Midostaurin - Uses, Side Effects, Dosage and Administration, Contraindications, and Precautions

Overview:

Midostaurin is a kinase inhibitor drug indicated for treating acute myeloid leukemia (AML). However, the drug is not administered as a single-agent induction therapy but is given in combination with other chemotherapy drugs for the treatment of acute myeloid leukemia and other conditions. The drug specifically targets leukemia cells that have FLT3 mutation. The drug was approved by the United States Food and Drug Administration (FDA) on April 28, 2017, for the treatment of acute myeloid leukemia in elderly patients who are newly diagnosed with this condition. In addition, the drug is also approved for treating microcytosis (red blood cells smaller than normal in size), associated with mast cell leukemia (blood cell cancer). The article talks in detail about drug usage, side effects, drug dosage, precautions, contraindications, and drug interactions, along with pharmacological implications.

Drug Group:

Midostaurin belongs to a class of drugs called kinase inhibitors, which are potent antineoplastic agents that block the action of protein kinase.

Indications:

• For the treatment of acute myeloid leukemia.

• For treating blood disorders, such as mastocytosis (abnormal mast cell proliferation).

Dose Form and Strength:

• Capsule: 25 mg (milligrams).

It is a pale, oblong, soft capsule with red ink imprinted on it. The capsules are available in two packings:

• 56 soft capsules (each carton with two inner packs, each with 28 capsules)

• 112 soft capsules (each carton with four inner packs, each with 28 capsules)

For Patients:

What Is Acute Myeloid Leukemia?

Acute myeloid leukemia, or AML, is a type of blood cancer that occurs in the blood-forming cells of the bone marrow and causes excess proliferation of immature white blood cells. The condition is characterized by fever, fatigue, bruising, and recurrent infections of the body.

What Is Midostaurin Prescribed For?

Midostaurin is prescribed for the treatment of acute myeloid leukemia, which is a cancer of white blood cells. The drug is also used to treat other blood disorders (mastocytosis), which have too many mast cells present.

How Should Midostaurin Be Used?

Midostaurin is available as an oral pill that is to be taken through the mouth, usually twice a day. Midostaurin should be taken at the same time daily as directed by the doctor or the pharmacist. If any part of the prescription or direction of the drug labels is not understood, one must ask the doctor or the pharmacist for the same.

Midostaurin should be taken exactly as prescribed, with the same drug dosage (not less or more), and frequency. Also, the medicine should be swallowed as a whole without crushing the medicine.

The doctor may decrease the drug dosage or stop the medication during the treatment course if any side effects are experienced by the person. Therefore, one must tell the doctor about how they feel after taking this medication. Even if a person is feeling well, the medication should not be stopped without consulting the doctor.

What Precautions Should Be Followed Before Taking Midostaurin?

• One should inform the doctor if they are allergic to Midostaurin or any of the ingredients present in the drug or any other drug.

• Inform the doctor or the pharmacist about any other drugs that one is taking, including herbal products, vitamins, or nutritional supplements, because these drugs can interact with Midostaurin and cause adverse effects.

• The doctor must also be told about any past or present medical condition, such as QT prolongation, irregular heartbeat, kidney, lung, or liver disease.

• One must also inform the doctor if they are pregnant or planning to get pregnant because women should avoid conceiving this drug for almost four months after taking the final dose of Midostaurin. Also, the pregnancy test of a woman should be negative one week before starting the first dose of Midostaurin. Therefore, a person should ask the doctor about various birth control methods. Both the partners (male and female) should use birth control methods during the treatment plan and also up to four months after the final dose of Midostaurin. If one becomes pregnant while taking this drug, one must consult the doctor immediately, as Midistaurin can cause harm to the fetus.

• Breastfeeding is also not recommended while taking this drug; therefore, one must not breastfeed during the treatment and also up to four months after taking the final dosage of Midostaurin.

• The drug can also decrease fertility in men and women.

What Is the Drug Dosage of Midostaurin?

Adult Drug Dosage for Acute Myeloid Leukemia:

• On days eight to 21 of each cycle of induction, 50 milligrams (mg) orally after every 12-hour interval, and on days eight to 21 of each cycle of consolidation.

Adult Drug Dosage for Mastocytosis:

• 100 milligrams orally twice daily after every 12-hour interval.

Adult Drug Dosage for Leukemias (Cancers of the Blood):

• 100 milligrams orally twice daily after every 12-hour interval.

What Are the Side Effects of Midostaurin?

Common Side Effects:

• Diarrhea.

• Nausea.

• Vomiting.

• Tiredness.

• Headache.

• Nosebleeds.

• Constipation.

• Weakness.

• Tiredness.

• Dizziness.

• Stomach pain.

• Hemorrhoids (piles).

• Increased Sweating.

• Sweating of the lower legs, hands, ankles, and feet.

• Difficulty sleeping and staying asleep.

• Muscle, back, limb, and joint pain.

• Sore or white patches in the throat, mouth, or on the lips.

Severe Side Effects:

• Shortness of breath (dyspnea).

• Flushing.

• Chest pain.

• Fever, chills, cough, and signs of infection.

• Difficulty swallowing or breathing.

• Irregular, rapid, or pounding heartbeats.

• Hives.

• Itching.

• Rash.

• Swelling of the lips, throat, and tongue.

• Wheezing.

• Unusual bruising or bleeding.

• Blood in vomiting.

• Worsening cough.

• Pain or burning sensation while peeing.

Missed Dose:

If the drug dose is missed, one should skip the missed dose and continue taking the next scheduled dose. Avoid taking a double dose of the drug to compensate for the missed dose.

Overdose:

In case of a drug overdose, the poison control department should be reached out. If a person has seizures, trouble breathing, or collapses, emergency healthcare services should be contacted immediately.

Drug Storage and Disposal

The drug should be stored in an air-tight container and away from the children’s reach. Also, store the drug at room temperature, 20 to 25 degrees Celsius (68 to 77 degrees Fahrenheit), away from excess moisture and heat.

The expired or unneeded medication should not be kept at home; rather, it should be discarded safely, ensuring that children, pets, and other people cannot consume the medication accidentally.

The drug should not be flushed into the toilets. They should be disposed of through a take-back program by contacting the nearest pharmacy or local garbage or recycling department. In case one does not have access to the take-back program, they can discard the drug following Food and Drug Administration (FDA) safe drug disposal guidelines and protocols given on their website.

For Doctors:

Clinical Pharmacology

Mechanism of Action

Midostaurin potently inhibits multiple receptor tyrosine kinases. Also, the drug and its active metabolites CGP6662221 and CGP52421 inhibit the activity of PKCalpha, which is a protein kinase C alpha, KIT, VEGFR2, WT, PDGFR and WT, or mutant FLT3 tyrosine kinase. The inhibition of FLT3 induces apoptosis of the infected leukemia cells, thus expressing target mast cells and receptors, along with its antiproliferative activity towards multiple cancer cell lines.

Additionally, the drug also interacts with 1A1, an organic anion transporter, and multidrug-resistant protein in vitro studies.

Pharmacodynamics

The drug targets mutated kinases and multiple WT, which, when activated, can stimulate aberrant signaling cascades that lead to malignancies, such as acute myeloid leukemia (AML). Additionally, the prolonged QT interval is not significant in a patient having acute myeloid leukemia when compared with Placebo studies.

Also, the drug is recommended therapeutically for combination therapy in patients undergoing chemotherapy.

Pharmacokinetics:

• Absorption: After oral administration, the drug reaches its maximum concentration in one to three hours after fasting. In the presence of a standard meal taken by a person, the drug concentration is reduced by approximately 20 percent.

• Distribution: The volume of distribution of the drug is 25.15 gallons. Midostaurin and its active metabolites are distributed in plasma in vitro, along with protein binding of about more than 99.8 percent.

• Metabolism: Midostaurin gets metabolized into CGP62221 and CGP52421 through the enzymatic activity of hepatic CYP3A4 (cytochrome).CGP62221 metabolism takes place in a linear relationship, and that of CGP52421 is an inducible process.

• Excretion: About 95 percent of the drug gets excreted via fecal excretion, 91 percent is found as metabolites, and four percent as an unchanged parent drug. The remaining five percent of the drug is eliminated via renal excretion.

The elimination half-life of the drug is 21 hours, 32 hours, and 482 hours for CGP62221 and CGP52421, respectively.

Ingredients

• Active Ingredients: Midostaurin

• Inactive Ingredients: Polyoxyl 40 hydrogenated castor oil, polyethylene glycol 400, glycerin 85 percent, gelatin, dehydrated alcohol, titanium dioxide, corn oil mono-di-triglycerides, ferric oxide yellow, vitamin E, ferric oxide red, propylene glycol, carmine, hypromellose 2910, propylene glycol, and purified water

What Are the Contraindications for Midostaurin?

The drug is contraindicated in people who are hypersensitive to Midostaurin or any of its ingredients.

Drug Warning and Precautions:

• Pulmonary Toxicity: Patients treated with monotherapy or chemotherapy have experienced pneumonitis and interstitial lung disease. Therefore, a person should be carefully monitored for any pulmonary symptoms, and the drug should be immediately discontinued if any symptoms of pneumonitis and interstitial lung disease occur without any underlying infection.

• Embryo-Fetal Toxicity: The drug’s mechanism of action has shown fetal harm in animal studies, and therefore, it may affect the human baby when administered to pregnant women. The drug has caused embryo-fetal toxicities, including reduced fetal birth weight, fetal death, and delay in fetal growth at smaller doses than the recommended human dose. Therefore, the doctor must inform the pregnant female about the potential risk to the fetus. Also, females of reproductive potential should be advised to use effective contraception during the treatment with Midostaurin.

Drug Interactions:

Strong CYP3A4 Inhibitors: It may increase exposure to Midostaurin and its active metabolites. Therefore, doctors must consider alternative therapies that do not strongly inhibit CYP3A4, and also monitor for increased risk of adverse side effects during the first week of drug administration in the acute myeloid leukemia population in each cycle of chemotherapy. These Drugs Include.

1. Boceprevir.

2. Clarithromycin.

3. Cobicistat.

4. Conivaptan.

5. Danoprevir.

6. Diltiazem.

7. Elvitegravir.

8. Grapefruit juice.

9. Idelalisib.

10. Indinavir.

11. Itraconazole.

12. Ketoconazole (strong CYP3A4 inhibitor).

13. Lopinavir.

14. Rifampicin (strong CYP3A4 inducer).

15. Nefazodone.

16. Nelfinavir.

17. Paritaprevir (Ombitasvir and/or Dasabuvir).

18. Posaconazole.

19. Ritonavir.

20. Saquinavir.

21. Tipranavir and Ritonavir.

22. Troleandomycin.

23. Voriconazole.

Strong CYP3A4 Inducers: A doctor should also avoid concomitant use of Midostaurin with strong CYP3A4 inducers as it decreases exposure to Midostaurin and its active metabolites, and also the efficacy of the drug. These drugs include

1. Carbamazepine.

2. Enzalutamide.

3. Mitotane.

4. Phenytoin.

5. Rifampin.

6. St. John’s wort.

Use in Special Populations:

• Pregnancy

Midostaurin causes fetal harm as per animal reproduction studies; however, there is no specific data or study on its effects on pregnant women showing miscarriages or birth defects. Therefore, the doctor must prescribe this drug cautiously to pregnant women and inform them about the potential risks it causes to the fetus.

• Breastfeeding

No data is showing the presence of Midostrium or its active metabolites in human milk, its effects on milk production, and breastfed infants.

In animal studies, the drug has caused serious adverse effects; therefore, women who are breastfeeding are advised to avoid breastfeeding during treatment with Midostrium.

• Pediatric Use

The safety and effectiveness of the drug have not yet been established in the pediatric population.

• Geriatric Use:

Studies have been conducted on people 65 and above age, and not much difference has been observed in the safety and effectiveness of the drug in the geriatric population than in the younger population. However, the sensitivity of the geriatric population to this drug cannot be ruled out. Also, necessary precautions need to be taken in elderly people while using this drug based on their needs and the frequency of the disease and drug therapy.

• Males and Females of Reproductive Potential

Before starting with Midostaurin, a pregnancy test is recommended seven days prior in females. Also, males and females of reproductive age are advised to during treatment and also at least for four months after taking the final dose of Midostaurin.

Animal studies also reveal that this drug causes infertility in males and females; however, it is still not known if its effects on fertility are reversible or not.