The Medical Letter. on Drugs and Therapeutics. Volume 60 August 27, Two New Intra-Articular Injections for Knee Osteoarthritis...

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1 The Medical Letter on Drugs and Therapeutics Volume 60 ISSUE ISSUE No Volume 56 IN THIS ISSUE Two New Intra-Articular Injections for Knee Osteoarthritis...p 142 Important Copyright Message FORWARDING OR COPYING IS A VIOLATION OF U.S. AND INTERNATIONAL COPYRIGHT LAWS The Medical Letter, Inc. publications are protected by U.S. and international copyright laws. Forwarding, copying or any distribution of this material is prohibited. Sharing a password with a non-subscriber or otherwise making the contents of this site available to third parties is strictly prohibited. By accessing and reading the attached content I agree to comply with U.S. and international copyright laws and these terms and conditions of The Medical Letter, Inc. For further information click: Subscriptions, Site Licenses, Reprints or call customer service at: Published by The Medical Letter, Inc. A Nonprofit Organization medicalletter.org

2 The Medical Letter publications are protected by US and international copyright laws. Forwarding, copying or any other distribution of this material is strictly prohibited. For further information call: The Medical Letter on Drugs and Therapeutics Volume 60 Take CME Exams Two New Intra-Articular Injections for Knee Osteoarthritis The FDA has approved a single-injection hyaluronic acid gel (Durolane Bioventus) and an extendedrelease (ER) formulation of the synthetic corticosteroid triamcinolone acetonide (Zilretta Flexion) for intraarticular (IA) treatment of osteoarthritic knee pain. Durolane: dur' o lane Pronunciation Key Zilretta: zil ret' a STANDARD TREATMENT Non-drug treatments such as exercise, weight loss, and physical therapy can relieve the pain of knee osteoarthritis (OA) in some patients. Oral acetaminophen has generally been the first drug used. It is less effective than full oral doses of nonsteroidal anti-inflammatory drugs (NSAIDs), but it has fewer adverse effects. Topical gel and solution formulations of the NSAID diclofenac (Voltaren Gel, Pennsaid, and others) appear to be modestly effective in reducing pain, with a low risk of systemic adverse effects. For patients who have inadequate responses or contraindications to systemic anti-inflammatory or analgesic drugs, IA corticosteroid and hyaluronic acid injections have been used as alternatives. HYALURONIC ACID In OA, the viscoelasticity of synovial fluid is reduced, in part due to decreases in the molecular weight and concentration of endogenous hyaluronic acid. Commercially available hyaluronic acid preparations injected into the joint space are claimed to increase the viscoelasticity of synovial fluid and possibly prevent degradation of articular cartilage. However, a meta-analysis of 14 double-blind, sham-controlled trials with at least 60 patients in each trial did not show clinically relevant differences in outcomes between hyaluronic acid treatment and placebo. 1 CLINICAL STUDIES Approval of Durolane was based on the results of a randomized, double-blind, 26-week trial in 349 patients with mild to moderate knee OA. A single Durolane injection was compared to a 5-injection regimen of Supartz, another hyaluronic acid product. The trial did not include a placebo arm. The primary assessment tool was the pain subscale of the Likert-type Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC; scores range from 0-20, with higher scores indicating more pain). Durolane was noninferior to Supartz at all time points assessed over 26 weeks. The least squares mean change in the WOMAC pain score over 18 weeks (from a baseline score of 7-17) was with Durolane versus with Supartz. 2 In two randomized, double-blind trials, a total of 564 patients with knee OA received an IA injection of Durolane or saline placebo. Patients were followed for 6 weeks in one trial and for 26 weeks in the other. In both trials, Durolane did not significantly increase the rate of clinical response ( 40% reduction in the WOMAC pain score with an improvement of 5 points) compared to saline at any time point. 3,4 In a double-blind, 26-week trial, 442 patients with pain due to OA in one knee without clinical effusion (WOMAC pain score 7-17) were randomized to receive an IA injection of Durolane or methylprednisolone acetate (MPA) 40 mg. Durolane was noninferior, but not superior, to MPA in eliciting a clinical response at 12 weeks, the primary endpoint. 5 In an open-label study in the United Kingdom, 182 patients with mild to moderate knee OA were randomized to receive a single injection of Durolane or Synvisc-One, another hyaluronic acid product. There was no placebo control. Durolane significantly reduced knee pain and analgesia use compared to Synvisc-One at 3 and 6 months. 6 ADVERSE EFFECTS Common adverse effects reported with use of Durolane in clinical trials were arthralgia and injection-site pain. PREGNANCY AND LACTATION Durolane has not been studied in pregnant or lactating women. IA administration of hyaluronic acid has not been associated with fetal toxicity in animal studies. Published by The Medical Letter, Inc. A Nonprofit Organization medicalletter.org 142

3 Table 1. Some Injectable Intra-Articular Agents Agent Some Available Formulations Usual Dosage Regimen Cost 1 Corticosteroids 2 Methylprednisolone acetate generic 40, 80 mg/ml vials 40 mg once $6.40 Depo-Medrol (Pfizer) 20, 40, 80 mg/ml vials Triamcinolone acetonide generic 40 mg/ml vials 40 mg once 6.50 Kenalog (BMS) 10, 40 mg/ml vials 9.40 extended-release Zilretta (Flexion) 32 mg powder for reconstitution 32 mg once Hyaluronic Acid 4 Durolane (Bioventus) 60 mg/3 ml syringes 60 mg once Euflexxa (Ferring) 20 mg/2 ml syringes 20 mg once/wk x 3 doses Gel-One (Zimmer) 30 mg/3 ml syringes 30 mg once Gelsyn-3 (Bioventus) 16.8 mg/2 ml syringes 16.8 mg once/wk x 3 doses Genvisc 850 (OrthogenRx) 25 mg/2.5 ml syringes 25 mg once/wk x 5 doses Hyalgan (Fidia Pharma USA) 20 mg/2 ml syringes, vials 20 mg once/wk x 5 doses Hymovis (Fidia Pharma USA) 24 mg/3 ml syringes 24 mg once/wk x 2 doses Monovisc (Depuy Mitek) 88 mg/4 ml syringes 88 mg once Orthovisc (Depuy Mitek) 30 mg/2 ml syringes 30 mg once/wk x 3-4 doses Supartz FX (Bioventus) 25 mg/2.5 ml syringes 25 mg once/wk x 5 doses Synvisc (Genzyme) 16 mg/2 ml syringes 16 mg once/wk x 3 doses Synvisc-One (Genzyme) 48 mg/6 ml syringes 48 mg once TriVisc (OrthogenRx) 25 mg/3 ml syringes 25 mg once/wk x 3 doses N.A. Visco-3 (Zimmer) 25 mg/2.5 ml syringes 25 mg once/wk x 3 doses N.A. = Price not yet available 1. Approximate WAC for one dosage regimen at the lowest usual dosage. WAC = wholesaler acquisition cost or manufacturer s published price to wholesalers; WAC represents a published catalogue or list price and may not represent an actual transactional price. Source: AnalySource Monthly. July 5, Reprinted with permission by First Databank, Inc. All rights reserved Pain relief usually lasts for at least one month; by 2 months, the effect tends to wane. Most clinicians wait a minimum of 3 months between injections. 3. Not FDA-approved for repeat administration. 4. Hyaluronic acid preparations have had modest beneficial effects, sometimes lasting for 6 months. 5. Some patients may experience benefit with three doses given at weekly intervals. DOSAGE AND ADMINISTRATION Durolane gel is supplied in 3-mL single-use glass syringes containing 60 mg of hyaluronic acid. An 18- to 22-gauge needle should be used to inject the contents of one vial into each affected knee. Administration of a second dose 26 weeks after the first appears to be safe. Disinfectants containing ammonium salts should not be used during administration of Durolane because they can cause precipitation of sodium hyaluronate. Any strenuous activities or prolonged weight-bearing activities should be avoided for 48 hours after injection. TRIAMCINOLONE About 80% of patients with symptomatic knee OA have a therapeutic response to IA injections of a corticosteroid. Pain relief usually lasts for at least one month; by two months, the effect tends to wane. 7,8 PHARMACOLOGY Zilretta is an ER formulation consisting of microspheres of poly(lactic-co-glycolic acid) (PLGA) containing triamcinolone acetonide. It is not interchangeable with other formulations of injectable triamcinolone acetonide. In a pharmacokinetic study, patients with knee OA received a single IA injection of triamcinolone aceto nide ER 32 mg or a standard crystalline suspension of immediate-release triamcinolone acetonide 40 mg. Use of the ER formulation prolonged the drug s IA residence time; synovial-fluid concentrations of the ER formulation were measurable for 12 weeks, whereas those of the standard formulation were either very low or not quantifiable at week 6. Peak plasma concentrations were much lower with the ER formulation than with the standard formulation. The median plasma half-life was 347 hours with the ER formulation versus 72.5 hours with the standard formulation. 9 CLINICAL STUDIES Approval of Zilretta was based on the results of a double-blind, 24-week trial in 484 patients years old with moderate to severe knee OA pain who were randomized to receive triamcinolone acetonide ER 32 mg, saline placebo, or a standard crystalline suspension of triamcinolone acetonide 40 mg (active control). The primary endpoint was the change from baseline to week 12 in the weekly mean of the average daily pain (ADP) intensity scores with triamcinolone acetonide ER compared to placebo. Mean ADP intensity score at baseline (on a 0-10 numeric rating scale) was 6.3 in all groups. Triamcinolone acetonide ER significantly reduced the ADP intensity score at week 12 compared to placebo (-3.12 vs -2.14), but not compared to the active control (-3.12 vs -2.86). 10 Approximately 30% of patients with type 2 diabetes also have knee OA. Use of IA corticosteroids can 143

4 elevate blood glucose levels in these patients. In a randomized, double-blind, phase 2 study in 33 patients with knee OA and type 2 diabetes (A1C %), the increase in serum glucose levels in the 3 days following a single IA injection was statistically significantly smaller with triamcinolone acetonide ER 32 mg than with standard triamcinolone acetonide 40 mg (14.7 vs 33.9 mg/dl). 11 There are no head-to-head trials comparing IA triamcinolone ER with other long-acting corticosteroids, such as methylprednisolone acetate (Depo-Medrol, and generics). ADVERSE EFFECTS In clinical trials, the incidence and severity of adverse reactions were generally similar with triamcinolone acetonide ER and placebo. In one randomized, double-blind trial, however, in 140 patients with knee OA, administration of a standard formulation of IA triamcinolone acetonide 40 mg every 3 months for 2 years was associated with significantly greater cartilage volume loss than administration of IA saline placebo. 12 Local post-injection inflammatory reactions have occurred in some patients treated with an IA corticosteroid. Septic arthritis is rare. Other uncommon local adverse effects include bleeding, tendinopathy, tendon rupture, lipoatrophy, skin atrophy, and avascular necrosis. Systemic adverse effects are also rare. Flushing can occur several hours after injection. Adverse effects commonly associated with systemic steroid use such as osteoporosis and gastric ulcers have not been reported with IA injection of corticosteroids. PREGNANCY AND LACTATION Zilretta has not been studied in pregnant or lactating women. In animal studies, IM or SC injection of triamcinolone acetonide during organogenesis caused developmental abnormalities in the fetus and fetal mortality. Corticosteroids have been detected in human breast milk and may suppress milk production; it is not known whether use of Zilretta could result in detectable quantities of triamcinolone acetonide in human breast milk. DOSAGE AND ADMINISTRATION Zilretta is supplied as a single-dose kit containing a vial of triamcinolone acetonide ER microsphere powder, a vial of sterile diluent, and a sterile vial adapter. After reconstitution, Zilretta delivers 32 mg of triamcinolone in 5 ml of diluent. The drug should be stored in a refrigerator before use; the reconstituted suspension can be stored in the vial for up to 4 hours at ambient conditions. to be safe for use in patients with mild to moderate osteoarthritic knee pain, but data supporting its efficacy are unconvincing. The efficacy of hyaluronic acid products in general continues to be controversial, and they are expensive. A single intra-articular injection of extendedrelease triamcinolone acetonide (Zilretta) can relieve moderate to severe osteoarthritic knee pain and appears to be well tolerated, but one clinical trial found that the new extended-release formulation was not significantly more effective in reducing pain after 12 weeks than a standard triamcinolone acetonide injectable suspension, which costs much less. Until more data become available, there is no good reason to use Zilretta. 1. D Jevsevar et al. Viscosupplementation for osteoarthritis of the knee: a systematic review of the evidence. J Bone Joint Surg Am 2015; 97: H Zhang et al. Comparison of two hyaluronic acid formulations for safety and efficacy (CHASE) study in knee osteoarthritis: a multicenter, randomized, double-blind, 26-week non-inferiority trial comparing Durolane to Artz. Arthritis Res Ther 2015; 17: RD Altman et al. Efficacy and safety of a single intra-articular injection of non-animal stabilized hyaluronic acid (NASHA) in patients with osteoarthritis of the knee. Osteoarthritis Cartilage 2004; 12: NK Arden et al. A randomized saline-controlled trial of NASHA hyaluronic acid for knee osteoarthritis. Curr Med Res Opin 2014; 30: R Leighton et al. NASHA hyaluronic acid vs. methylprednisolone for knee osteoarthritis: a prospective, multi-centre, randomized, non-inferiority trial. Osteoarthritis Cartilage 2014; 22: AF McGrath et al. A comparison of intra-articular hyaluronic acid competitors in the treatment of mild to moderate knee osteoarthritis. J Arthritis 2013; 2: RR Bannuru et al. Comparative effectiveness of pharmacologic interventions for knee osteoarthritis: a systematic review and network meta-analysis. Ann Intern Med 2015; 162: P Jüni et al. Intra-articular corticosteroid for knee osteoarthritis. Cochrane Database Syst Rev 2015; 10:CD VB Kraus et al. Synovial and systemic pharmacokinetics (PK) of triamcinolone acetonide (TA) following intra-articular (IA) injection of an extended-release microsphere-based formulation (FX006) or standard crystalline suspension in patients with knee osteoarthritis (OA). Osteoarthritis Cartilage 2018; 26: PG Conaghan et al. Effects of a single intra-articular injection of a microsphere formulation of triamcinolone acetonide on knee osteoarthritis pain: a double-blinded, randomized, placebocontrolled, multinational study. J Bone Joint Surg Am 2018; 100: SJ Russell et al. Triamcinolone acetonide extended-release in patients with osteoarthritis and type 2 diabetes: a randomized, phase 2 study. Rheumatology 2018, in press. 12. TE McAlindon et al. Effect of intra-articular triamcinolone vs saline on knee cartilage volume and pain in patients with knee osteoarthritis: a randomized clinical trial. JAMA 2017; 317:1967. CONCLUSION Like other intra-articular hyaluronic acid products, single-injection Durolane gel appears 144

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