Rufinamide - Indications, Side Effects, Warnings, and Precautions

Overview:

Rufinamide is an efficacious and promising medicine that is used in conjunction with other standard drugs to deal with seizures (uncoordinated electrical hyperactivities happening in the brain). The United States drug regulatory authority, the Food and Drug Administration (FDA), endorsed the usage of Rufinamide as a complementary therapy for dealing with a peculiar syndromic condition called Lennox-Gastaut syndrome, where the affected individual elicits seizure activities and collapsed muscular tonicity. Rufinamide received marketing authorization from the FDA on November 14, 2008. Following this, when producing a doctor's prescription, Rufinamide was made available in pharmacies under various brand names.

Drug Group:

Rufinamide falls under the category of anticonvulsant drug class. Anticonvulsant specifically works for convulsive disorders that are triggered by exaggerated electrical conduction happening inside the brain cells. Structurally, Rufinamide is a derivative of triazole, which makes it distinct from other medicines included under the anticonvulsant drug class.

Available Doses and Dosage Forms:

• Dosage Forms: Rufinamide is marketed in two distinct dosage forms: oral suspension form and tablet form. The oral suspension form is meant for those unable to ingest the tablet form, especially small children.

• Available Doses: The tablet form of Rufinamide is available in 400 milligrams (mg) and 200 milligrams. In contrast, the oral suspension form is marketed with 40 mg of Rufinamide in every milliliter solution.

For Patients:

What Is Lennox-Gastaut Syndrome?

Lennox-Gastaut syndrome (LGS) is a peculiar and exaggerated version of epilepsy (brain disorder), with characteristic seizure activity. Its manifestations are often elicited at a very young age. In addition to seizures, the affected children are occasionally noted with compromised growth, and their developmental milestones will be held up. The tonicity of the muscle will be remarkably impaired. Uncoordinated stiffening and tightening of the muscles precipitate in the form of seizures with jerking and uncontrollable movements of the limbs. Certain affected individuals exhibit collapsed cognitive skills and intellectual abilities.

Lennox-Gastaut syndrome is considered genetically linked; however, there is only limited information concerning the gene factor responsible for this condition's development. Certain hypotheses suggest its origin from altered gene expression of one or more genes concerned with brain functioning. One peculiar feature of this syndrome is the presence of diverse seizure forms rather than a single type of seizure. The seizure frequency is also remarkably higher with multiple times, even in a single day, which makes it challenging for the patient to have a normal life.

How Does Rufinamide Work?

Rufinamide elicits its actions in tackling seizures by impeding the electrical activity in the brain, which eventually terminates the exaggerated electrical brain activities. Certain ion channels in the body enable the electrical signal conveyance through the nerve cells. Rufinamide targets these ion channels and modulates and distorts their function so that only the abnormal signal conduction is impeded, leaving normal brain functions unhampered.

What Is the Dosage of Rufinamide?

• Dosage for the Under-17 Age Category: Dosages for the under-17 age category are determined by considering the patient’s body weight. The inceptive daily dose for the pediatric population is 10 milligrams per kilogram of body weight (mg/kg). The daily dose should be divided into two doses of equal value. The dosage is gradually and steadily titrated at 10 milligrams per kilogram once in two days until the daily dose attains 45 milligrams per kilogram.

• Dosage for Adults Over 17 Years: The daily inceptive dosage of Rufinamide for the adult population is estimated to be 400 to 800 milligrams. The steady dose titration is made on an alternate day basis at 400 to 800 milligrams; however, the daily dosage should always stay within the upper limit of 3200 milligrams.

How Effective Is Rufinamide?

Rufinamide is proven to be efficacious in dealing with the seizure manifestations elicited in association with Lennox-Gastaut syndrome when advised as an adjunctive therapy. Quick absorption and patient tolerability contribute to its effectiveness. Though it holds promising potency for LGS, its therapeutic effectiveness for other specific seizure entities is reported to be inferior to other anticonvulsant drugs when used alone.

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

The success and effectiveness of every treatment regimen mandate proper patient-doctor interaction. Effective and qualitative discussions with the doctors are integral in checking for unpleasant events during therapy.

• The doctors should be informed of the patient's prior hyperreactivity encounter with Rufinamide or any other medicines that come under the category of anticonvulsant. Hypersensitivity to even any of the components in the Rufinamide pill or liquid form needs to be discussed, as it can potentially trigger severe reactions upon ingestion.

• The patient’s comprehensive medical history is another key information that the doctors should be provided with beforehand. The presence of liver disease, cardiac conditions, or impaired kidney functions often necessitates caution, and the doctor needs to analyze and determine the patient's safety during Rufinamide therapy.

• In addition to medical history, a detailed drug history is also imperative before initiating therapy using Rufinamide and hence needs to be shared with the concerned doctor before therapy commencement. The drug history needs to be highly comprehensive, encompassing details of all the medications, dietary supplements, over-the-counter pills, and herbal and alternative medicines the person administers. Certain medications can impair and influence the activities of Rufinamide, which entails modification of the drug choice or drug dosage to counterbalance.

• The doctor should know the patient's pregnancy and lactation status beforehand. Rufinamide during pregnancy and lactation requires medical advice concerning the safety of the baby. Therefore, it is imperative to keep the doctors updated about it. In the event of unexpected conception while undergoing Rufinamide therapy, medical advice needs to be sought at the earliest.

How Is Rufinamide Administered?

Both pill and liquid forms of Rufinamide are fabricated for oral ingestion. The pill can be ingested even in fractured or powdered form if the patient has trouble swallowing it. It is preferably advised to be taken with food. Agitate the suspension-containing bottle before administration to ensure the homogeneity of the solution. A graded syringe and adapter are often enclosed within the medicine package, which enables prompt measuring of the liquid and proper sealing of the medicine bottle.

What Are the Side Effects of Rufinamide?

Rufinamide therapy precipitates certain adverse reactions in the body. Some are minor and transient, while others are alarming and mandate immediate medical interventions.

Some of the frequently reported side effects include the following:

• Rufinamide induces sleepiness and fatigue. The patient needs help in remaining attentive and active.

• Other side effects of Rufinamide therapy are headache, body pain, vomiting, stomach pain, and absence of hunger.

• Rapid eye movements, trembling, shakiness in certain body parts, trouble walking (ataxia), and trouble with body balance are some side effects that impact one’s routine activities.

• Apart from these minor effects, the therapy may also bring about facial puffiness, atypical stool and urine color, fever, and compromised vision. Upon the development of these alarming side effects, it is always advised to seek medical assistance.

Dietary Considerations:

No specific dietary guidelines need to be adhered to during Rufinamide therapy. However, each patient's condition is different, and the doctor analyzes their general health and decides on their dietary considerations. Rufinamide elicits utmost absorption when it is ingested with food.

Missed Dose:

Rufinamide is recommended to be taken twice daily. Sometimes, the patient may need help recalling the dose administration on time. In such cases, patients can ingest the dose once they become aware. But occasionally, the patient recalls the dose at subsequent dose intake times. In such scenarios, it is better to forgo the previous missed dose and proceed with the upcoming dose. Attempts should be made to take, at most, the stipulated dose to counterbalance the skipped dose.

Overdose:

Ingesting more than the prescribed dose, as suggested by the doctor, can bring about overdose issues. In the event of an overdose, it is better to seek medical advice or report to health centers. No specific medicine is available to counterbalance Rufinamide overdose. Induced vomiting (emesis) and stomach pumping (gastric lavage) are the general supportive strategies that are exercised for tackling Rufinamide overdose. The patient needs to be kept under surveillance for a particular period to ensure the smooth functioning of the vital organ system.

Storage:

Twenty-five degrees Celsius (77 degrees Fahrenheit) is the recommended storage temperature for Rufinamide's pill and suspension form. However, it is safe at 15 to 30 degrees Celsius (59 to 86 degrees Fahrenheit). Keep the medicine in the bottle with the cap sealed tightly until it is time for ingestion. The pill should be kept moisture-free. Special care should be taken to check inadvertent intake of pills by small kids.

For Doctors:

Indication:

• Adjunctive therapy for Lennox-Gastaut syndrome (patients over one year of age to older patients).

Dose:

• Pediatric Dosage: Pediatric dosage is indicated for children in the age range of one to 17 years. The daily dose of Rufinamide during the incentive stage is 10 milligrams per kilogram of body weight. On every second day, 10 milligrams per kilogram are added to the inceptive dose. These slow dose increments are continued until the daily ingested amount hits 45 milligrams per kilogram of body weight. The daily dose needs to be split into two equal doses for administration.

• Adult Dosage: 400 to 800 is the recommended daily adult dosage of Rufinamide during therapy initiation. Following this on every alternate day, 400 to 800 mg must be incremented to the daily inceptive dose until the daily dose strikes 3200 mg.

Dosing Considerations:

Certain dosing considerations are advised for patients with compromised vital organ functions in their bodies.

• When Rufinamide is advised for patients with severely impaired kidney functions who are supported with hemodialysis (machine-guided filtration when kidneys fail to filter out the waste efficiently), around 30 percent of the Rufinamide in the blood gets filtered out. Therefore, the dose must be reconsidered and modified when Rufinamide therapy is advised for hemodialysis patients.

• Rufinamide therapy is restricted in patients with compromised liver functions as there is only limited information available concerning their impact on an impaired liver.

• The inceptive dosage of Rufinamide, when concurrently administered with another anticonvulsant medicine, Valproate, must be depreciated below the standard daily inceptive dose.

What Are the Pharmacological Aspects of Rufinamide?

• Mechanism of Action: Rufinamide’s exact working methodology in tackling epileptic seizure is less known. However, in vitro studies favor the hypothesis that advocates Rufinamide-triggered sodium channel adjustments in the brain. The drug molecules alter the sodium channel functioning and create a check on repetitious action potential firing. Seizure activities require continuous action potential firing. By impeding the action potential firing in a continuous series, Rufinamide works to check seizure activities.

• Pharmacodynamics: Rufinamide extends the recovery period of the sodium channel. The neuronal membrane gets stabilized under the influence of Rufinamide. Only an excited and unstable neuronal membrane can trigger firing. Since the nerve membrane is stabilized, the synchronous firing will also be checked. It also curbs down the abnormal and exaggerated electrical activity in the brain.

• Pharmacokinetics: Within four to six hours following oral ingestion, Rufinamide precipitates its utmost concentration in the blood, which supports prompt uptake from the intestine. Food potentiates the uptake of Rufinamide by around 34 percent. It circulates in the blood as free Rufinamide molecules rather than being protein-bound. Hardly 34 percent of the up-taken Rufinamide seems to establish a bond with plasma proteins and circulates in bounded form. Liver enzymes, particularly cytochrome P450 (pigment 450) enzymes, are responsible for Rufinamide’s metabolism, broken down into smaller molecules. More than 98 percent of Rufinamide undergoes breakdown in the liver, sparing less than two percent. Unlike the parent molecules, none of the breakdown products possess any antiepileptic properties. It is through the kidney that Rufinamide, along with its breakdown products, is flushed out of the body.

Toxicity:

There is only limited information available concerning Rufinamide’s clinical toxicology profile. Rufinamide therapy is proven to be not associated with clastogenic or mutagenic properties upon in vitro analysis. Carcinogenicity and fertility impairment concerning Rufinamide therapy need to be explored more to obtain conclusive results.

Clinical Studies:

Various clinical studies were conducted to expose Rufinamide's potency and safety aspects. Randomized, placebo-controlled studies have successfully demonstrated the potency of Rufinamide in dealing with seizure activity precipitated by LGS. These studies were double-blinded to check the scope for bias and ensure the results' authenticity. Separate clinical studies were conducted on pediatric and adult populations to gauge the effectiveness of Rufinamide. The pharmacokinetic profile was reported to be analogous in both categories of subjects.

What Are the Contraindications of Rufinamide?

Rufinamide is supposed to be taken by only some of the patients. Certain conditions restrict Rufinamide therapy as it can bring adverse impacts on the patient’s body. Some of the potent contraindications include the following:

• Prior hypersensitivity encounter with Rufinamide or any components in the Rufinamide pill or suspension form.

• Patients were detected with familial short QT syndrome.

Warnings and Precautions:

• Enhanced Suicidal Tendency: Rufinamide, being an antiepileptic medication, bears the risk of modulating one’s thought process. Depressive and suicidal thoughts are often encountered in patients undergoing therapy using Rufinamide. In addition, unexplainable behavioral and mood alterations are occasional findings that necessitate surveillance and monitoring throughout the treatment course. Therefore, if the medication is advised for patients with known behavioral or depressive disorders, extreme caution needs to be warranted.

• Central Nervous System Issues: Dizziness, ataxia, troubled body balance, and gait issues are some of the central nervous issues noted in conjunction with Rufinamide therapy. The therapy can induce sleepiness, and hence, the patient should be warned about it beforehand. Undertaking activities that require close attention and fine motor skills can pose a danger, as these skills are often compromised during Rufinamide therapy.

• Collapsed QT Interval: It was reported in clinical studies that Rufinamide therapy precipitates an evident depreciation in the QT interval, which can be demonstrated with the help of electrocardiograms (ECG). The QT shortening induced by Rufinamide can bring in grave ventricular arrhythmias in patients with pre-existing ailments like familial short QT syndrome.

• Risk of Leukopenia: Clinical trial reports suggested Rufinamide triggered a white blood cell count collapse. Therefore, it is advised to have a periodic check on the blood picture of the patients undergoing the therapy.

• Contraceptive Failure: Rufinamide can depreciate the potency of hormonal contraceptive measures, and hence, the patient should be advised to stick to other contraceptive strategies to check unplanned pregnancy.

• Withdrawal-Induced Exacerbation: Upon abrupt withdrawal of Rufinamide, it can precipitate unanticipated worsening of epilepsy. At times, it can even pave the way for status epilepticus. Therefore, Rufinamide therapy withdrawal needs to be slow and steady rather than abrupt stoppage. However, if the patient’s condition necessitates a swift withdrawal, it is often executed by switching to another anticonvulsant, which, too, should be assisted by concerned doctors.

• Multiorgan Hypersensitivity Syndrome: Rufinamide therapy also carries the risk of precipitating an alarming condition, multiorgan hypersensitivity syndrome. Both clinical trials and post-marketing reports suggested incidences of multiorgan hypersensitivity syndrome where the person elicited extensive allergic reactions in the skin accompanied by vital organ involvement like hepatitis.

What Are the Drug Interactions of Rufinamide?

Rufinamide tends to elicit notable interactions when ingested alongside other medicines. Some of the drug interactions include the following:

• When concurrently ingested with other anticonvulsants, Rufinamide can bring in slight alterations in one or both medicines. Simultaneous administration of Carbamazepine and Rufinamide results in a considerable depreciation in the concentration of both medicines. Phenytoin or Phenobarbital, when coupled with Rufinamide, brings about obvious depreciation in the Rufinamide’s concentration, while the Phenytoin or Phenobarbital concentration elicits an appreciable hike.

• In the presence of an appreciable concentration of Rufinamide, hormonal contraceptives cannot work as effectively as they used to. It impairs the effectiveness of this form of contraceptive measures, which entails the introduction of other non-hormonal measures that could offer remarkable contraception.

• Patients who were treated with Valproate when starting with Rufinamide therapy or vice versa should incept the treatment with a dose lower than the standard inceptive dose.

Specific Considerations:

• Rufinamide During Pregnancy: Rufinamide is grouped under pregnancy category C drug. Nonclinical studies have exposed the toxicity aspect of Rufinamide when ingested during conception. Hence, generally, it is not advised for expectant women. However, the recommendation for undertaking Rufinamide therapy is exercised only after gauging the risks and benefits associated with the therapy for the expectant women and the baby in the womb.

• Rufinamide During Lactation: It is considered that Rufinamide gets discharged through the breastmilk when taken up by lactating women. There is no relevant source of information suggesting the effects that Rufinamide can precipitate once it gains access to the baby through breast milk. Hence, generally, Rufinamide therapy is not suggested for lactating women. However, if the maternal body necessitates the therapy, the concerned doctors assess the condition and make appropriate decisions.

• Rufinamide for the Pediatric Population: Rufinamide's therapeutic applicability is extended from one year to 17 years in the pediatric population, with proven safety and efficacy parameters. No studies have been conducted for pediatric populations below one year of age; therefore, the safety and therapeutic efficacy aspects could be more specific and clear.

• Rufinamide for the Geriatric Population: When advised for geriatric patients, the dose must be determined cautiously to avoid further strain on compromised organ functions.