Inbrija and Apokyn: On-Demand Therapies for OFF 

Apokyn pen Inbrija inhaler

You’re sitting in a lawn chair at your granddaughter’s soccer game, enjoying a warm afternoon outside. The score is tied. There are 20 minutes left in the game. Your granddaughter has the ball and is dribbling toward the goal. Your leg starts to tremor. You try sipping water but can’t get the lid off. You try to stand up but can’t quite make it out of the chair. It’s not quite time for your next dose of levodopa and you had lunch at halftime, so you know it wouldn’t be the best time to take a pill anyway. 

Maybe it’s the excitement and stress of the game causing your symptoms to intensify, or maybe it’s the beginning of an OFF period. Over time, you may have developed ways to get through moments like these, but there are also on-demand treatments that can help. 


As Parkinson’s progresses, many people experience fluctuations between ON and OFF: when medications are controlling symptoms well versus when they are not controlling symptoms well.  

One strategy for navigating fluctuations is to add an extra full tablet of immediate-release levodopa. Even a half-tablet can be enough to help ease troublesome ON-OFF fluctuations. Another strategy is to add a medication that extends how long your ON periods last. Two examples are extended-release levodopa formulations and COMT inhibitors. Unfortunately, adding doses or using an ON-extender is unreliable, partly due to medication absorption issues in the gut. 

To help manage complex ON-OFF fluctuations, there are also two on-demand therapies available in the United States to help navigate OFF periods: Apokyn and Inbrija. These treatments are sometimes referred to as “rescue therapies.” They are intended to be taken at the first sign of an OFF period to help you quickly return to an ON state.   


Apokyn is an injectable dopamine agonist intended to treat OFF periods associated with advanced Parkinson’s. The FDA approved Apokyn for use in the United States in 2004. They approved the first generic formulation of the treatment in 2022. 


Apokyn is taken by injection via a reusable device, and it can be used any time of day to help manage ON-OFF fluctuations.  

You may be asked to take your first dose of Apokyn at your doctor’s office. This is due to the possibility of blood pressure changes and variability related to how much Apokyn is necessary to help you return to an ON state.  

Apokyn is typically recommended for use at most five times a day. 


In clinical trials, Apokyn effectively reversed 95% of OFF episodes. The drug has multiple other benefits:

  • Apokyn begins to have a positive effect in roughly 10 minutes. Within 20 minutes of a dose, 90% of people using Apokyn experience the same degree of symptom relief they received from their standard oral medication regimen.   
  • In a study of people experiencing morning akinesia, people using Apokyn experienced symptomatic benefits 24 minutes after a dose. In contrast, people taking oral levodopa for morning akinesia experienced symptomatic benefit an average of 61 minutes after taking their oral medication.
  • As Parkinson’s progresses, some doses of treatment fail to take effect or to convey the typical degree of effect. In the morning akinesia study referenced above, 7% of Apokyn doses failed, while 46% of oral levodopa doses failed. 


While there are clear benefits to taking Apokyn, the following risks should be considered:

  • Apokyn can cause vomiting and nausea. The FDA prescribing information recommends the use of trimethobenzamide–an anti-nausea/vomiting medication–for at least six weeks when starting Apokyn. As you become accustomed to Apokyn, the severity of these side effects is likely to diminish. Use of trimethobenzamide for longer than two months is not recommended due to possible increase in fall risk and sleepiness. 
  • Several other medications—including multiple anti-nausea medications—are contraindicated for use with Apokyn. Talk with your doctor about your medications before taking Apokyn. 
  • Alcohol use while taking Apokyn may contribute to decreased blood pressure. 
  • Like oral dopamine agonists, Apokyn can contribute to impulse control disorders. There are also potential complications if you suddenly stop using Apokyn. 
  • People who have severe symptoms during OFF periods may have difficulty using the Apokyn injector. 


Inbrija is a formulation of levodopa designed to be inhaled as a treatment for OFF periods. Because Inbrija is absorbed through the lungs, the medication reaches the brain more quickly than other levodopa formulations.  

Inbrija was approved in the United States in 2018. 


Inbrija requires a special inhaler into which capsules containing the medication are inserted. This video describes how to use the inhaler 

Inbrija can be used up to five times daily and has the best effect if taken at the first signs of an OFF period.  


Inbrija can take effect in only 10 minutes, and the 12-month extension of the SPAN-PD study confirms the treatment has multiple benefits:

  • Nearly 60% of people taking Inbrija returned to an ON state and maintained their ON state for up to 60 minutes. 
  • Inbrija does not interfere with levodopa absorption in the digestive tract. 
  • Inbrija does not significantly impact lung function in people without lung-related comorbidity.  
  • Inbrija can be taken in the morning to reduce early morning akinesia.  
  • Inbrija’s effectiveness in reducing daily OFF time increases over the course of a year: After one month of use, OFF time was reduced by .55 hours on average; after 12 months, OFF time was reduced by .88 hours. 


Like Apokyn, Inbrija also has risks:

  • Because of the possibility that Inbrija use may cause tightening of airways, it should not be used by people with chronic lung conditions, including asthma and COPD.  
  • Inbrija may contribute to elevated eye pressure. People with glaucoma should be careful using the drug and should undergo regular monitoring. 
  • Two common side effects of Inbrija include cough and upper respiratory infection, which occurred in 15% and 7% of SPAN-PD extension study participants, respectively. Other frequent side effects in clinical trials were consistent with side effects of oral levodopa, including dyskinesia. 
  • As with Apokyn’s injector, people who have severe symptoms during their OFF periods may have difficulty using Inbrija’s inhaler. 


Apokyn and Inbrija have conventionally been used as additional treatments for people living with advanced Parkinson’s. In 2022, Isaacson et al. discussed reasons to use Apokyn and Inbrija early when managing motor fluctuations.  

In part, Isaacson et al. argue that ON-extenders like extended-release levodopa and COMT inhibitors have complications:  

  • Even with ON-extenders, some people can still have up to five hours of OFF time each day. 
  • The use of ON-extenders often involves frequent adjustments to doses of oral medication, which can be confusing and limit opportunities for eating. 

Isaacson et al. also note three benefits of using on-demand therapies earlier than has been conventional: 

  • OFF episodes can be prolonged only when managed by oral medications. This is partially because of variability in medication absorption in the digestive system. 
  • On-demand therapies may help you feel more confident in your daily activities because they provide a quicker way to resolve OFF periods. 
  • On-demand therapies may be helpful when navigating the period before or after DBS surgery.  

Another consideration is that OFF periods can disrupt your ability to exercise. This is a reason not to delay the use of these treatments: Using them can help you be confident in your ability to stick to your exercise schedule. 


When considering which on-demand therapy is best for you, discuss the decision with your care team. Apokyn and Inbrija are different in significant ways, including that they have different side effect profiles.  

The method of delivery is also something to consider. You may be uncomfortable using Inbrija’s inhaler or prefer not to use an injection-based treatment such as Apokyn.  

Cost is also a consideration: Apokyn and Inbrija can be expensive. Be sure to talk with your doctor’s office staff and your insurance provider to confirm your out-of-pocket expenses before filling a prescription. 


ON-OFF fluctuations are often challenging as Parkinson’s advances. Fortunately, there are multiple ways to navigate this. There are ON-extension treatments mentioned above, and there are surgical interventions 

Apokyn and Inbrija are two important options for managing fluctuations; there are also new treatments in the mid-to-late stages of development. These include continuous infusion therapies to new oral treatments like CVN424 that are exploring novel methods of treating Parkinson’s symptoms.

If you are experiencing troublesome ON-OFF fluctuations, talk with your care team about the best strategies and options for you. 


Apokyn FDA Prescribing Information 

Inbrija FDA Prescribing Information 

Inbrija Cost Savings 

More Information about Inbrija’s Inhaler System 

The Clinical Development of Levodopa Inhalation Powder 

Why do OFF Periods Still Occur During Continuous Drug Delivery in Parkinson’s 

OFF-time Treatment Options for Parkinson’s 

On-Demand Therapy for Parkinson’s: Opportunities and Choices 

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