Fingolimod: Indications, Pharmacology, Warnings, and Precautions

Overview:

Fingolimod is a receptor modulator medicine that works well for dealing with the manifestation of multiple sclerosis, more particularly the relapsing form of multiple sclerosis (a condition impairing the nerves). The use of Fingolimod was authorized and endorsed by the U.S. drug regulatory authority, the Food and Drug Administration (FDA), in 2010.

It is recognized as the first FDA-approved oral medication for multiple sclerosis. A pharmaceutical company based in Switzerland developed Fingolimod for the very first time. Now, it is manufactured and circulated under various brand names.

Drug Group:

Fingolimod belongs to the class of sphingosine 1-phosphate receptor modulator drug category.

Available Doses and Dosage Forms:

• Dosage Forms: The capsule form is the only marketed form of Fingolimod for the relapsing-remitting form of multiple sclerosis.

• Available Doses: Capsules of two distinct dosages are available in the market, namely 0.25 milligrams and 0.5 milligrams (mg).

For Patients:

What Is the Relapsing Form of Multiple Sclerosis?

Multiple sclerosis is a persistent autoimmune disease in which the immune cells impair the protective layer (myelin sheath) that surrounds the nerve cells, particularly in the central nervous system (the spinal cord and brain). In the relapsing form of multiple sclerosis, symptoms flare up from time to time. These flare-ups, or relapses, may worsen suddenly and can last a day or longer. This form is also called relapsing-remitting multiple sclerosis (RRMS).

Along with damaging myelin, multiple sclerosis also targets the nerve cell body. Combined impairment of the nerve cells and myelin precipitates functional troubles. The nerves become incapable of generating impulses or conducting signals.

Impaired signal conduction affects various bodily functions. Altered sensation in the limbs, visual challenges, weakness, loss of body balance, inability to concentrate, heat sensitivity, and emotional instability are some of the frequently reported manifestations of relapsing forms of multiple sclerosis.

How Does Fingolimod Work?

Fingolimod, being a potent sphingosine 1-phosphate receptor modulator, works on the sphingosine 1-phosphate receptors. These receptors are dispersed over the surface of certain immune cells, like lymphocytes (a type of white blood cell).

Fingolimod regulates and modifies these sphingosine 1-phosphate receptors, thereby blocking lymphocytes within the lymph nodes. This medicine prevents lymphocytes from entering the systemic circulation and the brain, where they would normally target nerve cells. Thus, fingolimod further reduces nerve damage by confining immune cells within the lymph node.

What Is the Dosage of Fingolimod?

The dosage of Fingolimod is largely based on age and body weight.

• 0.25 mg is the recommended daily dosage for patients with a body weight of less than 40 kilograms (kg).

• Meanwhile, a 0.5 mg daily dose of Fingolimod is advised for patients with a body weight exceeding 40 kg. 0.5 mg is identified as the maximum safe, tolerable dose;

• Administering more than this dosage carries the risk of potential adverse complications. Hence, dose modification should be done only under the guidance of a medical professional.

How Effective Is Fingolimod?

Fingolimod also helps prevent MS relapse frequency and enhances their quality of life. It slows down the progression of the condition. In addition, the effectiveness of Fingolimod was exposed by various clinical trials. Both the relapse rate and the impairment progression exhibited a drastic fall with Fingolimod therapy when compared with the placebo and standard drug therapy using interferon drugs.

What Are the Things to Inform the Doctor Before Taking the Drug?

• Before commencing therapy with Fingolimod, the patient's detailed and comprehensive medical history should be presented to the relevant doctor. This keeps the doctor informed about any other underlying medical conditions the person may be suffering from.

• Patients with existing or prior diseases, particularly involving the heart, are more susceptible to experiencing adverse complications with Fingolimod therapy and hence should inform their doctors without failing to ensure patient safety during the therapy.

• In addition to the medical history, doctors should be informed about the patient’s drug history, encompassing all forms of medication that the person is taking or has recently taken. Certain heart medications have a strong interaction with Fingolimod; an elaborate drug history aids doctors in identifying such drugs so that unwanted drug-to-drug associations can be checked beforehand. Even previous medication should also be disclosed, as Fingolimod is reported to intensify immune suppression when administered following certain anticancer medications or other immune-modulating medications.

• Any form of hypersensitivity encountered with Fingolimod or other medicines that belong to the same drug class should be properly communicated to the doctor. Patients who have had such allergic encounters upon exposure to Fingolimod or any of its components are more likely to develop serious allergic reactions upon subsequent exposure to the allergic ingredient.

• Vaccination history, including any recent vaccinations taken for disease prevention, should be disclosed. Certain vaccines may interact with Fingolimod, and therefore, they should be disclosed.

• Doctors should also be made aware of the pregnancy and lactating status of the person before commencing the Fingolimod therapy so that the doctor can consider the risk for the developing child in the womb and can advise alternate, safer choices. Sometimes, the doctor may advise certain birth control measures while undergoing Fingolimod therapy to prevent unwanted pregnancy during the treatment regimen.

How Should This Medicine Be Used?

The capsule form of Fingolimod is manufactured for oral administration. It is advised to be taken with a glass of water without breaking or fracturing the pill. First-dose monitoring is recommended for Fingolimod to assess the immediate body response to the medication.

Even if the drug therapy was temporarily withdrawn for more than two weeks, while reinstating the therapy using Fingolimod again, monitoring is required. Additionally, monitoring is also required when adjusting the dosage of the medicine.

Who Can Take Fingolimod?

The drug Fingolimod is primarily used to treat Multiple Sclerosis.

This drug is usually recommended for:

• Adults: Survivors who have the relapse forms of the disease and are living with Multiple Sclerosis.

• Age: Suitable for persons 18 years and above.

• Health Assessment: Before starting treatment, patients must undergo a comprehensive health check-up, with particular emphasis on the hepatic, infectious, and cardiovascular systems.

What Side Effects Can Fingolimod Medication Cause?

Fingolimod is associated with a wide spectrum of adverse reactions in the body. It is crucial to keep note of the possible side effects that could arise during Fingolimod therapy.

Some of the potential side effects include the following:

• Allergic Reactions: Skin reactions, such as redness, rashes, or bumps, may develop following the initiation of Fingolimod therapy. In more severe forms, swellings may extend into the respiratory and digestive tracts, precipitating trouble with breathing and swallowing, respectively.

• Skin Issues: Skin becomes more reactive to light (light sensitive) and touch. Additionally, it can lead to the development of rashes, itching, and a prickling sensation. Some parts of the skin show numbness, soreness, pigmentations, and even a burning sensation. An appreciable rise in hair fall is also a notable consequence of Fingolimod. These skin issues may even persist for a couple of months after withdrawing the medicine.

• Neurological Issues: Confusion, neck stiffness, headache, diminishing memory power, inability to focus and think, and trouble keeping body balance are also reported during Fingolimod therapy.

• Visual Troubles: Macular edema (swelling of a specific part of the retina), hazy vision, dark spots in the visual field, shadows, compromised vision, and light sensitivity are some of the visual troubles that can occur during Fingolimod therapy.

• Triggers Cancer Development: Fingolimod therapy is known to trigger the development of cancers in the skin cells (skin cancers) and immune cells (lymphoma).

• Gastrointestinal Troubles: Nausea, abdominal pain, diarrhea, loss of hunger, and vomiting are also reported with Fingolimod therapy.

• Effects on the Heart: Collapsed beating rate of the heart, impaired cardiac impulse conduction (conduction blocks), abnormal heartbeats, and boosted blood pressure are some of the potential effects of Fingolimod on the heart.

• Musculoskeletal Issues: General muscle weakness, body pain, back pain, and soreness in the feet and hands also develop in response to Fingolimod therapy.

• Infections: As Fingolimod restricts the immune cells within the lymph node, the number of active immune cells wandering in the circulation will be remarkably low, which in turn exposes the person to various forms of infections.

Dietary Considerations:

There is no specific dietary consideration that needs to be followed while undergoing therapy using Fingolimod. It can be consumed either after or before meals.

Missed Dose:

The patients are instructed to take the medicine at a specified time on a regular basis. However, at times, the patient may miss taking the pill on time. In such cases, it is better to take the pill once they become aware of the overlooked dose. Fingolimod is a daily pill that needs to be taken only once a day. If the patient misses one day’s pill and recalls the overlooked dose the next day at the time of the subsequent dose, it is advised to skip the missed dose and continue with the following dose. No attempt should be made to take twice the instructed dose to compensate for the missing dose. Inadvertent intake of more than the specified dose of the pill can bring in overdose issues and other side effects.

Overdose:

0.5 mg is the tested safe dose of Fingolimod; taking more than the prescribed dose of Fingolimod can precipitate overdose issues. Drug overdose often demands immediate medical attention to tackle the complications. The patient's cardiac function needs to be monitored to check for a decline in heart rate or associated conduction blockage.

Storage:

The ideal storage temperature for Fingolimod is identified to be 20 to 25 degrees Celsius (68 to 77 degrees Fahrenheit). However, the temperature range of 15 to 30 degrees Celsius (59 to 86 degrees Fahrenheit) is considered to be safe for Fingolimod. Refrigerating the pills alters their constituents and compromises their effectiveness; therefore, it is not recommended. Likewise, heat also deteriorates the pill components; therefore, it should be shielded from heat.

For Doctors:

Indication:

• Relapsing forms of multiple sclerosis (active secondary progressive disease, relapsing-remitting disease, and clinically isolated syndrome).

Dose:

0.25 mg is the recommended daily oral dosage of Fingolimod for patients who are over the age of ten with a body weight below 40 kilograms. For individuals weighing over 40 kilograms, 0.5 mg of Fingolimod is the advised daily dosage.

Dosing Considerations:

A necessary alteration in the Fingolimod dosage is made only by doctors who consider other patient factors. First-dose monitoring is typically required for fingolimod therapy, during which the patient should be evaluated and observed to identify any sudden changes in cardiac function.

The cardiac parameters, such as blood pressure and pulse rate, will be assessed hourly for the first six hours following the administration of Fingolimod. This first-dose monitoring is often conducted in a hospital setting, allowing for prompt treatment interventions in the event of bradycardia. Electrocardiogram monitoring is employed for approximately 24 hours following the administration of the first dose. While restarting the treatment regimen using Fingolimod after a break of over two weeks, this first dose monitoring needs to be employed again.

What Are the Pharmacological Aspects of Fingolimod?

• Mechanism of Action: Sphingosine kinase enzyme is responsible for the conversion of Fingolimod to its active form, fingolimod-phosphate. It is this active entity that modifies the sphingosine 1-phosphate receptors. These receptors are primarily distributed on the surface of lymphocytes. The Fingolimod-induced alterations in the sphingosine 1-phosphate receptors incapacitate the lymphocytes from entering and exiting the circulating blood. As a result, those lymphocytes become restricted within the lymph node, thereby reducing the number of active immune cells that can strike the myelin sheath, which in turn slows down the progression and relapse rate of multiple sclerosis.

• Pharmacodynamics: In addition to its primary role in modifying the sphingosine receptors, Fingolimod precipitates certain other effects in the body. Following the first intake of the medicine, there will be a momentary and brief dip in the heart rate. A dip in the cardiac conduction rate often accompanies it. It also collapses the lymphocyte count in the circulating blood.

• Pharmacokinetics: Following oral administration, the medicine is absorbed from the intestine into the bloodstream, with the maximum plasma concentration achieved within 12 to 16 hours. The bioavailability of Fingolimod is estimated to be 93 percent and is widely distributed among blood cells, particularly red blood cells. The Fingolimod drug is distributed mainly by binding to plasma proteins. The breakdown of drug molecules occurs through three distinct mechanisms. The formation of ceramide analogs, oxidative biotransformation, and stereoselective phosphorylation are the pathways through which the human body metabolizes the Fingolimod drug molecules. Cytochrome P450 4F2 (CYP4F2) and other isoenzymes of cytochrome P450 4F mediate the process of oxidative biotransformation. The terminal half-life for Fingolimod is estimated to be six to nine days. The expulsion of drug molecules and their metabolites occurs via the urinary and fecal routes. More than 80 percent of elimination occurs via urine, while the remaining occurs through the fecal route.

Toxicity:

Certain studies have suggested that, at higher doses, Fingolimod can cause cancerous changes in animal cells, while no such effects were reported in lower doses. Studies were also conducted to assess the influence of Fingolimod on the animal’s fertility, and the results were favorable, with no obvious fertility impairments. In addition, animal studies also concluded certain toxic effects on the lungs upon long-term therapy with Fingolimod. Alveolar hypertension, collagen proliferation, hypertrophy of respiratory cells, and bronchoconstriction are potential changes in the lungs induced by Fingolimod.

Clinical Studies:

Randomized clinical trials were carried out in patients who were diagnosed with a relapsing form of multiple sclerosis to evaluate and elaborate on the efficacy of Fingolimod. It successfully demonstrated its ability to tackle relapse and disease progression in individuals who were exposed to Fingolimod therapy. The subjects for the clinical trial were carefully chosen, and only those patients who had not received any recent pharmacological intervention for multiple sclerosis and had actively progressing conditions were chosen and randomized.

What Are the Contraindications of Fingolimod?

Fingolimod cannot be advised in certain conditions. Some of the absolute contraindications of Fingolimod include the following:

• Patients who have had recent cardiac events like unstable angina, decompensated heart failure, stroke, myocardial infarction, heart failure (class III or IV), or transient ischemic attack, particularly within the past six-month period.

• Patients with cardiac conduction blockages, particularly sinus node dysfunction or third-degree atrioventricular block.

• Prolonged QTc interval and cardiac arrhythmias are also considered important contraindications to Fingolimod therapy.

• Patients with allergic encounters with Fingolimod or any of its ingredients should not be advised to consume the medicine, as it carries the risk for severe hypersensitivity reactions.

Warnings and Precautions:

The following are the warnings and precautions to be taken:

• Collapse in Heart Rate: The initiation of Fingolimod therapy precipitates a notable decline in heart rate, particularly on the first day of treatment. Therefore, close monitoring is mandatory throughout the day of the first dose administration to track cardiac function.

• Pre-Existing Cardiac Conditions: Patients with active cardiac conditions or with a recent history of cardiovascular events are more likely to have complications upon the initiation of Fingolimod therapy. Hence, a prior assessment of the heart function needs to be done before undertaking the therapy using Fingolimod. Additionally, it has been reported that Fingolimod tends to increase blood pressure when taken over a prolonged period.

• Atrioventricular Blocks: Fingolimod can impede cardiac impulse conduction, thereby precipitating conduction delays and blocks.

• Infections: Fingolimod therapy increases susceptibility to various diseases, as it significantly reduces the number of active immune cells in the circulation. It could even expose an individual to severe infections; hence, it is always advised to monitor the blood picture even before treatment commences, and this should be continued routinely. In the event of active infections, the treatment should be deferred until the infection is under control.

• Macular Edema: Long-term therapy with Fingolimod can lead to the development of macular edema. As a result, the person may encounter trouble with their vision. Periodic evaluation of the retinal health is therefore mandatory to detect changes in the retina and vision.

• Hepatic Damage: Post-marketing surveillance of Fingolimod exposed functional impairment in the liver following long-term therapy. Hence, regular assessment of liver function by analyzing liver enzyme levels is advised for individuals undergoing Fingolimod therapy. Considering the potential of Fingolimod for triggering liver damage, caution should be exercised during the treatment period to look for hints of compromised hepatic functions.

• Progressive Multifocal Leukoencephalopathy: Patients should be informed about the possibility of acquiring brain infections, such as progressive multifocal leukoencephalopathy, while undergoing therapy with Fingolimod. Depreciation in immune status is recognized as the primary factor that can pave the way for the development of progressive multifocal leukoencephalopathy. Posterior reversible encephalopathy syndrome is also reported following long-term therapy using Fingolimod.

• Tumefactive Multiple Sclerosis: Rarely, after withdrawing the Fingolimod therapy, the person may manifest Tumefactive Multiple Sclerosis. However, it is also occasionally reported during the treatment regimen.

• Compromised Lung Capacity: A remarkable depreciation in lung capacity is also reported in patients undergoing Fingolimod therapy.

What Are the Drug Interactions of Fingolimod?

Simultaneous intake of Fingolimod with certain other drugs may bring in undesirable effects, and it could also impact the functions of either or both drugs.

Some of the potential drug interactions include the following:

• When Fingolimod is taken along with antifungal medicines like Ketoconazole, it can potentiate the concentration of Fingolimod in the plasma, thereby enhancing the risk of complications.

• Fingolimod, when simultaneously administered with medicines that can prolong the QT interval, can amplify the bradycardia effects. Concurrent administration of beta blockers and Fingolimod can precipitate a dramatic collapse in the heart rate, which can pose grave health challenges.

• The simultaneous intake of immunosuppressive medications or anticancer drugs with Fingolimod may further amplify immune suppression.

• Fingolimod has also been found to interact with certain vaccines, reducing their efficacy and potency.

Specific Considerations:

• Fingolimod in Pregnancy: Fingolimod usage is not recommended during pregnancy unless a physician recommends it. Please consult a doctor before using it.

• Fingolimod During Breastfeeding: No human studies have reported the presence of Fingolimod in breast milk following the consumption of the medicine by breastfeeding women. However, animal studies identified its presence in breast milk. The concerned doctor will assess the condition and prescribe the medicine accordingly, taking into account both the benefits and risks associated with the medicine intake.

• Fingolimod in the Pediatric Population: Fingolimod is authorized for use in children aged 10 to 18 years, as its safety and efficacy in this population group have been evaluated through various clinical trials. However, children who fall below the age range of 10 years are not routinely advised to have Fingolimod unless the doctor instructs them to have it. The safety concerning drug usage in the younger population is still unclear and, hence, not recommended.

• Fingolimod and Contraceptives: Fingolimod does not interact with hormonal birth control; however, consult a doctor. It must be used as a therapy for contraception in pregnancy and for two months after the termination of pregnancy.