Tolerability and Safety of Large-Volume Hyaluronidase-Facilitated Subcutaneous Immunoglobulin 10% Administered with or without Dose Ramp-Up: A Phase 1 Study in Healthy Participants.

PURPOSE: Facilitated subcutaneous immunoglobulin (fSCIG; immune globulin infusion 10% [human] with recombinant human hyaluronidase [rHuPH20]) permits high-volume subcutaneous immunoglobulin (SCIG) infusion, shorter infusion times and reduced dosing frequency relative to conventional SCIG. It is initiated by gradually increasing infusion volumes over time (dose ramp-up) to achieve target dose level (TDL). Whether ramp-up strategies have tolerability or safety advantages over direct initiation at full TDL has not been evaluated clinically. METHODS: This phase 1 open-label study assessed tolerability and safety of fSCIG 10% with accelerated or no ramp-up compared with conventional ramp-up in healthy adults (NCT04578535). Participants were assigned to one of the three ramp-up arms to achieve TDLs of 0.4 or 1.0 g/kg/infusion. The primary endpoint was the proportion of infusions completed without interruption or infusion rate reduction owing to treatment-emergent adverse events (TEAEs). Safety was assessed as a secondary endpoint. RESULTS: Of 51 participants enrolled, 50 (98.0%) tolerated all fSCIG 10% infusions initiated (n = 174). Infusion rate was reduced in one participant owing to headache in the 0.4 g/kg/infusion conventional ramp-up arm. Study discontinuations were higher in the no ramp-up arm (70%) versus the conventional (0%) and accelerated (22%) arms at the 1.0 g/kg/infusion TDL. Safety outcomes did not substantially differ between treatment arms. CONCLUSION: The favorable tolerability and safety profiles of fSCIG 10% in healthy participants support initiating treatment with fSCIG 10% with accelerated ramp-up at TDLs up to 1.0 g/kg. Data support no ramp-up at TDLs close to 0.4 g/kg but additional data are needed for higher doses.

Methods for the induction of labor: efficacy and safety.

This review assessed the efficacy and safety of pharmacologic agents (prostaglandins, oxytocin, mifepristone, hyaluronidase, and nitric oxide donors) and mechanical methods (single- and double-balloon catheters, laminaria, membrane stripping, and amniotomy) and those generally considered under the rubric of complementary medicine (castor oil, nipple stimulation, sexual intercourse, herbal medicine, and acupuncture). A substantial body of published reports, including 2 large network meta-analyses, support the safety and efficacy of misoprostol (PGE1) when used for cervical ripening and labor induction. Misoprostol administered vaginally at doses of 50 µg has the highest probability of achieving vaginal delivery within 24 hours. Regardless of dosing, route, and schedule of administration, when used for cervical ripening and labor induction, prostaglandin E2 seems to have similar efficacy in decreasing cesarean delivery rates. Globally, although oxytocin represents the most widely used pharmacologic agent for labor induction, its effectiveness is highly dependent on parity and cervical status. Oxytocin is more effective than expectant management in inducing labor, and the efficacy of oxytocin is enhanced when combined with amniotomy. However, prostaglandins administered vaginally or intracervically are more effective in inducing labor than oxytocin. A single 200-mg oral tablet of mifepristone seems to represent the lowest effective dose for cervical ripening. The bulk of the literature assessing relaxin suggests this agent has limited benefit when used for this indication. Although intracervical injection of hyaluronidase may cause cervical ripening, the need for intracervical administration has limited the use of this agent. Concerning the vaginal administration of nitric oxide donors, including isosorbide mononitrate, isosorbide, nitroglycerin, and sodium nitroprusside, the higher incidence of side effects with these agents has limited their use. A synthetic hygroscopic cervical dilator has been found to be effective for preinduction cervical ripening. Although a pharmacologic agent may be administered after the use of the synthetic hygroscopic dilator, in an attempt to reduce the interval to vaginal delivery, concomitant use of mechanical and pharmacologic methods is being explored. Combining the use of a single-balloon catheter with dinoprostone, misoprostol, or oxytocin enhances the efficacy of these pharmacologic agents in cervical ripening and labor induction. The efficacy of single- and double-balloon catheters in cervical ripening and labor induction seems similar. To date, the combination of misoprostol with an intracervical catheter seems to be the best approach when balancing delivery times with safety. Although complementary methods are occasionally used by patients, given the lack of data documenting their efficacy and safety, these methods are rarely used in hospital settings.

Isolated Ophthalmoplegia After Periorbital Hyaluronic Acid Filler Injection.

Facial filler injections are the second most commonly performed in-office cosmetic procedure. Vision loss is the most feared complication of hyaluronic acid (HA) filler injection, but isolated ophthalmoplegia can also occur. We report the case of a 45-year-old woman who developed nausea and diplopia following HA filler injection to the bilateral periorbital region. She presented with a left hypertropia and left-sided motility deficit without vision involvement. MRI of the orbits demonstrated mild enhancement and enlargement of the left inferior rectus and inferior oblique muscles. Treatment consisted of hyaluronidase injection and oral steroids. HA filler can cause isolated ocular misalignment and diplopia without associated vision loss. Patients should be counseled on these risks before undergoing soft tissue augmentation of the face with HA filler.

Atezolizumab Plus PEGPH20 Versus Chemotherapy in Advanced Pancreatic Ductal Adenocarcinoma and Gastric Cancer: MORPHEUS Phase Ib/II Umbrella Randomized Study Platform.

BACKGROUND: The MORPHEUS platform comprises multiple open-label, randomized, phase Ib/II trials designed to identify early efficacy and safety signals of treatment combinations across cancers. Atezolizumab (anti-programmed cell death 1 ligand 1 [PD-L1]) was evaluated in combination with PEGylated recombinant human hyaluronidase (PEGPH20). METHODS: In 2 randomized MORPHEUS trials, eligible patients with advanced, previously treated pancreatic ductal adenocarcinoma (PDAC) or gastric cancer (GC) received atezolizumab plus PEGPH20, or control treatment (mFOLFOX6 or gemcitabine plus nab-paclitaxel [MORPHEUS-PDAC]; ramucirumab plus paclitaxel [MORPHEUS-GC]). Primary endpoints were objective response rates (ORR) per RECIST 1.1 and safety. RESULTS: In MORPHEUS-PDAC, ORRs with atezolizumab plus PEGPH20 (n = 66) were 6.1% (95% CI, 1.68%-14.80%) vs. 2.4% (95% CI, 0.06%-12.57%) with chemotherapy (n = 42). In the respective arms, 65.2% and 61.9% had grade 3/4 adverse events (AEs); 4.5% and 2.4% had grade 5 AEs. In MORPHEUS-GC, confirmed ORRs with atezolizumab plus PEGPH20 (n = 13) were 0% (95% CI, 0%-24.7%) vs. 16.7% (95% CI, 2.1%-48.4%) with control (n = 12). Grade 3/4 AEs occurred in 30.8% and 75.0% of patients, respectively; no grade 5 AEs occurred. CONCLUSION: Atezolizumab plus PEGPH20 showed limited clinical activity in patients with PDAC and none in patients with GC. The safety of atezolizumab plus PEGPH20 was consistent with each agent's known safety profile. (ClinicalTrials.gov Identifier: NCT03193190 and NCT03281369).

Trastuzumab/Hyaluronidase-oysk: A New Option for Patients With HER2-Positive Breast Cancer.

OBJECTIVE: To assess the use of subcutaneous trastuzumab/hyaluronidase-oysk (SQ trastuzumab) in comparison to intravenous (IV) trastuzumab. DATA SOURCES: A comprehensive PubMed literature search was performed from August 2012 to August 2019 using search terms Herceptin Hylecta, trastuzumab, hyaluronidase, subcutaneous, preference, safety, efficacy, and cost. STUDY SELECTION & DATA EXTRACTION: English-language clinical trials focusing on SQ trastuzumab were evaluated. DATA SYNTHESIS: In phase III trials, adverse event (AE) rates ranged from 64% to 97.6% of patients receiving SQ trastuzumab in 3 studies compared to 94.6% of patients receiving IV trastuzumab. In the phase III trial comparing SQ trastuzumab to IV trastuzumab, six-year overall survival (OS) was 84% in both groups. In pharmacokinetic analyses, trough concentrations and AUC0-21 were slightly higher in patients receiving SQ trastuzumab and differences were larger at the extremes of body weight. Two pharmacoeconomic analyses reported cost-savings associated with a 52-week treatment cycle of trastuzumab of $2,090 USD and $4,600 USD. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Food and Drug Administration (FDA)-approved in February 2019, SQ trastuzumab, a monoclonal antibody that binds to human epidermal growth factor receptor 2 (HER2) protein in combination with hyaluronidase, offers an alternative dosage form for patients with breast tumors overexpressing HER2. CONCLUSIONS: SQ trastuzumab has a similar safety profile to IV trastuzumab. Although it may be slightly more cost-effective, its role in the treatment of HER2-overexpressing tumors requires further study in those at the extremes of body weight due to differences in drug exposure compared to IV trastuzumab.

Efficacy, Effectiveness, Safety, and Cost-effectiveness of Epidural Adhesiolysis for Treating Failed Back Surgery Syndrome. A Systematic Review.

BACKGROUND: Failed back surgery syndrome (FBSS) has a profound impact on patients' quality of life and represents a major clinical challenge and a significant economic burden for society. Adhesiolysis is used as a treatment to eliminate perineural/epidural adhesions in patients with chronic pain attributed to FBSS. OBJECTIVE: To evaluate the efficacy, effectiveness, safety, and cost-effectiveness of epidural adhesiolysis compared with other procedures for treating FBSS. METHOD: A systematic review was conducted. The electronic databases Medline/PreMedline, EMBASE, Cochrane Library Plus, Centre for Reviews and Dissemination databases, SCOPUS, Science Citation Index, and PEDRO were consulted through April 2017. Predefined criteria were used to determine inclusion of the studies and to assess their methodological quality. RESULTS: Ten reports were included. No randomized controlled trials (RCTs) on efficacy or cost-effectiveness were found. Three reports (corresponding to two RCTs, N = 212) suggested that adhesiolysis was effective, especially for pain and disability. However, both studies presented serious methodological flaws. In addition to RCTs, seven observational studies with high risk of bias reported data on effectiveness and safety. Fifty-eight adverse events were reported among 130 patients undergoing endoscopic adhesiolysis, and 19 among the 110 undergoing percutaneous adhesiolysis. CONCLUSIONS: The evidence on the efficacy and cost-effectiveness of adhesiolysis for treating FBSS is nonexistent, whereas evidence on its effectiveness and safety is insufficient. Incorporating data from observational studies did not improve the quality of the evidence on effectiveness.

Phase 1 trials of PEGylated recombinant human hyaluronidase PH20 in patients with advanced solid tumours.

BACKGROUND: Hyaluronan accumulation in tumour stroma is associated with reduced survival in preclinical cancer models. PEGPH20 degrades hyaluronan to facilitate tumour access for cancer therapies. Our objective was to assess safety and antitumour activity of PEGPH20 in patients with advanced solid tumours. METHODS: In HALO-109-101 (N=14), PEGPH20 was administered intravenously once or twice weekly (0.5 or 50 µg kg-1) or once every 3 weeks (0.5-1.5 µg kg-1). In HALO-109-102 (N=27), PEGPH20 was administered once or twice weekly (0.5-5.0 µg kg-1), with dexamethasone predose and postdose. RESULTS: Dose-limiting toxicities included grade ⩾3 myalgia, arthralgia, and muscle spasms; the maximum tolerated dose was 3.0 µg kg-1 twice weekly. Plasma hyaluronan increased in a dose-dependent manner, achieving steady state by Day 8 in multidose studies. A decrease in tumour hyaluronan level was observed in 5 of the 6 patients with pretreatment and posttreatment tumour biopsies. Exploratory imaging showed changes in tumour perfusion and decreased tumour metabolic activity, consistent with observations in animal models. CONCLUSIONS: The tumour stroma has emerging importance in the development of cancer therapeutics. PEGPH20 3.0 µg kg-1 administered twice weekly is feasible in patients with advanced cancers; exploratory analyses indicate antitumour activity supporting further evaluation of PEGPH20 in solid tumours.

Hyaluronidase allergy mimicking orbital cellulitis.

PURPOSE: Hyaluronidase enzyme is a common additive with local anesthetic agent to facilitate faster permeation of the anesthetic in periocular tissues during ophthalmic surgery. We report a series of five subjects presenting with clinical features mimicking orbital cellulitis following peribulbar anesthesia and consequently diagnosed with hyaluronidase hypersensitivity. SETTING: The study was conducted at a tertiary eye care center in Southern India. DESIGN: It was a retrospective interventional case series. METHODS: We retrospectively reviewed the case records of patients diagnosed as and treated for hyaluronidase allergy from 2011 to 2015. The presenting features included periocular edema, proptosis, and restriction of ocular movements. The symptoms appeared immediately after the injection to as late as 6 days after the surgery. All patients underwent comprehensive ophthalmic evaluation, relevant investigations, and dermal allergy tests. All five patients tested positive for hyaluronidase. Patients were treated with antihistaminics, systemic steroids, and emergency orbital decompression, when required. In majority of the patients, symptoms resolved in 3-5 days. Clinically, hyaluronidase allergy may mimic orbital cellulitis, which in the context of a recent intraocular surgery may be alarming for both the patient and the surgeon. However, with prompt intervention, the prognosis is extremely favorable in cases of hyaluronidase allergy. It is important for ophthalmic surgeons and anesthetists to recognize and differentiate this entity from the more serious vision threatening conditions.

Quantitative Correlation Between Hyaluronic Acid Filler and Hyaluronidase.

The hyaluronic acid-based filler (HA filler) is used worldwide in various applications. In particular, the HA filler is used in the plastics and cosmetic medical field for facial rejuvenation and contouring. In this setting, it is injected into the skin or underlying tissue. Complications of HA filler injection have been relieved using hyaluronidase. However, there is no standard dose to adjust for undesirable HA filler lumpness. In this study, the authors tried to analyze any quantitative correlation between HA filler and hyaluronidase. The back of each rat (total 14 rats) was divided into 4 sites. A volume of 0.5 mL HA filler was injected into the subdermal layer at each site and HA filler nodules were created on the dorsum of each rat. Each nodule was allocated to groups 1, 2, 3, and 4 according to the different concentrations of hyaluronidase. As a result, the injected HA filler volume doubled within 4 days of injection, and then decreased slowly thereafter in group 1 (control group with normal saline only). A 30 unit hyaluronidase treatment compensated for the initial volume increase (approximately 30%) with HA filler (0.5 ml) at the fourth day. Sixty units of hyaluronidase reduced the initial volume (0.5 mL) of overinjected or misplaced HA filler on the fourth day. Approximately 90 units of hyaluronidase can reduce to the volume by 0.25 mL (50%) of the injected HA filler on the fourth day. The authors believe that this quantitative analysis of hyaluronidase concentration is helpful to plan the amount of hyaluronidase for correction of HA filler injection errors.

Hyaluronidase: Understanding Its Properties and Clinical Application for Cosmetic Injection Adverse Events.

The recent global consensus on the management of cosmetic aesthetic injectable complications from hyaluronic acid (HA) has increased the focus on the use of hyaluronidase more than ever before (M. Signorini et al., 2016). A comprehensive knowledge of facial anatomy, including structural positioning of facial arteries and veins, and an extensive knowledge of HA products available for injection procedures, combined with best practice protocols, will assist to prevent adverse events. Despite the growing number of patients using cosmetic fillers for facial restoration, the incidents incidence of adverse events remains low. Indeed, the avoidance of complications through safe and effective injection practice remains the key to preventing the need to use hyaluronidase.

Long-Term Tolerability, Safety, and Efficacy of Recombinant Human Hyaluronidase-Facilitated Subcutaneous Infusion of Human Immunoglobulin for Primary Immunodeficiency.

PURPOSE: Treatment of primary immunodeficiency diseases (PIDD) with subcutaneous (SC) infusions of IgG preceded by injection of recombinant human hyaluronidase (rHuPH20) (IGHy) to increase SC tissue permeability was evaluated in two consecutive, prospective, non-controlled, multi-center studies. METHODS: Subjects >4 years of age received SC IgG replacement at a weekly dose equivalent of 108 % of their previous intravenous (IV) dose, facilitated by prior injection of 75 U/g IgG of rHuPH20. Starting with weekly SC infusions, the interval was increased (ramped-up) to a 3- or 4-week schedule. RESULTS: Eighty-three subjects (24 < 18 years; 59 ≥ 18 years) received 2729 infusions (excluding ramp-up) at a mean dose of 0.155 g/kg/week in the pivotal and 0.156 g/kg/week in the extension study. IGHy exposure exceeded 30 months in 48 subjects. During 187.7 subject-years of IGHy exposure, 2005 adverse events (AEs) (10.68 per subject-year) occurred. The rate of related systemic AEs during consecutive 1-year periods remained low; the rate of related local AEs decreased from 3.68/subject-year in months 1-12 to approximately 1.50/subject-year after 30 months of treatment. Fifteen subjects transiently developed anti-rHuPH20 binding antibody. There was no difference in AE rates in these subjects before and after the first titer increase to ≥1:160. The rate of infections during IGHy exposure was 2.99 per subject-year and did not increase during the studies. Annual infection rates were 3.02 in subjects <18 years and 2.98 in subjects ≥18 years. CONCLUSIONS: Long-term replacement therapy with IGHy was safe and effective in 83 pediatric and adult subjects with PIDD.

Subcutaneous administration of human C1 inhibitor with recombinant human hyaluronidase in patients with hereditary angioedema.

BACKGROUND: The currently approved method of C1 inhibitor (C1 INH) administration for patients with hereditary angioedema with C1 INH deficiency (HAE) is by intravenous injection. A C1 INH subcutaneous formulation may provide an attractive mode of administration for some patients. OBJECTIVE: To evaluate efficacy and safety of two doses of subcutaneous, plasma-derived C1 INH with the dispersing agent, recombinant human hyaluronidase (rHuPH20) to prevent angioedema attacks in patients with HAE. METHODS: A randomized, double-blind, dose-ranging, crossover study, patients 12 years of age (n = 47) with a confirmed diagnosis of HAE were randomly assigned to receive subcutaneous injections of 1000 U C1 INH with 24,000 U rHuPH20 or 2000 U C1 INH with 48,000 U rHuPH20 every 3 or 4 days for 8 weeks and then crossed-over for another 8-week period. The primary efficacy end point was the number of angioedema attacks during each treatment period. RESULTS: The study was terminated early as a precaution related to non-neutralizing antibodies to rHuPH20 in 45% of patients. The mean standard deviation number of angioedema attacks during the 8-week treatment periods were 1.58 1.59 with 1000 U C1 INH and 0.97 1.26 with 2000 U. The mean (95% confidence interval [CI]) within-patient difference (2000 U-1000 U, respectively) was 0.61 (95% CI, 1.23 to 0.01) attacks per month (p = 0.0523), and 0.56 (95% CI, 1.06 to 0.05) attacks that required acute treatment, (p = 0.0315). No deaths or other serious adverse events were reported. Injection-site reaction was the most common adverse event. CONCLUSION: Despite early termination, this study demonstrated a clinically and statistically significant difference in burden of disease, which favored 2000 U C1 INH, without associated serious adverse events.

Chemical Substances Used in the Treatment of Ganglions Located in the Hand and Wrist.

The aim of this work was to compare different chemical substances used in the treatment of ganglions located in the hand and wrist region. Their basic properties and mechanisms of action have been described. Moreover, the risks associated with the use of particular substances have been highlighted and potential complications connected with their administration have been discussed. On the basis of the available literature, the results of ganglion aspiration treatment followed by an injection of a chemical substance into the cyst cavity have been assessed. In the authors' opinion, due to the existing risk of complications associated with this treatment, as well as the relatively high rate of ganglion recurrence, this procedure should only be performed by qualified medical personnel. The authors recommend observation in cases of asymptomatic ganglions of the hand and wrist, and operative treatment in cases in which pain, restriction of limb mobility and weakening of handgrip strength are observed.

Allergic reaction to hyaluronidase use after hyaluronic acid filler injection.

Hyaluronic acid (HA) is biocompatible, easy to use and reversible. HA fillers are considered to be safe, although some complications can occur. At this time, hyaluronidase is used off-label for correction. A 41-year-old woman presented to our clinic for focal erythematous plaque on hyaluronidase injection site. She got the injection for correction of HA filler excess. The skin lesion continued for 7 days. Histopathologic findings were nonspecific. On intradermal skin test, allergic reaction to hyaluronidase were confirmed. Adverse effects of this hyaluronidase are uncommon with local injection site reactions most frequently reported. Allergy to hyaluronidase should be included in the differential diagnosis when focal erythema and swelling occur after hyaluronidase injection.

The safety of recombinant human hyaluronidase PH20 in nonclinical models: An overview of toxicology, pharmacology, and impact of anti-PH20 antibodies.

Hyaluronan (HA) is a glycosaminoglycan that forms a gel-like barrier in the subcutaneous (SC) space, limiting bulk fluid flow and the dispersion of SC-administered therapeutics. Recombinant human hyaluronidase PH20 (rHuPH20) facilitates the rapid delivery of co-administered therapeutics by depolymerizing HA in the SC space. Administration of rHuPH20 can induce the formation of anti-rHuPH20 antibodies, or anti-drug antibodies (ADAs), with the potential to bind endogenous PH20 hyaluronidase in the adult testes and epididymis. Using a variety of relevant animal models and multiple dose regimens of rHuPH20 across the full spectrum of animal development, we demonstrated that rHuPH20 administration resulted in the formation of ADAs. Although these ADAs can bind both the recombinant rHuPH20 enzyme and recombinant versions of animal model-specific hyaluronidases, they had no impact on fertility parameters (as measured by sperm concentration and motility, litter size, and litter viability) or fetal development. We present the result of our nonclinical studies in order of the developmental lifecycle, beginning with adults. Toxicology studies that extend beyond the standard package are also presented. These studies demonstrate the favorable safety profile of rHuPH20 and ADAs in nonclinical models. Additionally, we identified substantial safety margins for clinically relevant doses of rHuPH20.

Subcutaneous administration of rituximab (MabThera) and trastuzumab (Herceptin) using hyaluronidase.

BACKGROUND: Rituximab and trastuzumab were the first therapeutic monoclonal antibodies (mAbs) approved in oncology. Both antibodies are delivered by the intravenous (IV) route, but recently subcutaneous (SC) formulations have been developed. Subcutaneous administration of mAbs can offer substantial patient and resource benefits compared with IV, but SC administration of some mAbs can be limited by drug volume. Recombinant human hyaluronidase (rHuPH20) temporarily degrades hyaluronan, allowing SC delivery of drug volumes that might not otherwise be feasible. METHODS: Clinical trials assessing coformulation of rituximab or trastuzumab with rHuPH20 for SC administration were reviewed. RESULTS: Phase I trials of rituximab SC maintenance therapy in patients with follicular lymphoma and trastuzumab SC in healthy volunteers and patients with early breast cancer have demonstrated substantially shorter administration times and comparable tolerability and pharmacokinetics compared with IV formulations. Rituximab SC 1400-mg and trastuzumab SC 600-mg doses were identified for further study. Phase III clinical data for rituximab SC 1400 mg have shown comparable efficacy to rituximab IV, and initial clinical data suggest comparable efficacy of trastuzumab SC 600 mg and the IV formulation. CONCLUSION: Coformulation with rHuPH20 may enable effective, well-tolerated, cost-effective, and convenient SC administration of rituximab and trastuzumab. Additional studies are ongoing.

Pharmacokinetics and pharmacodynamics of single subcutaneous doses of tocilizumab administered with or without rHuPH20.

OBJECTIVES: To investigate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of tocilizumab with and without rHuPH20 (a recombinant human hyaluronidase) in healthy volunteers. METHODS: This was an open-label, single ascending dose study. Subjects were assigned to tocilizumab 162 mg or tocilizumab 162, 324, or 648 mg plus rHuPH20. PK and PD samples were collected after dosing and were estimated with non-compartmental methods. Geometric mean ratio (GMR) for area under the plasma concentration-time curve from zero to infinity (AUC0-∞) and (maximum serum concentration) Cmax with and without rHuPH20 was estimated using one-way analysis of variance. Safety and tolerability were monitored throughout the study. RESULTS: 48 subjects (12/cohort) received a single dose of tocilizumab with or without rHuPH20. For tocilizumab 162 mg, tocilizumab 162 mg/rHuPH20, tocilizumab 324 mg/rHuPH20, and tocilizumab 648 mg/rHuPH20, mean ± SD tocilizumab PK parameters were 2,510 ± 1,060, 2,860 ± 468, 10,800 ± 3,220, and 29,900 ± 5,280 µg×h/ml for AUC0-∞; 11.5 ± 3.7, 16.2 ± 2.8, 43.8 ± 12.4, and 77.8 ± 14.5 µg/ml for Cmax; and 89.1 ± 41.1, 54.0 ± 19.5, 66.0 ± 26.8, and 86.1 ± 50.6 h for tmax, respectively. Coadministration of tocilizumab 162 mg with rHuPH20 resulted in slightly increased exposure: GMR (90% confidence interval) for AUC0-∞, 1.20 (1.00 - 1.44) and Cmax, 1.45 (1.24 - 1.70). Increasing tocilizumab doses resulted in significant deviation from dose proportionality for tocilizumab Cmax (p = 0.0057) and AUC0-∞ (p < 0.0001). Changes in interleukin-6, soluble interleukin- 6 receptor, and C-reactive protein were also dose dependent and similar with and without rHuPH20. CONCLUSIONS: Tocilizumab in combination with rHuPH20 resulted in slightly increased tocilizumab exposure compared with tocilizumab alone, whereas PD markers were comparable. Subcutaneous administration of tocilizumab with rHuPH20 was well tolerated.

Hyaluronidase toxicity: a possible cause of postoperative periorbital inflammation.

BACKGROUND: Periorbital inflammation following regional anaesthesia is commonly attributed to hyaluronidase allergy. This case series suggests an alternative explanation in some patients. DESIGN: Retrospective case series. PARTICIPANTS: Seven patients presenting with postoperative non-infectious periorbital inflammation following peribulbar or sub-tenons anaesthesia, presenting at four different institutions, are described. METHODS: Data on patient demographics, operative data, clinical presentation, treatment and allergy testing were collected among the four institutions. MAIN OUTCOME MEASURES: Response to treatment and allergy testing were noted among the patients included in this study. RESULTS: Seven patients (five female) underwent uneventful phacoemulsification under a peribulbar or sub-tenon's block, all including hyaluronidase with concentrations ranging 50-250 IU/mL. The onset of inflammatory symptoms and signs varied from 12 h to 3 days after the surgery. The most common form of presentation was lid swelling and chemosis. Patients were treated with oral corticosteroids, with good clinical response. Four patients underwent skin prick and intradermal testing to the local anaesthetic used, and to the suspect and a control hyaluronidase batch. The results were all negative, excluding allergy as the aetiology of this toxic periorbital syndrome, in at least these four patients. CONCLUSION: Hyaluronidase toxicity, potentially related to concentration of hyaluronidase, may be a cause of postoperative periorbital inflammation after cataract surgery, rather than hypersensitivity.