Fostamatinib Disodium Hexahydrate Tablets - An Overview

Overview

Fostamatinib disodium hexahydrate is a prescription medicine used in the treatment of chronic immune thrombocytopenia (ITP) (a condition that causes unusual bleeding or bruising due to low platelets in the blood) in adult patients who have not obtained satisfactory results with other therapies. It belongs to a group of drugs called kinase inhibitors and acts by decreasing platelet destruction. Clinical studies have reported a manageable tolerability profile with no serious safety risks. Fostamatinib disodium hexahydrate was approved on April 17, 2018, by the United States Food and Drug Administration (US FDA) and on November 14, 2019, by the European Medicines Agency (EMA).

How Does Fostamatinib Work?

Chronic immune thrombocytopenia occurs when autoantibodies are directed against platelet antigens, leading to increased clearance of platelets from peripheral circulation. Dysfunction of the megakaryocytes can also play a role in the pathogenesis of this condition. This ultimately results in significant bleeding, requiring medical treatment or a combination therapy to maintain the platelet levels. Fostamatinib is a tyrosine kinase inhibitor that blocks the activity of spleen tyrosine kinase, an enzyme responsible for stimulating certain parts of the immune system. By inhibiting this activity, Fostamatinib minimizes the platelet destruction caused by the immune system, thus increasing the platelet count and reducing the risk of excess bleeding.

Indications of Fostamatinib

Fostamatinib disodium hexahydrate is indicated to treat adult patients with chronic immune thrombocytopenia (ITP) and who have experienced insufficient response to previous therapies.

Contraindications of Fostamatinib

• As such, there are no contraindications for Fostamatinib disodium hexahydrate; however, this drug must be avoided during pregnancy as it may harm the fetus.

• Fostamatinib disodium hexahydrate is also not recommended in children and lactating mothers.

Available Doses and Dose Forms

Fostamatinib disodium hexahydrate is available as 100 and 150 mg (milligrams) tablets. The initial recommended dose is 100 mg, taken orally twice a day with or without food. After about a month of treatment, if the platelet levels have not improved, the dose is increased to 150 mg twice daily. The lowest dose is recommended mainly to achieve and maintain a platelet count of approximately 50 x 109 /L and reduce the risk of bleeding.

Warnings and Precautions

• Fostamatinib can cause hypertension in some patients; therefore, blood pressure is monitored every two weeks until stable. Following this, blood pressure is monitored monthly, and antihypertensive medications are adjusted to maintain blood pressure during Fostamatinib treatment. If blood pressure is increased despite appropriate therapy, Fostamatinib may be reduced, withheld, or discontinued.

• Liver function tests, including alanine transaminase (ALT) and aspartate transaminase (AST), during the treatment with Fostamatinib. Therefore, liver function tests are performed every month during the treatment. If ALT or AST is higher than three times the upper limit of normal (ULN), Fostamatinib may be reduced, withheld, or discontinued to manage hepatotoxicity.

• Fostamatinib can cause neutropenia in some patients; therefore, the absolute neutrophil count (ANC) is monitored monthly to check for infections during treatment. If necessary, the treatment may be interrupted, reduced, or discontinued accordingly.

• Clinical studies have reported that Fostamatinib can cause diarrhea in some patients. Hence, patients must be monitored, and suitable measures must be considered, such as dietary modifications, adequate hydration, or antidiarrheal medicines for developing diarrheal symptoms. Fostamatinib may be interrupted, reduced, or discontinued in case of severe diarrhea.

• Animal studies have shown that Fostamatinib can harm the fetus when administered to pregnant women; hence, it must be avoided during pregnancy.

Adverse Effects of Fostamatinib

Some of the adverse effects of Fostamatinib include:

• Hypertension (increased blood pressure).

• Neutropenia (decreased neutrophil count).

• Diarrhea (loose or watery stools).

• Hepatotoxicity (liver damage).

For Patients

How Effective Is Fostamatinib in Chronic Immune Thrombocytopenia?

Chronic immune thrombocytopenia is a rare platelet disorder in which individuals experience excessive bleeding or bruising due to a low platelet count abnormality in the clotting mechanism. Fostamatinib is recommended as a second line of treatment for ITP; it belongs to a group of medicines called kinase inhibitors and works by reducing platelet destruction. Fostamatinib is a novel drug that can be taken orally; it reduces clinical time and the need for professional healthcare assistance. Studies have shown that Fostamatinib disodium hexahydrate is safe and effective in managing this condition, especially in patients who have not responded to other treatments. Most patients treated with this drug have achieved stable responses and long-term results within a few weeks of therapy, along with manageable side effects.

How Should Fostamatinib Be Taken?

Fostamatinib is available as a tablet and must be taken orally two times a day with or without food, around the same time every day, or exactly as the doctor prescribes. However, the treatment may be interrupted, or the dose can be modified depending on the patient’s tolerability and platelet levels. If the platelet count does not increase even after 12 weeks of therapy with Fostamatinib, the treatment may be discontinued. Fostamatinib must not be used by people other than prescribed, even though they have similar symptoms, as it can be harmful.

What Are the Side Effects of Fostamatinib?

Some of the common side effects of Fostamatinib include:

• Nausea and vomiting.

• Diarrhea.

• Fatigue.

• Dizziness.

• Abdominal pain.

• Rash.

Serious side effects of Fostamatinib that require immediate medical help include:

• Severe diarrhea.

• Headache.

• Chest pain.

• Shortness of breath.

• Confusion.

• Jaundice (yellowish discoloration of eyes and skin).

• Severe abdominal pain.

• Dark-colored urine.

What Must the Patient Inform the Doctor Before Taking Fostamatinib?

• Before starting treatment, patients must inform the doctor if they are allergic to Fostamatinib, its components, or other medications.

• The doctor must also be informed prior if the patient has or has ever had increased blood pressure, liver diseases, or any other medical conditions.

• Before taking Fostamatinib, patients must tell the doctor if they take any vitamins, nutritional supplements, herbal medicines, over-the-counter (OTC) drugs, or other medications.

• Female patients must inform the doctor if they are pregnant, planning pregnancy, or breastfeeding before starting the treatment with Fostamatinib.

What Are the Precautionary Measures to Be Followed While Taking Fostamatinib?

• Fostamatinib can potentially increase blood pressure (BP) during treatment; therefore, BP must be monitored periodically. Patients must inform the doctor immediately if their BP is elevated or if they experience any symptoms of high BP.

• Patients must inform the doctor if they experience severe diarrhea during the treatment, as the dose of Fostamatinib needs to be modified, or the treatment may be withheld or discontinued.

• Blood tests are performed to check the complete blood count and liver function tests are recommended as liver enzymes may be elevated in some patients during treatment. Therefore, based on the reports, Fostamatinib may be reduced, interrupted, or discontinued accordingly.

• Pregnant women and lactating mothers must not use Fostamatinib, as it may cause potential risks. An effective contraception must be used during the treatment and for up to one month following the last dose of Fostamatinib. Breastfeeding must not be done during the treatment and for up to one month following the previous dose of Fostamatinib.

Dietary Considerations

Standard dietary patterns can be continued during the treatment with Fostamatinib unless instructed by the prescribing doctor.

Missed Dose

If a dose of Fostamatinib is missed, it must be skipped, and the regular dosing schedule can be followed. A double dose must not be taken to compensate for the missed dose.

Overdose

The healthcare provider must be consulted immediately in case of an overdose of Fostamatinib or if any serious adverse effects are experienced.

Storage

Fostamatinib disodium hexahydrate tablets must be stored in their original packaging at room temperature or about 20 to 25 degrees Celsius (68 to 77 degrees Fahrenheit) away from excess light and moisture and out of reach of children.

For Doctors

Pharmacological Aspects of Fostamatinib

Mechanism of Action

Fostamatinib is an orally bioavailable tyrosine kinase inhibitor that exhibits its activity against spleen tyrosine kinase (SYK). R406 is the major metabolite of Fostamatinib, which inhibits the signal transduction of Fc-activating receptors and B-cell receptors. This prevents the cytoskeletal rearrangement required for phagocytosis of autoantibody-coated platelets, thus decreasing the antibody-mediated destruction of platelets.

Pharmacodynamics

R406, the active metabolite of Fostamatinib, blocks signal transduction by Fcγ receptors, mainly responsible for antibody-mediated platelet destruction by immune cells in chronic immune thrombocytopenia. It also inhibits the activation of T and B lymphocytes by T-cell receptors and B-cell receptors, respectively. An increase in 2.93 mmHg (millimeters of mercury) in systolic blood pressure and 3.53 mmHg in diastolic blood pressure was noticed after 100 mg twice daily doses were administered compared to a placebo. Approximately 31 percent of patients experienced an increase in blood pressure (more than 140/90 mmHg) compared to around 15 percent of patients in the placebo group. However, blood pressure returned to baseline in about 58 percent of patients within one week after discontinuing Fostamatinib.

Pharmacokinetics

Fostamatinib is a prodrug that gets converted into its primary active metabolite R406 in the gut.

The exposure of R 406 is estimated to be dose-proportional up to 200 mg twice daily and accumulates about 2 to 3-fold at a dosing of 100 to 160 mg twice daily.

• Absorption: Following an oral administration of the recommended dose of Fostamatinib, the bioavailability of the metabolite R406 was approximately 55 percent. The time taken to achieve maximum plasma concentration (T max) was about 1.5 hours.

• Distribution: About 98.3 percent of the significant metabolite R 406 is bound to plasma proteins, and the mean volume of distribution is approximately 256 L (liters).

• Metabolism: Fostamatinib is metabolized by the alkaline phosphatase enzyme through CYP450-mediated oxidation pathways and glucuronidation to form its primary active metabolite, R 406.

• Excretion: After administration of an oral dose of Fostamatinib, about 80 percent of the major metabolite was excreted in feces and 20 percent in urine. The mean half-life of the metabolite was approximately 15 hours.

Drug Interactions

Some of the drugs that interact with Fostamatinib include:

• Lonafarnib.

• Atorvastatin.

• Cetirizine.

• Ciprofloxacin.

• Clindamycin.

• Carbamazepine.

• Doxycycline.

• Furosemide.

• Levofloxacin.

• Prednisone.

• Pentobarbital.

• Phenytoin.

• Primidone.

• Repotrectinib.

• Rifampin.

• Rifapentine.

• Selumetinib.

• Siponimod.

• St. John’s wort.

Clinical Studies

Two identical, open-label, double-blind, randomized, placebo-controlled studies (FIT-1 and FIT-2) were conducted to evaluate the safety and efficacy of Fostamatinib in about 150 patients (median age of 54 years) with chronic immune thrombocytopenia who did not get a sufficient response from previous treatments such as splenectomy, immunoglobulins, corticosteroids, and other medications. In each study, patients were randomized in the ratio of 2:1 to Fostamatinib or a placebo for 24 weeks. All the patients were given an initial dose of 100 mg twice a day, and based on tolerability and platelet count, the dose was increased to 150 mg twice a day.

In the FIT-1 study, 76 patients were randomized (51 in the Fostamatinib group and 2 in the placebo group), and in the FIT-2 study, 74 patients were randomized (50 in the Fostamatinib group and 24 in the placebo group). The efficacy was based on stable platelet response.

The study's endpoint was that nine patients in FIT-1 and eight patients in FIT-2 received a stable response. Rescue medications were required for 30 percent of patients receiving Fostamatinib and 45 percent receiving a placebo.

Patients who did not respond to treatment after 12 weeks were enrolled in an extension study known as FIT-3, and they were given Fostamatinib at a dose of 100 mg twice a day. The study included 123 patients, of which 79 were randomized to get Fostamatinib and 44 received a placebo. Among the patients who got a stable response in the FIT-1, FIT-2, and FIT-3 trials, it was reported that 18 patients maintained a platelet count of approximately 50 x 109 /L for up to 12 months or longer.

Nonclinical Toxicology

• Carcinogenesis: Fostamatinib was not carcinogenic in the animal studies conducted in mice and rats at oral doses several times higher than the recommended dose in humans.

• Mutagenesis: Fostamatinib and its primary metabolite were not mutagenic in the in vitro bacterial reverse mutation assay (Ames) and in the in vitro chromosomal aberration assay.

• Fertility: No significant effects were seen in mating, sperm assessments, and organ weight parameters in animal studies at doses higher than the maximum recommended dose in humans. However, in female rats, a mild reduction in pregnancy rates and a rise in post-implantation loss were observed at doses up to 25 mg/kg/day (milligram per kilogram per day).

Specific Considerations

• Pregnancy: Sufficient data is unavailable to determine the drug-associated risk of Fostamatinib in pregnant women. Therefore, it must be avoided during pregnancy.

• Lactation: There is no information regarding the presence of Fostamatinib or its metabolites in breast milk, its effects on milk production, or the breastfed infant. Therefore, breastfeeding must be avoided during the treatment and for up to one month after the last dose.

• Pediatric Use: The safety and effectiveness of Fostamatinib have not been determined in children; hence, it must be avoided in individuals below 18 years of age.

• Geriatric Use: No significant differences were observed with Fostamatinib in patients over 65 years of age compared to younger patients.