Atogepant - Uses, Dosage, Side Effects, Drug Warnings, and Precautions

Overview

Research and studies in molecular biology and neuroscience have led to the discovery of calcitonin gene-related peptide (CGRP), a 37 amino-acid neuropeptide that plays an essential role in the pathogenesis of migraine. CGRP receptor antagonist is also known as gepant. It is an oral medication that impedes the CGRP-related nociceptor signaling pathway. To date, three gepants have been approved by the FDA (Food and Drug Administration) for the treatment of migraine.

Of the three, Atogepant is a second-generation gepant that antagonizes CGRP receptors inhibiting neurogenic inflammation and pain sensitization. On September 28, 2021, the United States Food and Drug Administration approved Atogepant. It is the first medication of its class to be approved principally for the treatment of migraine. In addition, it has a long half-life and negligible cardiovascular or liver toxicity.

How Does Atogepant Work?

Calcitonin gene-related peptide (CGRP) has many bodily functions, including vascular, digestive, sensory, vestibular, hematopoietic, immunomodulatory, and nociceptive processes.

CGRP is found in two forms - alpha CGRP and beta CGPR.

Alpha CGRP is located within the primary sensory neurons within the trigeminal system and dorsal root ganglia and is involved in the pathogenesis of migraine headaches. It is not permeable through the blood-brain barrier and acts on the close receptor cells, diffusing farther from the release site through volume transmission.

The CGRP receptor consists of a G-protein-coupled-receptor (GPCR), calcitonin receptor-like receptor (CLR), and an additional protein known as receptor activity modifying protein 1 (RAMP1). On activation, adenylyl cyclase catalyzes the formation of cAMP and other intracellular messengers. Atogepant is a second-generation oral CGRP receptor with a time-to-peak concentration or Tmax of around two hours and a half-life of eleven hours. It is a dynamic CGRP antagonist that non-competitively binds to the CGRP receptors. Unlike other gepants, Atogepant was developed explicitly for preventive treatment of migraine because of its long half-life. It works by obstructing the calcitonin gene-related peptide.

Uses of Atogepant

Atogepant is used to prevent episodic migraine attacks in people.

Limitations

The drug is not limited to use in any condition. However, it should be used cautiously in patients with end-stage kidney disease and severe liver disease.

Dosage Restriction

• Route of Administration - Oral.

Dosage Strengths

• The drug comes in three strengths 10 mg, 30 mg, and 60 mg.

Dosage Forms

• It is a white to off-white, oval-shaped biconvex tablet engraved with A30 on one of its sides.

• The physician would prescribe the smallest starting dose. The recommended dosage is once a day with or without food.

What Are the Warnings or Contraindications of Atogepant?

Pregnancy

• There is not much evidence to suggest the risk of drug usage in pregnant women. Certain controlled studies in pregnant women have found no risk involved with the fetus. However, migraine might increase the risk of high blood pressure during pregnancy.

Lactation

• There is no evidence of the presence of Atogepant in milk, its effects on breastfed infants, or milk production.

Renal Impairment

• For mild to moderate kidney impairment, no adjustment of dose is needed.

• The lowest dose is recommended for severe and end-stage kidney disease.

• The medicine should be taken after dialysis for end-stage kidney disease patients undergoing intermittent dialysis.

Hepatic Impairment

• For mild to moderate cases, no dose adjustment is required.

• For severe cases, it is best to avoid the medicine.

Pediatric Patients

• The safety and efficiency of the drug in pediatric patients have not been researched.

For Patients

What Is a Migraine?

A migraine is a headache that causes throbbing pain or a pulsating sensation on one side of the head. It usually occurs with nausea, vomiting, and sensitivity to light and noise. The headache can remain for hours to days. The pain is severe, interfering with one's daily chores. Some people get an aura or a warning sign before the appearance of the headaches, such as flashes of light, blind spots, tingling on one side of the face, arm, or leg, and difficulty speaking. Certain medications can prevent migraine, making them bearable.

Why Is Atogepant Prescribed for Migraine?

Atogepant is a medicine that is used to prevent episodic migraine headaches. It is a class of medication known as calcitonin gene-related peptide receptor antagonists. Our body has a protein known as calcitonin gene-related peptide (CGRP), which is thought to cause migraine headaches. Atogepant blocks the action of calcitonin gene-related peptides, thus preventing migraine attacks.

How Should Atogepant Be Used?

• Atogepant comes in three strengths, 10 mg, 30 mg, and 60 mg.

• It should be taken once a day.

• It should be taken orally.

• It can be taken with or without food.

• The medicine should be taken at the same time daily.

• Atogepant prevents headaches but does not cure them, so one should continue taking them.

• Do not stop the medicine without the doctor's consent, even after feeling well.

• In case of development of any side-effect, inform the doctor.

What Should One Inform the Doctor Before Beginning the Drug?

• The doctor should be informed if one is allergic to Atogepant, any of the constituents of the medication, or any other medicines in general.

• Inform the doctor about any other medications, vitamins, or nutritional supplements that one is taking. The following drugs should be mentioned without fail: Carbamazepine, Clarithromycin, Cyclosporine, Efavirenz, Etravirine, Itraconazole, Ketoconazole, Phenytoin, and Rifampin.

• Inform the physician about the herbal products in case one is taking them.

• The doctor should be informed if one has kidney or liver ailments or had them in the past.

• The doctor should know about pregnancy if one plans to get pregnant or is breastfeeding.

Is Atogepant Safe and Effective?

Atogepant is an effective medication to prevent migraine; however, it does not cure the condition. However, as long as it is taken within the recommended dose, it is safe.

What Are the Side Effects of Atogepant?

The following are the side effects of Atogepant:

• Nausea.

• Constipation.

• Fatigue.

• Loss in weight.

• Loss of appetite.

• Allergic reactions include rash, itching, swelling, severe dizziness, and trouble breathing.

Call the doctor as soon as one develops these reactions.

What Are the Dietary Restrictions To Consider While Taking Atogepant?

The doctor should be informed about one eating grapefruit and drinking grapefruit juice while taking the medication.

What Should Be Done On Missing a Dose?

• If one forgets to take the prescribed dose, the medicine should be taken as soon as one remembers.

• If it is almost time to take the next dose, skipping the amount and continuing the regular dosing should be a priority.

• Take the next dose at the same time.

• Avoid taking two medicines at the same time to catch up.

How To Store Atogepant?

• Atogepant should be stored at room temperature, away from heat, sunlight, and moisture.

• The apt temperature for storing the drugs is around 20 to 25 degrees Celsius.

• The medication should be kept away from kids and pets.

• Always lock the safety caps of the medicines to protect small kids from poisoning.

How To Dispose of Atogepant?

• The medicine should not be flushed down the toilet or poured into a drain.

• Discard the medicine once it expires through a medicine take-back program. The local pharmacist should be notified about the take-back program.

• If the medicine take-back program is not readily available, then any other drug disposal option should be sought.

What Should Be Done in Case of Atogepant Overdose?

• In case of an overdose, the doctor should be contacted immediately.

• Emergency services should be contacted immediately if the person taking the drug overdose collapsed, had a seizure, or had trouble breathing.

For Doctors:

Indications:

Atogepant is a drug that is indicated to prevent an episodic migraine attack.

What Is the Pharmacology of Atogepant?

Description

Atogepant is an orally administered calcitonin gene-related peptide (CGRP) receptor antagonist used to prevent migraine. Its formula is C29H23F6N503, with a mass of around 603.1705 and a molecular weight of 603.15.

Components

Atogepant, also known as MK-8031, is a CGRP receptor antagonist.

Clinical Pharmacology:

Mechanism of Action

Calcitonin gene-related peptide (CGRP) performs several bodily functions such as vascular, digestive, sensory, vestibular, hematopoietic, immunomodulatory, and nociceptive processes. Calcitonin gene-related peptide is found in two forms- alpha CGRP and beta CGPR. Alpha CGRP is located in the primary sensory neurons within the trigeminal system and dorsal root ganglia and is involved in migraine headaches' pathogenesis. It is not permeable through the blood-brain barrier and acts on the close receptor cells, diffusing farther from the release site through volume transmission.

The CGRP receptor consists of a G-protein-coupled-receptor (GPCR), calcitonin receptor-like receptor (CLR), and an accessory protein known as receptor activity modifying protein 1(RAMP1). On activation, adenylyl cyclase catalyzes the formation of cAMP and other intracellular messengers. CGRP is a cerebral vasodilator and is thought to play a significant role in migraine pathophysiology. The gepants bind to the CGRP receptors, thus reversing CGRP-induced neurogenic inflammation and vasodilation. Antogepant is a second-generation CGRP receptor with a half-life of eleven hours. It non-competitively binds to the CGRP receptor.

Pharmacokinetics

• A pharmacokinetic study showed that systemic exposure to Atogepant was around fifteen to thirty-eight percent higher in individuals with hepatic impairment compared to those with normal hepatic function.

• A phase one clinical study described that Atogepant could be tolerated in single doses as high as three hundred milligrams with no cardiovascular adverse effects such as prolonged QT/QTc.

• No ALT elevation above 1.5 x upper limit of normal (ULN) has been reported.

Distribution

• Protein Bound- 4.7 % (unbound).

• The Volume of Distribution- 292 L.

Metabolism

• Atogepant is primarily metabolized by CYP3A4.

• Atogepant and a glucuronide conjugate metabolite (M23) are the most widely circulating compounds in the plasma, approximately seventy-five percent and fifteen percent, respectively.

• Ten other metabolites have been found in the feces, representing less than ten percent of the administered dosage.

Elimination

• The elimination of Atogepant takes place through the metabolism of CYP3A4.

• Forty-two percent of the dose was found unchanged in the feces, and five percent of the unaltered drug was in the urine.

• Approximately eighty-one percent of the radioactivity was found in the feces and eight percent in the urine.

Special Considerations:

Renal Impairment

• For mild to moderate kidney impairment, no adjustment of dose is needed.

• The lowest dose is recommended for severe and end-stage kidney disease.

• The medicine should be taken after dialysis for end-stage kidney disease patients undergoing intermittent dialysis.

Hepatic Impairment

• For mild to moderate cases, no dose adjustment is required.

• For severe cases, it is best to avoid the medicine.

Pediatric Patients - The safety and efficiency of the drug in pediatric patients have not been researched.

Drug Interactions

Atogepant interacts with around one hundred and sixty-two drugs, of which seventy-five are major, two are moderate, and eighty-five are minor drug interactions. To list a few-

Atogepant administered with Sumatriptan was found to be safe and well tolerated.

Atogepant administered with either Acetaminophen or Naproxen was found to be safe.

Co-administered multiple daily doses of Atogepant with a single dose of Ethinyl Estradiol and Levonorgestrel was safe and well tolerated in healthy women.

CYP3A4 Inhibitors

• It was co-administered with potent CYP3A4 inhibitors. The recommended Atogepant dose is 10 mg once a day.

• Co-administered with moderate or weak CYP3A4 inhibitors. No dose adjustment is required.

• CYP3A4 inhibitors might increase the exposure of Atogepant.

CYP3A4 Inducers

• Co-administration with strong or moderate CYP3A4 inducers such as Rifampin, Carbamazepine, Phenytoin, St. John's wort, Efavirenz, and Etravirine. The recommended Atogepant dosage is 30 or 60 mg once a day.

• Co-administration with weak CYP3A4 inducers. No dose adjustment is needed.

• CYP3A4 inducers may reduce exposure to Atogepant.

OATP Inhibitors

• Co-administration with OATP inhibitors such as Cyclosporine, the Atogepant dosage is 10 or 30 mg daily.

• OATP inhibitors might increase the exposure of Atogepant.

What Have Clinical Trials Proven With Regards to Atogepant?

Interventional Clinical trial:

Advance - A phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study was carried out to evaluate the efficacy, safety, and tolerability of oral Atogepant for preventing migraine in participants with episodic migraine (ADVANCE).

• Atogepant 10 mg tablet was given once a day orally, and placebo matching Atogepant tablets once a day orally for 12 weeks.

• Atogepant 30 mg tablet was given once a day orally for 12 weeks.

• Atogepant 60 mg tablet was given once a day orally for 12 weeks.

Results:

At all doses, Atogepant is effective during the twelve-week double-blind treatment period starting the first four weeks, as shown by significant reductions in the mean MMDs at the participant's threshold level. In addition, higher doses of Atogepant were found to produce the most incredible responder rates, guiding physicians in prescribing doses.

Patient Counseling Information:

Administration Instructions

• Take Atogepant as prescribed by the doctor.

• Atogepant can be taken with or without food.

• The drug should be swallowed orally and not chewed.

• It should be taken once a day.

Side Effects of Atogepant:

General Side Effects

The usual common side-effects of Atogepant include:

• Nausea.

• Constipation.

• Fatigue.

Gastrointestinal Side Effects

• Nausea.

• Constipation.

Metabolic Side Effects

• Reduced appetite.

• Weight loss of more than seven percent has been found in around 3.8 % of patients receiving 10 mg/day, 3.2 % for 30 mg/day, and 4.9 % for patients receiving 60 mg/day.

Hepatic Side Effects

• An increase in transaminase more than three times the upper limit of normal (ULN) has been reported in patients receiving Atogepant. The patients were asymptomatic and resolved within eight weeks of stopping the drug.

Nervous System

• Fatigue.

• Drowsiness.