VIVLODEX® (meloxicam): The first low-dose SoluMatrix® meloxicam for osteoarthritis (OA) pain

VIVLODEX is a nonsteroidal anti-inflammatory drug (NSAID) indicated for management of OA pain.

  • VIVLODEX is US Food and Drug Administration (FDA) approved at 5 mg and 10 mg doses administered once daily.
    • 5 mg is the lowest FDA-approved dose of meloxicam available.1
    • For management of OA pain, the recommended starting dosage is 5 mg orally once daily. Dose may be increased to 10 mg in patients who require additional analgesia. The maximum recommended daily oral dose of VIVLODEX is 10 mg.
  • VIVLODEX may be appropriate for patients with OA pain who:
    • Are currently taking 15 mg of meloxicam per day and may benefit from a low-dose option.
    • May benefit from a low-dose meloxicam.

VIVLODEX was developed to align with FDA recommendations on NSAID dosing: Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals.2,3

VIVLODEX pharmacokinetic profile4

Meloxicam plasma concentrations during the first 24 hours

Meloxicam plasma concentrations during the first 12 hours

The clinical relevance of the differences in pharmacokinetic measurements is unknown.

Based on a phase 1 single-dose, crossover study in 28 healthy subjects under fasted and fed conditions.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 delivers early Tmax4

  • The median time to maximum plasma concentration (Tmax) occurred earlier for VIVLODEX capsules than for meloxicam tablets.
2 hours Vivlodex
4 hours Vivlodex

The clinical relevance of the differences in pharmacokinetic measurements is unknown.

Based on a phase 1 single-dose, crossover study in 28 healthy subjects under fasted and fed conditions.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 delivers low systemic exposure4

The US Food and Drug Administration (FDA) issued a Public Health Advisory recommending that NSAIDs be used at lowest effective dose for the shortest duration consistent with individual patient treatment goals.2

Although the 5 mg dose was not directly compared with meloxicam 15 mg, based on dose-proportional kinetics for VIVLODEX, the overall systemic exposure is 67% lower.LS mean=least squares mean.Based on a phase 1 single-dose, crossover study in 28 healthy subjects under fasted and fed conditions.The LS mean for meloxicam 15 mg is 41,617.

VIVLODEX provides lower systemic exposure

The clinical relevance of the differences in pharmacokinetic measurements is unknown.

VIVLODEX 10 mg delivered impressive efficacy at low doses in patients with OA pain5

Study Design: Randomized, double-blind, double-dummy, placebo-controlled study in 402 patients with clinically and radiographically confirmed hip or knee osteoarthritis.

Primary end point: Change from baseline in WOMAC Pain Subscale Scores at Week 12

Primary end point: Change from baseline in WOMAC Pain Subscale Scores at Week 12

Lower scores indicate greater reduction of OA pain.

In a 12-week study, patients taking VIVLODEX 10 mg once daily experienced significant improvements in WOMAC Pain Subscale Scores compared with placebo.

Secondary end point: Change from baseline in WOMAC Function and Stiffness Subscale Scores at Week 12

Secondary end point: Change from baseline in WOMAC Function and Stiffness Subscale Scores at Week 12

Lower scores indicate greater improvement.

Patients Taking VIVLODEX 10 mg experienced significant improvements in WOMAC Function and Stiffness Scores at Week 12.

n based on ITT population.WOMAC=Western Ontario and McMaster Universities Arthritis Index.For management of OA pain, the recommended starting dosage is 5 mg orally once daily. Dose may be increased to 10 mg in patients who require additional analgesia. The maximum recommended daily oral dose of VIVLODEX is 10 mg.

VIVLODEX 5 mg delivered impressive efficacy at low doses in patients with OA pain5

Study Design: Randomized, double-blind, double-dummy, placebo-controlled study in 402 patients with clinically and radiographically confirmed hip or knee osteoarthritis.

Primary end point: Change from baseline in WOMAC Pain Subscale Scores at Week 12

Primary end point: Change from baseline in WOMAC Pain Subscale Scores at week 12

Lower subscale scores indicate greater reduction of OA pain.

In a 12-week study, patients taking VIVLODEX 5 mg once daily experienced significant improvements in WOMAC Pain Subscale Scores compared with placebo.

  • In the same study, VIVLODEX 5 mg once daily also demonstrated significant improvement in WOMAC Pain Subscale Scores at Weeks 2 and 6.

Secondary end point: Change from baseline in WOMAC Function and Stiffness Subscale Scores at Week 12

Secondary end point: Change from baseline in WOMAC Function and Stiffness Subscale Scores at Week 12

Lower subscale scores indicate greater improvement.

Patients taking VIVLODEX 5 mg also experienced significant improvements in WOMAC Function and Stiffness Subscale Scores at Week 12.

n based on ITT population.WOMAC=Western Ontario and McMaster Universities Arthritis Index.For management of OA pain, the recommended starting dosage is 5 mg orally once daily. Dose may be increased to 10 mg in patients who require additional analgesia. The maximum recommended daily oral dose of VIVLODEX is 10 mg.

Clinical trial safety data

In a 12-week, phase 3 study in patients with OA pain, these adverse reactions occurred in ≥2% of patients treated with VIVLODEX and more frequently than with placebo

Two hundred sixty-nine (269) patients received VIVLODEX 5 mg or 10 mg once daily in the 12-week, double-blind, placebo-controlled, clinical trial of osteoarthritis pain of the knee or hip. The most frequent adverse reactions in this study are summarized in Table 1.

Table 1: Summary of Adverse Reactions (≥2%) – 12-Week, Phase 3 Study in Patients With Osteoarthritis Pain

Adverse ReactionVIVLODEX 5 mg or 10 mg (n=269)Placebo
(n=133)
Diarrhea 3% 1%
Nausea 2% 0
Abdominal discomfort 2% 0

Long-term safety of VIVLODEX

Summary of adverse reactions (≥2%): 52-week, open-label study in patients with OA pain

Six hundred (600) patients received VIVLODEX 10 mg once daily in a 52-week, open-label, clinical trial in osteoarthritis pain of the knee or hip. Of these, 390 (65%) patients completed the trial. The most frequent adverse reactions in this study are summarized in Table 2.

Table 2: Summary of Adverse Reactions (≥2%) – 52-Week, Open-Label Study in Patients With Osteoarthritis Pain

Adverse ReactionVIVLODEX
10 mg
N=600
Arthralgia 6%
Urinary tract infection 6%
Osteoarthritis 5%
Hypertension 4%
Diarrhea 4%
Headache 4%
Upper respiratory tract infection 4%
Back pain 4%
Nasopharyngitis 4%
Bronchitis 3%
Sinusitis 3%
Constipation 3%
Dyspepsia 3%
Nausea 2%
Edema peripheral 2%
Pain in extremity 2%

Dosing and administration for VIVLODEX

Available in low 5 mg and 10 mg doses

  • VIVLODEX is FDA approved at 5 mg and 10 mg doses administered daily.
    • 5 mg is the lowest FDA-approved dose of meloxicam available.1
    • For management of OA pain, the recommended starting dosage is 5 mg orally once daily. Dose may be increased to 10 mg in patients who require additional analgesia. The maximum recommended daily oral dose of VIVLODEX is 10 mg.
    • In patients on hemodialysis, the maximum daily dosage is 5 mg.
Vivlodex 5mg and 10mg capsules

FDA recommends that NSAIDs be used at the lowest effective dosage for the shortest duration consistent with individual patient treatment goals.2,3

Indication
VIVLODEX is indicated for management of osteoarthritis pain.
IMPORTANT SAFETY INFORMATION ABOUT VIVLODEX

Cardiovascular Thrombotic EventsNonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use.

VIVLODEX is contraindicated in the setting of coronary artery bypass graft (CABG) surgery.

Gastrointestinal Bleeding, Ulceration, and PerforationNSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events.

Use VIVLODEX at the lowest effective dosage for the shortest duration consistent with individual patient treatment goals.

Contraindications
VIVLODEX is contraindicated in the following patients:
  • a known hypersensitivity to meloxicam or any components of the drug product
  • a history of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients
  • in the setting of coronary artery bypass graft (CABG) surgery

Warnings and Precautions
Post-MI Patients: Avoid the use of VIVLODEX in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. Monitor these patients for signs of cardiac ischemia.

Hepatotoxicity: Elevation of one or more liver tests may occur during therapy with NSAIDs including VIVLODEX. Rare, sometimes fatal, cases of severe hepatic injury have been reported. Inform patients of the warning signs and symptoms of hepatotoxicity. Discontinue immediately if clinical signs and symptoms of liver disease develop.

Hypertension: NSAIDs, including VIVLODEX, can lead to the new onset or worsening of existing hypertension, either of which may contribute to the increased incidence of CV events. Monitor blood pressure during treatment with VIVLODEX.

Heart Failure and Edema: Avoid use of VIVLODEX in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure. If VIVLODEX is used in patients with severe heart failure, monitor patients for signs of worsening heart failure.

Renal Toxicity and Hyperkalemia: Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Avoid the use of VIVLODEX in patients with advanced renal disease unless the benefits are expected to outweigh the risk. Monitor for signs of worsening renal function.

Anaphylactic Reactions: Anaphylactic reactions may occur in patients taking meloxicam or those with or without a known hypersensitivity to VIVLODEX and in patients with aspirin-sensitive asthma. Seek emergency help if an anaphylactic reaction occurs.

Serious Skin Reactions: NSAIDs can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. Discontinue VIVLODEX if rash or other signs of local skin reaction occur.

Premature Closure of Fetal Ductus Arteriosus: Starting at 30 weeks of gestation, VIVLODEX and other NSAIDs should be avoided by pregnant women as premature closure of the ductus arteriosus in the fetus may occur.

Hematologic Toxicity: Anemia has occurred in patients treated with NSAIDs. Monitor hemoglobin or hematocrit in patients showing symptoms of anemia. VIVLODEX may increase the risk of bleeding.

Adverse Reactions
Most common adverse reactions (incidence ≥2%) in clinical trials with VIVLODEX included: diarrhea, nausea, abdominal discomfort, arthralgia, urinary tract infection, osteoarthritis, hypertension, headache, respiratory tract infections, back pain, constipation, dyspepsia, peripheral edema, and pain in extremity.

Drug Interactions
Drugs that Interfere with Hemostasis (e.g. warfarin, aspirin, SSRIs/SNRIs): Monitor patients for bleeding who are concomitantly taking VIVLODEX with drugs that interfere with hemostasis. Concomitant use of VIVLODEX and analgesic dose of aspirin is not generally recommended.

ACE Inhibitors, Angiotensin Receptor Blockers (ARB), or Beta Blockers: Concomitant use with VIVLODEX may diminish the antihypertensive effect of these drugs. Monitor blood pressure.

ACE Inhibitors and ARBs: Concomitant use with VIVLODEX in the elderly, volume depleted, or those with renal impairment may result in deterioration of renal function. In such high-risk patients, monitor for signs of worsening renal function.

Diuretics: NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects.

Digoxin: Concomitant use with VIVLODEX can increase serum concentration and prolong halflife of digoxin levels.

Use in Specific Populations
Pregnancy: Use of NSAIDs during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs in pregnant women starting at 30 weeks of gestation.

Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal of VIVLODEX in women who have difficulties conceiving.

Please see full Prescribing Information including Boxed Warning and Medication Guide.

To report SUSPECTED ADVERSE REACTIONS, contact Zyla Life Sciences at 1-800-518-1084 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

References

  1. US Food and Drug Administration. Orange book: Approved drug products with therapeutic equivalence evaluations. 39th Edition. https://www.fda.gov/media/71474/download. Accessed August 27, 2019.
  2. U.S. Food and Drug Administration. Public health advisory–FDA announces important changes and additional warnings for COX-2 selective and non-selective non-steroidal anti-inflammatory drugs (NSAIDs). Published April 2005. https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/cox-2-selective-includes-bextra-celebrex-and-vioxx-and-non-selective-non-steroidal-anti-inflammatory. Accessed August 27, 2019.
  3. US Food and Drug Administration. Drug Safety Communication: FDA strengthens warning that non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) can cause heart attacks or strokes. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-strengthens-warning-non-aspirin-nonsteroidal-anti-inflammatory. Published July 9, 2015. Accessed October 29, 2019.
  4. Hussaini A, Solorio D, Young C. Pharmacokinetic properties of low-dose SoluMatrix meloxicam in healthy adults. Clin Rheumatol. 2016;35(4):1099-1104.
  5. Altman R, Hochberg M, Gibofsky A, Jaros M, Young C. Efficacy and safety of low-dose SoluMatrix meloxicam in the treatment of osteoarthritis pain: a 12-week, phase 3 study. Curr Med Res Opin. 2015;31(12):2331-2343.