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 drug regulatory authority of the United States, the Food and Drug Administration (FDA), in the year 2010. It is recognized as the first FDA-licensed oral form of medicine for multiple sclerosis. A pharmaceutical company based out 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 sphingosine 1-phosphate receptor modulator drug category. It is considered to be a part of disease-modifying therapies, which help in modifying the progression and recurrence of the disease condition.

Available Doses and Dosage Forms:

• Dosage Forms: Capsule form is the only marketed form of Fingolimod for the relapsing 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). However, the exact dose required for a patient is often determined by the doctor by considering all other factors concerning the patient's health status and medical background.

For Patients:

What Is the Relapsing Form of Multiple Sclerosis?

Multiple sclerosis is a persisting disease condition that is identified to be an autoimmune disorder where the condition develops as a consequence of aberrant behavior of the immune system. In this ailment, the immune cells impair the protective blanket (myelin sheath) that envelops the nerve cells, particularly in the central nervous system (spinal cord and brain). This could have a direct reflection on nerve functions in these areas. The manifestations of the condition become more obvious in the adulthood stage.

The relapsing form of multiple sclerosis is a peculiar form of multiple sclerosis, where the manifestation of the condition tends to aggravate and progressively exacerbate flare-ups that could even last longer for a day. Relapsing-remitting multiple sclerosis (RRMS) is the alternate term that denotes a relapsing form of multiple sclerosis. In addition to the myelin, multiple sclerosis also targets the nerve cell’s body. Combined impairment of the nerve cells and myelin precipitates functional troubles. The nerves become incapable of impulse or signal conduction. The impaired signal conduction influences various functions in the body. 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 such that the lymphocytes get blocked within the lymph nodes. This medicine restricts the lymphocytes from moving into the systemic circulation and brain, where it would target the nerve cells. Thus, Fingolimod brings down further nerve damage by confining the immune cells within the lymph node.

What Is the Dosage of Fingolimod?

The dosage of Fingolimod is largely based on the patient’s age and body weight. 0.25 mg is the preferred daily dosage for patients whose body weight falls below 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 to be 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 is a highly effective and promising therapy for dealing with the relapsing form of multiple sclerosis. It gears down the progression of the condition. In addition, it also diminishes the frequency of relapse and enhances their quality of life. The effectiveness of Fingolimod was exposed by various clinical trials. Both the relapse rate as well as the impairment progression exhibited a drastic fallback 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 the therapy using Fingolimod, a detailed and comprehensive medical history of the patient should be presented to the concerned doctor. This keeps the doctor informed about other underlying medical conditions that the person is 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 the doctors without fail 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 recently took. 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 informed, as Fingolimod is reported to intensify immune suppression when given following certain anticancer medicines or other immune-modulating medicines.

• 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 or any recent vaccination that the person took for other disease prevention should be informed. Certain vaccines may develop interactions with Fingolimod, and hence, it 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 check unwanted pregnancy during the treatment regimen.

How Is Fingolimod Administered?

The capsule form of Fingolimod is manufactured to be taken orally. 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 look for immediate body response towards the medicine. Even if the drug therapy was temporarily withdrawn for more than two weeks, while reinstating the therapy using Fingolimod again, monitoring is required. In addition, monitoring is also demanded while altering the dosage of the medicine.

What Are the Side Effects of Fingolimod?

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 in the form of redness, rashes, or bumps develop following Fingolimod therapy initiation. In more intensive form, swellings may extend into the respiratory and digestive tract, precipitating trouble in breathing and swallowing, respectively.

• Skin Issues: Skins become more reactive to light (light sensitive) and touch. In addition, it also leads to the development of rashes, itching, and prickling sensation. Certain skin areas exhibit 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 (puffing up 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 are encountered during Fingolimod therapy.

• Triggers Cancer Development: Fingolimod therapy is known to trigger the development of cancers in the skin cells (skin cancers) and also in the 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 either consumed 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 one time in a day. If the patient misses out on one day’s pill and recalls the overlooked dose on the next day at the time of the subsequent dose, it is advised to skip the missed one and continue with the subsequent dose. No attempt should be made to take double the instructed dose to balance out 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 cardiac function of the patient needs to be monitored to check for collapse in heat 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 impacts their constituents and interferes with their effectiveness; hence, it is not advised. Likewise, heat also deteriorates the pill components, and therefore, it should be sheltered 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:

Necessary alteration in the Fingolimod’s dosage is only made by the doctors who consider other patient factors. Fingolimod therapy necessitates first-dose monitoring, during which the patient should be evaluated and observed to identify sudden changes in cardiac function. The cardiac parameters, such as blood pressure and pulse rate, will be assessed on an hourly basis for the first six hours following the intake of Fingolimod. This first dose monitoring is often done in a hospital setting so that in the event of bradycardia, prompt treatment interventions can be undertaken. Electrocardiogram monitoring is employed for almost 24 hours following the first dose administration. While restarting the treatment regimen using Fingolimod after a break over two weeks, this first dose monitoring needs to be employed again.

What Are the Pharmacological Aspects of Fingolimod?

• Mechanism: 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 to enter and exit the circulating blood. As a result, those lymphocytes get restricted within the lymph node, thereby bringing down the number of active immune cells to strike the myelin sheath, which in turn gears down the progression and relapsing 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. It is often accompanied by a dip in the cardiac conduction rate. It also collapses the lymphocyte count in the circulating blood.

• Pharmacokinetics: Following oral intake, the medicine is uptaken from the intestine into the bloodstream, and the utmost plasma concentration is achieved within a 12 to 16-hour time period. The bioavailability of Fingolimod is estimated to be 93 percent and is widely dispersed among the blood cells, more particularly red blood cells. The Fingolimod drug is largely distributed by binding to plasma proteins. The breakdown of the drug molecules takes place through three distinct mechanisms. The ceramide analog formation, 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 the drug molecules and their metabolites takes place via the urinary and fecal routes. The urinary route accounts for over 80 percent of elimination, while the remaining occurs through the fecal route.

Toxicity:

Non-clinical study reports concerning the toxicity of Fingolimod revealed the drug’s potential to induce carcinogenic changes in animal cells when exposed to a considerably higher dose. In lower doses, no potential carcinogenic effects were evident in mice and rats.

Studies were also conducted to assess the influence of Fingolimod on the animal’s fertility, and the results came out 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 hyperdistension, collagen proliferation, hypertrophy of respiratory cells, and bronchoconstriction are some of the 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 expose and elaborate the Fingolimod’s efficacy. 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 such that 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 months periods.

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

• Prolonged QTc interval and cardiac arrhythmias are also considered to be other important contraindications of 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:

• Collapse in Heart Rate: Inception of the Fingolimod therapy precipitates an appreciable collapse in the heart rate, more particularly on the first day of treatment initiation. Therefore, close monitoring is mandatory throughout the day of the first dose administration to keep track of cardiac functions.

• 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. In addition, it is reported that Fingolimod tends to enhance blood pressure when consumed over a considerable period.

• Atrioventricular Blocks: Fingolimod is capable of holding back the cardiac impulse conduction and thereby precipitating conduction delays and blocks.

• Infections: Fingolimod therapy makes one susceptible to various infections, as it dramatically brings down the number of active immune cells in the circulation. It could even expose an individual to grave infections; hence, it is always advised to monitor the blood picture even before the treatment commences and 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 using Fingolimod can bring in macular edema. As a result, the person may encounter trouble in 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 the liver function by analyzing the liver enzyme level 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 like progressive multifocal leukoencephalopathy while undergoing therapy using Fingolimod. Depreciation in the immune status is recognized to be the prime factor that could 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: Remarkable depreciation in the 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 potentially 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.

• Simultaneous intake of immunosuppressive medicine or anticancer drugs with Fingolimod may further amplify the immune suppression.

• In addition to medicines, Fingolimod also interacts with certain vaccines and diminishes the efficacy and potency of the vaccine.

Specific Considerations:

• Fingolimod During Pregnancy: The lack of clinical study reports concerning the use of Fingolimod in pregnant women makes it difficult to provide conclusive advice regarding the safety of Fingolimod during pregnancy. Therefore, expectant mothers are always advised to follow the instructions of the doctors regarding the consumption of Fingolimod. Doctors will look into the necessity of the medicine for maternal health during that stage and advise the medicine accordingly.

• Fingolimod During Breastfeeding: No human study reports concluded 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. So, the concerned doctor will assess the condition and prescribe the medicine accordingly by taking into account both the benefits and risks associated with the medicine intake.

• Fingolimod in Pediatric Population: Fingolimod is authorized for use in children within the age range of ten to 18 years, as its safety and potency in this population group are evaluated by 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.