About OFF Periods


Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons.2,3 Over time, this loss can lead to a range of symptoms and inconsistent symptom control.3,4

The primary goal of underlying PD therapy is to maintain dopamine levels in the brain.5 Many people with Parkinson's—even when taking their usual Parkinson's therapies—may experience a re-emergence of symptoms during the day and consequently fluctuate between ON states during which their symptoms are controlled and OFF periods during which their symptoms return.3,6

Prevalence of OFF periods

Michael J. Fox Foundation Survey

70% of more than 3,000 people with PD experienced

OFF periods
per day9
OFF periods can happen at any point in the disease10
Types of OFF periods

OFF periods can be variable and occur at any time during the day3,11,12


OFF symptoms experienced upon waking


Characterized by the return of symptoms prior to the next scheduled CD/LD dose

Unexpected OFF

Sudden and sometimes random transition from ON to OFF


When a dose takes longer than anticipated to improve symptoms

Dose Failure

When a dose does not provide improvement in symptoms

Factors Contributing to OFF Periods

Oral levodopa, combined with the dopa decarboxylase inhibitor carbidopa, is highly effective and the gold standard for baseline Parkinson’s therapy.13 However, absorption of oral levodopa through the gastrointestinal (GI) tract may vary from dose to dose and patient to patient, contributing to OFF periods.14,15 As PD progresses, Parkinson's-related GI issues may exacerbate these challenges.3

PD Progression4

Over time, the progressive loss of presynaptic dopaminergic cell terminals can result in:

  • Decreased striatal dopamine storage capacity
Gastrointestinal (GI) Challenges Related to Parkinson's16

Variable or slowed gastric emptying can contribute to:

  • Delayed or unpredictable absorption and effects of oral PD medications
Variability in Oral Levodopa Absorption
  • Can arise from competition with dietary amino acids/food effect17
  • Can result in widely differing absorption of oral CD/LD14

*No food at least 1 hour before and 1 hour after CD/LD dose.
Variable adjusted.

Figure from Lipp MM, Batycky R, Moore J, Leinonen M, Freed MI. Preclinical and clinical assessment of inhaled levodopa for OFF episodes in Parkinson’s disease. Sci Transl Med. 2016;8:360ra136. Reprinted with permission from the American Association for the Advancement of Science.

Asking patients about their OFF period symptoms and the timing of symptom return is critical to uncovering the problem and determining appropriate treatment.

INBRIJA™ Indication

Intermittent treatment of OFF episodes in patients with PD treated with CD/LD.

Important Safety Information

  • Contraindication: nonselective MAOIs (e.g., phenelzine, tranylcypromine) due to hypertension risk. Discontinue their use at least 2 weeks prior to initiating INBRIJA.
  • Not recommended in patients with asthma/COPD/other chronic lung disease due to bronchospasm risk.
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INBRIJA is indicated for intermittent treatment of OFF episodes in patients with Parkinson’s disease (PD) treated with carbidopa/levodopa.

Important Safety Information

  • INBRIJA is contraindicated in patients taking or who have recently taken (within 2 weeks) nonselective monoamine oxidase (MAO) inhibitors (e.g., phenelzine and tranylcypromine) due to risk of hypertension. Discontinue use of nonselective MAO inhibitors at least 2 weeks prior to initiating INBRIJA.
  • Patients treated with levodopa, the active ingredient in INBRIJA, have reported falling asleep during activities of daily living, including operation of motor vehicles, which sometimes resulted in accidents. Many patients reported somnolence but some reported no warning signs (sleep attack). This may occur more than a year after initiating treatment. Reassess patients for drowsiness/sleepiness including occurrence during specific activities. Advise patients of potential for drowsiness and ask about factors that may increase this risk (e.g., sedating medications, sleep disorders).
    • Consider discontinuing INBRIJA in patients who report significant daytime sleepiness or falling asleep during activities that require active participation. If continuing INBRIJA, advise patients not to drive and to avoid activities that may result in harm. There is insufficient information that dose reduction will eliminate episodes of falling asleep during activities of daily living.
  • Neuroleptic malignant syndrome-like symptoms (e.g., elevated temperature, muscular rigidity, altered consciousness, autonomic instability) have been reported with rapid dose reduction, withdrawal of, or changes in dopaminergic therapy.
  • Hallucinations (with or without confusion, insomnia, and excessive dreaming) may occur and may respond to reducing levodopa therapy. Abnormal thinking and behavior may present with paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium.
  • INBRIJA should ordinarily not be used in patients with major psychotic disorder due to risk of exacerbating psychosis. Dopamine antagonists used to treat psychosis may exacerbate symptoms of PD and may decrease INBRIJA efficacy.
  • Patients on medications that increase central dopaminergic tone such as INBRIJA can experience intense urges to gamble or spend money, increased sexual urges, binge eating, and/or other intense urges, and inability to control them. In some cases, these urges stopped with dose reduction or medication discontinuation. Since some patients may not recognize these behaviors as abnormal, ask patients or their caregivers about development of new or increased urges and consider stopping INBRIJA if this occurs.
  • INBRIJA may cause or exacerbate dyskinesias. If troublesome dyskinesias occur, consider stopping INBRIJA or adjusting other PD medications.
  • INBRIJA is not recommended in patients with asthma, COPD, or other chronic underlying lung disease because of the risk of bronchospasm.
  • Monitor patients with glaucoma for increased intraocular pressure.
  • Abnormalities in laboratory tests may include elevations of liver function tests (e.g., alkaline phosphatase, AST, ALT, lactic dehydrogenase, bilirubin), blood urea nitrogen, hemolytic anemia, and positive direct antibody test. Increased levels of catecholamines and their metabolites in plasma and urine may result in false-positive results suggesting pheochromocytoma.
  • The most common adverse reactions (≥ 5% and > placebo) were cough (15% vs 2%), upper respiratory tract infection (6% vs 3%), nausea (5% vs 3%), and sputum discolored (5% vs 0%).
  • Use of selective MAO-B inhibitors with INBRIJA may be associated with orthostatic hypotension. Monitor patients taking these drugs concurrently.
  • Dopamine D2 receptor antagonists (e.g., phenothiazines, butyrophenones, risperidone, metoclopramide) and isoniazid may reduce levodopa efficacy; monitor for worsening symptoms.
  • Iron salts or multivitamins with iron salts may reduce levodopa bioavailability.
  • INBRIJA should be used during pregnancy/nursing only if potential benefit justifies potential risk. There are no adequate data on INBRIJA in pregnant women or breastfed infants. Animal data shows carbidopa/levodopa is developmentally toxic (including teratogenicity). Levodopa may affect milk production, interfering with lactation. Levodopa has been detected in human milk.
  • Safety and effectiveness in pediatric patients have not been established.
  • Geriatric patients (n=56) experienced more of the following adverse reactions than patients <65 (n=58): cough (25% vs 5%), upper respiratory tract infection (11% vs 2%), nausea (7% vs 3%), vomiting (4% vs 2%), pain in extremities (4% vs 0%), and discolored nasal discharge (4% vs 0%).

Please see the Full Prescribing Information.