Edaravone - Indications, Pharmacology, Warnings, and Precautions

Overview:

Edaravone is an innovative medicine that is widely advised for tackling a peculiar medical condition called amyotrophic lateral sclerosis (an alarming neurological condition). Edaravone drug formulation gained authorization from the drug regulatory body of the United States, the Food and Drug Administration (FDA), on May 5, 2017. However, the first authorization for Edaravone was initiated in South Korea and Japan in the year 2015. Currently, it is being manufactured and marketed under various brand names. However, the application of Edaravone therapy does not extend to small babies and kids. Only adult and elderly populations benefit from this novel medicine.

Drug Group:

Edaravone belongs to the drug class of antioxidants. The chemical structure of Edaravone is pyrazoline, which is a tetracarbon compound. Edaravone works to gear down the progression of amyotrophic lateral sclerosis, by curbing the free radicals that are responsible for disease advancement.

Available Doses and Dosage Forms:

Dosage Forms: Edaravone is formulated in two specific dosage forms which are oral suspension and injection solution. The suspension formulation is intended to be taken via the mouth, while the injection formulation is in liquid form that can be delivered directly into the vein.

Available Doses: The suspension form is formulated in such a way that every five milliliters (ml) of the suspension encompasses 105 milligrams (mg) of Edaravone, while 100 milliliters of the injection solution incorporates 30 milligrams of Edaravone.

For Patients:

What Is Amyotrophic Lateral Sclerosis?

Amyotrophic lateral sclerosis is a peculiar degenerative medical condition, where certain nerve cells undergo impairment and destruction. Amyotrophic lateral sclerosis is also known by the name Lou Gehrig’s disease. It is a potentially grave and alarming condition that typically impacts the motor nerves. Motor nerves are concerned with the brain and muscle communication. It is through the motor nerve that the brain signals the muscles to elicit contractions. Muscular movements are made possible with the help of these motor nerves.

There is not much information available concerning the etiology behind amyotrophic lateral sclerosis (ALS). It is mostly encountered in individuals within the age range of 40 to 70 years. Muscle cramps, muscle weakness, trouble with postural stability, slurred speech, and frequent falling are some of the initial manifestations precipitated by amyotrophic lateral sclerosis. In more advanced stages, the person experiences trouble with breathing, which can endanger their life.

How Does Edaravone Work?

Edaravone, being a mighty antioxidant, can effectively curb the oxidative stress in the body, which develops in response to enhanced free radical production. These are reactive molecules that are capable of impairing the vital cells in the body, like nerve cells. Amyotrophic lateral sclerosis is associated with a dramatic hike in free radical production. Edaravone extends protective shielding for nerve cells, mitigating ALS progression by stamping out the excess free radicals.

What Is the Dosage of Edaravone?

Edaravone is an efficacious medicine that is generally advised for a once-a-day course. 105 mg is the oral adult dosage recommended for ALS patients. Five milliliters of the oral suspension is sufficient to deliver 105 mg of Edaravone. 60 milligrams is the infusion (delivered into the vein) dosage of Edaravone. Slow infusion is advised for Edaravone, lasting typically for one hour.

How Effective Is Edaravone?

Various studies have been conducted to expose Edaravone’s effectiveness. It was concluded that Edaravone can potentially bring down the pace of disease advancement, typically by around 30 percent. In addition, it also extends the longevity of the individuals who are detected with amyotrophic lateral sclerosis. It successfully modifies the disease and gears down its progression.

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

Before initiating therapy using Edaravone, there are certain things that the doctor should be informed about. Thorough doctor-patient communication is cardinal for the treatment's success.

• Prior allergic or hyper-reactivity encounters with Edaravone or any of the ingredients present in the Edaravone oral suspension or infusion formulation need to be disclosed beforehand. Subsequent encounters with an allergic component can potentially evoke grave reactions in the body.

• Medical history is another critical thing that the doctor needs to be informed about. The medical history should be comprehensive covering all the information concerning the underlying medical conditions, past health issues, and recently undergone surgeries. Medical history provides a clear picture of the patient’s general health status, which is essential for prompt treatment planning.

• Drug history is another important thing that requires the doctor’s attention. The drug history should encompass all the medicines, be it over-the-counter, herbal, or dietary supplements. Simultaneous intake of certain medicines requires dose modification of either or both. Similarly, certain medicines may interact with each other bringing unpleasant effects on the body. Understanding drug history aids in the choice of medicine and provides an opportunity for the doctor to check unpleasant drug-to-drug associations.

• The concerned doctors should be made aware of the expectant and lactating status, as it can influence the child’s health. The doctors analyze the potential toxicities associated with Edaravone for expectant and lactating women and plan accordingly.

How Is Edaravone Administered?

• Administration of Edaravone Oral Suspension Formulation: The oral suspension formulation of Edaravone is marketed in small medicine bottles. The bottle needs to be stirred before administration to ensure the homogeneity of the solution. Though it is primarily advised for intake by mouth, patients who are tube-fed can take the medicine through the feeding tube.

• Administration of Edaravone Infusion: The Edaravone is infused at a pace of one milligram per minute. Two 30 mg infusion bags are employed for delivering the intended dose of 60 mg. The two bags need to be infused one after the other and the infusion takes around 60 minutes.

What Are the Side Effects of Edaravone?

Just like any other medicine, Edaravone therapy also bears the risk of certain side effects. Some of the frequently encountered side effects concerning Edaravone therapy include the following:

• Skin rashes, in the form of flaky and itchy lesions, develop over the skin surface.

• Skin manifests areas of redness and pigmentation.

• The person may experience a severe and persisting form of headache.

• Bruising is also reported following Edaravone therapy, where blood tends to pool underneath the skin, eliciting discoloration.

• Certain people may experience trouble walking.

Apart from the above-mentioned side effects, there are few reports of certain alarming side effects like heavy and tight chest, and troubled breathing. In the event of these alarming side effects, immediate medical assistance needs to be sought.

Dietary Considerations:

The oral suspension formulation of Edaravone tends to be influenced by the presence of food. Therefore, it is advised to be taken under fasting conditions, preferably in the morning. In addition, the food intake needs to be halted for a minimum period of one hour. However, there is no restriction on water consumption. No specific dietary considerations need to be followed for the infusion formulation of Edaravone.

Missed Dose:

If the person misses the appointment for the Edaravone infusion, seek advice from the concerned doctor regarding the missed dose. In case, the oral dosage is missed, the patients can deliver the suspension once they become aware of it. However, if the person recalls the forgotten dose, the next morning, it is advised to disregard the missed one. No attempt should be made to compensate for the missed dose, as it can bring about overdose issues.

Overdose:

Taking more than the intended dosage of Edaravone can give rise to overdose issues. Edaravone overdose can precipitate alarming manifestations like troubled breathing or even collapse. Medical attention needs to be sought in such cases.

Storage:

The storage specifications for Edaravone tend to vary with the medicine formulation. 25 degrees Celsius (77 degrees Fahrenheit) is the ideal storage temperature advised for oral formulation of Edaravone. However, temperatures within the range of 15 to 30 degrees Celsius (59 to 86 degrees Fahrenheit) are estimated to be safer for the Edaravone suspension storage.

For the infusion solution, the ideal storage temperature range is two to eight degrees Celsius (36 to 46 degrees Fahrenheit). Exposure to sunlight can impair the composition and efficacy of both formulations, therefore, it should be kept away and safe.

For Doctors:

Indication:

Edaravone is a novel therapeutic agent employed for patients detected with amyotrophic lateral sclerosis. There is no other approved indication for Edaravone.

Dose:

• Oral Suspension Form: 105 mg is the recommended daily dosage for oral suspension forms. It is preferably administered in the morning before breakfast.

• Infusion Form: 60 mg is the preferred infusion dosage, which should be infused over one hour at a rate of one mg per minute.

The Edaravone dosing regimen encompasses alternating treatment cycles. In the initial cycle, lasting for 14 days, the Edaravone is administered daily throughout the first 14 days. It is then followed by a drug-free period for another 14 days. Following this, the next phase of treatment begins. The subsequent phase of Edaravone therapy typically lasts for another 14 days, in which the daily drug delivery is advised for only 10 days. Following this, again a break of 14 days is given with no drug delivery and the cycle repeats.

Dosing Considerations:

There are no specific dosing considerations that are advised for Edaravone therapy. However, in certain cases, the doctors may advise dose modifications taking into account the patient's health status and potential risk factors. In such cases, the patients should adhere to these guidelines.

Pharmacological Aspects of Edaravone

• Mechanism of Action: The exact way in which Edaravone works for amyotrophic lateral sclerosis is still unclear. However, it is believed that Edaravone’s antioxidant properties account for its therapeutic potential. Being an antioxidant, it scavenges the free radical molecules. In addition, it also interferes and depletes the production of peroxynitrite and hydroxyl radicals. The free radical molecules become reactive due to the deficient electron and can potentially deteriorate cellular functions and processes. Antioxidants can present electrons to these free radicals, thus contributing to their stability. The neutralized free radical molecules can no longer bring about cellular destruction.

• Pharmacodynamics: The free radical scavenging elicited by Edaravone also brings down oxidative stress. Oxidative stress contributes significantly to amyotrophic lateral sclerosis. It hinders the lipid peroxidation process. All these collectively shield the nerve cells from getting damaged and destructed, which in turn gears down the pace of ALS progression.

• Pharmacokinetics: Following oral delivery of Edaravone, the drug molecules are easily uptaken from the intestinal mucosa. Within 30 minutes, Edaravone achieves its utmost concentration in the blood, provided the oral delivery is done under overnight fasting conditions. For infusion formulation of Edaravone, the utmost concentration is achieved once the infusion is complete (post 60 minutes of infusion initiation). The remaining pharmacokinetic profiles for both the formulations are more or less the same. Edaravone is distributed through the bloodstream by attaching to plasma proteins. The breakdown process of Edaravone occurs within the liver. Glucuronidation and sulfo-conjugation are the two key metabolic pathways concerning Edaravone. Both the metabolic process gives rise to inactive breakdown products like conjugates of sulfate and glucuronide. It is through the urinary route that a major proportion of the Edaravone elimination occurs.

Toxicity:

There are only limited sources of reliable information concerning the toxicity profile of Edaravone. Once manifestations associated with potential toxicity are elicited, it is imperative to seek medical guidance. The doctors assess the patient’s condition and advise therapeutic and supportive measures to tackle the toxicity issues. It is often done by stamping out the excess drug concentration from the body. Certain clinical study reports suggested that Edaravone is in no association with carcinogenicity and mutagenicity potential. However, the toxicity profile for the intravenous Edaravone formulation needs to be explored more to have conclusive results.

Clinical Studies:

Various randomized clinical studies and trials have been conducted to expose Edaravone’s safety and efficacy profile. The study subjects were randomly categorized into two distinct groups. One of the groups receives the Edaravone therapy, while the other is a placebo. The final results of both groups are then compared to declare the beneficial effects of Edaravone therapy at the same time ensuring its safety aspects.

What Are the Contraindications of Edaravone?

Patients who have had prior hypersensitivity or allergic encounters towards Edaravone should refrain from Edaravone therapy. Anybody with a known drug allergy to Edaravone or any of the ingredients listed in the drug’s composition is contraindicated from undergoing Edaravone therapy, as it can potentially evoke severe forms of life-threatening reactions in the body upon subsequent encounter.

Warnings and Precautions:

• Sulfite Allergy: Sodium bisulfite, being an active component in both the oral and intravenous Edaravone formulations, makes the patient vulnerable to developing allergic reactions. Sulfites are known to trigger allergic responses in the body. Therefore, the patient must be cautioned about it beforehand. Sulfite-triggered allergic reactions can bring about asthmatic attacks, which can potentially endanger one's life. Asthmatic patients are more likely to precipitate sulfite allergy during Edaravone therapy.

• Hypersensitivity: Edaravone’s post-marketing surveillance reports exposed its potential for developing hypersensitivity issues. These reactions can be in the form of cutaneous manifestations like redness, itching, and puffiness. However, at times, it can also bring about alarming signs like dyspnea and collapsed blood pressure. In such cases, medical attention needs to be sought at the earliest to safeguard the patient's life.

Drug Interactions of Edaravone

Edaravone generally does not exhibit remarkable interactions with other drugs, particularly with cytochrome P450 (pigment450) inhibitors. Furosemide, Sildenafil, and Rosuvastatin are drugs that can be co-administered with Edaravone without evoking unpleasant drug interactions. In addition, Edaravone also does not interfere with the UDP (uridine diphosphate) -glucuronosyltransferase inhibitors. The absence of remarkable drug-to-drug association favors the simultaneous intake of Edaravone with other medicines. However, simultaneous drug intake is advised only after medical consultation.

Specific Considerations:

• Edaravone During Pregnancy: Edaravone is generally not advised for expectant women. The safety aspects of Edaravone in expectant women need to be established. Nonclinical study reports demonstrated fetal toxicity issues in association with Edaravone therapy in expectant women. Therefore, medical advice needs to be sought to determine the risks and benefits associated with it. Edaravone is preferred only if the maternal need for the therapy justifies the fetal risk.

• Edaravone During Breastfeeding: Limited information concerning the release of Edaravone through breast milk restricts theusage of the medicine in lactating women. If the medicine is capable of gaining access into the child’s body through the breastmilk, it can bring in unwanted and unpleasant events in the baby’s body.

• Edaravone in Pediatric Patients: Edaravone is generally not advised for pediatric patients as Edaravone’s safety and potency aspects are not explored in the pediatric population.

• Edaravone in Geriatric Patients: Edaravone therapy does not elicit appreciable differences in geriatric patients concerning both safety and potency aspects. However, geriatric populations tend to elicit enhanced hypersensitivity issues and warrant close medical follow-ups.