Belumosudil - Dosages, Indications, Contraindications, Pharmacology, and Side Effects

Overview

Chronic graft-versus-host disease is a disease that affects multiple systems in the body. It is diagnosed in up to 70 percent of patients post-allogeneic hematopoietic cell transplantation. In this disease, the immune cells of the donor attack the recipient cells, which results in inflammation and fibrosis in various tissues. Chronic graft-versus-host disease affects nearly any organ. It is the main cause of morbidity and mortality in transplant survivors.

Rho-associated coiled-coil-containing protein kinase (ROCK) is a signaling course that modulates inflammatory response and fibrotic processes and is dysregulated in autoimmune disorders. Numerous inhibitors target the ROCK pathway and lack isoform selectivity, leading to dose-limiting effects. Belumosudil is approved by the U.S. Food and Drug Administration (FDA) for treating adult and pediatric patients 12 years and older with chronic graft-versus-host reactions. It is the first and only approved therapy targeting ROCK2.

How Does Belumosudil Work?

Belumosudil helps rebalance the immune system. It is the only approved medicine by the FDA for treating chronic GVHD that blocks the ROCK2 pathway in the body. This may decrease the inflammation and fibrosis that can occur with chronic graft-versus-host disease. Various strategies in the bodywork through pathways.

These pathways are actions that occur among cells and molecules within the body. One such pathway is called the ROCK2 pathway. In people with chronic graft-versus-host disease, this ROCK2 pathway is very active. This results in a reduction in cells and molecules that help keep the immune system in check, and a gain in cells and molecules causes inflammation and fibrosis. The consequence is an immune system that is out of balance.

Uses

Belumosudil is used in the treatment of graft versus host disease, a complication of hematopoietic stem-cell transplant (HSCT; a procedure that replaces diseased bone marrow with healthy bone marrow) in adults and children above 12 years of age and older treated unsuccessfully with at least two other treatments. Belumosudil is a kinase inhibitor drug. It operates to treat graft-versus-host disease by blocking the signals of the cells that cause graft-versus-host disease.

Dosage

The recommended dose of the drug Belumosudil is 200 milligrams administered orally once daily with a meal at approximately the same time each day until the progression of cGVHD. When coadministered with either a PPI (proton pump inhibitor) or a strong CYP3A inducer, the dose should be increased to 200 milligrams twice daily. Total bilirubin, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) must be monitored monthly.

Warning

Embryo-Fetal Toxicity:

Based on the mechanism of action, Belumosudil can harm the fetus if administered to a pregnant woman. Studies with animal reproduction with the administration of Belumosudil to pregnant rabbits and rats during the period of organogenesis caused adverse developmental outcomes that included embryo-fetal mortality and malformations at maternal exposures less than those in patients at the recommended dose. Pregnant women are at the potential risk can harm the fetus. Therefore it is suggested that females of reproductive potential and males with female partners of reproductive potential use effective contraception during treatment with Belumosudil.

Carcinogenesis, Mutagenesis, and Impairment of Fertility:

Carcinogenicity examinations have not been performed with Belumosudil. Belumosudil was not a genotoxic in vitro bacterial mutagenicity assay, in vitro chromosome aberration assay in human peripheral blood lymphocytes (HPBL), or an in vivo rat bone marrow micronucleus assay.

For Patients

Learn About Chronic Graft-Versus-Host Disease

Chronic graft-versus-host disease appears when the graft (transplanted immune cells attack the host (the recipient’s body). The disease can involve almost every organ and result in many painful and concerning symptoms. It is difficult for patients with blood cancer as bone marrow and stem cell transplantation is a part of the standard treatments for blood cancers. The disease can grow fast (acute GVHD) or slowly (chronic GVHD). The chronic ghost-versus-host disease generally forms within 12 months after the transplant. It can take up to 3 to 5 years to resolve. Common symptoms of chronic GVHD include rashes, skin thickening, dry mouth, mouth sores, dry eyes, joint stiffness, and recurrent infections. In some patients, severe chronic GVHD can even cause death.

Learn More About Belumosudil

Before Starting Belumosudil

• Prior information to the doctor and pharmacist is necessary in case of an allergy to Belumosudil, any of the ingredients in Belumosudil tablets, or any other medications. In such cases, asking the pharmacist about the list of ingredients is a must.

• Prior information should be given to the doctor about other prescription and nonprescription medications, vitamins, and nutritional supplements.

• It is mandatory to mention Phenytoin, Phenobarbital, and proton pump inhibitors such as Dexlansoprazole, Esomeprazole, Lansoprazole, Omeprazole, Pantoprazole, Rabeprazole, Rifampin, steroids such as Methylprednisolone, Dexamethasone, or Prednisone.

• Also, inform the doctor about all the herbal products, especially St. John's wort.

Previous history of liver or kidney disease should be informed to the doctor on priority.

• Informing the doctor about planning the pregnancy or if there is any plan to become a father.

• Neither of the partners can become a father or mother while taking Belumosudil. In the case of a female, there needs to be a pregnancy test done before starting the treatment. Females should use birth control to prevent pregnancy during the Belumosudil treatment and for one week after the final dose.

• In the case of a male, too, care should be taken for birth control and to prevent pregnancy during the treatment with Belumosudil and for one week after the final dose. Talk to the doctor about birth control methods that can be used during the treatment.

• Belumosudil decreases fertility in both men and women. However, it does not mean they cannot have a child after the treatment. Belumosudil harms the fetus; therefore, pregnancy should be avoided during the treatment.

• Lactating mothers should inform the doctor about breastfeeding. They should avoid breastfeeding during the treatment with Belumosudil and for at least one week after the final dose.

What to Know About the Storage and Disposal of This Medication?

• This medication must be stored in a container it came in, tightly closed, and out of reach of children.

• Keep it at room temperature. Prevent the medication from excess heat and moisture. Do not remove the small packet contained with medication to absorb moisture.

• It is mandatory to keep all the medication out of sight of children as many containers, such as weekly pill reminders, creams, eye drops, patches, and inhalers, are not child-resistant. It should be kept from young children as they can open them easily.

• To protect children from poisoning, always lock safety caps and place the medication safely away and out of their reach.

• The medications that are not required should be disposed of to ensure that pets, children, and others cannot consume them.

• The best way to dispose of the medication is through a medicine take-back program. Contact the local garbage or recycling unit to learn about take-back programs in the community.

Things to Tell Physicians Before Prescribing Belumosudil:

• Before taking Belumosudil, inform the healthcare provider about all the medical conditions, including kidney or liver problems.

• If pregnant or planning to become pregnant, Belumosudil can harm the unborn baby. Or if pregnant, the healthcare provider will do a pregnancy test before starting the treatment with Belumosudil. Inform the doctor if pregnant during the treatment with Belumosudil.

• Females of reproductive age who can become pregnant must use effective birth control during the treatment with Belumosudil and for at least one week after the last dose.

• Males with female partners of reproductive and fertile age must use effective birth control during treatment with Belumosudil and for at least one week post the last dose.

• Lactating mothers who breastfeed or plan to breastfeed should avoid taking Belummosudil as it is unknown if the drug passes into breast milk. Avoid breastfeeding during the treatment with Belumosudil and for at least one week after the last dose.

• Inform the doctor about all the ongoing medicines, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Belumlsudil may affect how other medicines work or other medicines may affect the mechanism of how Belumosudil works.

• Keep a list of all the ongoing medications and show it to the healthcare provider and pharmacist before taking a new medicine.

Starting Belumosudil

How to Take Belumosudil?

Intake of Belumosudil at about the same time every day. Follow the prescription label's directions and ask the doctor or pharmacist to explain it. Take Belumosudil precisely as directed. Avoid taking more or less of it or more frequently than the doctor prescribes. Swallow the tablets whole and avoid splitting, chewing, or crushing them.

The doctor may ask for blood tests before and during the treatment to see the effect of the medication. The doctor may increase or decrease the dose of Belumosudil during the treatment or ask to stop taking Belumosudil for a while. This relies on the effect of the medication well the medication, lab test results, and the presence of side effects. Continue to take Belumosudil even if feeling well. Only stop taking Belumosudil after talking to the doctor.

Look Out for the Side Effects

Belumosudil can cause side effects. Inform the doctor if any of the following symptoms are severe or do not go away:

• Tiredness or weakness.

• Nausea.

• Difficulty swallowing.

• Shortness of breath.

• Diarrhea.

• Muscle or joint pain.

• Headache.

• Swelling of the hands, feet, or face.

• Rash or itching.

Some side effects can be serious and need emergency treatment:

• Fever, chills, cough, sore throat, or other signs of infection.

• Unusual bruising or bleeding.

For Doctors

Indication:

Regarding chemical taxonomy, Belumosudil is classified as a small organic molecule, specifically a pyridinyl imidazole derivative. Belumosudil is prescribed for treating adults and children over 12 years with chronic graft-versus-host disease (chronic GVHD) after failing at least two prior lines of systemic therapy.

Pharmacology

Mechanism of Action

Chronic graft-versus-host disease (GVHD) is a complication of allogeneic hematopoietic stem cell transplantation. In this disease, the transplanted donor T-cells identify the recipient's tissues as foreign and ascend an immune response. In this conditioning regimen, the host tissues can be destroyed before stem cell transplantation involving irradiation or chemotherapy. This results in downstream inflammatory reactions and the generation of inflammatory mediators like TNF-alpha and interleukin-1.

These cytokines increase the manifestation of host major histocompatibility (MHC) antigens and adhesion molecules. This enhances the power of mature donor T-cells to identify these molecules. The activation of these donor T-cells affects the activation of mononuclear phagocytes. The effector functions are triggered by stimulatory molecules originating from the damage during the conditioning phase of treatment. Activated macrophages and cytotoxic T-lymphocytes start to instantly lyse target cells and cause their apoptosis. This eventually directs to local tissue damage and also inflammatory responses.

Belumosudil is an inhibitor of Rho-associated coiled-coil kinase 2 (ROCK2), a protein that recreates a vital role in the pathogenesis of fibrotic and immune diseases. The inhibition of ROCK2 resolves the immune dysregulation by down-regulating pro-inflammatory Th17 cells and up-regulating regulatory T-cells by managing the phosphorylation of STAT3 and STAT5.

Pharmacodynamics

Belumosudil inhibits certain pro-fibrotic and pro-inflammatory processes to prevent and treat the damage caused by graft-versus-host disease. Considering its mechanism of action and findings in animal trials, Belumosudil is supposed to carry embryo-fetal toxicity and may cause significant harm to a developing fetus if a pregnant mother is exposed. Females of reproductive age, or male patients having female partners of reproductive age, should be instructed to use effective contraception during treatment with Belumosudil till one week after the last dose.

Absorption

After the oral administration of Belumosudil, the mean bioavailability is 64 percent. The median steady-state is 1.26 to 2.53 hours.

Metabolism

The in vitro metabolism of the drug Belumosudil happens primarily through CYP3A4 and, to a lesser extent, by CYP2C8, CYP2D6, and UGT1A9. The metabolites produced by the drug Belumosudil metabolism remain unclear.

Elimination

Belumosudil is eliminated mainly in the feces. After administering a radiolabeled oral dose of Belumosudil in healthy individuals, about 85 percent of it was recovered in the feces, 30 % was an unchanged drug, and less than 5 percent was recovered in the urine.

Warnings and Precautions

There are no contraindications of Belumosudil. The only warning with the administration of this drug is embryo-fetal toxicity, as it may cause fetal harm based on its mechanism of action and findings from animal studies. Women of reproductive potential and males with female partners of reproductive potential must use effective contraception during treatment and for more than one week following the last dose.

Dosage and Administration

The recommended dose of Belumosudil 200 milligrams is administered orally once daily until the progression of chronic GVHD requires new systemic therapy.

Instruct the patient on the following:

• Swallow the Belumosudil tablets whole. Do not crush, cut, or chew tablets.

• Take the tablet Belumosudil with a meal at about the same time each day.

• If a dose is missed, instruct the patient not to take extra doses to make up for the missed dose.

• The effects of Belumosudil with pre-existing severe renal or hepatic impairment have not been studied.

• The risks and potential benefits of treating patients with pre-existing severe renal or hepatic impairment need to be considered before starting the treatment.

Drug Interactions

The serum concentration of the drug Abemaciclib should be increased when combined with Belumosudil. The threat or severity of adverse effects can be increased when the drug Adalimumab is combined with Belumosudil. The severity of infection can increase when the Adenovirus type 7 vaccine live is combined with Belumosudil.

Belumosudil During Pregnancy

Intake of Belumosudil during pregnancy can harm the unborn baby. Women of childbearing age who can get pregnant must do tests to ensure they are not pregnant before starting treatment. Women must use an effective form of birth control during treatment and for one week after the last dose. Men must use an effective form of birth control during treatment and for one week after the last dose to preclude pregnancy with a sexual partner.

Breastfeeding and Belumosudil

It is not known if the Belumosudil drug passes through the milk. So, lactating mothers are advised to avoid breastfeeding or should breastfeed after one week of the last dose.

Geriatrics and Belumosudil

In clinical studies, there were no clinically significant discrepancies in the safety and effectiveness of Belumosudil in adults over 65 years old compared to younger patients.