The relative bioavailability of ZORVOLEX 35 mg capsules was compared to diclofenac potassium immediate-release (IR) tablets 50 mg in 39 healthy subjects under fasted and fed conditions in a single-dose crossover study. 

ZORVOLEX 35 mg capsules do not result in an equivalent systemic exposure to 50 mg diclofenac potassium IR tablets. 

When taken under fasted conditions, a 20% lower dose of diclofenac in ZORVOLEX capsules resulted in a 23% lower mean systemic exposure (AUCinf) and a 26% lower mean peak concentration (Cmax) compared to diclofenac potassium IR tablets. The time to reach peak concentration (Tmax) was similar for ZORVOLEX and diclofenac potassium IR tablets and was ~1 hour for both. 

When taken under fed conditions, a 20% lower dose of diclofenac in ZORVOLEX capsules resulted in a 23% lower mean systemic exposure (AUCinf) and a 48% lower mean Cmax compared to diclofenac potassium IR tablets. The Tmax for ZORVOLEX was delayed by approximately 1 hour compared to diclofenac potassium IR tablets (3.32 hours vs. 2.33 hours, respectively).

When taken under fed conditions, ZORVOLEX capsules resulted in an 11% lower mean systemic exposure (AUCinf) and a 60% lower mean Cmax compared to fasted conditions. Whereas diclofenac potassium IR tablets under fed conditions resulted in 8% - 10% lower mean systemic exposure (AUCinf) and 28% - 43% lower mean Cmax compared to fasted conditions, based on the results from two individual food effect studies. The Tmax for ZORVOLEX was delayed by approximately 2.32 hours under fed conditions compared to fasted conditions (3.32 hours vs. 1.00 hour, respectively), while the Tmax for diclofenac potassium IR tablets was delayed by approximately 1.00 - 1.33 hours under fed conditions compared to fasted conditions (1.70 vs. 0.74 hours and 2.33 vs. 1.00 hours, respectively in two studies).

There were no differences in elimination half-life between ZORVOLEX and diclofenac potassium IR tablets under fasted or fed conditions.

Absorption

Diclofenac is 100% absorbed after oral administration compared to IV administration as measured by urine recovery. However, due to first-pass metabolism, only about 50% of the absorbed dose is systemically available. After repeated oral administration, no accumulation of diclofenac in plasma occurred.

Administration of ZORVOLEX capsules 18 mg and 35 mg was associated with dose proportional pharmacokinetics. 

Taking ZORVOLEX with food causes a significant decrease in the rate but not the overall extent of systemic absorption of diclofenac compared with taking ZORVOLEX on an empty stomach. ZORVOLEX capsules results in 60% lower Cmax, 11% lower AUCinf, and 2.32 hours delayed Tmax (1.0 hour during fasted versus 3.32 hours during fed) under the fed condition compared to the fasted condition. The effectiveness of ZORVOLEX when taken with food has not been studied in clinical studies. The decreased Cmax may be associated with decreased effectiveness. Taking ZORVOLEX with food may cause a reduction in effectiveness compared to taking ZORVOLEX on an empty stomach.

Distribution

The apparent volume of distribution (V/F) of diclofenac potassium is 1.3 L/kg. Diclofenac is more than 99% bound to human serum proteins, primarily to albumin. Serum protein binding is constant over the concentration range (0.15-105 mg/mL) achieved with recommended doses.

Diclofenac diffuses into and out of the synovial fluid. Diffusion into the joint occurs when plasma levels are higher than those in the synovial fluid, after which the process reverses and synovial fluid levels are higher than plasma levels. It is not known whether diffusion into the joint plays a role in the effectiveness of diclofenac.

Elimination

Diclofenac is eliminated through metabolism and subsequent urinary and biliary excretion of the glucuronide and the sulfate conjugates of the metabolites. The terminal half-life of unchanged diclofenac is approximately 2 hours. 

Metabolism

Five diclofenac metabolites have been identified in human plasma and urine. The metabolites include 4'-hydroxy-, 5-hydroxy-, 3'-hydroxy-, 4',5-dihydroxy- and 3'-hydroxy-4'-methoxy diclofenac. The major diclofenac metabolite, 4'-hydroxy-diclofenac, has very weak pharmacologic activity. The formation of 4'-hydroxy-diclofenac is primarily mediated by CYP2C9. Both diclofenac and its oxidative metabolites undergo glucuronidation or sulfation followed by biliary excretion. Acylglucuronidation mediated by UGT2B7 and oxidation mediated by CYP2C8 may also play a role in diclofenac metabolism. CYP3A4 is responsible for the formation of minor metabolites, 5-hydroxy and 3'-hydroxy-diclofenac. In patients with renal dysfunction, peak concentrations of metabolites 4'-hydroxy and 5-hydroxy-diclofenac were approximately 50% and 4% of the parent compound after single oral dosing compared to 27% and 1% in normal healthy subjects.

Excretion

Diclofenac is eliminated through metabolism and subsequent urinary and biliary excretion of the glucuronide and the sulfate conjugates of the metabolites. Little or no free unchanged diclofenac is excreted in the urine. Approximately 65% of the dose is excreted in the urine, and approximately 35% in the bile as conjugates of unchanged diclofenac plus metabolites. Because renal elimination is not a significant pathway of elimination for unchanged diclofenac, dosing adjustment in patients with mild to moderate renal dysfunction is not necessary. The terminal half-life of unchanged diclofenac is approximately 2 hours.

Specific Populations

Pediatric: The pharmacokinetics of ZORVOLEX has not been investigated in pediatric patients.

Race: Pharmacokinetic differences due to race/ethnicity have not been identified.

Hepatic Impairment: No dedicated diclofenac pharmacokinetics studies in patients with hepatic impairment were conducted. Hepatic metabolism accounts for almost 100% of diclofenac elimination. Therefore, in patients with hepatic impairment, start with the lowest dose and if efficacy is not achieved, consider use of an alternate product [see Warnings and Precautions (5.3)].

Renal Impairment: Diclofenac pharmacokinetics has been investigated in subjects with renal insufficiency. No differences in the pharmacokinetics of diclofenac have been detected in studies of patients with renal impairment. In patients with renal impairment (inulin clearance 60-90, 30-60, and less than 30 mL/min; N=6 in each group), AUC values and elimination rate were comparable to those in healthy subjects [see Warnings and Precautions (5.6)].

Drug Interaction Studies

Aspirin: When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 4 for clinically significant drug interactions of NSAIDs with aspirin [see Drug Interactions (7)].