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 [see How Supplied/Storage and Handling (16.2)] .

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 [see Indications and Usage (1)].

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 [see Clinical Studies (14)], 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's disease and may decrease the effectiveness of INBRIJA [see Drug Interactions (7.2)].

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's daily medications for the treatment of Parkinson'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.

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.

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.

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'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.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Of the Parkinson's disease patients in Study 1 who took INBRIJA 84 mg, 49% (n=56) were 65 years of age and older and 51% (n=58) were under 65 years of age. Of these patients, the following age-related differences in adverse reactions were reported in patients 65 years of age and older vs. in patients under 65 years of age, respectively: cough 25% vs. 5%; upper respiratory tract infection 11% vs. 2%; nausea 7% vs. 3%; vomiting 4% vs. 2%; pain in the extremities 4% vs. 0%; and discolored nasal discharge 4% vs. 0%.

12.1 Mechanism of Action

Levodopa, the metabolic precursor of dopamine, crosses the blood-brain barrier and presumably is converted to dopamine in the brain. This is thought to be the mechanism whereby levodopa relieves symptoms of Parkinson's disease.

12.2 Pharmacodynamics

There are no relevant data on the pharmacodynamic effects of INBRIJA.

12.3 Pharmacokinetics

In the presence of carbidopa, the pharmacokinetics of levodopa are dose-proportional in healthy subjects taking up to 84 mg of INBRIJA. In the presence of carbidopa, the terminal elimination half-life (t 1/2) of levodopa following a single administration of INBRIJA 84 mg was 2.3 hours.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Study 1:

In Study 1, a total of 114 patients were treated with INBRIJA 84 mg (two 42 mg capsules), and 112 patients received placebo. Study medication could be administered up to five times a day. At baseline, patients had at least 2 hours of OFF time per day, and carbidopa/levodopa medication did not exceed 1600 mg levodopa per day. The mean UPDRS Part III scores at screening in the ON state were 14.9 for patients randomized to INBRIJA 84 mg and 16.1 for patients randomized to placebo. The UPDRS part III is designed to assess the severity of the cardinal motor findings (e.g., tremor, rigidity, bradykinesia, postural instability) in patients with Parkinson's disease.

The primary endpoint was the change in Unified Parkinson's Disease Rating Scale (UPDRS) Part III motor score from pre-dose OFF state to 30 minutes post-dose, measured at Week 12. The average use of INBRIJA 84 mg or placebo was approximately 2 doses per day. At Week 12, the reduction in UPDRS Part III motor score for INBRIJA 84 mg, compared to placebo at 30 minutes post-dose, were -9.8 and -5.9, respectively (See Table 2 and Figure 1). The proportion of patients who returned to an ON state and sustained that ON through 60 minutes post-dose was 58% for INBRIJA 84 mg and 36% for placebo (p=0.003).

Figure 1: Least-squares Mean Change in UPDRS Part III Motor Score After Administration of INBRIJA 84 mg vs. Placebo (at Week 12)

Study 2

The effect of INBRIJA on pulmonary function was evaluated in patients with Parkinson's disease treated with oral carbidopa/levodopa in a 12 month, randomized, controlled, open-labeled study (Study 2: NCT02352363). A total of 271 patients were treated with INBRIJA 84 mg (two 42 mg capsules), and 127 patients with Parkinson's disease in a control group were observed on their regular oral medication regimen for the treatment of Parkinson's disease. Patients with chronic obstructive pulmonary disease (COPD), asthma, or other chronic respiratory disease within the last 5 years were excluded [see Warnings and Precautions (5.6)]. Pulmonary function was assessed by spirometry every 3 months in both groups. After 12 months, the average reduction in the forced expiratory volume in 1 second (FEV 1) from baseline was the same in both groups (-0.1 L).

16.1 How Supplied

INBRIJA 42 mg contains foil blister strips of INBRIJA (levodopa inhalation powder) white capsules with two black bands on the body and "A42" in black on the cap, and one INBRIJA inhaler.

• Carton containing 4 INBRIJA capsules (1 blister card containing 4 capsules) and 1 INBRIJA inhaler: NDC 10144-342-04
• Carton containing 12 INBRIJA capsules (3 blister cards containing 4 capsules each) and 1 INBRIJA inhaler: NDC 10144-342-12
• Carton containing 60 INBRIJA capsules (15 blister cards containing 4 capsules each) and 1 INBRIJA inhaler: NDC 10144-342-60
• Carton containing 92 INBRIJA capsules (23 blister cards containing 4 capsules each) and 1 INBRIJA inhaler: NDC 10144-342-92

INBRIJA inhaler consists of a blue cap, blue handle with "INBRIJA" imprinted on it, and white mouthpiece covering the capsule chamber.

16.2 Storage and Handling

Store in a dry place between 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F).

INBRIJA capsules should always be stored in the blister packaging and only removed immediately before use. INBRIJA capsules should not be stored inside the INBRIJA inhaler.

INBRIJA capsules should be used only with the INBRIJA inhaler.

The INBRIJA inhaler should not be used to administer any other medicines.

Instructions for Administering INBRIJA

It is important for patients to understand how to correctly administer INBRIJA. It is recommended that patients be instructed in the proper administration of INBRIJA prior to use [see Dosage and Administration (2.1)] .

Patients should be counseled to take a dose of INBRIJA when the return of their Parkinson's symptoms (OFF periods) first occur [see Dosage and Administration (2.2)] .

Instruct patients to read the Instructions for Use before using INBRIJA. Remind patients that INBRIJA capsules should only be administered via the INBRIJA inhaler and the INBRIJA inhaler should not be used for administering other medications. Remind patients that the contents of INBRIJA capsules are for oral inhalation only and must not be swallowed. Instruct patients to keep INBRIJA capsules in their sealed blister packaging and to remove each INBRIJA capsule immediately before using [see Dosage and Administration (2.1)] .

Remind patients they need to orally inhale the contents of two capsules to take a full dose. They should not take more than 5 doses of INBRIJA in one day. Instruct patients they should not take more than one dose (2 capsules) per OFF period [see Dosage and Administration (2.2)] .

Lung Disease

Ask patients to report whether they develop asthma, COPD, or other chronic lung diseases, since INBRIJA is not recommended in patients with these conditions [see Warnings and Precautions (5.6)] .

Cough/Sensation of Choking

Inhalation of INBRIJA can lead to coughing or a sensation of choking at the time of administration [see Warnings and Precautions (5.6), and Adverse Reactions (6.1, 6.2)] .

Discoloration of Body Fluids

Patients should be advised that dark color may appear in bodily fluids (saliva, sputum, urine, or sweat) when using INBRIJA [see Adverse Reactions (6.1)] .

Falling Asleep

Advise patients that certain side effects such as sleepiness and dizziness may affect some patients' ability to drive and operate machinery safely. Advise patients of the possible additive sedative effects when taking other CNS depressants in combination with INBRIJA [see Warnings and Precautions (5.1)] .

Impulse Control Disorder

Inform patients of the potential for experiencing Impulse Control Disorder: patients may experience intense urges to gamble, increased sexual urges, and other intense urges and the inability to control these urges while taking one or more of the medications that increase central dopaminergic tone, that are generally used for the treatment of Parkinson's disease [see Warnings and Precautions (5.4)] .

Dyskinesia

Instruct patients to notify their healthcare provider if abnormal involuntary movements appear or get worse during treatment with INBRIJA [see Warnings and Precautions (5.5)] .

Hypotension and Syncope

Advise patients that while they are on levodopa therapy, including INBRIJA, that they may develop orthostatic hypotension with or without symptoms such as dizziness, nausea, syncope, and sweating [see Adverse Reactions (6.1)] . Advise patients to rise slowly after sitting or lying down, especially if they have been doing so for a prolonged period.

Iron Salts

Inform patients that iron salts or multivitamins containing iron salts can reduce the bioavailability of levodopa [see Drug Interactions (7.3)].

Pregnancy and Breastfeeding

Instruct patients to notify their physicians if they become pregnant or intend to become pregnant during therapy [see Use in Specific Populations (8.1)] .

Instruct patients to notify their physicians if they intend to breastfeed or are breastfeeding an infant [see Use in Specific Populations (8.2)] .