December 2014 FAQs

What evidence supports the efficacy of dalbavancin for the treatment of ABSSSIs?

Introduction

Acute bacterial skin and skin structure infections (ABSSSIs) are defined as bacterial infections of the skin including cellulitis, erysipelas, wound infections, or major cutaneous abscesses in which the lesion size is at least 75 cm².¹ Typical pathogens that cause ABSSSIs include gram-positive bacteria such as Streptococcus pyogenes andStaphylococcus aureus. Historically, skin infections caused by gram-positive organisms have been easily treatable with beta-lactam antibiotics.² However, in recent years, methicillin-resistant S. aureus (MRSA) has become a major threat in both community and healthcare settings because of its resistance to these agents. While new drugs have been developed to combat MRSA, increasingly resistant strains such as vancomycin-resistant S. aureus (VRSA), have risen as well. Standard-of-care treatment for serious MRSA skin infections include incision and drainage as well as pharmacotherapy using vancomycin, linezolid, daptomycin, telavancin, or clindamycin. ³ While these treatments are generally successful, the increasing prevalence of multi-drug resistant bacteria has renewed interest in the development of new potent antibiotics to combat this threat.²

Dalbavancin characteristics

Dalbavancin is a novel lipoglycopeptide antibiotic derived from a natural glycopeptide and chemically modified to enhance its antimicrobial activity and pharmacokinetic profile.² Like other glycopeptides, dalbavancin inhibits cell-wall synthesis by binding to terminal D-alanyl-D-alanine residues in peptidoglycan cell-wall precursors. The in vitro minimum inhibitory concentration (MIC) of dalbavancin is ≤1mg/L for over 99% of gram-positive isolates.

Dalbavancin has certain unique pharmacokinetic characteristics that distinguish it from other glycopeptides and enhance its utility for treating skin infections.² Likely due to its 93% protein binding, it has a half-life of approximately 8.5 days, allowing for a once-weekly dosing regimen. ⁴ Dalbavancin is also widely distributed and concentrations in skin blister fluid have been shown to be well above typical MIC values for over 7 days after the administration of 1 dose of 1000 mg. Moreover, dalbavancin does not interact with the cytochrome P450 enzyme system and has no known drug interactions. It is primarily excreted unchanged in the urine.

The approved dosing of dalbavancin is 1000 mg administered intravenously (IV) over 30 minutes on day 1 followed by 500 mg IV over 30 minutes on day 8. ⁴ For patients with severe renal failure (creatinine clearance below 30 mL/min and not on regular hemodialysis) the dose is reduced to 750 mg IV on day 1 followed by 375 mg IV on day 8. However, for patients on regularly scheduled hemodialysis, no adjustment is needed. Dalbavancin is generally well tolerated. Nausea, headache, and diarrhea are the most common adverse reactions to dalbavancin when taken at the usual dose. As with all antibiotics, dalbavancin may causeClostridium difficile-associated diarrhea. Anaphylactic reactions and infusion reactions have been observed as well.

Approval history

Dalbavancin was recently approved by the Food and Drug Administration (FDA) for the treatment of ABSSSIs caused by susceptible gram-positive organisms. ⁵ The New Drug Application (NDA) for dalbavancin for the treatment of complicated skin and skin structure infections (cSSSIs) had previously been submitted by Vicuron and Pfizer to the FDA for approval 3 times between 2004 and 2007, with evidence from phase 2 and phase 3 clinical trials. Each time, the FDA issued an approvable letter, stating that the drug could be approved after the correction of various deficiencies in the application, including chemistry, manufacturing, and labeling issues. In the 2007 letter, one of the issues cited was a lack of justification for the margin of inferiority used in one of the trials. Pfizer withdrew the NDA for dalbavancin in 2008 and transferred ownership to Durata Therapeutics in 2009. Meanwhile, in 2008, the Anti-Infective Drugs Advisory Committee (AIDAC) of the FDA proposed that a 10% noninferiority margin is acceptable for cSSSI trials. ⁶ This recommendation was incorporated into a 2013 FDA document offering guidance for conducting ABSSS trials.¹ This document also recommended a stricter primary end point of what was used in the earlier dalbavancin trials and defined the term ABSSSI in contrast with the previously used terminology of complicated and uncomplicated skin and skin structure infections. In 2012, dalbavancin became the first drug to be designated a qualified infectious disease product (QIDP) under the Generating Antibiotic Incentives Now (GAIN) provisions of the FDA Safety and Innovation Act, making it eligible for priority review and 5 additional years of exclusivity if approved.⁵After acquiring dalbavancin, Durata conducted 2 new phase 3 trials – DISCOVER 1 and 2 – in compliance with the new FDA recommendations.⁷ The approval of dalbavancin is primarily based on the results from these studies.

DISCOVER 1 & 2 trials

Data from both trials were pooled and reported in 1 publication.⁷ These were identically designed double-blind, double-dummy, multi-center, non-inferiority, randomized controlled trials that took place in 2011 and 2012 and included a total of 1312 patients with ABSSSIs. Patients could be included if they were adults with cellulitis, wound infection, or a major abscess, had a lesion size of at least 75 cm², were thought to require at least 3 days of IV antibiotic therapy, had one or more signs of systemic infection within 24 hours before randomization, and had at least 2 local signs of infection. Patients who had received antibiotics within the previous 2 weeks were excluded. All patients were stratified according to infection type and presence or absence of fever such that no more than 30% of patients in either group had major abscess and at least 25% had fever. They were randomized to receive either dalbavancin 1000 mg IV on day 1 and 500 mg IV on day 8 or vancomycin 1000 mg or 15 mg/kg IV every 12 hours for at least 3 days, optionally followed by oral linezolid 600 mg every 12 hours for a total duration of therapy of 10 to 14 days. The decisions of whether to use a fixed-dose or weight-adjusted dose of vancomycin and when to switch to oral linezolid were made by the clinician on site. Patients in the dalbavancin group were given placebo infusions or oral placebos every 12 hours for blinding purposes.

In compliance with FDA guidance, the primary end point was clinical response after 48 to 72 hours of therapy.⁷ Successful response was defined as no increase from baseline in the lesion area and absence of fever (defined as ≤37.6 ^○C) for 3 consecutive measurements taken 6 hours apart. Death within 72 hours, additional antibiotic treatment within 72 hours, requirement for unplanned surgical intervention, or missing data were all considered to be treatment failure. A pre-specified sensitivity analysis of the primary end point was conducted in which success was defined as a reduction in lesion size by 20% or more, without regard to fever. Secondary end points included clinical status at the end of therapy (defined in the supplemental material as decreased lesion size, temperature below 37.6 ^○C, absence of fluctuance and localized heat, and not worse than mild tenderness to palpation, swelling, or induration) as well as clinical response at the end of therapy as subjectively assessed by the investigators on-site. For the safety assessment, all adverse events that began or worsened between administration of the first dose of the study drug until day 70 were recorded and analyzed.

It was determined that 556 patients for each trial would be required to provide 90% power, assuming an 85% response rate for the primary end point and a one-sided alpha level of 0.025.⁷ A 10% non-inferiority margin was set for the primary end point such that the lower boundary of the 95% confidence interval (CI) must be above -10 percentage points in order to demonstrate noninferiority. All patients who underwent randomization were included in the intent-to-treat population which was analyzed for the primary end point. Adverse events were only analyzed in the population of patients who received at least 1 dose and secondary end points were only analyzed in the per-protocol population. Patients analyzed for microbiological outcomes had at least 1 gram-positive pathogen at baseline. Appropriate statistical tests were used.

Population characteristics at baseline – including age, sex, race, geographic region, history of IV drug use, infection type, diabetes status, fever, white blood cell (WBC) count above 12,000 cells/mm³, immature white blood cells (bands) above 10%, presence of systemic inflammatory response syndrome (SIRS), and size of infected area – were recorded and were similar among both groups in the pooled analysis.⁷ Most patients were male (59.6% in the dalbavancin group, 57.3% in the comparator group) and white (89.8% and 88.7%, respectively). Cellulitis was the most common infection type (53.7% and 53.4%, respectively). Slightly more than half of patients in each treatment group had SIRS (50.9% and 51.5%, respectively). It should be noted that while the median lesion size was 324 cm² in the pooled dalbavancin group and 367 cm² in the pooled comparator group, the smallest recorded lesions were 26 cm² (in DISCOVER 1) and 72 cm² (in DISCOVER 2), respectively. It is unclear why these subjects were included in the study as the minimum lesion size was set at 75 cm² according to the protocol. It is also unclear how many of these patients were included.

At the conclusion of both studies, it was determined in the pooled analysis of the primary end point that 79.7% of patients in the dalbavancin group had a successful early response to treatment compared with 79.8% of patients in the comparator group (difference of -0.1 percentage points; 95% CI -4.5 to 4.2), thus meeting the noninferiority margin.⁷ In DISCOVER 1, the success rates were 83.3% for dalbavancin and 81.8% for the comparator (difference of 1.5 percentage points; 95% CI -4.6 to 7.9) and in DISCOVER 2, they were 76.8% vs. 78.3%, respectively (difference of -1.5 percentage points; 95% CI -7.4 to 4.6). In the sensitivity analysis of the primary end point, a decrease of at least 20% of the infected area was found in 88.6% of patients in the dalbvancin group and 88.1% of patients in the comparator group (difference of 0.6 percentage points; 95% CI -2.9 to 4.1). The most common reason given for failure at 48 to 72 hours was missing temperature data, which partially accounts for the difference in success rates between the primary outcome and the sensitivity analysis. Other main reasons for failure were increased area of infection (6.2% of patients in the dalbavancin group and 5.1% of patients in the comparator group) and temperature > 37.6 ^○C (6.2% in the dalbavancin group and 6.6% in the comparator group).

For the secondary end point of clinical status at the end of therapy, 90.7% of patients in the dalbavancin group vs. 92.1% of patients in the comparator group were considered successes (difference of -1.5 percentage points; 95% CI -4.8 to 1.9).⁷ Ninety-six percent of patients in the dalbavancin group were considered to have improved at the end of therapy according to the subjective assessment of the investigator, compared with 96.7% in the comparator group (difference of -0.7 percentage points; 95% CI -3.0 to 1.5).

Pre-specified subgroup analyses were performed by infection type and pathogen.⁷ Overall, both early and end-of-therapy clinical response rates were found to be similar between the groups with the largest difference being in early response for major abscess (81.6% in the dalbavancin group vs. 86.1% in the comparator group). Analysis by pathogen was only performed for the secondary end points. Objective clinical response in patients with monomicrobial MRSA infection was reported in 66 out of 74 patients (89.2%) in the dalbavancin group compared with 48 out of 50 patients (96%) in the comparator group. However, the subjective investigator’s assessment of response at the end-of-therapy visit was reported to be positive in 72 out of 74 patients with MRSA in the dalbavancin group (97.3%) compared with 49 out of 50 patients in the comparator group (98%).

Total adverse events were experienced at a rate of 32.8% in the dalbavancin group compared with 37.9% in the comparator group (p=0.05).⁷ However, only 12.3% and 13.7% of patients in the respective groups experienced a treatment-related adverse event as determined by a blinded investigator (p=0.45). Serious adverse events related to treatment were experienced by 0.3% of patients in the dalbavancin group, compared with 0.6% in the comparator group (p=0.16). Serious treatment-related adverse events in the dalbavancin group included cellulitis and anaphylaxis, whereas in the comparator group they included gastrointestinal disorder, toxic nephropathy, and acute renal failure. The most common adverse events included nausea (2.5% in the dalbavancin group vs. 2.9% in the comparator group; p=0.62), diarrhea (0.8% vs. 2.5%, respectively; p=0.02), and pruritis (0.6% vs. 2.3%, respectively; p=.01). The authors report that some infusion-related events which occurred in the dalbavancin group were caused by placebo rather than dalbavancin infusions.

Based on the results, the authors concluded that once-weekly dalbavancin is noninferior to vancomycin/linezolid therapy for the treatment of ABSSSIs. ⁷ An ongoing phase 3 trial is being conducted to determine the efficacy of a single dose of 1500 mg of dalbavancin in comparison to the currently approved 2-dose regimen.⁸

Strengths and limitations

Overall, these studies provide strong evidence for the efficacy of dalbavancin in patients with ABSSSIs caused by gram-positive organisms.⁷ In contrast with earlier studies, the patient population is more strictly defined, and the primary end point is both stricter and more clinically relevant. The trials both were of a strong design (randomized controlled trials) and both contained objective and subjective measures of treatment success between the treatment groups. However, the studies do have some limitations to consider. First, there was a limited amount of data for infections caused by MRSA, yet the likely place in therapy for dalbavancin will be to combat MRSA-related infections. At least 2 patients with lesion sizes below the minimum requirement of 75 cm² were included, and while it unlikely that this had a significant effect on the outcome, the apparent unexplained violation of protocol compromises the internal validity of the study. Another limitation relates to the selection of the comparator regimen. While the authors claim that the comparator regimen is common in clinical practice, the guidelines that they reference do not mention linezolid.⁹ While other guidelines do recommend linezolid for MRSA skin infections², there is no specific data on the efficacy of a regimen consisting of vancomycin followed by linezolid.

Conclusion

The limitations of the studies do not significantly lessen the applicability of the authors conclusions, which is that dalbavancin is safe and effective for the treatment of ABSSSIs.⁷However, as the classification of ABSSSI is relatively new and might not be used in clinical practice, clinicians who intend to use dalbavancin should ensure that the infection being treated meets the criteria of ABSSSI as set forth in these trials. Moreover, while it may be safe to assume efficacy for certain less serious skin infections, such as minor cutaneous abscesses, caution should be exercised in order to prevent the emergence of resistance to dalbavancin. While dalbavancin has not been shown to be superior to any other agent in terms of efficacy, it does have an advantage over vancomycin and other IV-only agents in its ability to be used in an outpatient setting. It may also have an advantage over oral linezolid in outpatients for whom adherence is an issue. Data from these trials seem to indicate that dalbavancin may be safer than these agents, but long-term data is needed before this can be established.

References

1. Food and Drug Administration. Guidance for industry. Acute bacterial skin and skin structure infections: developing drugs for treatment. Food and Drug Administration website.http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071185.pdf. Published October 2013. Accessed December 1, 2014.

2. Bailey J, Summers K. Dalbavancin: a new lipoglycopetide antibiotic. Am J Health-Syst Pharm. 2008;65(7):599-610.

3. Liu C, Bayer L, Cosgrove SE, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011;52(3):e18-e55.

4. Dalvance [package insert]. Chicago, IL: Durata Therapeutics; 2014.

5. Nambiar S. Division director memo; NDA 21883, dalbavancin injection. Food and Drug Administration website.http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/021883Orig1s000SumR.pdf . Published May 23, 2014. Accessed December 1, 2014.

6. Kim J, Reller LB. Summary minutes of the anti-infective drugs advisory committee; November 18, 2008. Food and Drug Administration website.http://www.fda.gov/ohrms/dockets/ac/08/minutes/2008-4394m1-final%2018%20nov.pdf . Published December 9, 2008. Accessed December 1, 2014.

7. Boucher HW, Wilcox M, Talbot GH, et al. Once-weekly dalbavancin versus daily conventional therapy for skin infection. N Engl J Med. 2014;370(23):2169-2179.

8. Clinicaltrials.gov. http://clinicaltrials.gov/ct2/show/NCT02127970?term=dalbavancin&rank=1. Accessed December 1, 2014.

9. Rybak MJ, Lomaestro BM, Rotschafer JC, et al. Vancomycin therapeutic guidelines: a summary of consensus recommendations from the Infectious Diseases Society of America, the American Society of Health Systems Pharmacists, and the Society of Infectious Disease Pharmacists. Clin Infect Dis. 2009;49(3):325-327.

Prepared by:

Yaakov Samberg

Doctor of Pharmacy Candidate, 2015

College of Pharmacy

University of Illinois at Chicago

December 2014

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What treatment options are available for the reversal of novel oral anticoagulants?

Introduction

There are currently 3 Food and Drug Administration (FDA) approved novel oral anticoagulants (NOACs) agents: apixaban, rivaroxaban, and dabigatran. Apixaban and rivaroxaban are factor Xa inhibitors, which inhibit platelet activation and clot formation via reversible inhibition of factor Xa. These agents have been approved for use in the prevention and treatment of deep vein thrombosis (DVT), pulmonary embolism (PE), and stroke in postoperative patients with nonvalvular atrial fibrillation (AF).^1,2 Dabigatran is a direct thrombin inhibitor that inhibits both free and fibrin-bound thrombin. It has been approved for the prevention of stroke and treatment of DVT and PE in patients with nonvalvular AF.³ A major risk associated with any anticoagulant is bleeding, which is comparable or lower with the NOACs than with vitamin K antagonists (VKAs). When compared to VKAs, the NOACs have shown a reduction in the rates of major bleeding and intracranial hemorrhage.⁴ A recent meta-analysis found the rates for major bleeding to be 1.73% for VKAs and 1.08% for the NOACs (relative risk [RR] 0.63, 95% confidence interval [CI] 0.51 to 0.77, p<0.00001).⁵ The rates for clinically significant non-major bleeding were 8.5% for VKAs and 6.6% for NOACs (RR 0.74, 95% CI 0.59 to 0.93, p=0.01). Fatal bleeding was 0.18% for VKAs and 0.09% for NOACs (RR 0.51, 95% CI 0.26 to 1.01, p=0.05), with no difference between groups for all-cause mortality.

The new NOACs do not require routine laboratory monitoring, such as international normalized ratio (INR), prothrombin time (PT), or activated partial thromboplastin time (aPTT). These coagulation tests do not accurately reflect the effects these medications have on the patient’s hemodynamics, making reversal more challenging.⁶ In addition, there are currently no FDA approved reversal strategies for these agents, so knowing how to effectively reverse these agents is important for patient safety.

Current guideline and consensus recommendations

A consensus group at the Thrombosis and Hemostasis Summit of North America (THSNA) published a statement in 2012 to guide the reversal of the NOACs until more evidence-based guidelines were available.⁷ The authors first recommended supportive care (eg, fluid resuscitation, transfusions), identifying bleeding source, and surgical intervention as needed, after discontinuation of the drug. Activated charcoal or gastric lavage may be used an option in cases of overdoses, but only if the medication was taken within a few hours of presentation. Data support the use of dialysis for dabigatran, which can remove approximately two-thirds of the drug present. In animal studies, recombinant factor VIIa (rFVIIa) was shown to decrease bleeding time, but does not reverse the anticoagulant effect. Prothombin complex concentrates (PCCs) may increase the risk of thrombosis, and the available data for use of these agents are conflicting.⁷

Since the publication of the THSNA consensus statement, the American Society of Hematology has provided a clinical practice guide with information about the reversal of all 3 approved NOACs.⁸ The algorithm for reversal is dependent on the urgency of the need for reversal and patient renal function.

The first step in the algorithm is to hold any further doses of the NOAC.⁸ Table 1 provides data on how long the NOACs should be held, depending on the renal function of the patient, in cases of non-urgent bleeding. Table 1 also includes the assays that can be used to monitor the coagulation status of a patient.

For urgent bleeding, the recommendation is to first hold the NOAC and check an aPTT and PT.⁸ If the patient recently ingested the medication, activated charcoal can be used to remove some of the medication from the stomach. Activated charcoal can be given with 6 hours of apixaban ingestion, within 2 hour of dabigatran ingestion, and within 8 hours of rivaroxaban ingestion. If there is a normal aPTT or PT, then the source of the bleeding should be investigated. Supportive care with blood transfusions and local or surgical hemostatic measures should be considered. If there is a prolonged aPTT, it is possible that dabigatran may be contributing to the bleeding. With a prolonged PT, rivaroxaban may be present in the body and contributing. The guidelines recommend PCC, aPCC, or rFVIIa as possible reversal agents, with hemodialysis (for dabigatran only in the presence of renal failure).

Agents for reversal of NOACsFor urgent bleeding, the recommendation is to first hold the NOAC and check an aPTT and PT.⁸ If the patient recently ingested the medication, activated charcoal can be used to remove some of the medication from the stomach. Activated charcoal can be given with 6 hours of apixaban ingestion, within 2 hour of dabigatran ingestion, and within 8 hours of rivaroxaban ingestion. If there is a normal aPTT or PT, then the source of the bleeding should be investigated. Supportive care with blood transfusions and local or surgical hemostatic measures should be considered. If there is a prolonged aPTT, it is possible that dabigatran may be contributing to the bleeding. With a prolonged PT, rivaroxaban may be present in the body and contributing. The guidelines recommend PCC, aPCC, or rFVIIa as possible reversal agents, with hemodialysis (for dabigatran only in the presence of renal failure).

Unlike the NOACs, there are well-established recommendations for the reversal of VKAs.⁹Vitamin K can be used with fresh frozen plasma (FFP) or PCC to quickly reverse the INR and restore normal hemostasis in major bleeding. rFVIIa has also been used to reverse INR when used with vitamin K. ¹⁰

PCCs, aPCCs and rFVIIa have shown promising results in animal studies in reversing NOACs and improving aPTT, PT, and bleeding times, although there was no effect on total blood loss.¹¹ FFP has also been studied, but may require large volumes to be effective.¹⁰ Table 2 provides a description of the agents available for anticoagulant reversal with the doses used, as well as limitations associated with the use of each.

Case Reports

There have been a number of case reports that have described methods used to reverse or treat bleeding from the NOACs. These reports included 17 patients, 15 of whom were taking dabigatran. Two reports described successful treatment of bleeding due to rivaroxaban, and no case reports have been published concerning bleeding with apixaban. Out of the 17 patients described, 13 patients were successfully treated and made a recovery from their bleeding episode or injury. Fifteen patients on dabigatran presented with various active bleeding sites including gastrointestinal and intracranial. Five of the dabigatran patients were treated via hemodialysis, removing 62% to 87% of dabigatran from the body after treatment based on the case reports presented below. ¹⁴ Hemodialysis, aPCC, blood transfusions, and FFP were successful and the patients recovered; but the treatment with rFVIIa alone was not successful.

Table 3 provides a summary of case reports where patients presented with bleeding and needed the anticoagulant effects of the NOACs to be reversed. Baseline laboratory data, interventions used, and outcomes are presented.

Clinical Studies

Several clinical trials have been conducted to study the effects of the reversal agents, including rFVIIa, PCC, and aPCC, on rivaroxaban and dabigatran. Current studies have been conducted with small populations of healthy volunteers.

In a study by Eerenberg and colleagues, the authors studied if PCC could be used as an option to reverse the anticoagulant effects of either rivaroxaban or dabigatran. ²⁴ Twelve healthy subjects received either rivaroxaban 20 mg twice daily or dabigatran 150 mg twice daily for 3 days, followed by administration of PCC or placebo. The PCC used in this trial was a dose of 50 IU/kg of Cofact, a 4-factor PCC not available in the United States. After 11 days, the study procedure was repeated, but the anticoagulants were crossed-over between study populations. The study used surrogate markers for the endpoints of the study, including the coagulation tests of PT, aPTT, ecarin clotting time (ECT), and thrombin time (TT). After rivaroxaban administration, the PT was prolonged. Post PCC administration, the PT returned to within normal limits. After dabigatran administration, the aPTT, ECT, and TT were increased, but neither PCC nor saline infusion had any effect on reducing these prolongations. The authors only used a single high-dose of PCC for this trial, which may have contributed to why the coagulations tests in patients on dabigatran were not affected. Overall, only subjects in the rivaroxaban group had the effects reversed after PCC administration.

In another ex vivo study, Marlu and colleagues studied the effects of rFVIIa, a 4-factor PCC (Kanokad), and aPCC (FEIBA) to reverse the anticoagulant effects of the NOACs.²⁵ Ten healthy subjects received a one-time dose of either rivaroxaban 20 mg or dabigatran 150 mg. After a 15-day washout period, the study protocol was repeated. The investigators used peak concentration of thrombin, endogenous thrombin potential (ETP), lag time (LT), and time to peak (TTP) thrombin concentration as the outcomes, measured at baseline and 2 hours after administration of the NOACs. These outcomes were measured in vitro. The anticoagulant effects of rivaroxaban and dabigatran were shown by significant increases in PT and aPTT, respectively. Rivaroxaban also decreased thrombin peak concentrations and to a lesser extent ETP. For dabigatran, thrombin peak concentrations were not affected but ETP was reduced similar to rivaroxaban.

Three different concentrations of the reversal agents were mixed with plasma samples exposed to rivaroxaban and dabigatran; 0.5, 1.5, and 3 (~120 mcg/kg) mcg/mL for rFVIIa; 0.25, 0.5, 1 (~80 U/kg), and 2 U/mL for aPCC; and 0.25, 0.5 (~25 U/kg), and 1 U/mL for PCC.²⁵ The thrombin returned close to baseline with the 1 IU/mL concentration of PCC in the rivaroxaban-treated plasma samples. All 3 concentrations of rFVIIa kept the ETP close to rivaroxaban baseline, with no correction seen. Higher concentrations of PCC (> 0.5 IU/mL) overcorrected the ETP, while the 0.25 IU/mL concentration returned ETP to pre-rivaroxaban levels. All 3 concentrations of aPCC overcorrected the ETP in a dose-related fashion. For peak thrombin, only aPCC at 2 U/mL increased the value to near pre-rivaroxaban baseline. All 3 agents had some effect on increasing peak thrombin, with the greatest effects seen by aPCC, PCC, and then rFVIIa. For LT, rFVIIa had returned the value to near pre-rivaroxaban baseline, followed by aPCC, with PCC having little effect. TTP was not affected by PCC, but both rFVIIa and aPCC resulted in significant reductions (44% and 30%, respectively) versus rivaroxaban values.

For dabigatran, all concentrations of rFVIIa brought the ETP and TTP back to pre-dabigatran baseline. The highest concentration, 3 µg/mL, brought the LT back to pre-dabigatran baseline. All concentrations of aPCC and PCC increased ETP in a dose-dependent manner, with overcorrection for doses >0.25 U/mL. No concentration of PCC or aPCC corrected the LT to pre-dabigatran baseline. brought the ETP, LT or TTP back to baseline. Higher doses of aPCC (0.5 to 2 U/mL) reduced the LT significantly from dabigatran baseline.

Based on the results, all 3 reversal agents had some effect on the anticoagulant activity of dabigatran and rivaroxaban.²⁵ Lower doses of PCC corrected the ETP, but higher doses overcorrected, which may provide harm if used in an actual patient. Higher doses of aPCC also overcorrected, but lower doses returned the parameters closer to baseline, showing that it could work as an option for reversal. rFVIIa affected ETP, with little effects on TTP or LT. PCC and aPCC show better reversal profile that may benefit patients if they present with bleeding in the presence of NOACs.

In another study, Levi and colleagues compared 3-factor and 4-factor PCCs in reversal of rivaroxaban.²⁶ Thirty-five healthy subjects first received rivaroxaban 20 mg twice daily with meals for 4 days. On day 5, after the morning dose, the subjects received a 50U/kg bolus dose of either a 3-factor PCC (Profilnine), a 4-factor PCC (Beriplex, marketed as Kcentra in the United States), or placebo saline. The authors studied PT, ETP, TTP thrombin concentration, aPTT, and anti-Xa activity. The 4-factor PCC had a greater effect on the PT, reducing by 2.5 to 3.5 seconds compared to 0.6 to 1 seconds by the 3-factor PCC after 30 minutes. The 4-factor PCC also produced a sustained effect, lasting about 12 hours after the rivaroxaban dose compared to 5 hours for the 3-factor PCC. In comparison to placebo, ETP was increased by both PCCs used, with the 3-factor PCC having a faster onset (2 to 4 hours vs 6 to 8 hours). The 3-factor PCC had a greater effect on peak thrombin concentrations, with increases seen 4 hours after administration. TTP was reduced by both PCCs. Neither PCC reduced the aPTT back to the baseline. The authors determined that both PCCs could be used to reverse rivaroxaban, with the 4-factor PCC showing a greater effect in reducing PT prolongations, and 3-factor showing a greater effect on thrombin generation.

Reversal agents under development for NOACs

There are currently no FDA approved reversal agents for the NOACs. Several new reversal agents are in the process of phase II and III clinical trial testing through the FDA.

Andexanet alfa is a form of inactive factor Xa. In animal studies, this drug has been shown to bind to rivaroxaban and apixaban to neutralize the anticoagulant effects of these agents. Andexanet may have similar effects on low molecular weight heparin and fondaparinux.²⁷Idarucizumab, a monoclonal antibody, has shown evidence of reversal with dabigatran. Idarucizumab has been granted a Breakthrough Therapy Designation from the FDA, which will accelerate development and review of the medication.²⁸ As more data are published about these compounds, a reversal agent may soon be approved for use.

Table 4 summarizes a description of the new reversal agents that are currently under investigation by the FDA as well as the targeted agents they will reverse.

Conclusion

Bleeding with the NOACs can be serious and life-threatening. Current evidence, though limited , give support for the use of PCC, aPCC, rFVIIa, or dialysis; but treatment is dependent on the patient and the medication needing reversal. Recommendations from the American Society of Hematology have offered some guidance for the use of agents for reversal, with a treatment algorithm including supportive care and use of PCC, aPCC, or rFVIIa. From the case reports, some patients have been successfully treated with hemodialysis, aPCC, rFVIIa, FFP, and/or PCCs. However, most case reports have been for bleeding associated with dabigatran.

Based on primarily on ex vivo studies, both PCCs and aPCCs may be effective for bleeding and correction of coagulations parameters, especially for rivaroxaban. Overall these agents have had a greater effect on thrombin generation in comparison to rFVIIa. However, these trials were in vitro, so it may be difficult to extrapolate data for patients with active bleeding. No reports or studies about apixaban were available, which makes it difficult to extrapolate the data for bleeding episodes with this agent. In addition, there are reversal agents specific for NOACs currently being studied, which will impact the management of overdoses, hemorrhages, or major bleeding episodes associated with the NOACs.

References

1. Eliquis [prescribing information]. Princeton, NJ: Bristol-Myers Squibb; 2014.

2. Xarelto [prescribing information]. Gurabo, PR: Janssen Pharmaceuticals Inc; 2014.

3. Pradaxa [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; 2014.

4. Dentali F, Riva N, Crowther M, et al. Efficacy and safety of the novel oral anticoagulants in atrial fibrillation: a systematic review and meta-analysis of the literature. Circulation.2012;126(20):2381-2391.

5. Kakkos SK, Kirkilesis GI and Tsolakis IA. Efficacy and safety of the new oral anticoagulants dabigatran, rivaroxaban, apixaban, and edoxaban in the treatment and secondary prevention of venous thromboembolism: a systematic review and meta-analysis of phase III trials. [published online ahead of print] Eur J Vasc Endovasc Surg. 2014;S1078-5884. doi: 10.1016/j.ejvs.2014.05.001.

6. Siegal DM, Cuker A. Reveral of novel oral anticoagulants in patients with major bleeding. JThromb Thrombolysis. 2013;35(3):391-398.

7. Kaatz S, Kouides PA, Garcia DA, et al. Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors. Am J Hematol. 2012;87(Suppl 1):S141-145.

8. Cushman M, Lim W, and Zakai NA. Practice guideline on anticoagulant dosing and management of anticoagulant-associated bleeding complications in adults.http://www.hematology.org/Clinicians/Guidelines-Quality/Quick-Ref/2869.aspx . Updated Feb 2014. Accessed August 8, 2014.

9. Holbrook A, Schulman S, Witt DM, et al. Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012; 141(2)(Suppl):e152S-e184S.

10. Bauer KA. Reversal of antithrombotic agents. Am J Hematol. 2012;87(Suppl 1):S119-S126.

11. Suryanarayan D and Schulman S. Potential antidotes for reversal of old and new oral anticoagulants. Thromb Res. 2014;133(Suppl 2):S159-S166.

12. Patanwala AE. Acquisto NM, Erstad BL. Prothrombin complex concentrate for critical bleeding. Ann Pharmacother. 2011;45(7-8):990-999.

13. Bershad EN, Suarez JI. Prothrombin complex concentrates for oral anticoagulant therapy-related intracranial hemorrhage: a review of the literature. Neurocrit Care. 2010;12(3):403-413.

14. Singh T, Maw YY, Henry BL, et al. Extracorporeal therapy for dabigatran removal in the treatment of acute bleeding: a single center experience. Clin J Am Soc Nephrol. 2013;8(9):1533-1539.

15. FEIBA [prescribing information]. Westlake Village, CA: Baxter Healthcare Corporation; 2013.

16. NovoSeven RT [prescribing information]. Bagsvaerd, Denmark: Novo Nordisk; 2014.

17. Chiew AL, Khamoudes D, Chan BS. Use of continuous veno-venous hemodiafiltration therapy in dabigatran overdose. Clin Toxicol. 2014;52(4):283-287.

18. Schulman S, Ritchie B, Goy JK, et al. Activated prothrombin complex concentrate for dabigatran-associated bleeding. Br J Haematol. 2014;164(2):308-310.

19. Dumkow LE, Voss JR, Peters M, et al. Reversal of dabigatran inducing bleeding with a prothrombin complex concentrate and fresh frozen plasma. Am J Health-Sys Pharm. 2012;69(19):1646-1650.

20. Garber ST, Sivakumar W, Schmidt RH. Neurosurgical complications of direct thrombin inhibitors–catastrophic hemorrhage after mild traumatic brain injury in a patient receiving dabigatran. J Neurosurg. 2012;116(5):1093-1096.

21. Béné J, Said W, Rannou M, et al. Rectal bleeding and hemostatic disorders induced by dabigatran etexilate in 2 elderly patients. Ann Pharmacother. 2012;46(6):e14.

22. Kiraly A, Lyden A, Periyanayagam U, Chan J, and Pang PS. Management of hemorrhage complicated by novel oral anticoagulants in the emergency department: case report from the Northwestern Emergency Medicine Residency. Am J Ther. 2013;20(3):300-306.

23. Kasiwal MK, Panos NG, Munoz LF, et al. Outcome following intracranial hemorrhage associated with novel oral anticoagulants. [published online ahead of print]. J Clin Neurosci. 2014; doi.org/10.1016/j.jocn.2014.05.025 .

24. Eerenberg ES, Kamphuisen PW, Sijpkens MK, et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate. Circulation. 2011;124(14):1573-1579.

25. Marlu R, Hodaj E, Paris A, et al. Effect of non-specific reversal agents of anticoagulant activity of dabigatran and rivaroxaban. Thromb Haemost. 2012;108(2):217-224.

26. Levi M, Moore KT, Castillejos CF, et al. Comparison of three-factor and four-factor prothrombin complex concentrates regarding reversal of the anticoagulant effects of rivaroxaban in healthy volunteers. [published online ahead of print]. J Thromb Haemostat. 2014; doi: 10.1111/jth.12599.

27. Lu G, DeGuzman FR, Hollenback SJ, et al. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med. 2013;19(4):446-451.

28. Boehringer Ingeheim. Press Release Archive. Boehringer Ingelheim’s Investigational Antidote for Pradaxa®(dabigatran etexilate mesylate) Receives FDA Breakthrough Therapy Designation. http://us.boehringer-ingelheim.com/news_events/press_releases/press_release_archive/2014/06-26-14-boehringer-ingelheim-investigational-antidote-pradaxa-dabigatran-etexilate-mesylate-fda-breakthrough-therapy-designation.html . Updated June 26, 2014. Accessed August 15, 2014.

29. Clinical Developments. Portola Pharmaceuticals. http://www.portola.com/clinical-development/andexanet-alfa-prt4445-fxa-inhibitor-antidote/ . Accessed July 30, 2014.

30. Portola Pharmaceuticals. Phase 2 healthy volunteer study to evaluate the ability of PRT064445 to reverse the effects of several blood thinner drugs on laboratory tests. 2012. Clinical Trials Identifier, NCT01758432. http://clinicaltrials.gov/show/ NCT01758432. Accessed August 14, 2014.

31. Boehringer Ingelheim. A phase III case series clinical study of the reversal of the anticoagulant effects of dabigatran by intravenous administration of 5.0 g idarucizumab (BI 655075) in patients treated wtih dabigatran etexilate who have uncontrolled bleeding or require emergency surgery or procedures. RE-VERSE AD (A Study of the RE-VERSal Effects of Idarucizumab on Active Dabigatran) Trial. 2014. Clinical Trials Identifier, NCT02104947. http://clinicaltrials.gov/show/NCT02104947. Accessed July 30, 2014.

Prepared by:

Carol Posky, PharmD

PGY2 Drug Information Resident

College of Pharmacy

University of Illinois at Chicago

December 2014

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What is the evidence for the safety and efficacy of tedizolid for the treatment of ABSSSIs?

Introduction

Acute bacterial skin and skin-structure infections (ABSSSIs) are frequently seen in healthcare settings.¹ Between 2001 and 2003, over 400 per 10,000 outpatient visits were due to ABSSSIs. The Food and Drug Administration (FDA) considers cellulitis, erysipelas, wound infections, and major cutaneous abscesses to be ABSSSIs.² These types of infections are primarily caused by Staphylococcus aureus and Streptococcus pyogenes. Treatment of ABSSSIs involves a combination of supportive care, surgery, and antibiotic therapy.³ The overuse of antibiotics has led to an increase in multidrug-resistant (MDR) pathogens, of which methicillin-resistant S. aureus (MRSA) is of primary concern. Vancomycin and linezolid are the gold standards for treatment of ABSSSIs caused by MDR pathogens.⁴ However, growth of vancomycin resistance and the risk of serious adverse effects associated with linezolid (reversible thrombocytopenia and bone marrow suppression) has increased the demand for new antimicrobial agents for the treatment of ABSSSIs.

In June 2014, the FDA approved tedizolid, a novel second-generation oxazolidinone antibacterial agent, for the treatment of ABSSSIs caused by gram-positive pathogens.^4,5 It works by binding to 23S ribosomal RNA of the 50S subunit, which prevents formation of the 70S initiation complex and inhibits protein synthesis. As a result of its unique mechanism of action, cross-resistance with other classes of antibiotics is unlikely. The results of phase 3 published clinical trials showed that tedizolid was noninferior to linezolid for the treatment of ABSSSIs.^6,7

Tedizolid characteristics

Tedizolid is given in its prodrug form, tedizolid phosphate.⁵ When tedizolid phosphate is taken orally, it is converted into its active form, tedizolid, which has a bioavailability of 91%. Studies have shown similar pharmacokinetic profiles between tedizolid and its prodrug when administered orally as single or multiple daily doses.⁸ Tedizolid is available as an intravenous (IV) and oral formulation; dose adjustments are not necessary when converting from one formulation to the other. Tedizolid exhibits similar inhibitory effects when given with or without food.^4,8 The volume of distribution ranges from 108 to 143 L in adults, and is primarily distributed in muscle. Tedizolid is metabolized via sulfation and excreted as an inactive sulfate in the feces and urine. The half-life ranges from 9.3 to 13.4 hours, depending on the dose given and route of administration. Dose modifications are not required for patients with renal or hepatic dysfunction; however, patients should be closely monitored.

Tedizolid has antimicrobial activity against S. aureus (including MRSA), Streptococcusspecies, Enterococcus species, and few anaerobes.⁴ In vitro, tedizolid was seen to be 4 to 8 times more potent against staphylococci and 4 times more potent against enterococci and streptococci compared to linezolid. Numerous studies have demonstrated tedizolid’s antimicrobial activity against linezolid-resistant staphylococci, vancomycin-susceptible enterococci, vancomycin-resistant enterococci (VRE), and streptococcus species.

The recommended dose of tedizolid is 200 mg orally or as an IV infusion once daily for 6 days.^4,5 The most common adverse effects included nausea, headache, diarrhea, vomiting, and dizziness. A clinical review by Das and colleagues addressed the safety concerns and potential drug interactions with tedizolid.⁹ An in vitro study showed tedizolid reversibly inhibited monoamine oxidase (MAO), but to a lesser degree than linezolid.^9,10 The concomitant use of selective serotonin receptor inhibitors (SSRIs) and tedizolid was examined in an animal study and showed that tedizolid does not exhibit serotonergic effects.⁹ Another study monitored blood pressure and heart rate with tedizolid and the known adrenergic agents, pseudoephedrine and tyramine. An elevation in blood pressure or heart rate was not observed when tedizolid was given with pseudoephedrine, but an increase in palpitations was seen with tyramine. Overall, tedizolid is shown to have a favorable safety profile with few drug-drug interactions.

Literature review

ESTABLISH-1 was a randomized, double-blind, double-dummy, multicenter, multinational, phase 3 noninferiority trial of 667 patients with ABSSSIs. ⁷ The objective of this trial was to establish noninferiority of tedizolid against linezolid in treating ABSSSIs, and to compare the safety of the 2 agents. Patients were at least 18 years old and had to present with an ABSSSI with at least 1 local and 1 regional or systemic sign of infection. Participants were randomized to oral tedizolid 200 mg daily for 6 days (n=332) or oral linezolid 600 mg daily for 10 days (n=335). Participants were also stratified based on presence of fever, study center location, and the type of ABSSSI present. The types of infection present for tedizolid and linezolid groups, respectively, were cellulitis/erysipelas (40.7% vs. 41.5%), major cutaneous abscesses (30.1% vs. 29.3%), and infected wounds (29.2% vs. 29.3%). The median infection area was 188 cm² for the tedizolid group, and 190 cm² for linezolid. The most common pathogen isolated from the primary ABSSSI site was S. aureus (82%), with MRSA making up 42.1% of those pathogens in the tedizolid group and 43.1% in the linezolid group.

The primary endpoint measured in ESTABLISH-1 was early clinical response 48 to 72 hours after the first dose was administered.⁶ Early clinical response was defined as no increase in lesion surface area and no fever (oral temperature of ≤36.7 °C). Secondary endpoints included sustained clinical response at the end of treatment and up to 14 days post-treatment. Adverse event were also reported.

Results of the trial showed that the primary endpoint was met with a clinical response rate at 48 to 72 hours of 79.5% vs. 79.4% (tedizolid vs. linezolid) and a treatment difference of 0.1% (95% confidence interval [CI] -6.1% to 6.2%).⁶ Secondary endpoints included a sustained clinical response at the end of treatment of 69.3% vs. 71.9% (tedizolid vs. linezolid), with a treatment difference of -2.6% (95% CI -9.6% to 4.2%). Additionally, investigator-assessed clinical treatment response at post-treatment evaluation was 85.5% vs. 86% (tedizolid vs. linezolid), with a treatment difference of -0.5% (95% CI -5.8% to 4.9%). The most common adverse events reported for the tedizolid and the linezolid groups, respectively, included nausea (8.5% vs. 13.4%), headache (6.3% vs. 5.1%), and diarrhea (4.5% vs. 5.4%). The occurrence of serious adverse events was low, excluding a single death attributed to sepsis and unrelated to the study treatment. The authors concluded that tedizolid was noninferior to linezolid for the treatment of ABSSSIs.

ESTABLISH-2 was a randomized, double-blind, multi-centered, multi-national, phase 3, noninferiority trial involving 666 participants.⁷ The objective of this trial was to establish noninferiority of IV to oral tedizolid 200mg daily for 6 days (n=332) to linezolid 600 mg twice daily for 10 days (n=334) in treating ABSSSIs, and document associated adverse events. Participants were age 12 or older, with an ABSSSI of 75 cm² or greater and at least 1 systemic or regional sign of infection. The types of infection present included cellulitis or erysipelas (50% in both groups) major cutaneous abscess (20% in both groups), and infected wounds (30% tedizolid vs. 29% linezolid). The most common pathogen isolated from the primary ABSSSI site was S. aureus (82%), with MRSA making up 27% of those pathogens in the tedizolid group and 56% in the linezolid group.

In the ESTABLISH-2 trial, the primary endpoint was early clinical response at the 48 to 72 hour assessment after the first dose.⁷ Early clinical response was defined as >20% reduction in lesion size from baseline. Secondary endpoints were response at day 7, at the end of treatment, and 7 to 14 days after the end of treatment. Patients were administered IV therapy at the start of treatment. Patients were switched to oral administration if they met at least 2 of the following criteria: no increase in primary lesion area from baseline, temperature <37.7 °C, no worsening of local signs and symptoms at primary infection site, or improvement of 1 or more local signs and symptoms from the previous visit.

Primary endpoint results in ESTABLISH-2 showed an early clinical response of 85% vs. 83% (tedizolid vs. linezolid), with a treatment difference of 2.6% (95% CI -3% to 8.2%). Secondary endpoint results showed a clinical response at day 7 of 93% vs. 92% (tedizolid vs. linezolid), with treatment difference of 0.9% (95% CI -3.2% to 4.9%); clinical response at end of treatment (day 11) of 92% vs. 90% (tedizolid vs. linezolid), with a treatment difference of 1.4% (95% CI -3% to 5.9%); and clinical response 7 to 14 days post-treatment of 88% vs. 88% (tedizolid vs. linezolid), with a treatment difference of 0.3% (95% CI -4.8% to 5.3%). The adverse events in the ESTABLISH-2 trial were similar to ESTABLISH-1 with 16% of the tedizolid group and 21% of the linezolid group experiencing gastrointestinal effects. Data from the trial showed tedizolid, given IV with the option to be switched to oral, was noninferior to linezolid for the treatment of ABSSSIs.

Conclusion

Tedizolid is a novel oxazolidinone antimicrobial with potent in vitro activity against MRSA, VRE, and linezolid-resistant staphylococci. It was found to be noninferior to linezolid in treatment of ABSSSIs in 2 phase 3 trials. Tedizolid has similar to lower rates of adverse effects when compared to linezolid. Regarding drug-drug interactions, tedizolid does not have the same adverse effects with MAO-inhibitors and SSRIs compared to linezolid. Tedizolid has a linear predictable pharmacokinetic profile with a 1:1 IV to oral switch. In comparison to linezolid, tedizolid has a shorter duration of therapy with once daily dosing. With the increasing bacterial resistance to linezolid and vancomycin, tedizolid is a potential alternative for the treatment of ABSSSIs.

References

1. Corey GR, Stryjewski ME. New rules for clinical trials of patients with acute bacterial skin and skin-structure infections: do not let the perfect be the enemy of the good. Clin Infect Dis. 2011;52(suppl 7):S469-S476.

2. Food and Drug Administration. Guidance for Industry. Acute bacterial skin and skin structure infections: developing drugs for treatment. Food and Drug Administration website.http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071185.pdf. Updated October 2013. Accessed December 1, 2014.

3. Dryden MS. Novel antibiotic treatment for skin and soft tissue infection. Curr Opin Infect Dis. 2014;27(2):116-124.

4. Kisgen JJ, Mansour H, Unger NR, Childs LM. Tedizolid: a new oxazolidinone antimicrobial.Am J Health Syst Pharm. 2014;71(8):621-633.

5. Sivextro [package insert]. Lexington, MA: Cubist; 2014.

6. Prokocimer P, De Anda C, Fang E, Mehra P, Das A. Tedizolid phosphate vs linezolid for treatment of acute bacterial skin and skin structure infections: the ESTABLISH-1 randomized trial. JAMA. 2013;309(6):559-569.

7. Moran GJ, Fang E, Corey GR, Das AF, De anda C, Prokocimer P. Tedizolid for 6 days versus linezolid for 10 days for acute bacterial skin and skin-structure infections (ESTABLISH-2): a randomised, double-blind, phase 3, noninferiority trial. Lancet Infect Dis. 2014;14(8):696-705.

8. Flanagan SD, Bien PA, Muñoz KA, Minassian SL, Prokocimer PG. Pharmacokinetics of tedizolid following oral administration: single and multiple dose, effect of food, and comparison of two solid forms of the prodrug. Pharmacotherapy. 2014;34(3):240-250.

9. Das D, Tulkens PM, Mehra P, Fang E, Prokocimer P. Tedizolid phosphate for the management of acute bacterial skin and skin structure infections: safety summary. Clin Infect Dis. 2014;58(suppl 1):S51-S57.

10. Flanagan S, Bartizal K, Minassian SL, Fang E, Prokocimer P. In vitro, in vivo, and clinical studies of tedizolid to assess the potential for peripheral or central monoamine oxidase interactions. Antimicrob Agents Chemother. 2013;57(7):3060-3066.

Prepared by:

Daniel Ky

Doctor of Pharmacy Candidate, 2015

College of Pharmacy

University of Illinois at Chicago Rockford Campus

December 2014

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