Auvelity

Generic name: Bupropion and Dextromethorphan

Dosage form: Extended-release tablets

What is Auvelity?

Auvelity is a prescription medicine used to treat a certain type of depression called Major Depressive Disorder (MDD) in adults. It is not known if this medicine is safe and effective for use in children.

• Auvelity is not approved for uses other than the treatment of MDD.
• The ingredients in Auvelity, bupropion and dextromethorphan. Are the same ingredients found in some other medicines approved for other uses.

Important information

Auvelity may cause serious side effects, including:

• Increased risk of suicidal thoughts and actions. Auvelity and other antidepressant medicines may increase suicidal thoughts and actions. In some children, adolescents, and young adults,
• Especially within the first few months of treatment or when the dose is changed.
• Auvelity is not for use in children.

Depression or other mental illnesses are the most important causes of suicidal thoughts or actions.

How can you watch for and try to prevent suicidal thoughts and actions in yourself or a family member?

• Pay close attention to any changes, especially sudden changes. In mood, behavior, thoughts, or feelings or if you develop suicidal thoughts or actions.
• This is very important when an antidepressant medicine is started or when the dose is changed.
• Call your healthcare provider right away to report new or sudden changes. In mood, behavior, thoughts, or feelings or if you develop suicidal thoughts or actions.
• Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you have concerns about symptoms.

When you should call your healthcare provider?

Call your healthcare provider or get emergency help right away. If you have any of the following symptoms, especially if they are new, worse, or worry you:

1. thoughts about suicide or dying
2. new or worse depression
3. feeling very agitated or restless
4. trouble sleeping (insomnia)
5. attempts to commit suicide
6. new or worse anxiety
7. panic attacks
8. new or worse irritability
9. acting aggressive, being angry, or violent
10. an extreme increase in activity and talking (mania)
11. acting on dangerous impulses
12. other unusual changes in behavior or mood

Contraindications

Do not take Auvelity if you:

1. Have or had a seizure disorder
2. Have or had an eating disorder such as anorexia nervosa or bulimia
3. Have recently suddenly stopped drinking alcohol. Or use medicines called benzodiazepines, barbiturates, or anti-seizure medicines. And you have recently suddenly stopped taking them.
4. Taken a monoamine oxidase inhibitor (MAOI)
5. Have stopped taking an MAOI in the last 14 days
6. Are being treated with the antibiotic linezolid or intravenous methylene blue
7. Are allergic to dextromethorphan, bupropion, or any of the other ingredients.
8. Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI. Or one of these medicines, including the antibiotic linezolid or intravenous methylene blue.
9. Do not start Auvelity if you stopped taking an MAOI in the last 14 days.
10. Do not start taking an MAOI for at least 14 days after you stop treatment with Auvelity.

Cautions while taking Auvelity

Before taking Auvelity following things to keep in mind:

Before you start treatment, tell your healthcare provider about all your medical conditions, including if you:

1. have or had seizures or convulsions
2. have had a head injury
3. have had a heart attack or have heart problems
4. have a tumor in your nervous system (brain or spine)
5. have had a stroke
6. have low blood sugar
7. have low sodium levels in your blood
8. have liver problems
9. have kidney problems
10. drink a lot of alcohol
11. abuse prescription medicines or street drugs
12. have diabetes and take oral diabetes medicines or use insulin to control your blood sugar
13. have high blood pressure
14. have history of falls
15. have or had bipolar disorder, or have a family history of bipolar disorder, suicide, or depression
16. have high pressure in the eye (glaucoma)

Use of Auvelity in pregnancy

• When you are pregnant or plan to become pregnant. Auvelity may harm your unborn baby if you take Auvelity during pregnancy.
• Auvelity is not recommended during pregnancy.
• Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment. Your healthcare provider will prescribe another treatment for females who plan to become pregnant.
• There is a pregnancy registry for females who are exposed to Auvelity during pregnancy. The purpose of the registry is to collect information about the health of females exposed to Auvelity and their baby.
• If you become pregnant during treatment, talk to your healthcare provider. About registering with the National Pregnancy Registry for Antidepressants.
• When you are breastfeeding or plan to breastfeed. One of the ingredients in Auvelity, bupropion, passes into your breast milk. Do not breastfeed during treatment with Auvelity and for 5 days after the final dose.

What other drugs will affect Auvelity?

• Tell your healthcare provider about all the medicines you take. Including prescription and over-the-counter medicines, vitamins, and herbal supplements.
• Auvelity and some other medicines may affect each other causing possible serious side effects. Auvelity may affect the way other medicines work and other medicines may affect the way Auvelity works.

Especially tell your healthcare provider if you take:

1. other medicines containing bupropion or dextromethorphan
2. medicines used to treat mood, anxiety, psychotic or thought disorders, including selective serotonin reuptake inhibitors (SSRIs)
3. tricyclic antidepressants
4. theophylline
5. corticosteroids
6. oral diabetes medicines or use insulin to control your blood sugar
7. medicines to control appetite (anorectic)
8. nicotine medicines to help you stop smoking
9. street (illicit) drugs
10. benzodiazepines, sedatives-hypnotics (sleep medicines), or opiates
11. CNS stimulants

• Ask your healthcare provider if you are not sure if you are taking any of these medicines. Your healthcare provider can tell you if it is safe to take Auvelity with your other medicines.
• Do not start or stop any other medicines during treatment without talking to your healthcare provider first. Stopping treatment suddenly may cause you to have serious side effects.
• Know the medicines you take. Keep a list of them to show to your healthcare provider and pharmacist when you get a new medicine.

How should you take Auvelity?

• Take Auvelity exactly as your healthcare provider tells you to take it.
• Swallow the Auvelity tablets whole. Do not crush, chew, or divide the tablets.
• Auvelity may be taken with or without food.
• Take Auvelity 1 time a day for 3 days, then increase your dose to 2 times a day (taken at least 8 hours apart).
• Do not take more than 2 Auvelity tablets in 24 hours.
• If you miss a dose, do not take an extra dose to make up for the dose you missed. Wait and take your next dose at the regular time. Do not take more than 1 dose of Auvelity at a time.

Dosing information

Usual Adult Dose for Auvelity

1. One tablet: once daily in the morning for three days. Then increase to the maximum recommended dosage of one tablet twice daily, separated by at least 8 hours.
2. Each extended-release tablet: contains dextromethorphan hydro bromide 45 mg and / bupropion hydrochloride 105 mg.
3. Comment: Prior to initiating treatment with Auvelity, assess blood pressure; screen patients for history of bipolar disorder, mania, or hypomania. And determine if patients are receiving any other medications that contain bupropion or dextromethorphan.
4. Use: treatment of major depressive disorder (MDD) in adults.

What should you avoid while taking Auvelity?

• Limit or avoid using alcohol during treatment. If you usually drink a lot of alcohol, talk with your healthcare provider before suddenly stopping.
• If you suddenly stop drinking alcohol, you may increase your chance of having seizures.
• Do not drive a car or use heavy machinery until you know how Auvelity affects you. Auvelity can affect your ability to do these things safely.

Auvelity side effects

Auvelity may cause serious side effects, including:

1. Seizures. There is a risk of seizures during treatment with Auvelity. The risk is higher in people who:
2. Take higher doses of Auvelity
3. Have certain medical problems
4. Take Auvelity with certain other medicines

• Do not take Auvelity with other medicines unless your healthcare provider tells you to.
• If you have a seizure during treatment, stop taking Auvelity. And call your healthcare provider right away. Do not take Auvelity again if you have a seizure.
• Increases in blood pressure (hypertension). Some people may get high blood pressure during treatment. Your healthcare provider should check your blood pressure before you start taking and during treatment.

Manic episodes

Manic episodes may happen in people with bipolar disorder who take Auvelity. Symptoms may include:

1. greatly increased energy
2. racing thoughts
3. unusually grand ideas
4. talking more or faster than usual
5. severe trouble sleeping
6. reckless behavior
7. excessive happiness or irritability
8. unusual thoughts or behaviors

• One of the ingredients in Auvelity (bupropion), can cause unusual thoughts or behaviors. Including delusions (believing you are someone else), hallucinations (seeing or hearing things that are not there), paranoia (feeling that people are against you). Or feeling confused. If this happens to you, call your healthcare provider.
• Eye problems (angle-closure glaucoma):
• Auvelity may cause a type of eye problem called angle-closure glaucoma in people with certain other eye conditions.
• You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are. Call your healthcare provider if you have eye pain, changes in your vision. Or swelling or redness in or around the eye.

• Dizziness:

Auvelity may cause dizziness which may increase your risk for falls.

Serotonin syndrome

A potentially life-threatening problem called serotonin syndrome can happen when you take Auvelity with certain other medicines.

Call your healthcare provider or go to the nearest hospital emergency room right away if you have any of the following signs and symptoms of serotonin syndrome:

1. agitation
2. seeing or hearing things that are not there (hallucinations)
3. confusion
4. coma
5. fast heartbeat
6. changes in blood pressure
7. dizziness
8. sweating
9. flushing
10. high body temperature (hyperthermia)
11. shaking (tremors), stiff muscles, or muscle twitching
12. loss of coordination
13. seizures
14. nausea, vomiting, diarrhea

The most common side effects include:

1. dizziness
2. diarrhea
3. dry mouth
4. excessive sweating
5. headache
6. feeling sleepy
7. sexual function problems

These are not all the possible side effects. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should you store Auvelity?

1. Store at room temperature between 68°F to 77°F (20°C to 25°C)
2. Keep all medicines out of the reach of children and pets
3. General information about the safe and effective use of Auvelity
4. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.
5. Do not use this medicine for a condition for which it was not prescribed. Do not give it to other people, even if they have the same symptoms you have. It may harm them.
6. You can ask your pharmacist or healthcare provider for information that is written for healthcare professionals.
7. If you take a urine drug screening test, Auvelity may make the test result positive for amphetamines.
8. If you tell the person giving you the drug screening test that you are taking Auvelity. They can do a more specific drug screening test that should not have this problem.

What are the ingredients in Auvelity?

1. Active ingredients: dextromethorphan hydrobromide, bupropion hydrochloride.
2. Inactive ingredients: l-cysteine hydrochloride monohydrate, carbomer homopolymer, microcrystalline cellulose, colloidal silicon dioxide, crospovidone, stearic acid, and magnesium stearate.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

Auvelity approved by FDA-2022

• The FDA has approved Axsome Therapeutics’ Auvelity (dextromethorphan-bupropion). Extended-release tablets to treat major depressive disorder (MDD) in adults.
• Axsome anticipates Auvelity (formerly called AXS-05) to be commercially available in the United States in the fourth quarter of 2022.
• “The approval of Auvelity represents a milestone in depression treatment based. On its novel oral N-methyl D-aspartate (NMDA) antagonist mechanism. It is rapid antidepressant efficacy demonstrated in controlled trials, and a relatively favorable safety profile.” Maurizio Fava, M.D., psychiatrist-in-chief, department of Psychiatry, Massachusetts General Hospital, said in a press release.
• He is also executive director, Clinical Trials Network & Institute, associate dean for Clinical & Translational Research. And Slater Family Professor of Psychiatry at Harvard Medical School.

Nearly two thirds of patients treated with currently available antidepressants do not adequately respond, Fava said. “Auvelity represents the first new oral non-monoamine-based mechanism of action approved to treat major depressive disorder in over sixty years.”

Auvelity- first and only rapid-acting oral medicine

• Auvelity is the first and only rapid-acting oral medicine approved for the treatment of MDD. With labeling of statistically significant antidepressant efficacy compared with placebo starting at one week.
• The rapid antidepressant effects were sustained at all subsequent timepoints.

Approval of Auvelity- On basis of which studies?

1. The approval was based on two trials, including the GEMINI placebo-controlled study. And confirmatory evidence and the ASCEND study comparing Auvelity to bupropion sustained-release tablets.
2. Data from the GEMINI study: were published in May 2022 in The Journal of Clinical Psychiatry. And data from the ASCEND study were published in May 2022 in The American Journal of Psychiatry.
3. In the GEMENI study, Auvelity was statistically significantly superior to placebo in improvement of depressive symptoms. As measured by the change in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score at week six. The study’s primary endpoint. To evaluate speed of onset of action, the change in MADRS total score from baseline to week one. And from baseline to week two were pre-specified secondary efficacy endpoints.
4. In the ASCEND study: Auvelity was statistically significantly superior to bupropion sustained-release tablets. 105 mg twice daily on the primary outcome measure.
5. The most common adverse reactions were dizziness, headache, diarrhea, somnolence, dry mouth, sexual dysfunction, and hyperhidrosis.
6. The FDA granted breakthrough therapy designation for Auvelity for the treatment of MDD in March 2019, and the new drug application (NDA) was evaluated by the FDA under priority review.

Mode of action of Auvelity

• Auvelity works on the NMDA receptor, an ionotropic glutamate receptor. And on the sigma-1 receptor in the brain via its dextromethorphan component.
• The bupropion component of Auevelity is an aminoketone. Which increases blood levels of dextromethorphan by competitively inhibiting cytochrome P450 2D6. Which catalyzes a major biotransformation pathway for dextromethorphan.
• Major depressive disorder is a debilitating, chronic, biologically-based disorder. An estimated 21 million U.S. adults experienced MDD each year, according to the Department of Health and Human Services.

• Axome is also studying Auvelity in Alzheimer’s disease agitation and smoking cessation. The company is initiating a new placebo-controlled parallel group trial (ADVANCE-2) this quarter for the Alzheimer’s indication.

• Axome has amended the relapse criteria for its trials in this indication and is conducting a new trial to generate additional data. Topline results from ACCORD are now anticipated in the fourth quarter of 2022.

• In smoking cessation, Axsome plans to proceed to a pivotal phase 2/3 trial, and will provide information on the timing of this study later this year.

FDA approval:

Axsome touts Auvelity- as a potential game changing depression treatment

• The lack of adequate treatment options for major depressive disorder has been well documented. Then came the pandemic, adding more patients diagnosed with MDD and heightening the unmet need.
• With that, the timing is good for the approval of a potentially game-changing drug to treat MDD. On Friday, the FDA signed off on Axsome Therapeutics’ Auvelity, the first rapid-acting oral treatment for MDD.
• The major difference between Auvelity and the current roster of antidepressants on the market is its ability to work quickly.
• While the typical response time for current antidepressants is six to eight weeks or longer. New York University depression expert Dan Iosifescu, M.D., said during a conference call, Auvelity’s benefits can be seen within a week.

“With symptom improvement happening at week one and then remission happening by week two, the combination of those two is incredibly differentiating in the marketplace right now,”

• Lori Englebert, Axsome’s EVP, commercial and business development, said. “If you look at the high unmet need that remains in the market. Two-thirds of patients don’t achieve remission and physicians are now moving. Toward remission as the goal of treatment we are pretty excited about the product.”

RELATED:

• Axsome sees depression drug decision delayed as FDA kicks expected CRL can down the road.
• As an N-methyl D-asparate (NMDA) receptor antagonist, Auvelity is the first oral MDD drug to enter the market. With a new mechanism of action in more than 60 years, the press release noted.
• In 2020, Johnson & Johnson’s nasal spray Spravato was sanctioned as the first NMDA receptor antagonist for MDD. But its label is narrower than that of Auvelity, which can be used as a front-line treatment. 
• Axsome said it expects to launch Auvelity in the fourth quarter. Its price will be determined in the coming weeks, Englebert said during the call. To market the drug outside of the U.S., the company said it will seek a commercial partner.
• In the clinic, Auvelity was tested on 1,100 depression patients. In the Gemini study, Auvelity showed statistically significant superiority to placebo in improvement of depressive symptoms.
• As measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) total score at Week 6, the study’s primary endpoint. The difference between Auvelity and placebo in change from baseline in the MADRS total score was statistically significant at Week 1 and at Week 2. 
• In the Ascend study, Auvelity was statistically significantly superior to bupropion sustained-release tablets on the primary outcome measure. Which was calculated by assessing the change from baseline in MADRS total scores from Week 1 to Week 6 and then taking the average of those scores.

“It’s rapid acting. It does have a very substantial magnitude of effect. You get remission quickly and at high rates and it’s also very well tolerated.” Axsome CEO Herriot Tabuteau said during the call. “It is the confluence of all those attributes which make it compelling.”

It’s been a busy time for Axsome. To secure the delayed approval, the company had to answer for deficiencies that the FDA identified in its application last year. On Friday, Tabuteau said those related to chemistry. Manufacturing and controls (CMC) and were resolved early in the year.

Axsome’s migraine drug- finally slated for FDA inspection

• But investors want to know about stalled depression therapy
• Axsome acquired sleep apnea and narcolepsy drug Sunosi from Jazz Pharmaceuticals for an upfront payment of $53 million. The drug generated sales of $58 million last year for Jazz.
• But also in May, the FDA rejected Axsome’s migraine treatment AXS-07. The company has two candidates in phase 3 AXS-12 for narcolepsy. And ASX-14 for fibromyalgia both of which have “potential NDA filings in 2023,” Tabuteau added during the call.