Meloxicam Capsules

VIVLODEX (meloxicam) capsules are a nonsteroidal anti-inflammatory drug, available as pink and blue capsules containing 5 mg or 10 mg for oral administration. The chemical name is 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1dioxide. The molecular weight is 351.4. Its molecular formula is C14H13N3O4S2, and it has the following chemical structure.

Meloxicam is a pale yellow solid, practically insoluble in water, with higher solubility observed in strong acids and bases. It is very slightly soluble in methanol. Meloxicam has an apparent partition coefficient (log P)app=0.1 in n-octanol/buffer pH 7.4. Meloxicam has pKa values of 1.1 and 4.2.

The inactive ingredients in VIVLODEX include: lactose monohydrate, sodium lauryl sulfate, sodium stearyl fumarate, microcrystalline cellulose, and croscarmellose sodium. The capsule shells contain gelatin, titanium dioxide, and dyes FD&C blue #2, FD&C red #40, FD&C yellow #6, and carmine. The imprinting on the gelatin capsules is white edible ink. The 5 mg capsules have a light pink body with “IP-205” imprinted in white ink and a dark blue cap with “5 mg” imprinted in white ink. The 10 mg capsules have a pink body with “IP-206” imprinted in white ink and a dark blue cap with “10 mg” imprinted in white ink.

VIVLODEX is indicated for management of osteoarthritis pain.

Dosage Forms And Strengths

VIVLODEX (meloxicam) capsules: 5 mg – light pink body with a dark blue cap (imprinted IP-205 on the body and 5 mg on the cap in white ink).

VIVLODEX (meloxicam) capsules: 10 mg – pink body and a dark blue cap (imprinted IP-206 on the body and 10 mg on the cap in white ink).

Storage And Handling

VIVLODEX (meloxicam) capsules are supplied as:

5 mg - light pink body and dark blue cap (imprinted IP-205 on the body and 5 mg on the cap in white ink)

NDC (42211-205-23), Bottles of 30 capsules
NDC (42211-205-29), Bottles of 90 capsules

10 mg - pink body and dark blue cap (imprinted IP-206 on the body and 10 mg on the cap in white ink)

NDC (42211-206-23), Bottles of 30 capsules
NDC (42211-206-29), Bottles of 90 capsules

Store at 25°C (77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Store in the original container and keep the bottle tightly closed to protect from moisture. Dispense in a tight container if package is subdivided.

Manufactured (under license from iCeutica Pty Ltd.) for and Distributed by: Iroko Pharmaceuticals, LLC Philadelphia, PA 19112. Revised: October/2015

Included as part of the PRECAUTIONS section.

Mechanism Of Action

VIVLODEX has analgesic, anti-inflammatory, and antipyretic properties.

The mechanism of action of VIVLODEX, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2).

Meloxicam is a potent inhibitor of prostaglandin synthesis in vitro. Meloxicam concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because meloxicam is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues.

Pharmacokinetics

The relative bioavailability of VIVLODEX 10 mg capsules compared to meloxicam 15 mg tablets was assessed in 28 healthy subjects under fasted and fed conditions in a single-dose crossover study.

VIVLODEX 10 mg capsules do not result in an equivalent systemic exposure compared to 15 mg meloxicam tablets. When taken under fasted conditions, a 33% lower dose of meloxicam in VIVLODEX 10 mg capsules resulted in a 33% lower overall systemic exposure (AUCinf) and a comparable mean peak plasma concentration (Cmax) to meloxicam 15 mg tablets. The median time to maximum plasma concentration (Tmax) occurred earlier for VIVLODEX capsules (2 hours for both 5 mg and 10 mg) than for meloxicam tablets (4 hours for 15 mg).

Single oral doses of VIVLODEX 5 mg and 10 mg were associated with dose-proportional pharmacokinetics. Mean Cmax was achieved within 2 hours post-dose for both VIVLODEX 5 mg and 10 mg capsules when taken under fasted conditions. A second meloxicam concentration peak occurs around 8 hours post-dose.

Taking VIVLODEX with food causes a decrease in the rate but not the overall extent of systemic meloxicam absorption compared with taking VIVLODEX on an empty stomach. VIVLODEX capsules administered under fed conditions results in 22% lower mean Cmax and a 3 hour delay in median Tmax (5 hours for fed versus 2 hours for fasted) compared to the fasted condition. Significant changes in AUCinf were not observed. VIVLODEX can be administered without regard to timing of meals.

The mean volume of distribution (Vss) of meloxicam is approximately 10 L. Meloxicam is ~99.4% bound to human plasma proteins (primarily albumin) within the therapeutic dose range. The fraction of protein binding is independent of drug concentration, over the clinically relevant concentration range, but decreases to ~99% in patients with renal disease. Meloxicam penetration into human red blood cells, after oral dosing, is less than 10%.

Following a radiolabeled dose, over 90% of the radioactivity detected in the plasma was present as unchanged meloxicam.

Meloxicam concentrations in synovial fluid, after a single oral dose, range from 40% to 50% of those in plasma. The free fraction in synovial fluid is 2.5 times higher than in plasma, due to the lower albumin content in synovial fluid as compared to plasma. The significance of this penetration is unknown.

Metabolism

Meloxicam is extensively metabolized in the liver. Meloxicam metabolites include 5'-carboxy meloxicam (60% of dose), from P-450 mediated metabolism formed by oxidation of an intermediate metabolite 5'-hydroxymethyl meloxicam which is also excreted to a lesser extent (9% of dose). In vitro studies indicate that CYP2C9 (cytochrome P450 metabolizing enzyme) plays an important role in this metabolic pathway with a minor contribution of the CYP3A4 isozyme. Patients' peroxidase activity is probably responsible for the other two metabolites which account for 16% and 4% of the administered dose, respectively. The four metabolites are not known to have any in vivo pharmacological activity.

Excretion

Meloxicam excretion is predominantly in the form of metabolites, and occurs to equal extents in the urine and feces. Only traces of the unchanged parent compound are excreted in the urine (0.2%) and feces (1.6%). The extent of the urinary excretion was confirmed for unlabeled multiple 7.5 mg doses: 0.5%, 6%, and 13% of the dose were found in urine in the form of meloxicam, and the 5'-hydroxymethyl and 5'-carboxy metabolites, respectively. There is significant biliary and/or enteral secretion of the drug. This was demonstrated when oral administration of cholestyramine following a single IV dose of meloxicam decreased the AUC of meloxicam by 50%. The mean elimination half-life (t½) for VIVLODEX 5 mg and 10 mg is approximately 22 hours.

Specific Populations

Pediatric: The pharmacokinetics of VIVLODEX have not been investigated in pediatric patients.

Hepatic Impairment: Following a single 15 mg dose of meloxicam tablets there was no marked difference in plasma concentrations in patients with mild (Child-Pugh Class I) or moderate (Child-Pugh Class II) hepatic impairment compared to healthy volunteers. Protein binding of meloxicam was not affected by hepatic impairment. No dosage adjustment is necessary in patients with mild to moderate hepatic impairment. Patients with severe hepatic impairment (Child-Pugh Class III) have not been adequately studied [see WARNINGS AND PRECAUTIONS, Use in Specific Populations].

Renal Impairment: Meloxicam pharmacokinetics have been investigated in subjects with mild and moderate renal impairment. Total drug plasma concentrations of meloxicam decreased and total clearance of meloxicam increased with the degree of renal impairment while free AUC values were similar in all groups. The higher meloxicam clearance in subjects with renal impairment may be due to increased fraction of unbound meloxicam which is available for hepatic metabolism and subsequent excretion. No dosage adjustment is necessary in patients with mild to moderate renal impairment. Patients with severe renal impairment have not been adequately studied. The use of VIVLODEX in subjects with severe renal impairment is not recommended.

Following a single dose of meloxicam, the free Cmax plasma concentrations were higher in patients with renal failure on chronic hemodialysis (1% free fraction) in comparison to healthy volunteers (0.3% free fraction). Hemodialysis did not lower the total drug concentration in plasma; therefore, additional doses are not necessary after hemodialysis. Meloxicam is not dialyzable [see WARNINGS AND PRECAUTIONS, Use In Specific Populations].

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 3 clinically significant drug interactions of NSAIDs with aspirin [see DRUG INTERACTIONS].

Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t½, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established.

Cimetidine: Concomitant administration of 200 mg cimetidine four times daily did not alter the single-dose pharmacokinetics of 30 mg meloxicam.

Digoxin: Meloxicam tablets 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after β-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam [see DRUG INTERACTIONS].

Lithium: In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg twice daily with meloxicam tablets 15 mg once per day every day as compared to subjects receiving lithium alone [see DRUG INTERACTIONS].

Methotrexate: A previous study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites [see DRUG INTERACTIONS].

Warfarin: The effect of meloxicam tablets on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering VIVLODEX with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced [see DRUG INTERACTIONS].

Clinical Studies

Osteoarthritis Pain

The efficacy of VIVLODEX in the management of osteoarthritis pain was demonstrated in a randomized, double-blind, multicenter, parallel-arm, placebo-controlled study comparing VIVLODEX 5 mg or 10 mg taken once daily and placebo in patients with pain due to osteoarthritis of the knee or hip. The study evaluated 402 patients with a mean age of 61 (range 40 to 87 years). Osteoarthritis pain was measured using the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) Pain Subscale. The mean baseline WOMAC Pain Subscale Score across treatment groups was 73 mm using a 0 to 100 mm visual analog scale.

The primary efficacy endpoint was the change from baseline to Week 12 in the WOMAC Pain Subscale Score. VIVLODEX 5 mg and 10 mg once daily significantly reduced osteoarthritis pain compared with placebo, as measured by changes in WOMAC Pain Subscale Scores. Although both the 5 mg and 10 mg doses significantly reduced pain compared to placebo, the proportion of responders achieving various percentage reductions in pain intensity from baseline to Week 12 is similar for both the 5 mg and 10 mg once daily doses. The proportion (%) of patients in each group who demonstrated reduction in their pain intensity score from baseline to Week 12 is shown in Figure 1. The figure is cumulative, so patients whose change from baseline is, for example, 30%, are also included in every level of pain reduction below 30%. Patients who did not complete the study were classified as non-responders.

Figure 1 : Proportion (%) of Patients Achieving Various Percentage Reductions in Pain Intensity from Baseline to Week 12

• COX-2 Inhibitor Medications
• Osteoarthritis (OA)