ZORVOLEX®(diclofenac): The first low-dose SoluMatrix® diclofenac for patients with mild to moderate acute pain or osteoarthritis (OA) pain

ZORVOLEX is a nonsteroidal anti-inflammatory drug (NSAID) indicated for management of mild to moderate acute pain or OA pain.
  • ZORVOLEX is approved for the management of mild to moderate acute pain at low dosages (18 mg TID and 35 mg TID).
    • ZORVOLEX 54 mg per day (18 mg TID) is the lowest effective daily dosage for diclofenac.
  • ZORVOLEX is approved for management of OA pain at a dosage of 35 mg TID.

ZORVOLEX was developed to align with US Food and Drug Administration (FDA) recommendations on NSAID dosing: ZORVOLEX should be used at the lowest effective dosage for the shortest duration consistent with individual patient treatment goals.

Similar pharmacokinetics1

To diclofenac potassium IR 50 mg

Diclofenac plasma concentrations during the first 12 hours

Diclofenac plasma concentrations during the first 12 hours

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

  • The relative bioavailability of ZORVOLEX 35 mg capsules compared to diclofenac potassium 50 mg tablets was assessed in 39 healthy subjects under fasted and fed conditions in a single-dose crossover study.
  • 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.
Lower dose | Less Exposure

ZORVOLEX provides lower systemic exposure

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 18-mg dose was not directly compared to diclofenac potassium IR 50 mg, based on dose-proportional kinetics for ZORVOLEX, the overall systemic exposure is 62% lower. (LS mean = 487)

LS mean = least squares mean.
Based on phase 1 study in healthy subjects.

ZORVOLEX provides lower systemic exposure
Proven efficacy

ZORVOLEX delivered impressive efficacy at low doses to patients with mild to moderate acute pain3

Primary end point: Sum of pain intensity differences over 48 hours was proved significantly different than placebo.

Sum of pain intensity differences over 48 hours was proved significantly different than placebo

Study Design: Multicenter, randomized, double-blind, placebo-controlled, parallel-arm study comparing ZORVOLEX 18 mg or 35 mg TID to placebo in 428 patients with pain following bunionectomy.

n based on ITT Population.
LS mean = least squares mean; VAS SPID = visual analog scale sum of pain intensity difference (the sum of pain measurement differences from baseline at all measurement points).

CLINICAL TRIAL SAFETY DATA

Table 1: Summary of Adverse Reactions (≥2% in ZORVOLEX 18 mg or 35 mg group) – Phase 3 Study in Patients With Postsurgical Pain

Two-hundred sixteen (216) patients received ZORVOLEX in the completed, 48-hour, double-blind, placebo-controlled, clinical trial of acute pain following bunionectomy. The most frequent adverse reactions in this study are summarized in Table 1.

Adverse ReactionZORVOLEX
18 mg or 35 mg
three times daily*
N=216
Placebo*
N=106
Edema 33% 32%
Nausea 27% 37%
Headache 13% 15%
Dizziness 10% 16%
Vomiting 9% 12%
Constipation 8% 4%
Pruritus 7% 6%
Flatulence 3% 2%
Pain in Extremity 3% 1%
Dyspepsia 2% 1%
  • One tablet of hydrocodone/acetaminophen 10 mg/325 mg was permitted every 4 to 6 hours as rescue medication for pain management. There was a greater use of concomitant opioid rescue medication in placebo-treated patients than in ZORVOLEX-treated patients. About 82% of patients in the ZORVOLEX 35 mg group, 85% of the patients in the ZORVOLEX 18 mg group, and 97% of patients in the placebo group took rescue medication for pain management during the study.
Proven efficacy

ZORVOLEX delivered impressive efficacy at low doses in patients with OA pain4

Primary End Point: Change from baseline at 12 weeks in the WOMAC Pain Subscale was proved significantly different than placebo.

Change from baseline in WOMAC Pain Subscale Score at weeks 2, 6, and 12.

 Change from baseline in WOMAC Pain Subscale Score at weeks 2, 6, and 12

Study Design: Random, double-blind, double-dummy, placebo-controlled, study comparing 305 men and women with clinically and radiographically confirmed hip and/or knee osteoarthritis.

LS mean = least squares mean; WOMAC = Western Ontario and McMaster Universities Arthritis Index. Measurements at weeks 2 and 6 were secondary endpoints.

ZORVOLEX reduced the impact of OA pain4

ZORVOLEX reduced the impact of OA pain
  • 63% of patients treated with ZORVOLEX 35 mg TID reported ≥50% improvement in the WOMAC Pain Subscale at 12 weeks (secondary endpoint).
  • Treatment success can be defined as at least a ≥30% improvement (thresholds) from baseline in pain or function score.
  • 60% of patients taking placebo reported ≥30% improvement and 46% of patients taking placebo reported a ≥50% improvement.
CLINICAL TRIAL SAFETY DATA

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

Two-hundred two (202) patients received ZORVOLEX in the completed, 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 2.

Adverse ReactionZORVOLEX 35 mg
N=202
Placebo
N=103
Nausea 7% 2%
Diarrhea 6% 3%
Headache 4% 3%
Abdominal Pain Upper 3% 1%
Sinusitis 3% 1%
Vomiting 3% 1%
Alanine Aminotransferase Increased 2% 0%
Blood Creatinine Increased 2% 0%
Dyspepsia 2% 1%
Flatulence 2% 0%
Hypertension 2% 1%
  • Adverse reactions that occurred in ≥2% of patients treated with ZORVOLEX and occurred more frequently than in patients treated with placebo.

Six-hundred one (601) patients received ZORVOLEX 35 mg either twice or three times daily in a 52-week, open-label, clinical trial in osteoarthritis pain of the knee or hip. Of those, 360 (60%) patients completed the trial. The most frequent adverse reactions in this study are summarized in Table 3.

Table 3: Summary of Adverse Reactions (≥2%) –
52-week Open-label Study in Patients With Osteoarthritis Pain

Adverse ReactionZORVOLEX
35 mg
N=601
Upper Respiratory Tract Infection 8%
Headache 8%
Urinary Tract Infection 7%
Diarrhea 6%
Nasopharyngitis 6%
Nausea 6%
Constipation 5%
Sinusitis 5%
Osteoarthritis 5%
Cough 4%
Alanine Aminotransferase Increased 4%
Back Pain 3%
Dyspepsia 3%
Procedural Pain 3%
Bronchitis 3%
Hypertension 3%
Abdominal Pain Upper 3%
Influenza 3%
Arthralgia 3%
Contusion 3%
Vomiting 3%
Abdominal Discomfort 2%
Aspartate Aminotransferase Increased 2%
Dizziness 2%
Fall 2%
Abdominal Pain 2%

Dosing and administration for ZORVOLEX

Available in low 18-mg and 35-mg doses1
  • ZORVOLEX is approved for management of mild to moderate acute pain at low dosages (18 mg TID and 35 mg TID).
    • ZORVOLEX 54 mg per day (18 mg TID) is the lowest effective daily dosage available for diclofenac.
  • ZORVOLEX is approved for management of OA pain at a dosage of 35 mg TID.
  • ZORVOLEX has no therapeutic equivalent.1
  • The effectiveness of ZORVOLEX when taken with food has not been studied in clinical studies. Taking ZORVOLEX with food may cause a reduction in effectiveness compared to taking ZORVOLEX on an empty stomach.
  • Patients with hepatic disease may require reduced doses of ZORVOLEX; if efficacy is not achieved with the lowest dose, discontinue use.
Zorvolex 18mg and 35mg capsules

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

Indication
ZORVOLEX is indicated for:
  • Management of mild to moderate acute pain
  • Management of osteoarthritis pain
Important Safety Information About Zorvolex

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

ZORVOLEX 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.

Contraindications
ZORVOLEX is contraindicated in the following patients:
  • a known hypersensitivity to diclofenac or any components of the drug
  • 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 ZORVOLEX 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 ZORVOLEX. 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 ZORVOLEX, 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 ZORVOLEX.

Heart Failure and Edema: Avoid use of ZORVOLEX in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure. If ZORVOLEX 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 ZORVOLEX 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 diclofenac or those with or without a known hypersensitivity to ZORVOLEX 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 ZORVOLEX if rash or other signs of local skin reaction occur.

Premature Closure of Fetal Ductus Arteriosus: Starting at 30 weeks of gestation, ZORVOLEX 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. ZORVOLEX may increase the risk of bleeding.

Adverse Reactions
Most common adverse reactions (incidence ≥2%) in clinical trials with ZORVOLEX include: edema, nausea, headache, dizziness, vomiting, constipation, pruritus, diarrhea, flatulence, pain in extremity, abdominal pain, sinusitis, alanine aminotransferase increased, blood creatinine increased, hypertension, and dyspepsia.

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

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

ACE Inhibitors and ARBs: Concomitant use with ZORVOLEX 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 ZORVOLEX can increase serum concentration and prolong half-life 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 ZORVOLEX 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. Desjardins PJ, Olugemo K, Solorio D, Young CL. Pharmacokinetic properties and tolerability of low-dose SoluMatrix diclofenac. Clin Ther. 2015;37(2):448-461.
  2. US 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. Gibofsky A, Silberstein S, Argoff C, Daniels S, Jensen S, Young CL. Lower-dose diclofenac submicron particle capsules provide early and sustained acute patient pain relief in a phase 3 study. Postgrad Med. 2013;125(5):130-138.
  4. Gibofsky A, Hochberg MC, Jaros MJ, Young CL. Efficacy and safety of low-dose submicron diclofenac for the treatment of osteoarthritis pain: a 12 week, phase 3 study. Curr Med Res Opin. 2014;30(9):1883-1893.