INBRIJA Inhalation powder, capsule Ref.[10858] Active ingredients: Levodopa

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

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.

Absorption

After a single dose of INBRIJA 84 mg (two 42 mg capsules), the median T_max for plasma levodopa was approximately 0.5 hours (range 0.17–2.00 hours). In fasted healthy volunteers the bioavailability of levodopa from INBRIJA was approximately 70% relative to immediate-release oral levodopa tablets. The dose-normalized C_max of levodopa from INBRIJA is approximately 50% of that following immediate-release oral tablets.

Distribution

Apparent volume of distribution (Vz/F) was 168 L for INBRIJA 84 mg.

Metabolism and Elimination

Levodopa is extensively metabolized, and the two major metabolic pathways are decarboxylation by dopa decarboxylase and O-methylation by catechol-O-methyltransferase (COMT).

Specific Populations

Geriatric Population

Clinical studies specifically designed to analyze the effects of age on the pharmacokinetics of levodopa were not conducted with INBRIJA.

Male and Female Patients

After a single dose administration of INBRIJA 84 mg, the body-weight adjusted C_max and AUC_0-24 were similar between women and men. No adjustment in dosage is required based on sex.

Hepatic/Renal Impairment

INBRIJA has not been studied in patients with hepatic or renal impairment.

Smokers

In a pharmacokinetic study following a single administration of INBRIJA 84 mg dose in the presence of carbidopa, levodopa exposure (AUC and C_max) in smokers (N=25) and non-smokers (N=31) were similar.

Carcinogenesis

In rats, oral administration of carbidopa/levodopa for two years resulted in no evidence of carcinogenicity.

Mutagenesis

Studies to assess the potential mutagenic or clastogenic effects of levodopa have not been conducted.

Impairment of Fertility

In reproduction studies in rats, oral administration of carbidopa/levodopa resulted in no effects on fertility.

The efficacy and safety of INBRIJA for the treatment of OFF episodes in patients with Parkinson’s disease treated with oral carbidopa/levodopa was evaluated in a 12-week, randomized, placebo-controlled, double-blind study (Study 1; NCT02240030).

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).

Table 2. Mean Change in UPDRS Part III Motor Score at 30 minutes post-dose (INBRIJA 84 mg) for the Intent-to-Treat Population at Week 12*:

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 (FEV₁) from baseline was the same in both groups (-0.1 L).