Opicapone - Indication, Contraindication, Side Effects, and Dosage

Overview:

Opicapone is a drug belonging to the COMT inhibitors and is recommended in managing Parkinson's disease. It is the first and foremost approved catechol-O-methyltransferase (COMT) inhibitor. Opicapone received the approval from Food and Drug Administration (FDA), in April 2020. Opicapone is used as a supplementary drug to Carbidopa and Levodopa and is mainly used when Parkinsonian signs and symptoms have re-emerged. Thus, Opicapone is considered an add-on medication during off-episodes of Parkinson's disease. An off-episode is defined as the period when a patient is not on medications, and there is a re-appearance of Parkinsonian symptoms such as rigidity, difficulty in understanding, abnormal posture, and tremors.

How Does Opicapone Work?

Opicapone is a reversible and selective catechol-O-methyltransferase COMT inhibitor. catechol-O-methyltransferase catalyzes and brings about the shift of the methyl group present in S-adenosyl-L-methionine to the phenolic group of substrates that consists of a catechol structure. Physiological substrates of catechol-O-methyltransferase include dihydroxyphenylalanine or DOPA, catecholamines such as norepinephrine, dopamines, and epinephrine as well as their respective hydroxylated metabolites. As the decarboxylation of levodopa is hindered by carbidopa, catechol-O-methyltransferase turns into the major enzyme for metabolizing Levodopa and thus catalyzing the metabolism of Levodopa into 3-methoxy-4-hydroxy-L-phenylalanine or 3-OMD.

When Is Opicapone Indicated?

• Opicapone is used as supplementary management along with Carbidopa or Levodopa in patients who have Parkinson's disease.

• Opicapone is an adjunctive drug mainly used during off episodes of Parkinson's disease.

• An off episode is a period when a Parkinsonian drug does not give the desired results or is not working well for the patient. This eventually leads to the symptoms of Parkinson's disease getting worse or snapping back again. In addition, sometimes, there is a gap between two scheduled doses of medications, during which many patients suffer from the re-emergence of parkinsonian symptoms.

• An episode of Parkinson's disease is when the medication is being observed and metabolized quite well within the patient with clear signs of improvement from Parkinson's disease.

• To overcome the worsening signs and symptoms of Parkinson's disease, during the scheduled gap, Opicapone is strongly indicated.

What Are the Contraindications of Opicapone?

The use of Opicapone is contraindicated in the patients suffering from the following medical conditions;

• Long-term pheochromocytoma.

• Paraganglioma.

• End-stage renal impairment.

• Neoplasms that secrete catecholamine.

• Severe hepatic impairment.

• Patients who are undergoing treatment with non-selective monoamine oxidase or MAO inhibitors.

Opicapone for Patients:

What Is Opicapone?

Opicapone is a medication prescribed by a healthcare professional to be consumed along with Carbidopa and Levodopa in patients suffering from Parkinson’s disease or PD while the patient is going through the “Off” episodes. The safety and effectiveness of Opicapone are unknown in children.

When Should Opicapone Not Be Taken?

Below are the key points to keep in mind before going ahead with Opicapone. Opicapone should not be taken if the patient,

• Is under medications that are MAO inhibitors or non-selective monoamine-oxidase for example Isocarboxazid, Phenelzine, and Tranylcypromine.

• Secreting catecholamines, which is a hormone secreted by tumors.

• Presence of pheochromocytoma.

• Presence of paraganglioma.

• Presence of any type of adrenal gland tumor.

What Should the Patient Inform the Healthcare Provider Before Taking Opicapone?

Before going ahead with Opicapone therapy, the patient must inform the healthcare provider about every medication they are currently on and had taken in the past, any underlying cardiovascular disease as well as the presence of any of the below-mentioned conditions.

• History of hallucinations.

• History of sudden and uncontrolled jerking movements.

• Pregnancy.

• Breastfeeding.

• Planning for pregnancy.

• Daytime sleepiness.

• An unexpected period of sleepiness.

• History of sleep disorders.

• Urges of gambling.

• Urges of binge eating.

• Increased sexual arousal.

• Urges of compulsive shopping.

• History of liver disorders.

• Psychosis.

• Under any prescribed medication.

• Over-the-counter medications.

• Vitamin supplements.

• Herbal medications.

• Nonselective monoamine-oxidase or MAO inhibitors.

• Medications such as Tranylcypromine, Phenelzine, and Isocarboxazid.

• Medications such as Epinephrine, Isoproterenol, Dopamine, Norepinephrine, or Dobutamine are catecholamine medications.

How Should Opicapone Be Taken?

Opicapone should be taken strictly as advised and instructed by the healthcare provider or the concerned professional. Mentioned below are the key points of administration of Opicapone.

• Opicapone is taken once daily before bedtime.

• Eating one hour before Opicapone should be avoided.

• Eating one hour after Opicapone should be avoided.

• In case a dose is missed, the usual dose of Opicapone should be taken the next day.

• Opicapone administration should not be abruptly stopped without the healthcare provider's consultation.

• In case of development of fever, muscle stiffness, confusion or other symptoms arise, the healthcare provider should be informed on priority.

• Overdosage of Opicapone should be monitored and in case it occurs, the patient should immediately be taken to the emergency room.

What Activities Should Be Avoided While Taking Opicapone?

Mentioned below are the activities that should be avoided in case a patient is suggested to undergo Opicapone therapy.

• Driving.

• Working with heavy machines.

• Aggressive physical workout.

• Dangerous activities.

What Are the Possible Side Effects of Opicapone?

Every medication has certain side effects. Opicapone is known for having the below-mentioned side effects.

• Falling asleep during the daytime.

• Suddenly falling asleep during activities.

• Dizziness.

• Uncontrolled muscular jerks.

• Low blood pressure.

• Auditory hallucinations.

• Visual hallucinations.

• Feelings that are not true or real.

• An unusual ringing in the ears.

• Increased sexual urges.

• Binge eating.

• Urges to continue shopping.

• Excessive greed for money.

• Urges for gambling.

• Urges to start spending heavy amounts of money.

• Unusual behavior.

• Constipation.

• Weight loss.

• Increased blood creatine kinase.

How Should Opicapone Be Stored?

Opicapone should be stored at a temperature below 30 degrees celsius. Opicapone must be kept out of the reach of children.

What Are the Ingredients in Opicapone?

• The active ingredient in this drug is Opicapone.

• The inactive ingredients are magnesium stearate, lactose, pregelatinized starch, sodium starch glycolate, and the capsule shell.

• The shell contains gelatin, FD&C Red#3, FD&C Blue#2, and titanium dioxide.

Opicapone for Doctors:

What Is Opicapone?

• Opicapone is a selective, peripheral and reversible catechol-O-methyltransferase or COMT inhibitor.

• Opicapone is chemically referred to as, 2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol3-yl)-4,6-dimethylpyridine-1-oxide. The molecular formula of Opicapone is C15H10Cl2N4O6. The molecular weight of Opicapone is 413.17. This drug is a yellow crystalline or powder solid with restricted aqueous solubility. Opicapone capsules are indicated for the oral route of administration. Each capsule is 25 mg or 50 mg. The inactive ingredients present in Opicapone are the following mentioned below.

• Magnesium stearate.

• Lactose.

• Pregelatinized starch.

• Sodium starch glycolate.

The shell of Opicapone capsules contains the following mentioned below.

• FD&C Blue#2.

• FD&C Red#3.

• Gelatin.

• Titanium dioxide.

What Is the Mechanism of Action of Opicapone?

Opicapone is a reversible and selective catechol-O-methyltransferase COMT inhibitor. Catechol-O-methyltransferase catalyzes and brings about the shift of the methyl group present in S-adenosyl-L-methionine to the phenolic group of substrates that consists of a catechol structure. Physiological substrates of catechol-O-methyltransferase include dihydroxyphenylalanine or DOPA, catecholamines such as norepinephrine, dopamines, and epinephrine as well as their respective hydroxylated metabolites. As the decarboxylation of levodopa is hindered by carbidopa, catechol-O-methyltransferase turns into the major enzyme for metabolizing Levodopa and thus catalyzing the metabolism of Levodopa into 3-methoxy-4-hydroxy-L-phenylalanine or 3-OMD.

What Are the Pharmacodynamics of Opicapone?

There is a visible inhibition of catechol-O-methyltransferase in the daily administration of 50 mg of Opicapone in erythrocytes. The highest inhibition was 84 % and was maintained at less than 65 % over a period of a 24-hour interval between doses in patients suffering from Parkinson’s disease. After the treatment with Opicapone is over, catechol-O-methyltransferase inhibition returns slowly but surely to baseline levels, with less than 35 % inhibition being observed post five days of the final dose. Results on Levodopa Peak or Cmax, as well as overall exposure of Levodopa or AUC, drastically was seen to increase by approximately 43 % and 62 % to 94 %, respectively, in patients suffering from Parkinson's disease after the standard following once a day oral administration of Opicapone during bedtime along with administration of Levodopa or Carbidopa given every three to every four hours, as against the sole administration of Levodopa Carbidopa. Opicapone does not extend the QT interval even at a dose of sixteen times the recommended dosage.

What Are the Pharmacokinetics of Opicapone?

Opicapone exemplifies dose-proportional pharmacokinetics over a 25 mg to 50 mg dose. The pharmacokinetics of Opicapone are parallel in both healthy patients and patients suffering from Parkinson’s Disease.

• Absorption:

The median range of plasma Tmax values after administering a single dose of Opicapone 50 mg is 2.0 or more.

• Effect of Food:

In one of the studies, Opicapone was administered without contemplating food while in another study, Opicapone intake and food consumption were segregated by one hour. The result established that the Cmax or the mean peak plasma concentration for Opicapone following a moderate calorie diet decreases significantly to 62 % and the AUC or the mean overall plasma exposure drops by around 31 %. Additionally, there is a delay of four hours in Tmax.

• Distribution:

Opicapone is extremely attached to plasma proteins, more than approximately 99 %, and these proteins are not dependent on concentration.

• Elimination:

Opicapone’s mean half-life of elimination is approximately one or two hours.

• Metabolism:

Based on in vitro assessments and clinical studies, Opicapone is primarily metabolized through the pathway of sulphation. However, there are several alternative metabolic pathways, such as reduction, glucuronidation, glutathione conjugation, and methylation by catechol-O-methyltransferase.

• Excretion:

Around 70 % of Opicapone 100 mg after administration of the dose two times to healthy individuals, was recuperated of which 22 % was unchanged whereas 20 % was in expired air and 5 % was present in urine that included less than 1 % unchanged.

• Specific Populations:

There was no significant change in the pharmacokinetics of Opicapone among different races such as Asian, Caucasian, Black, and Japanese. There was no pharmacokinetic alteration even amongst different genders or age groups such as individuals between 18 to 40 years of age or individuals more than or equal to 65.

• Renal Impairment:

Using the Cockcroft-Gault equation, there was no severe alteration in the pharmacokinetic analysis of the population in patients suffering from mild to moderate renal impairment when treated with Opicapone. Patients suffering from severe impairment of the renal system have not been examined.

• Hepatic Impairment:

The pharmacokinetics of Opicapone was checked among the patients who were suffering from mild or Child-Pugh: A, or, moderate or Child-Pugh: B hepatic impairment and were given a single dose of Opicapone. In patients suffering from a mild hepatic impairment, the mean Opicapone plasma exposure or AUC was increased by approximately 35 %, not clinically significant. In patients suffering from a moderate amount of hepatic impairment, the overall Opicapone plasma exposure or AUC was increased by around 84 %. Adjusting the dose of Opicapone is necessary for patients who are going through moderate hepatic impairment. Opicapone has not been examined in patients suffering from severe hepatic impairment or Child-Pugh: C.

• Clinical Studies:

There have not been any significant alterations in the pharmacokinetics of Opicapone observed after its administration along with quinidine with index substrate acetaminophen or rasagiline. Parallel to this finding, there has not been any difference in the evaluation of pharmacokinetics of other drugs concomitant with Opicapone such as S-Warfarin, R-Warfarin, and Repaglinide, and other Parkinson’s drug-like Selegiline, Ropinirole, Pramipexole, and Amantadine.

• In Vitro:

The in vitro studies of Opicapone have shown that there is no effect on the capacity of binding the proteins in Digoxin, Warfarin, Diazepam, and Tolbutamide.

What Is the Recommended Dose of Opicapone With Hepatic Impairment?

Patients suffering from mild to moderate hepatic impairment and related conditions are recommended a dosage of Opicapone which is 25 mg and has to be taken once daily before bedtime. This dose is via oral administration.

What Are the Nonclinical Toxicology Aspects of Opicapone?

The non-clinical toxicology study of Opicapone was done for understanding three aspects- mutagenesis, carcinogenesis, and impairment of fertility.

• Mutagenesis:

In vitro studies of Opicapone were negative through Ames or bacterial reverse mutation tests and aberrations in chromosomal factors in human peripheral blood lymphocytes. In vivo studies of Opicapone were negative as well as seen in the bone marrow of rat micronucleus assays.

• Carcinogenesis:

There was no presence of tumors when Opicapone was administered via an oral route to mice for up to two years or 84-93 weeks at a higher dose. The highest dosage of Opicapone tested is around seventy times the recommended dose in human beings which is 50 mg/day on a surface area of mg/m2. A zero increase in tumors was seen when Opicapone was administered via an oral route to rats for two years. The level of plasma exposure at the highest Opicapone dosage tested is around twenty-four times that in human beings.

• Impairment of Fertility:

In females and male rats, the oral administration of Opicapone before and during the process of mating in addition to continuing the dose in females to the sixth day of gestation ended up with no adverse effects on the general reproductive system or the performance of fertility. The plasma exposure level at the highest Opicapone dose tested is around forty times that in human beings.

What Should the Patient Be Counseled About Before Prescribing Opicapone?

The patient must be informed and explained in detail about the below-mentioned points by the healthcare provider and team before going ahead with Opicapone prescriptions.

• Concomitant medication:

Cardiovascular effects with concomitant use of drugs that are metabolized by catechol-O-methyltransferase or COMT may prove to be harmful because of their interaction with Opicapone regardless of the oral route of administration or inhalation route. There is a possibility of increased heart rate, abnormal heart rhythms, and alterations in blood pressure due to the same. A few drugs that are metabolized by catechol-O-methyltransferase are Epinephrine, Norepinephrine, Dobutamine, and Dopamine. Thus, the patients are advised to inform the healthcare provider and team regarding all the medication they are on and have been in the past. These include prescription drugs, over-the-counter medications, supplements for the diet, herbal supplements, and related products.

• Administration:

Opicapone should be taken during bedtime and this message should be passed on to the patient or the patient's caretaker. In addition to this, patients should not eat food an hour before administration of Opicapone or at least one hour after the intake of Opicapone along with food.

• Somnolence:

Falling asleep during the day or during regular activities has been regularly seen among patients undergoing therapy with Opicapone. In addition to this, patients who have been treated with medications that are dopaminergic in nature have given multiple reports of falling asleep while being actively engaged in day-to-day tasks. There are records of accidents or injuries after Opicapone intake and working with heavy machinery or driving a car. Patients generally do not understand the warning signs in them such as drowsiness or feeling lightheaded but do feel an extreme amount of alertness just before the event or accident occurs. Thus, machinery use and driving should be avoided when Opicapone is administered. Additionally, the patient should inform the healthcare provider in case a sleep disorder is already being treated for the patient. It is advised to discontinue Opicapone if the patient starts developing drowsiness and falls asleep during the daytime. Another way is to adjust the sedation medicines. The healthcare provider is the best person to decide how to go about dose adjustment after carefully observing the patient’s pattern of drowsiness.

• Hypotension:

In the studies done for Opicapone, approximately 5 % of participants underwent episodes of non-orthostatic as well as orthostatic syncope and presyncope signs. In such cases, the patient needs a dose adjustment or other drugs that may aid in balancing the blood pressure. Thus patients should immediately inform the healthcare provider regarding episodes of syncope or hypotension. In severe cases of drastic changes in blood pressure, Opicapone can be discontinued after consulting the respective professional.

• Dyskinesia:

In controlled Opicapone clinical trials, 20 % of the participants had shown clear signs of dyskinesia. It should also be noted that dyskinesia was one of the most common adverse effects established after all the studies done on Opicapone. Thus, patients should be advised about the possible risks of exacerbation of pre-existing dyskinesia or dyskinesia itself. The healthcare professional must be informed about the same because dyskinesia during the treatment of Opicapone can be alleviated by adjusting the patient’s daily dose of Levodopa or any other dopaminergic medications.

• Hallucinations:

In the studies done with Opicapone, approximately 3 % of participants complained of visual as well as auditory hallucinations and mixed hallucinations. Agitation, delusions, and aggressive behavior were additionally observed in 1 % of the patients who suffered from hallucinatory signs. Thus, patients should be advised about the auditory and visual hallucinations as well as aggressive behavior and symptoms of delusion. Any of these mental changes must be immediately reported to the healthcare provider because they may go through some major psychotic disorder and Opicapone has the potential to exacerbate the psychotic behavior. It should be kept in mind that medications used for psychosis can have a negative effect on patients suffering from Parkinson’s disease by elevating the clinical manifestations of the disorder.

• Compulsive disorder:

The patient generally loses the ability to control such urges post-therapy with Opicapone because of the increase in the amount of dopaminergic tone centrally that is used for the treatment of Parkinson's disease. Any signs and symptoms as such must be immediately reported to the healthcare provider. Thus patients should be addressed about the strong potential of Opicapone to increase sexual urges, feeling to gamble, intense greed for money or strong feelings to spend money, eating continuously as well as other related compulsive disorders and impulse control manifestations.

• Withdrawal-emergent hyperpyrexia:

It has been observed that with a decrease in the dosage of Opicapone, patients may show signs of a lesser-known symptom complex that is parallel to a malignant neuroleptic syndrome such as muscular rigidity, elevated temperatures of the body, autonomic instability, and altered consciousness. There may be a need for adjusting the dose of the medications. Thus, the patients must inform the healthcare provider about confusion, fever, and stiffness of muscles after discontinuation of Opicapone.

What Are the Drug Interactions With Opicapone?

Opicapone as well as non-selective monoamine oxidases such as tranylcypromine, phenelzine, and isocarboxazid hinder the standard metabolism of catecholamines. This results in a directly proportional escalation of catecholamines in the body. Thus, an increased pulse rate, arrhythmias, and alteration in blood pressure may be the end result of administering Opicapone with neuropsychiatric medications. In case there is a definite need to administer drugs that get metabolized by catechol-O-methyltransferase, caution should be taken and heart rate, as well as blood pressure, should be monitored continuously.

What Are the Renal and Hepatic Considerations of Opicapone?

Elimination of Opicapone through the renal route does not play a major role in the removal of the drug. Opicapone is avoided in patients who are at the end stage of renal impairment. There is no specific requirement to adjust the dose of Opicapone in patients who are currently suffering from mild to moderate renal disorders.

Opicapone is not advised in patients suffering from severe hepatic impairment because of the increased exposure to the drug. Dosage adjustment may be required for patients suffering from moderate hepatic impairment. On the other hand, taking the clinical manifestations of the patient into consideration, no adjustment of dosage is necessary for patients suffering from mild hepatic impairment.

What Is the Recommended Dosage for Opicapone?

The advised dose of Opicapone is 50 milligrams once daily. The route of administration is primarily oral. It is recommended not to eat food one hour before and after the intake of Opicapone. The oral route is fast-acting compared to other routes, such as the intravenous and intramuscular routes.

What Happens in Case a Dose of Opicapone Is Missed?

Patients should not miss even a single dose of prescribed Opicapone. Nevertheless, if a dose of Opicapone is missed, the next dose should be taken as usual on the next day. It is not advised to discontinue or deliberately miss a dose of Opicapone without prior discussion and consultation with the respective healthcare provider. The healthcare provider should be made aware of any missed dose as well as any kind of discontinuation of Opicapone done on the patient’s behalf so that the patient can be monitored for certain clinical manifestations and the healthcare provider may consider adjustments with other medications or therapies such as dopaminergic therapy if the need arises.

What Is the Dosage Form and Strength of Opicapone?

Opicapone should be stored at a temperature below 30 degrees Celsius. Opicapone capsules are available in two strengths and two forms.

• A dark blue and opaque cap with a dark pink opaque body of 50 mg.

• A light blue opaque cap with a light pink and opaque body 25 mg.

How to Handle a Case of Opicapone Overdosage?

There are currently no known antidotes for Opicapone. Mentioned below are the measures of management that can be considered based on the clinical appearance of the patient and the decision made by the health care provider.

• Gastric lavage.

• Administration of activated charcoal to inactivate the drug.

• Supportive care.

• Strict monitoring of vital signs.

• Medical supervision.

What Are the Warning and Precautions of Opicapone?

Mentioned below is the list of warnings against the administration of Opicapone that needs precautions to be taken.

• Cardiovascular effects with concomitant use of drugs metabolized by catechol-O-methyltransferase or COMT.

• Somnolence.

• Syncope.

• Falling asleep during routine activities.

• Hypotension.

• Psychosis.

• Dyskinesia.

• Hallucinations.

• Compulsive disorder.

• Confusion.

• Impulse control.

• Withdrawal-emergent hyperpyrexia.

What Are the Adverse Reactions of Opicapone?

Clinical trials with Opicapone have shown the below-mentioned adverse effects. Amongst all, dyskinesia or rapid jerking and spasm of muscles was the most common adverse effect.

• Dizziness.

• Constipation.

• Dry mouth.

• Insomnia.

• Hallucinations.

• Weight loss.

• Hypertension.

• Syncope.

• Dyskinesia.

• Hypotension.

• Increase in blood creatine kinase levels.

• Confusion.

• Psychosis.

• Compulsive disorder.

• Somnolence.

• Impulse control.

• Withdrawal-emergent hyperpyrexia.

• Cardiovascular effects with concomitant use of drugs metabolized by catechol-O-methyltransferase or COMT.

• Orthostatic hypotension.

How Can Opicapone Be Used in Pregnancy?

The use of Opicapone during pregnancy does not have much information available. Thus, there is insufficient data on the risks of fetal development connected with Opicapone administration in pregnant patients. There has been an increase in fetal abnormalities in few animal studies. Additionally, oral administration of Opicapone in laboratory animals during pregnancy has shown evidence of embryofetal development that is quite abnormal. Opicapone is always given as an accessory drug and other medications for Parkinson’s disease and this has resulted in toxic development in rabbits such as skeletal and visceral malformations. Maternal toxicity has also been observed in studies done on pregnant rats. There has not been any study done on the offspring of pregnant rats who underwent oral administration of Opicapone and thus there are no adequate statistics about their neurobehavioral development.

How Can Opicapone Be Used in Lactation?

There is no shared evidence on the existence of Opicapone in lactating females or the aftermath of infants breastfed by patients who had received Opicapone medication. There is also no data on the consequences of the human milk being produced. However, studies have been done on lactating rats via an oral route of administering Opicapone. The results showed traces of Opicapone parallel to that of maternal plasma.

Can Opicapone Be Used in Pediatrics and Geriatrics?

There has not been any establishment of the effectiveness as well as safety of Opicapone among the pediatric group of patients. There is no difference in the dose that must be prescribed for adults above 65 years of age. There was no presence of any difference in patients of the younger or geriatric age group. It should be kept in mind that adverse effects of Opicapone are more sensitive in the geriatric group.

What Is the Overview of Clinical Studies Done With Opicapone?

Clinical trials for drugs are done under extensively varying circumstances. Because of this, the rate of reaction for adverse effects, cannot be considered to be directly proportional to the clinical trials of another drug. The safety and harmlessness of Opicapone had been gauged in 265 patients suffering from Parkinson’s disease. The trial was conducted in two studies of fourteen weeks and fifteen weeks. The first study was among placebo and active control groups. The second study was between placebo and placebo-controlled groups. The entirety of the patients had the intake of a stable dose of Levodopa and a DOPA or dihydroxyphenylalanine decarboxylase inhibitor along with other Parkison’s disease medication or without any other medications for the same. Mentioned below are the significant points regarding the clinical trial.

• The mean age of the participants in the trial was 63 years.

• 59 % of the participants were male.

• 89 % of the participants were caucasian.

• The mean duration of Parkinson’s disease amongst the participants was 7.6 years.

• Dyskinesia or rapid jerking and spasms was the most common adverse effect.

• The medication was discontinued in 6 % of placebo and 8 % of the participants who were treated with 50 mg Opicapone.

• For the same reason, 4 % of patients receiving placebo discontinued the medication as well as 3 % of participants who were treated with 50 mg of Opicapone.