LEVODOPA: 6,610 Adverse Event Reports & Safety Profile

INBRIJA consists of a dry powder formulation of levodopa for oral inhalation with the INBRIJA inhaler. The inhalation powder is packaged in white hypromellose capsules. Each capsule contains a spray-dried powder of 42 mg levodopa active ingredient with 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and sodium chloride. The active component of INBRIJA is levodopa, an aromatic amino acid. Its chemical name is (2S)-2-amino-3-(3,4-dihydroxyphenyl) propanoic acid and its structural formula is: Levodopa has a molecular weight of 197.19 g/mol and molecular formula C 9 H 11 NO 4 . Levodopa is a white to slightly off-white powder and is readily soluble in formic acid, slightly soluble in water, and practically insoluble in ethanol and diethyl ether; it dissolves in dilute hydrochloric acid. The INBRIJA inhaler is a plastic device with a blue body, blue cap, and white mouthpiece used for inhaling INBRIJA powder. The INBRIJA inhaler is breath-actuated by the patient. Under standardized in vitro testing conditions, the INBRIJA inhaler delivered 36.1 mg of levodopa (emitted dose) for the 42 mg capsule from the mouthpiece. No significant difference in emitted dose was observed when varying the flow rate and volume from 20 liters per minute/1L up to 90 liters per minute/2L. Peak inspiratory flow rates (PIFR) achievable through the INBRIJA inhaler were evaluated in 24 adult patients with mild to moderate Parkinson's disease. The mean PIFR was 64 L/min (range 39–98 L/min) for patients in the ON state and 57 L/min (range 29–98 L/min) in the OFF state.

Chemical

Structure

AND USAGE INBRIJA is indicated for the intermittent treatment of OFF episodes in patients with Parkinson's disease treated with carbidopa/levodopa. INBRIJA is an aromatic amino acid indicated for the intermittent treatment of OFF episodes in patients with Parkinson's disease treated with carbidopa/levodopa ( 1 )

AND ADMINISTRATION INBRIJA capsules are for oral inhalation only and should be used only with the INBRIJA inhaler. For oral inhalation only. DO NOT swallow INBRIJA capsules. Only use INBRIJA capsules with the INBRIJA inhaler ( 2.1 ) Inhale the contents of two INBRIJA capsules (84 mg) as needed for OFF symptoms, up to 5 times daily ( 2.2 ) The maximum dose per OFF period is 84 mg, and the maximum recommended daily dosage of INBRIJA is 420 mg ( 2.2 )

2.1 Important Administration Instructions INBRIJA capsules are for oral inhalation only and should be used only with the INBRIJA inhaler. INBRIJA capsules must not be swallowed as the intended effect will not be obtained. INBRIJA capsules should be stored in their blister package and only removed immediately before use <span class="opacity-50 text-xs">[see How Supplied/Storage and Handling (16.2) ]</span> .

2.2 Recommended Dosage INBRIJA should be taken when symptoms of an OFF period start to return. The recommended dosage of INBRIJA is oral inhalation of the contents of two 42 mg capsules (84 mg) as needed, up to 5 times a day. The maximum dose per OFF period is 84 mg, and the maximum daily dosage is 420 mg. INBRIJA has been shown to be effective only in combination with carbidopa/levodopa <span class="opacity-50 text-xs">[see Indications and Usage (1) ]</span>.

INBRIJA is contraindicated in patients currently taking a nonselective monoamine oxidase (MAO) inhibitor (e.g., phenelzine and tranylcypromine) or who have recently (within 2 weeks) taken a nonselective MAO inhibitor. Hypertension can occur if these drugs are used concurrently [see Drug Interactions (7.1) ]. INBRIJA is contraindicated in patients currently taking a nonselective monoamine oxidase (MAO) inhibitor or who have recently (within 2 weeks) taken a nonselective MAO inhibitor ( 4 , 7.1 )

REACTIONS The following serious adverse reactions are discussed below and elsewhere in the labeling: Falling Asleep During Activities of Daily Living and Somnolence [see Warnings and Precautions (5.1) ] Withdrawal-Emergent Hyperpyrexia and Confusion [see Warnings and Precautions (5.2) ] Hallucinations/Psychosis [see Warnings and Precautions (5.3) ]

Impulse Control/Compulsive

Behaviors [see Warnings and Precautions (5.4) ] Dyskinesia [see Warnings and Precautions (5.5) ] Bronchospasm in Patients with Lung Disease [see Warnings and Precautions (5.6) ] Glaucoma [see Warnings and Precautions (5.7) ] The most common adverse reactions (incidence ≥ 5% and higher than placebo) were cough, nausea, upper respiratory tract infection, and sputum discolored ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Acorda Therapeutics, Inc. at 1-800-367-5109 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Adverse

Reactions in Study 1 Table 1 lists the adverse reactions that occurred in at least 2% of patients with Parkinson's disease who were treated with INBRIJA 84 mg and higher than placebo for OFF periods in Study 1 [see Clinical Studies (14) ].

Study

1 was a double-blind, placebo-controlled study, in which 114 patients received INBRIJA 84 mg (two 42 mg capsules) for an average of 2 doses per day, to a maximum of 5 times a day, and 112 patients received placebo. INBRIJA-treated patients were 45-82 years of age (mean 63.5 years of age) and were predominantly male (72%) and white (94%). All patients were also treated with oral carbidopa/levodopa. The most common adverse reactions (≥ 5% and higher than placebo) in Study 1 were cough, nausea, upper respiratory tract infection, and sputum discolored.

Table

1: Adverse Reactions at an Incidence ≥2% and More Frequent with INBRIJA than with Placebo in Study 1 Adverse Reactions INBRIJA 84 mg N=114 % Placebo N=112 % Respiratory, thoracic and mediastinal disorders Cough 15 2 Sputum discolored 5 0 Nasal discharge discoloration 2 0 Oropharyngeal pain 2 0 Gastrointestinal disorders Nausea 5 3 Vomiting 3 0 Infections and infestations Upper respiratory tract infection 6 3 Nasopharyngitis 3 2 Bronchitis/pneumonia 2 0 Nervous system disorders Dyskinesia 4 1 Headache 2 0 Injury, poisoning and procedural complications Fall 3 2 Laceration 2 0 Skin abrasion 2 0 General disorders and administration site conditions Chest discomfort 2 0 Investigations Blood bilirubin increased 2 0 Red blood cell count decreased 2 0 Musculoskeletal and connective tissue disorders Pain in extremity 2 1 Psychiatric disorders Insomnia 2 1 Vascular disorders Orthostatic hypotension/blood pressure decreased 2 0 Adverse Reactions Leading to Discontinuation in Study 1 In Study 1, 6 of 114 patients (5%) in the INBRIJA 84 mg group and 3 of 112 patients (3%) in the placebo group discontinued because of adverse reactions. The most common of these adverse reactions was cough, which lead to discontinuation in 2% of patients in the INBRIJA 84 mg group and none in the placebo group.

6.2 Postmarketing Experience The following adverse reaction has been identified during post approval use of INBRIJA. Because adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: sensation of choking immediately following administration.

AND PRECAUTIONS May cause falling asleep during activities of daily living ( 5.1 ) Avoid sudden discontinuation or rapid dose reduction to reduce the risk of withdrawal-emergent hyperpyrexia and confusion ( 5.2 ) Hallucinations/exacerbation of psychosis may occur. Patients with a major psychotic disorder should not be treated with INBRIJA ( 5.3 , 7.2 )

Impulse Control

Disorders: consider dose reduction or stopping INBRIJA ( 5.4 ) May cause or exacerbate dyskinesia: adjustment of levodopa therapy may be considered, including stopping INBRIJA ( 5.5 ) Not recommended in patients with asthma, COPD, or other chronic underlying lung disease ( 5.6 )

5.1 Falling Asleep During Activities of Daily Living and Somnolence Patients treated with levodopa, the active ingredient in INBRIJA, have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles, which sometimes resulted in accidents. Although many of these patients reported somnolence, some reported no warning signs (sleep attack) and believed that they were alert immediately prior to the event. Some of these events have been reported more than 1 year after the initiation of treatment. Prescribers should reassess patients for drowsiness or sleepiness. Prescribers should also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities. Before initiating treatment with INBRIJA, advise patients about the potential to develop drowsiness and ask about factors that may increase the risk for somnolence with INBRIJA such as the concomitant use of sedating medications and the presence of sleep disorders. Consider discontinuing INBRIJA in patients who report significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.). If treatment with INBRIJA continues, patients should be advised not to drive and to avoid other activities that might result in harm if the patients become somnolent. There is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.

5.2 Withdrawal-Emergent Hyperpyrexia and Confusion A symptom complex that resembles neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in dopaminergic therapy.

5.3 Hallucinations/Psychosis In placebo-controlled trials <span class="opacity-50 text-xs">[see Clinical Studies (14) ]</span>, hallucinations were reported in less than 2% of patients treated with INBRIJA. Hallucinations may be responsive to reducing levodopa therapy. Hallucinations may be accompanied by confusion, insomnia, and excessive dreaming. Abnormal thinking and behavior may present with one or more symptoms, including paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium. Because of the risk of exacerbating psychosis, patients with a major psychotic disorder should ordinarily not be treated with INBRIJA. In addition, medications that antagonize the effects of dopamine used to treat psychosis may exacerbate the symptoms of Parkinson&apos;s disease and may decrease the effectiveness of INBRIJA <span class="opacity-50 text-xs">[see Drug Interactions (7.2) ]</span>.

5.4 Impulse Control/Compulsive Behaviors Patients treated with INBRIJA can experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medications that increase central dopaminergic tone. In some cases, although not all, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending or other urges while being treated with INBRIJA. Consider stopping the medication if a patient develops such urges while taking INBRIJA.

5.5 Dyskinesia INBRIJA may cause or exacerbate dyskinesias. If troublesome dyskinesias occur, prescribers may need to consider stopping treatment with INBRIJA and/or adjusting the patient&apos;s daily medications for the treatment of Parkinson&apos;s disease.

In Study

1, 4% of patients treated with INBRIJA 84 mg reported dyskinesia, compared with 1% for patients on placebo [see Adverse Reactions (6.1) ] .

5.6 Bronchospasm in Patients with Lung Disease Because of the risk of bronchospasm, use of INBRIJA in patients with asthma, COPD, or other chronic underlying lung disease is not recommended. In a double-blind, placebo-controlled, crossover clinical study, 25 otherwise healthy subjects with mild or moderate asthma on a stable regimen of asthma medication received placebo or INBRIJA 84 mg every 4 hours for a total of three doses. Cough was the most frequent adverse reaction, reported by 60% of subjects following administration of INBRIJA and 0% following administration of placebo. Following administration of INBRIJA, 10 subjects (40%) had temporary reductions from baseline (between 15% and 59%) for FEV 1 ; 4 of these subjects also had a reduction in FEV 1 following administration of placebo. Subjects with a reduction in FEV 1 remained asymptomatic and did not require rescue treatment.

5.7 Glaucoma INBRIJA may cause increased intraocular pressure in patients with glaucoma. Monitor patients for increased intraocular pressure during therapy with INBRIJA.

5.8 Laboratory Test Abnormalities Abnormalities in laboratory tests may include elevations of liver function tests such as alkaline phosphatase, AST, ALT, lactic dehydrogenase (LDH), and bilirubin. Abnormalities in blood urea nitrogen (BUN), hemolytic anemia and positive direct antibody test have also been reported. Patients taking levodopa or carbidopa-levodopa may have increased levels of catecholamines and their metabolites in plasma and urine giving false positive results suggesting the diagnosis of pheochromocytoma in patients on levodopa and carbidopa-levodopa.

INTERACTIONS Monitor patients on MAO-B inhibitors for orthostatic hypotension ( 7.1 ) Dopamine D2 antagonists, isoniazid, and iron salts: May reduce the effectiveness of INBRIJA ( 7.2 , 7.3 )

7.1 Monoamine Oxidase (MAO)

Inhibitors

The use of nonselective MAO inhibitors with INBRIJA is contraindicated [see Contraindications (4) ] . Discontinue use of any nonselective MAO inhibitors at least two weeks prior to initiating INBRIJA. The use of selective MAO-B inhibitors with INBRIJA may be associated with orthostatic hypotension. Monitor patients who are taking these drugs concurrently.

7.2 Dopamine D2 Receptor Antagonists and Isoniazid Dopamine D2 receptor antagonists (e.g., phenothiazines, butyrophenones, risperidone, metoclopramide) and isoniazid may reduce the effectiveness of levodopa. Monitor patients for worsening Parkinson&apos;s symptoms.

7.3 Iron Salts Iron salts or multivitamins containing iron salts can form chelates with levodopa and consequently reduce the bioavailability of levodopa.

ACTIVE INGREDIENTS: (in each drop): 49.95% of L-Dopa 12C, 30C; 0.03% of L-Dopa 6X, 12X, 30X.

INACTIVE INGREDIENTS: Demineralized Water, 20% Ethanol.