Monovisc (High Molecular Weight Hyaluronan Injection): Side Effects, Uses, Dosage, Interactions, Warnings (2024)

Description for Monovisc

Monovisc™ is a sterile, non-pyrogenic, viscoelastic solution of hyaluronan contained in a single-use syringe. Monovisc™ consists of high molecular weight, ultra-pure, natural hyaluronan, a complex sugar of the glycosaminoglycan family. The hyaluronan in Monovisc™ is derived from bacterial cells and is cross-linked with a proprietary cross-linker.

Uses for Monovisc

Monovisc™ is indicated for the treatment of pain in osteoarthritis (OA) of the knee in patients who have failed to respondadequately to conservative non-pharmacologic therapy or simple analgesics(e.g., acetaminophen).

Dosage for Monovisc

Detailed Device Description

The Monovisc™ device is aproprietary high molecular weight hyaluronic acid (HA) visco-supplementationintended for the treatment of pain in patients with moderate osteoarthritis(OA) of the knee who have failed conservative non-pharmacologicaltherapy and simple analgesics. The device is administered by a single injectionvia the para-patellar approach under sterile conditions. The dosage deliveredby the single injection is equivalent to three injections of Anika's FDAapproved (P030019) Orthovisc HA product.

Sodium hyaluronate is a naturalcomplex sugar of the glycosaminoglycan family. The sodium hyaluronate polymerconsists of repeating disaccharide units of sodiumglucuronate-N-acetylglucosamine. The molecular weight range of hyaluronic acidin Monovisc™ is between 1 and 2.9 million Daltons. Monovisc™ has anominal sodium hyaluronate concentration of 22 mg/mL, dissolved in physiologic saline. It is supplied in a 5.0 mL syringe containing 4.0 mL of Monovisc™ Thecontents of the syringe are sterile, non-pyrogenic and non-inflammatory.

Monovisc™ is prepared by cross-linking hyaluronan(hyaluronic acid, HA) with proprietary cross-linking agent. The HA is derivedfrom bacterial fermentation (Streptococcus equi). The HA used in Monovisc™ isthe same grade and specification that is used in Orthovisc® (P030019), anddelivers a comparable amount of HA to the 3-injection Orthovisc® regimen.

Each pre-filled syringe with 4 mL of Monovisc™contains:

Directions For Use

Monovisc™ is injected into the knee joint and isadministered as a single intra-articular injection. Standard intra-articularinjection site preparation and precautions should be used. Strict aseptic administration technique must be followed.

1. Using an 18 – 20 gauge needle, remove synovial fluid or effusion before injecting Monovisc™. Do not use the same syringe for removing synovial fluid and for injecting Monovisc™; however, the same 18 – 20 gauge needle should be used.
2. Remove the protective rubber cap on the tip of the syringe and securely attach a small gauge needle (18 - 20 gauge) to the tip. Twist the tip cap before pulling it off, as this will minimize product leakage.
3. To ensure a tight seal and prevent leakage during administration, secure the needle tightly while firmly holding the luer hub. Do not over tighten or apply excessive leverage when attaching the needle or removing the needle guard, as this may break the syringe tip.
4. Inject the full 4 mL in one knee only (do not overfill the joint). If treatment is bilateral, a separate syringe should be used for each knee.

HOW SUPPLIED

Monovisc™ is supplied in a single-use 5 mL syringe containinga 4 mL dose of treatment. Each syringe is labeled Monovisc™ for readyidentification. The contents of the syringe are sterile and non-pyrogenic. Thesyringe components contain no latex.

Manufactured byAnika Therapeutics, Inc., 32 Wiggins Avenue, Bedford, MA 01730. Distributed by DePuy Mitek, Inc., 325 ParamountDrive, Raynham, MA 02767. Revised: Dec 2013

Side Effects for Monovisc

Potential Adverse Effects Of The Device On Health

Reported Device-Related Adverse Events

The most common reportedadverse events associated with Monovisc™ are the following:

• Arthralgia
• Joint swelling
• Injection site pain

Incidences of rash, headache,dizziness, chills, hives, itching, nausea, muscle cramps, peripheral edema, and malaise have also been reported in association with intra-articular injections.

A complete listing of thefrequency and rate of adverse events identified in the clinical studies isprovided in the Safety section.

Drug Interactions for Monovisc

No information provided.

Warnings for Monovisc

• Do not concomitantly use disinfectants containing quaternary ammonium salts for skin preparation as hyaluronan can precipitate in their presence.
• Transient increases in inflammation in the injected knee following Monovisc™ injection have been reported in some patients with inflammatory osteoarthritis.

Precautions for Monovisc

General

• Strict aseptic injection technique should be used during the application of Monovisc™.
• The safety and effectiveness of the use of Monovisc™ in joints other than the knee have not been demonstrated.
• The effectiveness of Monovisc™ has not been established for more than one course of treatment.
• STERILE CONTENTS. The pre-filled syringe is intended for single use only. The contents of the syringe should be used immediately after opening. Discard any unused Monovisc™. Do not resterilize.
• Do not use Monovisc™ if the package has been opened or damaged.
• Store Monovisc™ in its original package at room temperature (below 77°F/25°C). DO NOT FREEZE.
• Remove joint effusion, if present, before injecting Monovisc™.
• Only medical professionals trained in accepted injection techniques for delivering agents into the knee joint should inject Monovisc™ for the indicated use.

Information for Patients

• Transient pain or swelling may occur after the intra-articular (IA) injection.
• As with any invasive joint procedure, it is recommended that patients avoid strenuous or prolonged (i.e., more than one hour) weight-bearing activities such as running or tennis within 48 hours following the intra-articular injection.

Use In Specific Populations

Pregnancy

The safety and effectiveness ofthe use of Monovisc™ in pregnant women has not been tested.

Nursing Mothers

It is not known if Monovisc™ isexcreted in human milk. The safety and effectiveness of the use of the productin lactating women has not been tested.

Pediatrics

The safety and effectiveness ofthe use of Monovisc™ in pediatric patients ( ≤ 21 years of age) has notbeen tested.

Overdose Information for Monovisc

No information provided.

Contraindications for Monovisc

• Do not administer to patients with known hypersensitivity (allergy) to hyaluronate preparations.
• Do not administer to patients with known hypersensitivity (allergy) to gram positive bacterial proteins.
• Do not inject Monovisc™ in the knees of patients with infections or skin diseases in the area of the infection site or joint.
• Do not administer to patients with known systemic bleeding disorders

Clinical Pharmacology for Monovisc

Clinical Studies

Monovisc 0702 Pivotal Clinical Trial

Study Design

The Monovisc 0702 study was a randomized, double-blinded, saline-controlled study conducted under IDE at 31 centers in the U.S. andCanada to evaluate the safety and effectiveness of a single injection ofMonovisc™ in patients with symptomatic osteoarthritis of the knee. A total of369 patients were enrolled. Patients were randomized in a 1:1 ratio to eitherMonovisc™ or saline injection. The outcome measures collected included the painand physical function subscales from the Western Ontario and McMasterUniversities Osteoarthritis Index (WOMAC) Visual Analog Scale, investigator andpatient global assessments and the use of rescue medication. The primaryendpoint was to determine the superiority of Monovisc™ compared to saline byevaluating the proportion of patients achieving ≥ 40% relativeimprovement and ≥ 15mm absolute improvement from baseline in the WOMACVAS Pain Score (100mm scale) through Week 12.

Study Population

The patients enrolled in the study were between 35 and 75years old and had the diagnosis of idiopathic OA based upon clinical and/orradiographic criteria of the American College of Rheumatology. Patientexclusion criteria generally included conditions or medications that couldconfound the assessment of pain and conditions that could be adversely affectedby an intra-articular injection. A total of 369 patients were randomized toeither Monovisc™ (n=184) or saline (n=185). These 369 patients comprised theSafety Population. The Intent to Treat (ITT) Population included all randomizedsubjects who received the study injection and had at least one follow-up visit(n=365). The Per-protocol (PP) Population included all randomized subjects whoreceived the study injection, had at least one follow-up visit, and had nomajor protocol deviations (n=334). Table 1 summarizes the baseline and patientdemographic characteristics for the ITT population.

Table 1: Monovisc 0702 Baseline and PatientDemographic Summary

Treatment and Evaluation Schedule

Patients were followed for 26 weeks. Study visits werescheduled for screening, baseline, and weeks 2, 4, 8, 12, 20, and 26.Injections were performed aseptically at the baseline visit. Patients wererequired to discontinue all analgesics, including NSAIDs, for 7 days prior tothe baseline visit and to accept “rescue” acetaminophen (up to a maximum of 4grams per day) as the only medication for treatment of joint pain during thestudy. “Rescue” medication was not permitted within 24 hours of any study visit.

Safety Results

Safety analyses were performed on the Safety Population,which was defined as all randomized patients. Regardless of the cause anddevice relatedness there were 244 (66.1%) patients that experienced adverseevents for the total study cohort, where 121 (65.8%) were observed in theMonovisc™ group and 123 (66.5%) were observed in the control group. There wereno significant differences between the treatment and control study groups inthe frequency or type of observed adverse events.

The adverse events (AEs) most frequently reported ( > 5% in each group) and not related to the index knee were arthralgia (17.4% inthe Monovisc™ group and 14.6% in the saline group); headache (13.0% in theMonovisc™ group and 15.1% in the saline group); back pain (8.7% in theMonovisc™ group and 8.6% in the saline group); pain in extremity (8.2% in theMonovisc™ group and 7.0% in the saline group); and upper respiratory tractinfections (6.0% in the Monovisc™ group and 7.6% in the saline group). Adverseevents considered related to the treatment are listed in Table 2. AdverseEvents were considered typical of viscosupplementation injections in thispatient population and were mild or moderate in severity.

Table 2: 0702 Patients with Treatment-Related AdverseEvents

Effectiveness Results For Monovisc 0702

In the 0702 study, Monovisc™did not demonstrate superiority over saline for the primary effectivenessendpoint of patients with ≥ 40 % relative improvement from baseline and ≥ 15 mm absolute improvement from baseline in the WOMAC VAS Pain Scorethrough Week 12 (p=0.145).

Monovisc vs. Orthovisc Non-inferiority Analysis

A non-inferiority analysis wasperformed to support the effectiveness of Monovisc™ for its intended use thatcompared Monovisc™ with Orthovisc® , which was approved in PMA P030019 fortreatment of knee pain due to osteoarthritis. Monovisc™ offers in a singleinjection the equivalent dose of three injections of Orthovisc® . Theeffectiveness of Orthovisc® for the treatment of knee pain due toosteoarthritis was demonstrated for either 3 or 4 injections of Orthovisc® usinga combined data set from two randomized, controlled, double-blind multicenterIDE studies; OAK9501 and OAK2001. The combined dataset included the followinggroups listed in Table 3, and included a combined 3-injection Orthovisc® group(O3A1/O3) that consisted of 173 patients (83 patients from the OAK9501 studyand 90 patients from the OAK2001 study). The primary non-inferiority analysiscompared both the Monovisc 0702 ITT and PP populations to the Orthovisc® 3-injectiongroups (O3A1, O3, and the combined O3A1/O3 group).

Table 3: Orthovisc® CombinedDataset Treatment Arms

The non-inferiority margins were set conservatively atΔ5.0mm (on a 100mm WOMAC VAS Scale), or 5% for endpoints expressed aspercentages. The mean differences between treatment groups are calculated and alower one sided 97.5% confidence interval is constructed. If the lower bound isgreater than -Δ, then 'Non-inferiority' is obtained for Monovisc™ relativeto the three-injection Orthovisc® group. If, in addition, the lower bound ofthe confidence interval is above zero, the Monovisc™ comparison is determinedto be 'Non-inferior and Superior.'

Primary and secondary endpoints for the non-inferiorityanalysis were the same used for Orthovisc® approval. The primary endpoints werethe comparison of the Proportion of Responders at the 20%, 40%, and 50% thresholdlevels. Secondary endpoints were the change from baseline for the WOMAC PainScore, Pain on Standing Score, Investigator Global Assessment Score, andPatient Global Assessment Score.

Non-inferiority Analysis Results

The mean Proportions of Responders for the primaryendpoints are summarized in Table 4. For all the threshold levels, theMonovisc™ ITT or PP populations have a higher Proportion of Responders ascompared to the three-injection Orthovisc® groups.

Table 4: Mean Proportion of Responders from GEE Model(Weeks 7-22)

Non-inferiority analyses for all endpoints were conductedusing the GEE repeated measures model for weeks 7-22. The Monovisc™ ITT and PPstudy populations were each compared to the Orthovisc® three-injection groups(O3A1, O3, and the combined effectiveness O3A1/O3 group) for the purposes ofestablishing non-inferiority. Additional comparisons to the other treatmentarms (O4, A4, and Saline) that were used to support the Orthovisc® PMA approvalwere also made.

The results of the primary endpoint analysis show thatMonovisc™ (ITT or PP) is non-inferior to three injections of Orthovisc® for theO3A1 group and also for the combined O3A1/O3 group for all threshold levels.Non-inferiority was not demonstrated against the O3 group with the chosenmargin.

The results from the secondary endpoints show thatMonovisc™ (ITT or PP) was non-inferior to the three-injection Orthovisc® groupsO3 and combined O3A1/O3 for Change in WOMAC Pain Score, Pain on Standing Score,Investigator Global Score, and Patient Global Score. Monovisc™ (ITT or PP) wasnon-inferior to the O3A1 group for Change in WOMAC Pain Score, InvestigatorGlobal Score, and Patient Global Score (PP only).

Monovisc™ was not shown to be non-inferior to fourinjections of Orthovisc® (O4). The four-injection series of Orthovisc® representsa 33% increase in HA dose compared to a single injection of Monovisc™.

Monovisc™ (ITT or PP) was non-inferior or 'non-inferiorand superior' against the control groups A4 and Saline for primary andsecondary endpoints.

The clinical significance for the change from baselinefor each of the secondary endpoints was demonstrated using CumulativeDistribution Function (CDF) plots comparing the Monovisc 0702 PP Population tothe Orthovisc® three-injection combined effectiveness subgroup (O3A1/O3) ateach timepoint. Figure 1 shows an example plot for the Change in WOMAC PainScore at 20-22 weeks. The vertical dashed black line in the plot is set at the“minimum clinically important difference” (MCID). The MCID of 6.0mm waspreviously determined to be an acceptable difference for HA injectable productsbased on a meta-analysis of literature.

Figure 1: CDF Plot for Change in WOMAC Pain Score forM1 PP vs. O3A1/O3 (Weeks 20-22)

The CDF curves for the endpoints (WOMAC Pain Score, Painon Standing Score, Investigator Global Score and Patient Global Score) showthat the Monovisc™ PP population demonstrates a higher degree of clinicalimprovement at every timepoint relative to the Orthovisc® 3-injection combinedeffectiveness group (O3A1/O3).

Monovisc 0802 Repeat Injection Extension Study

Study Design and Results:

An open label study, Monovisc 0802, was conducted as anextension study of Monovisc 0702 in order to evaluate the safety of a repeatinjection of Monovisc™. The extension study enrolled 240 patients, 119 of whomreceived a second injection of Monovisc™ and 121 of whom received an injectionof Monovisc™ after receiving a saline injection during the initial treatment.

The percentage of patients experiencing AEs, regardlessof cause and device relatedness, was similar for those who were previouslyinjected with Monovisc™ (49.6%) and those previously injected with saline(45.5%). The local adverse event profile for the injected knee for thosereceiving a second injection of Monovisc™ was similar to the adverse eventprofile seen in the Monovisc 0702 study, regardless of whether patients hadinitially received a Monovisc™ injection or a saline injection (Table 5).

Table 5: Monovisc 0802 Adverse Events of the InjectedKnee Regardless of Relatedness

Patient Information for Monovisc

MONOVISC™
High Molecular Weight Hyaluronan

What is MONOVISC™?

MONOVISC™ is a viscous (thick)sterile mixture made from highly purified hyaluronan from bacterialfermentation. Hyaluronan is a natural chemical found in the body. High amountsof hyaluronan are found in the joint tissues and in the fluid that fills thejoints. The body's own hyaluronan acts like a lubricant and a shock absorber inthe joint. It is needed for the joint to work properly. When you have osteoarthritis, there may not be enough natural hyaluronan in the joint, andthe quality of that hyaluronan may be poorer than normal. MONOVISC™ is given ina shot (injection) directly into the knee joint.

What is MONOVISC™ used for?

MONOVISC™ is used to relieveknee pain due to osteoarthritis. It is used for patients who do not getadequate pain relief from simple pain relievers like acetaminophen or fromexercise and physical therapy.

What are the benefits ofMONOVISC™?

Data from clinical trialsconducted in the U.S. have shown that MONOVISC™ provides pain relief to aproportion of patients who have not been able to find pain relief with simplepain medication or exercise.

What other treatments areavailable for osteoarthritis?

If you have pain due toosteoarthritis of the knee, there are things you can do that do not involveMONOVISC™ injections.

These include:

Non-drug treatments:

• Avoiding activities that cause pain in your knee
• Exercise
• Physical therapy
• Removal of excess fluid from the knee

Drug therapy:

• Pain medication such as acetaminophen and narcotics
• Drugs that reduce inflammation, such as aspirin and
• other “nonsteroidal anti-inflammatory” agents (NSAIDs)
• (such as ibuprofen and naproxen)
• Corticosteroids that are injected directly into the knee
• joint

Are there any reasons why you should not takeMONOVISC™?

• You should not take this product if you are allergic to hyaluronate products.
• If you have any known allergies, you should consult with your healthcare professional to determine if you are able to take MONOVISC™.
• You should not have an injection into the knee if you have infections or skin diseases around the injection site.

Things you should know about MONOVISC™

• MONOVISC™ should be injected by a qualified physician or properly licensed practitioner.
• Tell your healthcare professional if you have any known allergies before MONOVISC™ is administered.
• For 48 hours after you receive the injection, you should avoid activities such as jogging, tennis, heavy lifting or standing on your feet for a long time (more than one hour).
• The safety and effectiveness of MONOVISC™ in joints other than the knee has not been demonstrated in U.S. studies.
• The safety and effectiveness of MONOVISC™ has not been shown in pregnant or nursing women. You should tell your healthcare professional if you are pregnant or nursing.
• The safety and effectiveness of MONOVISC™ has not been shown in children.
• The effectiveness of MONOVISC™ has not been established for more than one course of treatment.

Possible complications

• Side effects are sometimes seen when MONOVISC™ is injected into the knee joint. These can include: pain, swelling, heat, rash, itching, bruising and/or redness. You may also feel achy. These reactions are generally mild and do not last long.
• If any of these symptoms or signs appear after you are given MONOVISC™ or if you have any other problems, you should call your healthcare professional.

How is MONOVISC™ given?

Your healthcare professional will give a single injectionof MONOVISC™ (88 mg/4 mL) into your knee.