDAPT capsules should not be opened, crushed or chewed.

For patients with acute myeloid leukemia, RYDAPT is administered according to a dosage regimen together with other chemotherapy treatments. It is very important to follow your doctor's recommendation.

When to take it

Take your medicine at about the same time each day. Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

Take RYDAPT twice a day at approximately 12 hours intervals (for example during breakfast and during dinner).

Take your medicine with food. Take RYDAPT with food to help to prevent nausea.

How long to take it

Continue taking your medicine for as long as your doctor tells you.

Your doctor will regularly monitor your condition to check that the treatment is having the desired effect.

If you are treated for AML, after the period where RYDAPT is used together with other chemotherapies, you will get RYDAPT alone for up to 12 months.

If you are treated for advanced systemic mastocystosis this is a long-term treatment, possibly lasting for months or years.

If you forget to take it

If you miss a dose, skip the dose you missed and take your next dose when you are meant to.

Do not take a double dose to make up for the dose that you missed. This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much RYDAPT. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Keep the telephone numbers for these places handy.

While you are using RYDAPT

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking RYDAPT.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine.

Both men and women (who are able to become pregnant) need to take precautions so that a pregnant woman is not exposed to RYDAPT. Both men and women will need to do this for 4 months after stopping treatment.

Talk to your doctor immediately if you have unprotected sex or if you think your contraception has failed.

If you become pregnant while taking this medicine, tell your doctor immediately.

Keep all of your doctor's appointments so that your progress can be checked. Your doctor may do some blood tests such as checking blood cells (white blood cells, red blood cells and platelets) and electrolytes (e.g. calcium, potassium, magnesium) in your body from time to time to make sure the medicine is working and to prevent unwanted side effects. Your heart and lung function will also be checked regularly.

Women taking RYDAPT

Women who are able to become pregnant will need to show a negative pregnancy test done by your doctor before starting treatment with RYDAPT. If you become pregnant while taking this medicine or suspect you could be pregnant, stop taking RYDAPT and tell your doctor immediately.

Men taking RYDAPT

Always use a condom when you have sex with a female partner, even if you have had a vasectomy. Do this during treatment and for 4 months after your final dose of the medicine.

Do not donate semen while on treatment with RYDAPT and for 4 months after your final dose of the medicine.

Tell your doctor immediately if your partner becomes pregnant or thinks she is pregnant while you are taking RYDAPT.

Things you must not do

Do not take RYDAPT to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not stop taking your medicine or lower the dosage without checking with your doctor. If you stop taking it suddenly, your condition may worsen or you may have unwanted side effects.

Things to be careful of

Be careful driving or operating machinery until you know how RYDAPT affects you. This medicine may cause (dizziness, light-headedness, tiredness) in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking RYDAPT.

This medicine helps most people with AML or advanced systemic mastocystosis, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • Infection at catheter site (device related infection)
  • Red or purple, flat, pinhead spots under the skin (petechiae)
  • Problem to fall asleep (insomnia)
  • Urinary tract infection
  • Upper respiratory tract infection
  • Headache
  • Dizziness
  • Shortness of breath, laboured breathing (dyspnoea)
  • Cough
  • Fluid collection on the lungs/chest cavity, which if severe, could make you breathless (pleural effusion)
  • Dizziness, light headedness (hypotension)
  • Nose bleeding (epistaxis)
  • Throat pain (laryngeal pain)
  • Mouth sores (stomatitis)
  • Nausea
  • Vomiting
  • Upper abdominal pain
  • Haemorrhoids
  • Diarrhoea
  • Constipation
  • Excessive sweating (hyperhidrosis)
  • Skin rash with flaking or peeling (dermatitis exfoliative)
  • Back pain
  • Joint pain (arthralgia)
  • Rapid weight gain, swelling of the extremities (calves, ankles) (oedema peripheral)
  • Fatigue
  • Fever (pyrexia)
  • Thirst, low urine output, dark urine, dry flushed skin (signs of high level of sugar in blood known as hyperglycaemia)
  • Muscle weakness, drowsiness, confusion, convulsions, impaired consciousness (signs of high level of sodium in the blood known as hypernatraemia)
  • Muscle weakness, muscle spasms, abnormal heart rhythm (signs of low level of potassium in the blood known as hypokalaemia)
  • Defect in blood clotting (activated partial thromboplastin time prolonged)
  • Nausea, vomiting, constipation, stomach pain, frequent urination, thirst, muscle weakness and twitching (signs of high level of calcium in the blood known as hypercalcaemia)
  • High level of uric acid in the blood (abnormal blood results known as hyperuricaemia)
  • Fainting (syncope)
  • Involuntary shaking of the body (tremor)
  • Fast heart beat (sinus tachycardia)
  • Sore throat and runny nose (nasopharyngitis)
  • Swelling of the eyelid (eyelid oedema)
  • Anorectal discomfort
  • Dry skin
  • Eye pain, blurred vision, abnormal intolerance to light (keratitis)
  • Neck pain
  • Bone pain
  • Pain in extremity
  • Weight increased
  • Cough with phlegm, chest pain, fever (bronchitis)
  • Cold sores in the mouth due to viral infection (oral herpes)
  • Painful and frequent urination (cystitis)
  • Feeling of pressure or pain in the cheeks and forehead (sinusitis)
  • Red, swollen painful rash on any part of the skin (erysipelas)
  • Herpes zoster
  • Disturbance in attention
  • Dizziness with spinning sensation (vertigo)
  • Bruise (haematoma)
  • Upset stomach, indigestion (dyspepsia)
  • Weakness (asthenia)
  • Chills
  • Generalized swelling (oedema)
  • Contusion
  • Fall
  • Coagulated blood in catheter (catheter-related thrombosis).

The above list includes the more common side effects of your medicine.

Tell your doctor as soon as possible if you notice any of the following:

  • fever, sore throat or mouth ulcers because these may be signs of low level of white blood cells
  • new or worsening symptoms such as fever, cough with or without mucous, chest pain, trouble breathing or shortness of breath because these may be signs of lung problems
  • chest pain or discomfort, lightheadedness, fainting, dizziness, blue discoloration of your lips or extremities, shortness of breath, or swelling of your lower limbs (edema) or skin because these may be signs of heart problems.

The above list includes serious side effects that may require medical attention. Serious side effects are rare.

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • Weakness, spontaneous bleeding or bruising, frequent infections with signs such as fever, chills, sore throat or mouth ulcers (signs of low level of blood cells)
  • Fever, cough with or without mucous, chest pain, trouble breathing or shortness of breath (signs of infections or lung problems)
  • Fever, sore throat or mouth ulcers due to infections (signs of lymphopenia or neutropenia)
  • Severe shortness of breath, labored and unusually rapid breathing, low blood pressure, confusion and extreme tiredness (signs of acute respiratory distress syndrome)
  • Fever, cough, difficult or painful breathing, wheezing, chest in pain when breathing (signs of pneumonia)
  • Infections, fever, decreased urination, rapid pulse, rapid breathing (signs of sepsis or neutropenic sepsis)
  • Vomiting of blood, black or bloody stools (signs of gastrointestinal haemorrhage).

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation. These side effects are generally rare.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

Some of these side effects (for example, high levels of the following enzymes, lipase and/or amylase (pancreas function), alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) (liver function), high blood sugar levels, low or high blood pressure, unusual electrocardiogram) can only be found when your doctor does tests from time to time to check your progress.

After using RYDAPT

Storage

Keep your capsules in the pack until it is time to take them. If you take the capsules out of the pack they may not keep well.

Keep your capsules in a cool dry place where the temperature stays below 30°C.

Do not store RYDAPT or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

RYDAPT capsules are pale orange oblong capsules with red imprint "PKC NVR".

RYDAPT is available in blister packs of 112 and 56 capsules.

Ingredients

RYDAPT contains 25 mg of midostaurin as the active ingredient.

It also contains the following inactive ingredients:

  • PEG40 hydrogenated castor oil
  • macrogol 400
  • Glycerol
  • ethanol anhydrous
  • Corn oil PEG6 esters
  • titanium dioxide (E171)
  • dl-alpha-tocopherol
  • carmine (E120)
  • hypromellose
  • propylene glycol
  • purified water.

The capsule shell contains:

  • gelatin (may contain sulfites)
  • iron oxide yellow (E172)
  • iron oxide red (E172)
  • Edible ink Red

This medicine does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Sponsor

RYDAPT is supplied in Australia by:

NOVARTIS Pharmaceuticals Australia Pty Limited
ABN 18 004 244 160
54 Waterloo Road
Macquarie Park NSW 2113
Telephone 1 800 671 203
Web site: www.novartis.com.au

RYDAPT is supplied in New Zealand by:

NOVARTIS New Zealand Ltd
PO Box 99102, Newmarket
Auckland 1149
Telephone: 0800 652 422

® = Registered Trademark
© Novartis Pharmaceuticals Australia Pty Limited 2022

This leaflet was prepared in August 2022.

Australian Registration Number:

RYDAPT 25mg capsules AUST R 287013

(ryd030822c.doc) based on PI (ryd030822i.doc)

Published by MIMS September 2022

BRAND INFORMATION

Brand name

Rydapt

Active ingredient

Midostaurin

Schedule

S4

 

1 Name of Medicine

Midostaurin.

2 Qualitative and Quantitative Composition

Each capsule contains 25 mg of midostaurin.

Excipients with known effect.

May contain traces of sulfites in gelatin and 6.5% m/m alcohol.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Soft gelatin capsule.
Pale orange oblong capsules with red imprint "PKC NVR".

4 Clinical Particulars

4.1 Therapeutic Indications

Rydapt is indicated:
in combination with standard anthracycline and cytarabine induction and cytarabine consolidation chemotherapy, followed in patients in complete response by single agent maintenance therapy for adult patients with newly diagnosed acute myeloid leukemia (AML) who are FLT3 mutation-positive;
for the treatment of adult patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated haematological neoplasms (SM-AHN), or mast cell leukaemia (MCL).

4.2 Dose and Method of Administration

Treatment with Rydapt should be initiated by a physician experienced in the use of anticancer therapies.
Rydapt should be taken orally, twice daily at approximately 12 hour intervals. Rydapt should be taken with food to help prevent nausea (see Section 5.2 Pharmacokinetic Properties).
Prophylactic anti-emetics should be administered in accordance with local medical practice as per patient tolerance.
Rydapt capsules should be swallowed whole with a glass of water. Rydapt capsules should not be opened, crushed or chewed.
If a dose is missed, the dose should not be made up and the patient should only take the next scheduled dose at the scheduled time.
If vomiting occurs, the patient should not take an additional dose of Rydapt, but should take the next scheduled dose.

Monitoring during treatment with Rydapt.

Consider interval assessments of QT by ECG if Rydapt is taken concurrently with medications that can prolong the QT interval.

Dosage regimen.

Target population.

Recommended dose in AML.

The recommended dose of Rydapt is 50 mg twice daily. Rydapt is dosed on days 8-21 of induction and consolidation chemotherapy cycles and then twice daily as single agent maintenance therapy until relapse for up to 12 cycles of 28 days each. Midostaurin should not be used as a single agent for induction or consolidation. In patients receiving haematopoietic stem cell transplant (SCT), Rydapt should be discontinued prior to the conditioning regimen for SCT.

Recommended dose in advanced SM.

The recommended starting dose of Rydapt is 100 mg twice daily.
Treatment should be continued as long as clinical benefit is observed or until unacceptable toxicity occurs.

Dose modifications.

Dose modifications in AML.

Recommendations for dose modifications of Rydapt in patients with AML are provided in Table 1.

Dose modifications in advanced SM.

Recommendations for dose modifications of Rydapt in patients with advanced SM are provided in Table 2.

Special populations.

Patients with renal impairment.

No dose adjustment is required for patients with mild or moderate renal impairment. Clinical experience in patients with severe renal impairment is limited. No data are available in patients with end-stage renal disease (see Section 5.2 Pharmacokinetic Properties).

Patients with hepatic impairment.

No dose adjustment is required in patients with mild or moderate (Child-Pugh A or B) hepatic impairment (see Section 5.2 Pharmacokinetic Properties). Exposure to midostaurin and its active metabolite CGP62221 is substantially lower in patients with severe hepatic impairment than that in patients with normal hepatic function (see Section 5.2). However, there are insufficient efficacy data in patients with severe hepatic impairment to suggest a dose adjustment is required.

Elderly patients.

No dosage regimen adjustment is required in patients over 65 years of age (see Section 4.4 Special Warnings and Precautions for Use).

Paediatric patients.

Rydapt should not be used in combination with intensive paediatric AML combination chemotherapy regimens including anthracyclines, fludarabine and cytarabine (see Section 4.4 Special Warnings and Precautions for Use; Section 5.1, Clinical trials).

4.3 Contraindications

Rydapt is contraindicated in patients with hypersensitivity to midostaurin or to any of the excipients.
Concomitant administration of potent CYP3A4 inducers, e.g. rifampicin, St. John's Wort (Hypericum perforatum), carbamazepine, enzalutamide, phenytoin (see Section 4.5).

4.4 Special Warnings and Precautions for Use

Neutropenia/infections.

Neutropenia has occurred in patients receiving Rydapt as monotherapy and in combination with chemotherapy (see Section 4.8 Adverse Effects (Undesirable Effects)). Severe neutropenia (ANC less than 0.5 x 109/L) was generally reversible by withholding Rydapt until recovery or discontinuation in the advanced SM studies. White blood cells (WBCs) should be monitored regularly, especially at treatment initiation.
In patients who develop unexplained severe neutropenia, treatment with Rydapt should be interrupted until ANC is greater than or equal to 1.0 x 109/L in patients with AML or 1.5 x 109/L in patients with advanced SM, as recommended in Tables 1 and 2. Rydapt should be discontinued in patients who develop recurrent or prolonged severe neutropenia that is suspected to be related to Rydapt (see Section 4.2 Dose and Method of Administration).
Any active serious infections should be under control prior to starting treatment with Rydapt monotherapy. Patients should be monitored for signs and symptoms of infection and if a diagnosis of infection is made, appropriate treatment should be instituted promptly, including as needed, the discontinuation of Rydapt.

Cardiac dysfunction.

In the advanced SM studies with Rydapt, cardiac dysfunction such as congestive heart failure (CHF), some of which were fatal, and transient decreases in left ventricular ejection fraction (LVEF) occurred. No difference in CHF was observed between the Rydapt + chemotherapy and placebo + chemotherapy arms in the randomized AML study. In patients at risk, Rydapt should be used with caution and patients should be closely monitored (at baseline and during treatment).

Pulmonary toxicity.

Interstitial lung disease (ILD) and pneumonitis, some cases fatal, have occurred in patients treated with Rydapt monotherapy or in combination with chemotherapy. Patients should be monitored for pulmonary symptoms indicative of ILD or pneumonitis and Rydapt should be discontinued in patients who experience pulmonary symptoms indicative of ILD/pneumonitis without an infectious etiology which are ≥ Grade 3 (NCI CTCAE).

Use in the elderly.

No dosage regimen adjustment is required in patients over 65 years of age (see Section 5.2 Pharmacokinetic Properties). There is limited experience with midostaurin in AML patients aged 60-70 years (46 patients in supportive study) and no experience in AML patients above 70 years. No patients aged ≥ 60 years were included in the pivotal study. In patients aged ≥ 60 years, Rydapt should be used only in patients eligible to receive intensive induction chemotherapy with adequate performance status and without significant comorbidities.

Paediatric use.

Rydapt should not be used in combination with intensive paediatric AML combination chemotherapy regimens including anthracyclines, fludarabine and cytarabine because of the risk of prolonged haematological recovery (such as prolonged severe neutropenia and thrombocytopenia) (see Section 5.1, Clinical trials).

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Midostaurin undergoes extensive hepatic metabolism through CYP3A4 enzymes which are either induced or inhibited by a number of concomitant drugs. Based on in vitro data, midostaurin and/or its metabolites have the potential to inhibit and induce CYP enzymes and inhibit transporters (see Section 5.2 Pharmacokinetic Properties). Therefore, Rydapt may be a victim or a perpetrator of drug-drug interactions in vivo.

Effect of other drugs on Rydapt.

Drugs or substances known to affect the activity of CYP3A4 may affect the plasma concentrations of midostaurin and therefore the safety and/or efficacy of Rydapt.

Strong CYP3A4 inhibitors.

Strong CYP3A4 inhibitors may increase midostaurin blood concentrations. In a study with 36 healthy subjects, co-administration of the strong CYP3A4 inhibitor ketoconazole to steady-state with a single dose of Rydapt led to a significant increase in midostaurin exposure (1.8-fold Cmax increase and 10-fold AUCinf increase) while the peak concentrations of the active metabolites, CGP62221 and CGP52421, decreased by half (see Section 5.2 Pharmacokinetic Properties). Another study evaluated the concomitant administration of multiple dose midostaurin 50 mg twice daily with the strong CYP3A4 inhibitor itraconazole at steady-state in a subset of patients (N = 7), and showed that itraconazole increased midostaurin steady-state exposure (Cmin) by only 2.09-fold. During the induction phase of the AML study, up to 62% of patients received midostaurin concomitantly with strong inhibitors of CYP3A4. Upon co-administration with CYP3A4 inhibitors, a 1.44-fold increase in midostaurin exposure (Cmin) was observed. No impact was observed for CGP62221 and CGP52421. Caution should be advised when concomitantly administering with midostaurin, medicinal products that are strong inhibitors of CYP3A4, such as, but not limited to antifungals (e.g. ketoconazole), certain antivirals (e.g. ritonavir), and macrolide antibiotics (e.g. clarithromycin). Alternative therapeutics that do not strongly inhibit CYP3A4 activity should be considered. In situations where satisfactory therapeutic alternatives do not exist, patients should be closely monitored for toxicity.

Strong CYP3A4 inducers.

Concomitant use of Rydapt with strong inducers of CYP3A4 (e.g. carbamazepine, rifampicin, enzalutamide, phenytoin, St. John's Wort [Hypericum perforatum]) is contraindicated (see Section 4.3). Strong CYP3A4 inducers decrease exposure of midostaurin and its active metabolites (CGP52421 and CGP62221). In a study in healthy subjects, co-administration of the strong CYP3A4 inducer rifampicin (600 mg daily) to steady state with a 50 mg single dose of midostaurin decreased midostaurin Cmax by 73% and AUCinf by 96% on average, respectively. Both metabolites, CGP62221 and CGP52421, exhibited a similar pattern.

Effect of Rydapt on other drugs.

Substrates of CYP enzymes.

In healthy subjects, co-administration of a single dose of bupropion (CYP2B6 substrate) with multiple doses of midostaurin (50 mg twice daily) at steady-state decreased bupropion AUCinf and AUClast by 48% and 49% respectively and Cmax by 55% compared to administration of bupropion alone. This indicates that midostaurin is a mild inducer of CYP2B6. Medicinal products with a narrow therapeutic range that are substrates of CYP2B6 should be used with caution when administered concomitantly with midostaurin, and may need dose adjustment to maintain optimal exposure.
Based on in vitro data, midostaurin and its active metabolites, CGP52421 and CGP62221 are considered as inhibitors of CYP1A2, and CYP2E1 and inducers of CYP1A2.
Therefore, medicinal products with a narrow therapeutic range that are substrates of CYP1A2 and CYP2E1 should be used with caution when administered concomitantly with midostaurin, and may need dose adjustment to maintain optimal exposure.
In healthy subjects, co-administration of a single dose of midazolam (CYP3A substrate) with multiple doses of midostaurin (50 mg twice daily) at steady-state decreased midazolam AUCinf and AUClast by 3% and 4% respectively and increased Cmax by 10% compared to administration of midazolam alone. Therefore, midostaurin has neither inhibitory nor inducing effect on CYP3A substrates.
In healthy subjects, co-administration of a single dose of pioglitazone (CYP2C8 substrate) with multiple doses of midostaurin (50 mg twice daily) at steady-state did not cause any clinically significant decrease in pioglitazone exposure (6% decrease in AUCinf and AUClast respectively, and 10% decrease in Cmax) compared to the administration of pioglitazone alone. Clinically relevant drug-drug interactions between midostaurin and CYP2C8 substrates are unlikely to occur.
In healthy subjects, co-administration of a single dose of dextromethorphan (CYP2D6 substrate) with a single dose of midostaurin (100 mg) did not cause any increase in dextromethorphan exposure (13% decrease in AUCs and 28% decrease in Cmax) compared to administration of dextromethorphan alone. Therefore, midostaurin has no inhibitory effect on CYP2D6 and clinically relevant drug-drug interactions between midostaurin and CYP2D6 substrates are unlikely to occur.

Substrates of transporters.

In healthy subjects, co-administration of a single dose of rosuvastatin (BCRP substrate) with a single dose of midostaurin (100 mg) increased rosuvastatin AUCinf and AUClast by 37% and 48% respectively; Cmax was approximately doubled (2.01 times) compared to administration of rosuvastatin alone. This indicates that midostaurin has a mild inhibitory effect on BCRP substrates. Medicinal products with a narrow therapeutic range that are substrates of the transporter BCRP should be used with caution when administered concomitantly with midostaurin, and may need dose adjustment to maintain optimal exposure.
In healthy subjects, co-administration of a single dose of digoxin (P-gp substrate) with a single dose of midostaurin (100 mg) increased digoxin AUCinf and AUClast by 23% and 21% respectively, and Cmax by 20% compared to administration of digoxin alone. This indicates that midostaurin has a minor inhibitory effect on P-gp substrates. Clinically relevant drug-drug interactions between midostaurin and P-gp substrates are unlikely to occur.

Hormonal contraceptives.

There was no clinically significant pharmacokinetic drug-drug interaction between multiple doses of midostaurin (50 mg twice daily) at steady-state and oral contraceptives containing ethinyl estradiol and levonorgestrel in healthy women. Therefore it is not anticipated that the contraceptive reliability of this combination will be compromised by co-administration of midostaurin.

In vitro evaluation of drug interaction potential.

Based on in vitro data, midostaurin and its active metabolites, CGP52421 and CGP62221, are considered as inhibitors of CYP1A2 and CYP2E1 and inducers of CYP2B6 (induction mediated by CAR) and CYP1A2 (induction mediated by AhR). Based on in vitro data midostaurin and its active metabolites may inhibit BCRP and BSEP. Simulations using physiologically based pharmacokinetic (PBPK) models predicted that midostaurin given at a dose of 50 mg twice daily at steady-state is unlikely to cause clinically relevant inhibition of OATP1B.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Rydapt may impair fertility in humans. Oral administration of midostaurin at 10, 30 and 60 mg/kg/day was associated with reproductive toxicity in male and female rats. In males, testicular degeneration and atrophy were observed at all doses, and alterations in epididymides (aspermia, epididymal spermatid stasis, epididymal oligospermia) and sperm motility, a decrease in sperm counts, and a decrease in reproductive organ weights were observed at 60 mg/kg/day. In females, increased resorptions, decreased pregnancy rate, number of implants and live embryos were observed at 60 mg/kg/day. Inhibition of spermatogenesis was also seen in dogs at doses ≥ 3 mg/kg/day. The plasma midostaurin concentrations in rats at 60 mg/kg/day and dogs at 3 mg/kg/day are approximately 8- and 100-fold below the human therapeutic exposures at the recommended doses of 50 or 100 mg twice daily based on AUC.
(Category D)
Based on mechanism of action and findings in animal reproduction studies, Rydapt can cause fetal harm when administered to a pregnant woman.
There are no adequate and well-controlled studies in pregnant women. Pregnant women should be advised of the potential risk to the fetus. Midostaurin is not recommended during pregnancy or in women of childbearing potential not using contraception.
In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of midostaurin at 3, 10, and 30 mg/kg/day and at 2, 10 and 20 mg/kg/day, respectively, during the period of organogenesis. An increase in number of late resorptions and in the incidence of dilated lateral brain ventricles in low weight fetuses was observed at all dose levels and a reduction in fetal weight, associated for some of them with an increase in the incidence of renal pelvic cavitation and delayed skeletal ossification was observed in rats at the high dose of 30 mg/kg/day; no maternal toxicity was observed. In rabbits, maternal toxicity was observed at all dose levels. Mortality in dams, reduced fetal weight and delayed ossification was observed at 10 and 20 mg/kg/day, and abortions secondary to maternal toxicity at all doses. The plasma midostaurin concentrations at the lowest embryofetal toxicity dose in both species are 200-300 fold below the human therapeutic exposures at the recommended doses of 50 and 100 mg twice daily based on AUC comparisons across species.
In a pre- and post-natal developmental study, rats were given oral doses of 5, 15, and 30 mg/kg/day during gestation through lactation up to weaning. Maternal toxicity including excessive salivation, signs of dystocia and reduced litter size were observed at 30 mg/kg/day. Lower body weights, accelerated complete eye opening and delayed auricular startle ontogeny were noted in the rat pups (F1 generation) at 30 mg/kg/day. Maternal systemic exposure at 30 mg/kg (based on AUC) was 10-fold below the human therapeutic exposures at the human doses of 50 and 100 mg twice daily.
 It is unknown whether midostaurin or its active metabolites are excreted in human milk. There are no data on the effects of Rydapt on the breastfed child or the effects of Rydapt on milk production. Studies show that orally administered midostaurin and its active metabolites pass into the milk of lactating rats (milk:plasma midostaurin AUC ratio ~7). Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Rydapt, a nursing woman should be advised on the potential risks to the child and breast-feeding should be discontinued during treatment with Rydapt and for at least 4 months after stopping treatment.

Women of child-bearing potential and sexually active men.

Sexually-active females of reproductive potential are advised to have a pregnancy test within seven days prior to starting treatment with Rydapt.
Females of reproductive potential should be advised that animal studies show Rydapt to be harmful to the developing fetus. Sexually-active females of reproductive potential should use effective contraception (methods that result in less than 1% pregnancy rates) when using Rydapt and for at least 4 months after stopping treatment with Rydapt.
Sexually-active males taking Rydapt should use a condom during intercourse with females of reproductive potential or pregnant women and for at least 4 months after stopping treatment with Rydapt to avoid conception or embryo-fetal harm.

4.7 Effects on Ability to Drive and Use Machines

Rydapt has minor influence on the ability to drive and use machines. Dizziness and vertigo have been reported in patients taking Rydapt and should be considered when assessing a patient's ability to drive or use machines.

4.8 Adverse Effects (Undesirable Effects)

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

AML - summary of the safety profile.

The safety evaluation of Rydapt (50 mg twice daily) in patients with newly diagnosed FLT3 mutated AML is based on a phase III, randomized, double-blind, placebo-controlled study. A total of 717 patients were randomized (1:1) to receive Rydapt or placebo sequentially (on days 8 to 21) in combination with standard daunorubicin (60 mg/m2 on days 1 to 3) / cytarabine (200 mg/m2 on days 1 to 7) induction and high dose cytarabine (3 g/m2 on days 1, 3, 5) consolidation, followed by maintenance with continuous Rydapt or placebo treatment according to initial assignment for up to 12 cycles (28 days/cycle). The overall median duration of exposure was 42 days (range 2 to 576 days) for patients in the Rydapt plus standard chemotherapy arm versus 34 days (range 1 to 465 days) for patients in the placebo plus standard chemotherapy arm. For the 205 patients (120 in Rydapt arm and 85 in placebo arm) who entered the maintenance phase, the median duration of exposure in maintenance was 11 months for both arms (16 to 520 days for patients in the Rydapt arm and 22 to 381 days in the placebo arm).
The most frequent (incidence ≥ 30%) adverse drug reactions (ADRs) in the Rydapt plus standard chemotherapy arm were febrile neutropenia, nausea, exfoliative dermatitis, vomiting, headache, petechiae and pyrexia. The most frequent Grade 3/4 ADRs (incidence ≥ 10%) were febrile neutropenia, lymphopenia, device related infection, exfoliative dermatitis, and nausea.
Serious AEs occurred in 46.3% of patients in the Rydapt plus standard chemotherapy arm versus 51.8% in the placebo plus standard chemotherapy arm. The most frequent serious AE in patients in the Rydapt plus standard chemotherapy arm was febrile neutropenia (16.2%) and this occurred at a similar rate in the placebo arm (15.9%).
Discontinuation due to any adverse event occurred in 9.2% of patients in the Rydapt arm versus 6.2% in the placebo arm. The most frequent Grade 3/4 adverse event leading to discontinuation in the Rydapt arm was exfoliative dermatitis (1.2%).
Deaths occurred in 4.3% of patients in the Rydapt plus standard chemotherapy arm versus 6.3% in the placebo plus standard chemotherapy arm. The most frequent cause of death in the Rydapt plus standard chemotherapy arm was sepsis (1.2%) and occurred at a similar rate in the placebo arm (1.8%).
Tabulated summary of adverse drug reactions from clinical trials in AML. Table 3 presents the frequency category of ADRs reported in the phase-III study in patients with newly diagnosed FLT3 mutated AML. ADRs are listed according to MedDRA system organ class. Within each system organ class, the ADRs are ranked by frequency, with the most frequent reactions first. In addition, the corresponding frequency category using the following convention (CIOMS III) is also provided for each ADR: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data). Table 4 presents the key laboratory abnormalities from the same phase-III study in patients with newly diagnosed FLT3 mutated AML.
Safety profile during maintenance phase. While Table 3 provides the incidence for ADRs over the total duration of the study, when the maintenance phase (single agent Rydapt or placebo) was assessed separately, a difference in the type and severity of ADRs was observed. The overall incidence of ADRs during the maintenance phase was also generally lower. Adverse drug reactions during the maintenance phase with at least ≥ 5% difference between the Rydapt and placebo arms were: nausea (46.4% vs 17.9%), hyperglycaemia (20.2% vs 12.5%), vomiting (19% vs 5.4%) and lymphopenia (16.7% vs 8.9%).
Most of the haematological abnormalities reported occurred during the induction and consolidation phase when the patients received Rydapt or placebo in combination with chemotherapy. The most frequent grade 3/4 haematological abnormalities reported in patients during the maintenance phase with Rydapt were absolute neutrophil count decrease (20.8% vs 18.9%) and leukopenia (7.5% vs 5.9%).
Overall, ADRs reported during the maintenance phase were of mild to moderate intensity and led to very few discontinuations (1.2% in Rydapt arm vs 0% in placebo arm).
Description of selected adverse drug reactions.

Gastrointestinal disorders.

In AML patients during the maintenance phase, low grade nausea and vomiting were observed. These were well managed with supportive prophylactic medication and led to treatment discontinuation in 2 patients, one in each treatment group.

Advanced SM - summary of the safety profile.

The safety of Rydapt (100 mg twice daily) as a single agent in patients with advanced SM was evaluated in 142 patients in two single-arm, open-label, multicenter studies. The median duration of exposure to Rydapt was 11.4 months (range: 0 to 81 months).
The most frequent ADRs (incidence ≥ 30%) were nausea, vomiting, diarrhoea, peripheral oedema, and fatigue. The most frequent Grade 3/4 ADRs (incidence ≥ 6%) were fatigue, sepsis, pneumonia, febrile neutropenia, and diarrhoea. The most frequent non-haematologic laboratory abnormalities (incidence ≥ 30%) were glucose increased, total bilirubin increased, lipase increased, AST increased, and ALT increased while the most frequent haematologic laboratory abnormalities (incidence ≥ 25%) were absolute lymphocyte decreased and neutrophils decreased. The most frequent Grade 3/4 laboratory abnormalities (incidence ≥ 10%) were absolute lymphocyte decreased, absolute neutrophils decreased, glucose increased, and lipase increased.
Dose modifications (interruption or adjustment) due to ADRs occurred in 31% of patients. The most frequent ADRs that led to dose modification (incidence ≥ 5%) were nausea and vomiting.
Adverse events that led to treatment discontinuation occurred in 23.9% of patients. The most common AEs leading to discontinuation were GI related events (5.6%).
Deaths occurred in 18.3% of patients. The most frequent causes of death were disease progression and sepsis.
Tabulated summary of adverse reactions from clinical trials in advanced SM. Table 5 presents the frequency category of ADRs based on pooled data from two studies in patients with advanced SM. ADRs are listed according to MedDRA system organ class. Within each system organ class, the ADRs are ranked by frequency, with the most frequent reactions first. In addition, the corresponding frequency category using the following convention (CIOMS III) is also provided for each ADR: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data). Table 6 presents the key laboratory abnormalities based on pooled data from two studies in patients with advanced SM.
Table 6 presents the frequency of laboratory abnormalities reported in the advanced SM trials.

Adverse drug reactions from spontaneous reports and literature cases (frequency not known).

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. See Table 7.

Description of selected adverse drug reactions.

Gastrointestinal disorders.

In the advanced SM patient population 17 (12%) patients had a dose adjustment or interruption for nausea, 13 (9.2%) for vomiting, and 7 (4.9%) for diarrhoea. The treatment discontinuation rate was low with 3 (2.1%) patients discontinued for nausea, 2 (1.4%) patients for vomiting, and 1 (0.7%) patient for diarrhoea. Most of the events occurred within the first 6 months of treatment and were well managed with supportive prophylactic medication.

4.9 Overdose

Reported experience with overdose in humans is very limited. Single doses of up to 600 mg have been given with acceptable acute tolerability.
General supportive measures should be initiated in all cases of overdose.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: antineoplastic agents, protein kinase inhibitors, ATC code: L01XE39.

Mechanism of action.

Midostaurin inhibits multiple receptor tyrosine kinases, including FLT3 and KIT kinase. Midostaurin inhibits FLT3 receptor signaling and induces cell cycle arrest and apoptosis in leukemic cells expressing ITD and TKD mutant receptors or overexpressing wild type receptors. Midostaurin inhibits both the wild type and D816V mutant KIT, leading to interference with the aberrant signaling of KIT and inhibits mast cell proliferation and survival, and histamine release.
In addition, it inhibits several other tyrosine kinases such as PDGFR or VEGFR2, as well as members of the serine/threonine kinase families, such as the isoforms of PKC (protein kinase C). Midostaurin binds to the catalytic domain of these kinases and inhibits the mitogenic signaling of the respective growth factors in cells, resulting in growth arrest.

Pharmacodynamics.

Midostaurin is a high affinity inhibitor for the receptor tyrosine kinase of FLT3 (Kd of 11 nanoM) and is equally active against ITD- and TKD-mutated FLT3.
The affinity constant of midostaurin to the receptor tyrosine kinase KIT D816V mutant has been determined as 7.7 nanoM.
Two major metabolites have been identified in murine models and humans.
In proliferation assays with FLT3-ITD expressing cells, CGP62221 showed similar potency compared to the parent compound, whereas CGP52421 was approximately 10 fold less potent.

Interactions with conventional chemotherapeutic drugs.

In cell proliferation assays, midostaurin displayed complex interactions with conventional antileukemic drugs in neoplastic cells of different genotype. In human leukemia cell lines bearing FLT3 mutations and MLL rearrangements, midostaurin displayed additive to synergistic activity with cytarabine, doxorubicin, idarubicin, mitoxantrone, etoposide, 4-hydroperoxy cyclophosphamide and vincristine, but antagonistic with methotrexate. In leukemia cell lines that did not bear FLT3 mutations but had MLL rearrangements, midostaurin displayed antagonistic effects with cytarabine, doxorubicin, etoposide and methotrexate but displayed additive or synergistic effects with vincristine, 4-hydroperoxy cyclophosphamide, mitoxantrone and idarubicin. In human leukemia cell lines that lacked both FLT3 mutations and MLL rearrangements, midostaurin mostly displayed antagonistic interactions with conventional chemotherapeutic agents (except vincristine and 4-hydroperoxy cyclophosphamide). Careful evaluation of the patient's leukemia genotype should be undertaken before using midostaurin in combination with conventional chemotherapeutic agents.

Cardiac electrophysiology.

A dedicated QT study in 192 healthy subjects with a dose of 75 mg twice daily did not reveal clinically significant prolongation of QT by midostaurin and CGP62221 and the study duration was not long enough to estimate the QTc prolongation effects of the long-acting metabolite CGP52421. Therefore, the change from baseline in QTcF with the concentration of midostaurin and both metabolites was further explored in a phase II study in 116 patients with advanced SM. At the median peak Cmin concentrations attained at a dose of 100 mg twice daily, neither midostaurin, CGP62221 nor CGP52421 showed a potential to cause clinically significant QTcF prolongation, since the upper bounds of predicted change at these concentration levels were less than 10 msecs with 6.3, 2.4, and 4.7 msecs, respectively.
The risk of hERG related-QT prolongation appears to be low. In the repeat dose studies in dogs, a decrease in heart rate and a prolongation of the P-Q interval was seen in individual animals at 10 and 30 mg/kg; there were no morphological changes in the heart.

Clinical trials.

Acute myeloid leukaemia (AML).

The efficacy and safety of Rydapt in combination with chemotherapy versus placebo plus chemotherapy and as single agent maintenance therapy was investigated in 717 patients (18 to 60 years of age) in a randomized, double-blind, phase III study. Patients with newly diagnosed FLT3 mutated AML as determined by a clinical trial assay were randomized (1:1) to receive Rydapt 50 mg twice daily (n = 360) or placebo (n = 357) (dosed on days 8-21 of induction and consolidation chemotherapy cycles) sequentially in combination with daunorubicin (60 mg/m2 daily on days 1 to 3) / cytarabine (200 mg/m2 daily on days 1 to 7) induction (1 - 2 cycles) and high dose cytarabine (3 g/m2 every 12 hours on days 1, 3, 5) consolidation (3-4 cycles), followed by continuous Rydapt or placebo treatment according to initial assignment for up to 12 additional cycles (28 days/cycle). While the study included patients with various AML related cytogenetic abnormalities, patients with acute promyelocytic leukemia (M3) or therapy related AML were excluded. Patients were stratified by FLT3 mutation status: TKD, ITD with allelic ratio < 0.7, and ITD with allelic ratio ≥ 0.7.
The two treatment groups were generally balanced with respect to the baseline demographics of disease characteristics and details are shown in Table 8.
Patients who proceeded to hematopoietic stem cell transplant (SCT) stopped receiving study treatment on or before the time of stem cell infusion. The overall rate of SCT was 59.4% (214/360) of patient in the Rydapt plus standard chemotherapy arm versus. 55.2% (197/357) in the placebo plus standard chemotherapy arm. All patients were followed for survival.
The primary endpoint of the study was overall survival (OS), measured from the date of randomization until death by any cause. The primary analysis was conducted after a minimum follow-up of approximately 3.5 years after the randomization of the last patient. The study demonstrated a statistically significant improvement in OS for Rydapt plus chemotherapy over placebo plus chemotherapy (HR = 0.774 [95% CI: 0.629, 0.935]; p = 0.0078, 1-sided log-rank test stratified by FLT3 mutation status). The median survival times could not be reliably estimated in Rydapt arm because the survival curves plateaued before reaching the median (see Table 9, Figure 1).
The key secondary endpoint was event free survival (EFS; an EFS event is defined as a failure to obtain a complete remission (CR) within 60 days of initiation of protocol therapy, or relapse, or death from any cause). The EFS showed a statistically significant improvement for Rydapt plus standard chemotherapy over placebo plus standard chemotherapy (see Table 9, Figure 2).
Sensitivity analyses for both OS and EFS when censored at the time of SCT also supported the clinical benefit with Rydapt plus standard chemotherapy over placebo. There was a trend favoring Rydapt for CR rate by day 60 for the midostaurin arm (58.9% versus 53.5%; P = 0.073) that continued when considering all CRs during induction (65.0% versus 58.0%; P = 0.027). In addition, in patients who achieved complete remission in induction, the cumulative incidence of relapse (CIR) at 12 months was 26% in the midostaurin arm vs. 41% in the placebo arm based on an exploratory analysis.
In a subgroup analysis, a gender imbalance was observed for OS benefit, however, a gender imbalance was not observed for all secondary efficacy endpoints (EFS, CR, DFS and CIR), where female patients demonstrated a benefit from midostaurin.
Efficacy and safety in patients 18-70 years old were evaluated in a phase II, single-arm, investigator-initiated study of midostaurin in combination with intensive induction, consolidation including allogeneic SCT and single-agent maintenance in patients with FLT3-ITD mutated AML. Based on the interim analysis conducted in the first 145 patients enrolled (99 patients were ≤ 60 years of age; 46 were > 60 years of age), the EFS rate - as per protocol-defined EFS definition - at 2 years (primary endpoint) was 34.6% (95% CI: 27.4, 43.6) in all patients, 38.2% (95% CI: 29.5, 49.6) in patients aged 60 years or younger and 27.1% (95% CI: 16.6, 44.1), in patients older than 60 years of age.

Paediatric patients with acute myeloid leukaemia (AML).

In a phase 2 study, midostaurin was investigated in combination with chemotherapy in newly diagnosed pediatric patients with FLT3-mutated AML. Among the three FLT3-mutated AML patients enrolled in the study, two patients (10 and 14 years old) experienced Dose Limiting Toxicities (DLTs) following the second induction cycle with midostaurin (at 30 mg/m2 twice daily) in combination with chemotherapy (containing cytarabine 2 g/m2/day, day 1 to 5; fludarabine 30 mg/m2/day, day 1 to 5 and idarubicin 12 mg/m2/day, day 2, 4 and 6). Both patients showed markedly delayed haematological recoveries (i.e. prolonged grade 4 thrombocytopenia lasting for 44 days in the first patient and 51 days in the second patient and grade 4 neutropenia lasting for 46 days in the second patient). In the first induction cycle, both patients received midostaurin in combination with cytarabine, etoposide and idarubicin.

Advanced systemic mastocytosis (ASM).

The efficacy of Rydapt in patients with aggressive systemic mastocytosis (ASM) or mast cell leukemia (MCL), with or without an associated hematologic non-mast cell lineage disorder (AHNMD), collectively referred to as Advanced SM, was evaluated in two open-label, single-arm, multicenter studies (142 patients in total).
The pivotal study was a multicenter, single-arm phase II study in 116 patients with advanced SM (Study CPKC412D2201). Rydapt was administered orally at 100 mg twice daily until disease progression or intolerable toxicity. Of the 116 patients enrolled, 89 were considered eligible for response assessment and constituted the primary efficacy population (PEP). Of these, 73 patients had ASM (57 with an AHNMD), and 16 patients had MCL (6 with an AHNMD). The median age in the PEP was 64 years with approximately half of the patients ≥ 65 years). Approximately one-third (36%) received prior anti-neoplastic therapy for advanced SM. At baseline in the PEP, 65% of the patients had > 1 measurable C-finding. The KIT D816V mutation was detected in 82% of patients.
The primary endpoint was overall response rate (ORR). Response rates were assessed based on the modified Valent and Cheson criteria and responses were adjudicated by a study steering committee. Secondary endpoints included duration of response, time to response, and overall survival. Responses to Rydapt are shown in Table 10. Activity was observed regardless of KIT D816V status, number of prior therapies, and presence or absence of an AHNMD. Forty-six percent of patients had a decrease in bone marrow infiltration exceeded 50% and 58% had a decrease in serum tryptase levels exceeded 50%. Spleen volume decreased by ≥ 10% in 68.9% of patients with at least 1 post-baseline assessment (26.7% of patients had a reduction of ≥ 35%, which correlates with a 50% decrease by palpation).
The median time to response was 0.3 months (range: 0.1 to 3.7 months). The median duration of follow-up was 43 months.
Although the study was designed to be assessed with the modified Valent and Cheson criteria, as a post-hoc exploratory analysis, efficacy was also assessed per the 2013 International Working Group - Myeloproliferative Neoplasms Research and Treatment - European Competence Network on Mastocytosis (IWG-MRT-ECNM) consensus criteria. Response to Rydapt was determined using a computational algorithm applied without any adjudication. Out of 116 patients, 113 had a C-finding as defined by IWG response criteria (excluding ascites as a C-finding). All responses were considered and required a 12-week confirmation (see Table 11).
Patient-reported outcome assessments were evaluated using the Memorial Symptom Assessment Scale (MSAS) and SF-12 questionnaires. The most commonly reported baseline symptoms (> 65% of prevalence) on the MSAS were "lack of energy", "feeling drowsy", and "difficulty sleeping". The prevalence of all symptoms had decreased at Cycle 12, with the exception of nausea and vomiting. The results from the SF-12 indicated that patients had a worse status at baseline for both the physical and mental component scales as compared to a healthy population. During the study, the status of these components improved and approached that of a healthy population, especially among responders.
The supportive study was a single arm, multicenter, open-label phase II study of 26 patients with advanced SM (CPKC412A2213). Rydapt was administered orally at 100 mg twice daily. Lack of a major response (MR) or partial response (PR) by the end of the second cycle resulted in discontinuation from the study treatment. Twenty (76.9%) patients had ASM (17 [85%] with AHNMD) and 6 patients (23.1%) had MCL (2 [33.3%] with AHNMD). The median age was 64.5 years with half of the patients ≥ 65 years. At baseline, 88.5% had > 1 C-finding and 69.2% had received at least one prior anti-neoplastic regimen.
The primary endpoint was ORR evaluated by the Valent criteria during the first two cycles of treatment. Nineteen patients (73.1%; 95% CI = [52.2, 88.4]) achieved a response during the first two cycles of treatment (13 MR; 6 PR). The median duration of follow-up was 73 months, and the median duration of response has not been reached. Median overall survival was 40.0 months (patients were only followed for up one year after treatment discontinuation for survival).

5.2 Pharmacokinetic Properties

Absorption.

In humans, the absorption of midostaurin is rapid after oral administration, with Tmax of total radioactivity observed at 1 to 3 hours post dose. In healthy subjects, the extent of midostaurin absorption (AUC) was increased by an average of 22% when Rydapt was co-administered with a standard meal, and by an average of 59% when co-administered with a high-fat meal. Peak midostaurin concentration (Cmax) was reduced by 20% with a standard meal and by 27% with a high-fat meal versus on an empty stomach. Time to peak concentration was also delayed in presence of a standard meal or a high-fat meal (median Tmax = 2.5 hrs to 3 hrs). In clinical studies, midostaurin was administered with a light meal, in order to decrease potential nausea and vomiting events and it is recommended that midostaurin is administered to patients with food.

Distribution.

Midostaurin has a high tissue distribution of geometric mean Vz/F = 98.9 L. Midostaurin and its metabolites are distributed mainly in plasma rather than red blood cells. In vitro data showed midostaurin and its metabolites CGP62221 and CGP52421 are greater than 99.8% bound to plasma protein.

Metabolism.

Midostaurin is metabolized by CYP3A4 mainly via oxidative pathways and the major plasma components included midostaurin and two major active metabolites; CGP62221 and CGP52421 accounting for 27.7 ± 2.7% and 37.97 ± 6.6% respectively of the total plasma exposure. O-demethylation, oxidation at benzene ring, oxidation at pyrrolidine ring, amide bond hydrolysis, and N-demethylation were the major pathways of metabolism in man, leading to formation of 16 metabolites. CYP1A1, CYP3A4, and CYP3A5 were found capable of metabolizing both CGP62221 and CGP52421, with CYP3A4 being the main contributor to the clearance of these active metabolites.

Excretion.

Based on a single-dose study, the median terminal half-lives of midostaurin, CGP62221 and CGP52421 in plasma are approximately 20.3, 33.4 and 495 hours. The Human Mass Balance study results indicate that fecal excretion is the major route of excretion (78% of the dose), and mostly as metabolites (73% of the dose) while unchanged midostaurin accounts for 3% of the dose. Only 4% of the dose is recovered in urine. At least 16 radiolabeled metabolites were characterized and quantitated in the excreta. In feces, the predominant metabolite was P29.6B (26.7%). In urine, the predominant metabolite was P6B (hippuric acid).

Linearity/non-linearity.

In general, midostaurin and its metabolites showed no major deviation from dose-proportionality after a single dose in the range of 25 mg to 100 mg. However, there was a less than dose-proportional increase in exposure after multiple doses within the dose range of 50 mg to 225 mg daily.
Following multiple oral doses, midostaurin displayed time-dependent pharmacokinetics with an initial increase in plasma concentrations during the first week (peak Cmin) followed by a decline with time to a steady-state after approximately 28 days. While the exact mechanism for the declining concentration of midostaurin is unclear, it may be possibly due to CYP3A4 enzyme auto-induction. The pharmacokinetics of the CGP62221 metabolite showed a similar trend. However, CGP52421 concentrations increased up to 2.5 fold with advanced SM to and up to 9-fold for AML, compared to midostaurin after one month of treatment.

Pharmacokinetics in special patient groups.

Patients with hepatic impairment.

A dedicated hepatic impairment study assessed the systemic exposure of midostaurin in subjects with baseline mild, moderate and severe hepatic impairment (Child-Pugh Class A, B and C, respectively) and control subjects with normal hepatic function. There was no increase in exposure (AUC) to plasma midostaurin and its metabolites (CGP62221 and CGP52421) in subjects with mild, moderate or severe hepatic impairment compared to subjects with normal hepatic function. No dosage adjustment is necessary for patients with baseline mild or moderate hepatic impairment. Exposure to midostaurin and its active metabolite CGP62221 is substantially lower in patients with severe hepatic impairment than that in patients with normal hepatic function (see Section 4.2). However, there are insufficient efficacy data in patients with severe hepatic impairment to suggest a dose adjustment is required.

Patients with renal impairment.

No dedicated renal impairment study was conducted for midostaurin. Population pharmacokinetic (popPK) analyses were conducted using data from clinical trials in patients with AML (n = 180) and advanced SM (n = 141). Out of the 321 patients included, 177 patients showed pre-existing mild (n = 113), moderate (n = 60) or severe (n = 4) renal impairment (15 mL/min ≤ creatinine clearance [CrCL] < 90 mL/min). 144 patients showed normal renal function (CrCL > 90 mL/min) at baseline. Based on the population PK analyses, midostaurin clearance was not significantly impacted by renal impairment and therefore, no dosage adjustment is necessary for patients with mild or moderate renal impairment.

Paediatric.

The pharmacokinetics of midostaurin in pediatric patients were explored in phase 1 dose escalation monotherapy study with 22 patients (ages 3 months to 18 years of age) with AML or MLL-rearranged ALL using a population PK approach. After adjusting for body weight, exposures of midostaurin and its two metabolites in pediatrics fell within the ranges predicted by modeling data from adults.

Elderly (65 years or above).

Based on population PK model analyses of the effect of age on clearance of midostaurin and its active metabolites, there was no statistically significant finding and the anticipated changes in exposure were not deemed to be clinically relevant. In adult patients with advanced SM or AML, no midostaurin dose adjustment is required based on age.

Effect of gender.

Based on population PK model analyses of the effect of gender on clearance of midostaurin and its active metabolites, there was no statistically significant finding and the anticipated changes in exposure were not deemed to be clinically relevant. No midostaurin dose adjustment is required based on gender.

Effect of ethnicity.

There are no differences in the pharmacokinetic profile between Caucasian and Black subjects. Based on the phase 1 study in healthy Japanese volunteers, pharmacokinetic profiles of midostaurin and its metabolites (CGP62221 and CGP52421) are similar compared to those observed in other PK studies conducted in Caucasians and Blacks. No midostaurin dose adjustment is required based on ethnicity.

5.3 Preclinical Safety Data

Genotoxicity.

In vitro and in vivo genotoxicity studies covering relevant genotoxicity endpoints showed no evidence of mutagenic or clastogenic activity.
Midostaurin was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test), did not induce forward mutations in Chinese hamster V79 cells, did not induce chromosomal aberrations in Chinese hamster ovary cells and was not clastogenic in an in vivo rat bone marrow micronucleus assay when tested to the maximum tolerated dose of 200 mg/kg (approximately 2 fold below the human therapeutic exposures at the human doses of 50 and 100 mg twice daily based on AUC). Based on the available data midostaurin has no mutagenic potential.

Carcinogenicity.

No carcinogenicity studies have been performed.

6 Pharmaceutical Particulars

6.1 List of Excipients

Corn oil PEG-6 esters, PEG-40 hydrogenated castor oil, macrogol 400, ethanol, dl-alpha-tocopherol.

Capsule shell.

Gelatin, purified water, iron oxide yellow, titanium dioxide, glycerol and iron oxide red.

Proprietary ingredient.

Edible ink Red (PI No 3115).

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C, protect from moisture. Store in the original package to protect from moisture.

6.5 Nature and Contents of Container

Al/Al blister packs containing 112 and 56 capsules.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

Structural formula:
Chemical name (IUPAC): 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.
INN: midostaurin.
CAS name: N-[(9S,10R,11R,13R)-2,3,10,11,12,13- Hexahydro-10-methoxy-9-methyl-1-oxo-9,13-epoxy-1H,9H-diindolo [1,2,3-gh:3',2',1'-lm] pyrrolo[3,4-j][1,7] benzodiazonin-11-yl]-N methylbenzamide.

CAS number.

120685-11-2.
Molecular formula: C35H30N4O4.
Molecular weight: 570.65.

Description.

The drug substance is a white to light yellow or light green powder. The drug substance is poorly soluble in water (< 0.001 mg/mL). The compound is slightly hygroscopic. Midostaurin is a highly permeable compound, has four chiral centers and is optically active.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes