July 2018 FAQs

What is the efficacy and safety of IV acetaminophen when compared to oral acetaminophen?

What is the efficacy and safety of IV acetaminophen when compared to oral acetaminophen?

Introduction

Previously, in July 2016, the Drug Information Group reviewed the comparative evidence on the use of intravenous (IV) acetaminophen versus oral acetaminophen, which can be accessed here.¹ At that time, the number of studies that were available regarding IV acetaminophen compared to the oral formulation in various populations were limited.^2-5 Studies had a small sample population and were limited to single centers. Literature published since the previous frequently asked question (FAQ) have compared the efficacy of IV acetaminophen to oral acetaminophen primarily in patients undergoing orthopedic surgery. This article summarizes the recent orthopedic surgical data regarding the use of IV acetaminophen over oral acetaminophen postoperatively.

Update

Guideline recommendations

While there are no specific guidelines for the management of postoperative pain in orthopedic patients, the American Pain Society, American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists published a general guideline on the management of postoperative pain in 2016.⁶ The guideline recommends that patients are given multimodal analgesia including options and techniques that incorporate both pharmacologic and non-pharmacologic interventions. This specifically includes utilizing acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) in these multimodal analgesic protocols to control pain among other therapies. In regards to IV versus oral administration, studies showed no obvious difference between the two other than faster onset with IV administration.^2,5 Studies comparing acetaminophen to placebo showed clinical outcomes favoring acetaminophen but previous studies comparing IV to oral did not show significant clinical benefit.^2-5,7 The 2016 guideline concludes that no clear differences in efficacy between IV and oral acetaminophen have been demonstrated.⁶

Evidence

The Table below summarizes recent comparative studies of IV acetaminophen to oral acetaminophen in orthopedic surgical patients.^8,9,11,12 There were 2 randomized controlled trials, one retrospective review, and one quasi-experimental study that evaluated clinical outcomes comparing the two arms. The results of the randomized controlled trials showed minimal benefit provided by IV acetaminophen over oral acetaminophen.^8,9 No statistical difference was demonstrated in terms of pain scores or opioid consumption at 24 hours postoperatively. Politi and colleagues found a statistical difference in pain scores between 0 to 4 hours postoperatively but scores only differed by 1 point on the visual analogue scale.⁹ While this was statistically significant, clinical significance seems limited. In both studies, the sample size was small and was limited to a single center.

A recent systematic review and meta-analysis of these 2 randomized clinical trials was conducted by Sun and colleagues.¹⁰. The meta-analysis evaluated pooled clinical outcomes that included visual analogue scale (VAS) scores, opioid consumption, length of hospital stay, and postoperative complications such as nausea, vomiting, and constipation. The meta-analysis did not show a significant difference between the two arms when comparing the mean difference between pain scores at 12 hours (weighted mean difference [WMD] = -0.407, 95% confidence interval [CI]: -0.944 to 0.131, P = 0.138) or 24 hours postoperatively (WMD = -0.340, 95% CI: -0.888 to 0.208, P = 0.223). There was no significant difference between opioid consumption at 12, 24 and 48 hours, length of hospital stay, or postoperative complications (nausea, vomiting, or constipation). The authors concluded that there was no significant difference in clinical outcomes or postoperative-related complications when using IV acetaminophen compared to oral acetaminophen.

Hansen et al conducted a retrospective review that looked at IV acetaminophen compared to oral acetaminophen in the first 3 days after spine surgery.¹¹ They evaluated length of stay, average unadjusted hospitalization cost, opioid consumption, and complication rates. The study demonstrated a statistical benefit of IV acetaminophen in surgical spine patients in all outcomes. The evidence provided by this study is weak due to the lack of randomization, the retrospective nature of the study, and the inability to control for all confounding factors. The funding was also provided by a manufacturer of IV acetaminophen which could impact the cost analysis of the medication. They reported lower hospitalization cost with IV acetaminophen compared to oral but this could be biased due to the nature of the funding.

Foley et al [abstract] conducted a before and after study in which the protocol for patients undergoing hip or knee replacement was switched from use of IV acetaminophen (before) to oral acetaminophen (after).¹² They showed that mean opioid consumption from 0 to 6 hours was statistically higher in the IV acetaminophen group and there was no difference at 24 hours between the two groups. They also showed that switching to oral acetaminophen did not negatively affect the outcomes when comparing mean pain scores, time to first rescue medication, or post-anesthesia care unit (PACU) length of stay. They also did not observe any adverse events in either group. The information from this is limited though because the full study is yet to be published.

Conclusion

Intravenous acetaminophen has a quicker onset of action compared to oral acetaminophen but in the use of adequate pain control, the IV formulation compared to the oral route in orthopedic surgical patients showed no clinically significant differences in outcomes. The trials comparing oral to IV acetaminophen in orthopedic surgical patients were small in nature and most were limited to single center designs. The literature supporting use of IV acetaminophen in orthopedic surgical patients is limited and of poor quality. Without a significant difference in outcomes, use of either oral or IV acetaminophen should be based on other patient and cost factors.

Table 1. Comparative studies between IV and oral acetaminophen in orthopedic surgical patients.^8-9,11-12

Study design and duration	Subjects	Interventions	Results	Conclusions/Limitations
O’Neal 2017⁸ RCT, DB, SC, PC Duration: 4 hours post-operatively	N=174 patients undergoing unilateral TKA under spinal anesthesia	IV APAP 1 g and oral placebo (n=57) Oral APAP 1 g and volume-matched normal saline (100 mL) (n=58) Oral placebo and volume-matched normal saline (100 mL) (n=59) Medications were administered at the conclusion of surgery and before PACU admission All patients received standard preoperative and perioperative multimodal analgesia.	Average (± standard deviation) pain scores in PACU using a NRS from 0-10 were similar across all groups IV APAP: 0.56 ± 0.99 Oral APAP: 0.67 ± 1.20 Placebo: 0.58 ± 0.99 IV vs. oral APAP: p=0.84 IV vs. placebo: p=0.71 Total opiate consumption within 6 hours and 24 hours after surgery was not statistically significant (p=0.46) Time to rescue analgesia (p=0.47) or time to breakthrough pain (p=0.92) in minutes was not statistically significant Time to breakthrough pain in minutes was not statistically different (p=0.92) Time until ready for PACU discharge was not statistically significant between groups and among all 3 groups	Conclusion: No statistically significant benefit was demonstrated favoring IV APAP over oral APAP or placebo for pain control for perioperative TKA patients Limitations: Small sample size SC design
Hansen 2017¹¹ Retrospective cohort study Duration: 3 days post-operatively	N=112,586 patients given either IV APAP or oral APAP during the first 3 post-operative days after spine surgery	IV APAP started on day of surgery and continued to post-operative day 3 (N = 51,835) Oral APAP started on day of surgery and continued to post-operative day 3 (N = 60,751)	Mean unadjusted LOS for IV APAP was statistically significant (3.2 vs 4.9 days, p < 0.0001) IV APAP was significantly lower than oral APAP for average unadjusted hospitalization cost ($24,800 vs. 29,366, p < 0.0001) Average opioid MED for IV APAP was 43.1 mg vs 50.8 mg for oral APAP (p <0.0001) Opioid related complication rates consisting of nausea and vomiting, respiratory depression, and bowel obstruction were statistically lower for IV APAP 30-day readmission to same hospital was significantly lower in the IV APAP group (OR: 0.78, 95% CI: 0.65-0.91, p < 0.0001)	Conclusion: IV APAP showed statistical benefit in surgical spine patients in regards to LOS, hospital cost, decrease opioid consumption, less complication rates, and decrease in 30-day readmission rates Limitations: Lack of randomization Confounders in the form of additional sources of pain control or regional anesthesia Limited to data from database Source of funding from the manufacturer
Politi 2017⁹ Prospective, SC, RCT Duration: 24 hours post-operatively	N=120 patients undergoing hip and knee arthroplasties performed by a single joint arthroplasty surgeon	IV APAP 1g preoperatively and every 6 hours post-operatively (n=63) Oral APAP 1g preoperatively and every 6 hours post-operatively (n=57) All patients received standard multimodal perioperative pain regimen	24 hour mean visual analog scale scores were 3.00 in IV APAP and 3.40 in oral APAP (p=0.06) Only the first 4-hour interval of VAS scores was statistically significant which favored IV APAP (3.375 vs 4.402, p=0.033) 24-hour average hydromorphone equivalents given to patients were not statistically different between the groups (3.71 vs 3.48 mg, p=0.76) or at any 4-hour interval	Conclusion: IV APAP provides little additional benefit over oral APAP in hip and knee arthroplasties Statistical significance was only seen in the first 4 hours post-operatively with only 1 point difference in scores, thus limiting clinical significance Limitations: Information regarding pain assessment was not provided Small sample size
Foley 2016¹² [Abstract] Quasi-experimental study	N=149 patients undergoing hip or knee replacement surgery	Before: IV APAP 1 g one time perioperative dose (N = 78) After: Oral APAP 1 g 30-60 minutes preoperatively (N = 71)	Median opioid consumption from 0 to 6 hour postoperatively statistically higher in the IV APAP group vs oral APAP (65 mg vs 45 mg, p=0.010) while no difference was found from 6 to 24 hours postoperatively Median pain score postoperatively, time to 1^st rescue medication, and PACU LOS were similar between groups No adverse effects were seen in either group	Conclusion Use of oral APAP did not negatively affect outcomes when compared to IV APAP Oral APAP demonstrated decrease opioid consumption immediately postoperatively Limitations Abstract only Quasi-experimental study design
Abbreviations: APAP = acetaminophen; CI = confidence interval; DB = double blind; IV = intravenous; LOS = length of stay; MED = morphine equivalent dose; NRS = numeric rating scale; OR = odds ratio; PACU = post-anesthesia care unit; PC = placebo-controlled; RCT = randomized control trial; SC = single-center; TKA = total knee arthroplasty.

References

UIC Drug Information Group. What is the comparative evidence on use of IV acetaminophen versus oral acetaminophen? UIC Drug Information Group website. https://pharmacy.uic.edu/departments/pharmacy-practice/centers-and-sections/drug-information-group/2014/2016-faq-s/jul-2016-faqs. Published June 2016. Accessed May 21, 2018.
Pettersson PH, Jakobsson J, Owall A. Intravenous acetaminophen reduced the use of opioids compared with oral administration after coronary artery bypass grafting. J Cardiothorac Vasc Anesth. 2005;19(3):306-309.
Nour C, Ratsiu J, Singh N, et al. Analgesic effectiveness of acetaminophen for primary cleft palate repair in young children: a randomized placebo controlled trial. Paediatr Anaesth. 2014;24(6):574-581.
Fenlon S, Collyer J, Giles J, et al. Oral vs intravenous paracetamol for lower third molar extractions under general anaesthesia: is oral administration inferior? Br J Anaesth. 2013;110(3):432-437.
Brett CN, Barnett SG, Pearson J. Postoperative plasma paracetamol levels following oral or intravenous paracetamol administration: a double-blind randomised controlled trial. Anaesth Intensive Care. 2012;40(1):166-171.
Chou R, Gordan D, de Leon-Casasola O. Management of postoperative pain: a clinical practice guideline from the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists’ Committee on Regional Anesthsia, Excutive Committee, and Administrative Council. J Pain. 2016;17(2): 131-157.
McNicol ED, Ferguson MC, Haroutounian S, Carr DB, Schumann R. Single dose intravenous paracetamol or intravenous propacetamol for postoperative pain. Cochrane Database Syst Rev. 2016;(5): CD007126. doi: 10.1002/14651858.CD007126.pub3.
O'Neal JB, Freiberg AA, Yelle MD. Intravenous vs oral acetaminophen as an adjunct to multimodal analgesia after total knee arthroplasty: a prospective, randomized, double-lind clinical trial. J Arthroplasty. 2017;32(10):3029-3033.
Politi JR, Davis RL, Matrka AK. Randomized prospective trial comparing the use of intravenous versus oral acetaminophen in total joint arthroplasty. J Arthroplasty. 2017;32(4):1125-1127.
Sun L, Zhu X, Zou J, Li Y, Han W. Comparison of intravenous and oral acetaminophen for pain control after total knee and hip arthroplasty: A systematic review and meta-analysis. Medicine (Baltimore). 2018;97(6):e9751. doi: 10.1097/MD.0000000000009751.
Hansen RN, Pham AT, Böing EA, Lovelace B, Wan GJ, Miller TE. Comparative analysis of length of stay, hospitalization costs, opioid use, and discharge status among spine surgery patients with postoperative pain management including intravenous versus oral acetaminophen. Curr Med Res Opin. 2017;33(5):943-948.
Foley K., Skrupky L., Waise J. Perioperative use of single dose intravenous versus oral acetaminophen in patients undergoing orthopedic surgery. ACCP Annual Meeting Scientific Abstracts. Pharmacotherapy. 2016;36: e206-e344. doi:10.1002/phar.1877.

Prepared by:

Khushbu Tejani, Pharm.D.

PGY1 Pharmacy Practice Resident

College of Pharmacy

University of Illinois at Chicago

July 2018

The information presented is current as of May 9, 2018. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making

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What is the clinical efficacy of fish-oil containing lipid emulsion products compared to soybean oil-based lipid emulsion products for parenteral nutrition?

What is the clinical efficacy of fish-oil containing lipid emulsion products compared to soybean oil-based lipid emulsion products for parenteral nutrition?

Introduction

Intralipid and Nutrilipid, both soybean oil lipid emulsion (SOLE) products, were the only lipid emulsions that were Food and Drug Administration (FDA)-approved for use in the United States until SMOFlipid 20% lipid emulsion was approved in July 2016 as a source of calories and essential fatty acids (such as omega-3 fatty acids) when total parenteral nutrition (TPN) is required.^1,2 SMOFlipid’s fatty acid profile includes 30% soybean oil (SO), 30% medium-chain triglycerides (MCTs), 25% olive oil (OO), and 15% fish oil (FO).² Omegaven is another 10% intravenous lipid emulsion product that only contains FO (and excipients).³ This product is not currently FDA-approved but can be obtained from the manufacturer for individual patients who cannot tolerate available lipid emulsions by submitting an Investigational New Drug application to the FDA. The availability of these FO-containing lipid emulsions (FOLE) has prompted clinicians to evaluate the evidence supporting their use. This article summarizes randomized controlled trials (RCTs) and meta-analyses (MAs) that compare clinical outcomes with SOLE and FOLE products.

Guideline Recommendations

The Society of Critical Care Medicine (SCCM) and American Society of Parenteral and Enteral Nutrition (ASPEN) 2017 guideline on nutrition support in critically ill children classifies FOLE as a type of immunonutrition and states that they do not recommend immunonutrition over standard nutrition.⁴ This recommendation is based on a lack of trials demonstrating superiority of FOLE over standard lipid emulsions (SOLE). Similarly, ASPEN does not have any recommendations about the use of SMOFlipid in children with peripheral nutrition (PN)-associated liver disease primarily due to its recent introduction to the US market and a lack of clinical experience with its use.⁵ However, using a reduced dose of SOLE (another potential management strategy for PN-associated liver disease) is only supported by very low quality evidence, so additional treatment options are needed in this population.

For adults, the 2016 SCCM/ASPEN guideline did not make a recommendation on the use of alternative lipid emulsions (such as FOLE) because no products were yet available in the United States at the time that the guideline was written.⁶If available in the future, the guideline suggested (based on expert opinion) that their use should be considered in critically ill patients. An additional FOLE-related recommendation in the setting of lipid emulsion drug shortages is available from ASPEN.⁷ In January 2017, ASPEN stated that an alternative lipid emulsion such as SMOFlipid could be considered for use during SOLE shortages, especially in adults. They also recommended that dosing should be well-informed with adequate education for healthcare providers regarding the differences between SMOFlipid and SOLE products.

Clinical Evidence

Children

In preliminary studies, children who received SMOFlipid experienced decreased serum bilirubin concentrations compared to patients who received Intralipid.^8-11 Patients tolerated both therapies well, and there were no differences in growth and development between groups. Significant differences in clinical outcomes were not observed, in part due to small sample sizes (n=24 to 133).

Based on these promising results, further studies have been conducted in children to compare clinical outcomes with FOLE and SOLE (Table 1).^12,13 SMOFlipid significantly decreased the incidence of retinopathy as well as hypoglycemia compared to Intralipid in preterm infants.¹² In infants with PN-associated cholestasis, there was no difference in resolution of cholestasis between Omegaven and Intralipid but there was a significant improvement in weight gain and improved patient disposition with Omegaven.¹³

Table 1. Clinical outcomes of FOLE vs SOLE products in children.^12,13

Design	Population	Intervention	Results
Beken 2013¹² DB, SC, RCT	N=80 preterm infants (<32 weeks gestation) without congenital complications or metabolic errors and weight <1500 g	SMOFlipid vs Intralipid; 0.5 g/kg/day if patient weight <1000 g, 1 g/kg/day if patient weight >1000 g; titrated up every 24 hours by 0.5 to 1 g to max 3 g/kg/day Median duration 14 days (both groups)	SMOFlipid significantly reduced the risk of the primary outcome (incidence of retinopathy of prematurity) vs Intralipid (2/40 vs 13/40; OR, 9.1; 95% CI, 1.9 to 43.8; p=0.004). SMOFlipid also significantly decreased the risk of hypoglycemia (0/40 vs 3/40; p=0.039). Hospital LOS was the same in both groups (median 34 days). There was no difference between groups in the rate of cholestasis or bilirubin or cholesterol levels.
Lam 2014¹³ DB, SC, RCT	N=16 infants with PNAC, conjugated bilirubin ≥34 μmol/L, and anticipated duration of PN >2 weeks	Omegaven vs Intralipid; 0.5 to 1.5 g/kg/day, titrated up by 0.5 g every 2 days Mean duration 40 and 74 days, respectively	Resolution of cholestasis (the primary outcome) did not differ between groups after 4 months (median 110 days vs 137 days; p=0.74). Weight gain was significantly greater with Omegaven vs Intralipid (128 g/week vs 83 g/week; p=0.02). 2 infants in the Intralipid group died. No patients in the Omegaven group died. The Omegaven group had a significantly slower rate of increase in conjugated bilirubin and ALT vs the Intralipid group.
Abbreviations: ALT=alanine aminotransferase; CI=confidence interval; DB=double-blind; LOS=length of stay; OR=odds ratio; PN=parenteral nutrition; PNAC=parenteral nutrition-associated cholestasis; RCT=randomized controlled trial; SC=single center.

Adults

Several RCTs in adults have demonstrated clinically significant benefits of using FOLE over SOLE in adult patients who have undergone surgery, are critically ill, or have sepsis (Table 2).^14-18

Table 2. Clinical outcomes of FOLE vs SOLE products in adults.^14-18

Design	Population	Intervention	Results
Mertes 2006¹⁴ DB, MC, RCT	N=249 patients who required PN following elective abdominal or thoracic surgery	SMOFlipid vs a SOLE product not available in the US at 1.5 g/kg/day Duration 5 days	LOS was similar between groups overall (15.7 vs 17.8 days; p-value not reported); LOS was significantly lower with SMOFlipid vs SOLE (13.4 vs 20.4 days; p<0.05) in a subgroup analysis of 33 patients from 2 of 18 centers. Mortality was similar between groups. Changes in liver enzymes (AST, ALT), total bilirubin, and glucose levels 6 days after surgery were similar between groups.
Hall 2015¹⁵ OL, SC, RCT	N=60 patients with sepsis (infection plus at least 2 SIRS criteria)	Omegaven 0.2 g FO/kg/day vs control (no lipid emulsion therapy) Mean duration 8.8 and 12.3 days, respectively	Mortality in the total population was similar between groups. In patients with less severe sepsis, there was a significant decrease in total inpatient mortality with Omegaven vs control (1/17 vs 7/18; p=0.041). There was no difference in ICU or hospital LOS. Change in SOFA scores was significantly improved with Omegaven vs control (2.2 vs 1.0; p=0.005).
Wu 2012¹⁶ DB, SC, RCT	N=63 patients with hepatitis B virus-associated hepatocellular carcinoma undergoing hepatectomy who required ≥5 days of PN	Omegaven vs a SOLE product not available in the US at 1.5 g/kg/day Mean duration 5.8 and 5.6 days, respectively	Hospital LOS was significantly shorter with Omegaven vs SOLE (12.71±2.58 vs 15.91±3.23 days; p<0.01). Rate of infection was significantly lower with Omegaven vs SOLE (6/31 vs 14/32; p<0.05). No patients died after 6 months of follow-up. Liver enzymes (AST, ALT) and total bilirubin 6 days after surgery were significantly lower with Omegaven.
Jiang 2010¹⁷ DB, MC, RCT	N=206 patients with gastrointestinal or colon cancer who required PN after surgery	Omegaven + Intralipid vs Intralipid at 1.2 g/kg/day Duration 7 days	Mean hospital LOS was significantly shorter with Omegaven + Intralipid vs Intralipid (15 vs 17 days; p=0.041). Patients receiving Omegaven + Intralipid had significantly fewer cases of SIRS vs Intralipid (4/100 vs 13/103; p=0.039). The rate of postoperative infections was similar between groups.
Chen 2017¹⁸ SB (patients), SC, RCT	N=48 patients with sepsis who required mechanical ventilation and PN	SOLE + Omegaven 10 g FO/day vs SOLE Duration not specified	Mortality was significantly lower with SOLE + Omegaven vs SOLE after 28 days (3/24 vs 10/24; p=0.023). ICU LOS was significantly less in the SOLE + Omegaven group (13.8 vs 24.4 days; p=0.046). APACHE II scores, and Marshall scores were significantly lower after 7 days of SOLE + Omegaven vs SOLE.
Abbreviations: ALT=alanine aminotransferase; APACHE II=Acute Physiology and Chronic Health Evaluation II; AST=aspartate aminotransferase; DB=double-blind; FO=fish oil; ICU=intensive care unit; LOS=length of stay; MC=multicenter; OL=open-label; PN=parenteral nutrition; RCT=randomized controlled trial; SB=single-blind; SC=single center; SIRS=systemic inflammatory response syndrome; SOFA= Sequential Organ Failure Assessment; SOLE=soybean oil lipid emulsion.

Many of these studies in adults measured surrogate outcomes, including laboratory parameters relevant to liver function and inflammatory/immune response.^14-18 In addition to statistically significant differences in interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, liver transaminases, and bilirubin levels, clinical outcomes were also improved in many studies. In particular, patients in the majority of trials had shorter hospital length of stay (LOS), as well as lower rates of organ dysfunction and complications post-surgery. One study reported significantly lower total inpatient mortality in patients with non-severe sepsis who received Omegaven, but this was compared to a control group of patients who did not receive lipid emulsion therapy.¹⁵In another small study, fewer patients with sepsis died after receipt of supplemental Omegaven in addition to SOLE.¹⁸

Meta-analyses

The MAs described in Table 3 demonstrate significant differences in clinical outcomes between FOLE and SOLE products and are supported by a large number of patients.^19-21 Although none of these analyses report significant differences in mortality, decreased LOS is an important clinical outcome that appears to favor patients receiving FOLE over SOLE therapy. Additionally, infectious complications were significantly lower in patients receiving FOLE therapy, which may reduce the need for post-surgical antibiotics and have a beneficial effect on LOS.

Table 3. Meta-analyses with FOLE products.^19-21

Design	Results
Bae 2017¹⁹ 19 RCTs (n=1167) in adults undergoing surgery (mostly gastrointestinal procedures) who received ≥3 days of PN (median 6 days) 8 studies (n=715) directly compared SOLE to FOLE	Events associated with infectious morbidities were significantly less frequent with FOLE vs SOLE (27/359 vs 55/356; OR, 0.42; 95% CI, 0.25 to 0.72; p=0.001; I²=0%). LOS was significantly shorter with FOLE vs SOLE (weighted mean difference -2.7 days; 95% CI, 3.60 to -1.79; p<0.00001; I²=0%). No mortality results for FOLE vs SOLE were reported.
Li 2014²⁰ 21 RCTs (n=1487) in adult surgical patients (mostly gastrointestinal procedures) 10 studies compared FOLE-containing regimens to SOLE	The number of infection-related adverse events was significantly less with FOLE vs SOLE (9/731 vs 21/732; OR, 0.42; 95% CI, 0.19 to 0.93; p=0.03; I²=0%). Mean LOS was significantly shorter with FOLE vs SOLE (difference -2.17 days; 95% CI, -0.84 to -3.50; p=0.001; I²=0%) and SMOFlipid vs SOLE (difference -3.21 days; 95% CI, -0.68 to -5.73; p=0.01; I²=60%). There were no significant differences in mortality for FOLE vs SOLE comparisons.
Park 2014²¹ 7 studies including RCTs, case-control studies, and cohort studies in children <1 year of age with known or suspected PNAC	In an analysis of 3 studies, rate of recovery from PNAC was significantly greater with Omegaven vs Intralipid or Liposyn* (28/57 vs 9/46; OR, 6.14; 95% CI, 2.27 to 16.6; p<0.01; I²=22.3%). * A soybean/safflower oil emulsion that is not available in the United States.
Abbreviations: CI=confidence interval; FOLE=fish oil lipid emulsion; LOS=length of stay; OR=odds ratio; PN=parenteral nutrition; PNAC=parenteral nutrition-associated cholestasis; RCT=randomized controlled trial; SOLE=soybean oil lipid emulsion.

Conclusion

A number of RCTs and MAs in adults and children have reported promising clinical outcomes which favor the use of FOLE products compared to SOLE, in addition to beneficial changes in laboratory parameters (eg, inflammatory markers, liver function).^12-21 The degree to which changes in laboratory parameters with FOLE may affect clinical outcomes such as infectious complications and mortality is not well-documented. There is not enough data to make any general conclusions about the effect on mortality of FOLE vs SOLE products. Further studies are needed to confirm the specific patient populations that would benefit most from FOLE and whether FOLE is more effective when used alone or in combination with SOLE. In 2014, an ASPEN position paper on the clinical role of alternative lipid emulsions stated that the widespread use of these products (including FOLE) in Europe adds to the safety profile of FOLE that has been observed in clinical trials.²² Clinicians will need to continue to stay informed of new evidence demonstrating the comparative efficacy and safety of FOLE and SOLE along with future guideline updates that address these new products.

References

US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations. https://www.accessdata.fda.gov/scripts/cder/ob/. Accessed June 18, 2018.
Smoflipid [package insert]. Uppsala, Sweden: Fresenius Kabi; 2016.
US Food and Drug Administration. How to request Omegaven for Expanded Access Use. https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/InvestigationalNewDrugINDApplication/ucm368740.htm. Accessed June 18, 2018.
Mehta NM, Skillman HE, Irving SY, et al. Guidelines for the provision and assessment of nutrition support therapy in the pediatric critically ill patient: Society of Critical Care Medicine and American Society for Parenteral and Enteral Nutrition. JPEN J Parenter Enteral Nutr. 2017;41(5):706-742.
Wales PW, Allen N, Worthington P, George D, Compher C; American Society for Parenteral and Enteral Nutrition. A.S.P.E.N. clinical guidelines: support of pediatric patients with intestinal failure at risk of parenteral nutrition-associated liver disease. JPEN J Parenter Enteral Nutr. 2014;38(5):538-557.
McClave SA, Taylor BE, Martindale RG, et al. Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). JPEN J Parenter Enteral Nutr. 2016;40(2):159-211.
American Society for Parenteral and Enteral Nutrition. 2017 Parenteral Nutrition Lipid Injectable Emulsion Product Shortage Considerations. http://www.nutritioncare.org/News/General_News/2017_Parenteral_Nutrition_Lipid_Injectable_Emulsion_Product_Shortage_Considerations/. Accessed June 18, 2018.
Goulet O, Antébi H, Wolf C, et al. A new intravenous fat emulsion containing soybean oil, medium-chain triglycerides, olive oil, and fish oil: a single-center, double-blind randomized study on efficacy and safety in pediatric patients receiving home parenteral nutrition. JPEN J Parenter Enteral Nutr. 2010;34(5):485-495.
Diamond IR, Grant RC, Pencharz PB, et al. Preventing the progression of intestinal failure-associated liver disease in infants using a composite lipid emulsion: a pilot randomized controlled trial of SMOFlipid. JPEN J Parenter Enteral Nutr. 2017;41(5):866-877.
Uthaya S, Liu X, Babalis D, et al. Nutritional evaluation and optimisation in neonates: a randomized, double-blind controlled trial of amino acid regimen and intravenous lipid composition in preterm parenteral nutrition. Am J Clin Nutr. 2016;103(6):1443-1452.
Rayyan M, Devlieger H, Jochum F, Allegaert K. Short-term use of parenteral nutrition with a lipid emulsion containing a mixture of soybean oil, olive oil, medium-chain triglycerides, and fish oil: a randomized double-blind study in preterm infants. JPEN J Parenter Enteral Nutr. 2012;36(1 Suppl):81S-94S.
Beken S, Dilli D, Fettah ND, Kabataş EU, Zenciroğlu A, Okumuş N. The influence of fish-oil lipid emulsions on retinopathy of prematurity in very low birth weight infants: a randomized controlled trial. Early Hum Dev. 2014;90(1):27-31.
Lam HS, Tam YH, Poon TC, et al. A double-blind randomised controlled trial of fish oil-based versus soy-based lipid preparations in the treatment of infants with parenteral nutrition-associated cholestasis. Neonatology. 2014;105(4):290-296.
Mertes N, Grimm H, Fürst P, Stehle P. Safety and efficacy of a new parenteral lipid emulsion (SMOFlipid) in surgical patients: a randomized, double-blind, multicenter study. Ann Nutr Metab. 2006;50(3):253-259.
Hall TC, Bilku DK, Al-Leswas D, et al. A randomized controlled trial investigating the effects of parenteral fish oil on survival outcomes in critically ill patients with sepsis: a pilot study. JPEN J Parenter Enteral Nutr. 2015;39(3):301-312.
Wu Z, Qin J, Pu L. Omega-3 fatty acid improves the clinical outcome of hepatectomized patients with hepatitis B virus (HBV)-associated hepatocellular carcinoma. J Biomed Res. 2012;26(6):395-399.
Jiang ZM, Wilmore DW, Wang XR, et al. Randomized clinical trial of intravenous soybean oil alone versus soybean oil plus fish oil emulsion after gastrointestinal cancer surgery. Br J Surg. 2010;97(6):804-809.
Chen H, Wang W, Hong Y, Zhang H, Hong C, Liu X. Single-blinded, randomized, and controlled clinical trial evaluating the effects of Omega-3 fatty acids among septic patients with intestinal dysfunction: A pilot study. Exp Ther Med. 2017;14(2):1505-1511.
Bae HJ, Lee GY, Seong JM, Gwak HS. Outcomes with perioperative fat emulsions containing omega-3 fatty acid: A meta-analysis of randomized controlled trials. Am J Health Syst Pharm. 2017;74(12):904-918.
Li NN, Zhou Y, Qin XP, et al. Does intravenous fish oil benefit patients post-surgery? A meta-analysis of randomised controlled trials. Clin Nutr. 2014;33(2):226-239.
Park HW, Lee NM, Kim JH, Kim KS, Kim SN. Parenteral fish oil-containing lipid emulsions may reverse parenteral nutrition-associated cholestasis in neonates: a systematic review and meta-analysis. J Nutr. 2015;145(2):277-283.
Vanek VW, Seidner DL, Allen P, et al. A.S.P.E.N. position paper: Clinical role for alternative intravenous fat emulsions. Nutr Clin Pract. 2012;27(2):150-192.

Prepared by:

Eric Baehr, PharmD Candidate

College of Pharmacy

University of Illinois at Chicago

Reviewed by:

Heather Ipema, PharmD, BCPS

Clinical Assistant Professor

College of Pharmacy

University of Illinois at Chicago

July 2018

The information presented is current as of June 1, 2018. This information is intended as an educational piece and should not be used as the sole source for clinical decision making.

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What is the evidence on the use of valbenazine (Ingrezza) for tardive dyskinesia?

What is the evidence on the use of valbenazine (Ingrezza) for tardive dyskinesia?

Introduction

Tardive dyskinesia (TD) is a persistent, rhythmic, repetitive movement of the body, such as the face, mouth, tongue, trunk and extremities.¹ In order for a patient to be diagnosed with TD, the symptoms must be a result of chronic exposure to a dopamine receptor blocker (eg, antipsychotics, neuroleptics), and the symptoms of TD should persist, or worsen at least 1 month after a switch or discontinuation of the drug.¹^,2 Interestingly, even though antipsychotic agents can cause TD they can also mask the symptoms of TD. Other drugs, such as antidepressants (eg, tricyclic antidepressants), metoclopramide, and lithium, can also cause TD, although the incidence and risk is unknown.² Although TD can affect 25% of patients treated with a dopamine receptor blocker, the prevalence of TD due to antipsychotic agents varies from 8.5% to 75% depending on the population studied.^2,3 In patients with schizophrenia on antipsychotics the incidence of TD is 1% and the prevalence up to 30%.⁴ The pathophysiology of TD remains unclear. However, it is postulated that TD occurs due to dopamine hypersensitivity that occurs because of the upregulation of dopamine receptors after dopamine receptor blockade, which is caused by antipsychotic use or other dopamine receptor blockers such as metoclopramide.³

Tardive dyskinesia differs from drug-induced Parkinsonism and acute akathisia because these disorders are reversible after the discontinuation of the causative drug, whereas TD is long lasting and can be permanent.¹ Non-modifiable risk factors for TD include older age, female gender, and African American race, whereas modifiable risk factors can include the presence of mood disorder or dementia, alcohol or substance abuse, duration of antipsychotic drug exposure, dose of antipsychotic drug, and use of anticholinergic drugs.²^,³

Guidelines

According to the American Academy of Neurology (AAN) guideline on the treatment of tardive syndromes, there is limited or insufficient data to recommend various treatments such as the withdrawal of dopamine receptor blockers, switching to different antipsychotics, electroconvulsive therapy, use of anticholinergic drugs, bromocriptine, levetiracetam, buspirone, botulinum toxin, or deep brain stimulation.⁵ Furthermore, AAN states that clonazepam and gingko biloba probably improves TD, and amantadine and tetrabenazine might be considered for treatment.

Valbenazine (Ingrezza) is approved by the Food and Drug Administration (FDA) for the treatment of tardive dyskinesia.⁴ It is a reversible, highly selective inhibitor of the vesicular monoamine transporter 2 (VMAT2).⁴^,6The inhibition of the VMAT2 receptor results in the degradation of neurotransmitters, including dopamine, which is responsible for motor control.⁴

Clinical Efficacy

Valbenazine was studied in 2 randomized, double-blind, placebo-controlled clinical trials, KINECT 2 and KINECT 3.⁴ The KINECT 2 trial was a 6-week, phase 2, dose-titration study of valbenazine 25 mg once daily titrated to a maximum dose of 75 mg in increments of 25 mg every 2 weeks.⁷ The study included 102 patients aged 18 to 85 years old with schizophrenia, schizoaffective disorder, or mood disorder with neuroleptic-induced TD, or patients with a gastrointestinal disorder with metoclopramide-induced TD. The primary endpoint, change at week 6 from baseline in the Abnormal Involuntary Movement Scale (AIMS) score was significant for valbenazine vs. placebo (-2.4, 95% confidence interval [CI]-3.7 to -1.1; P=0.0005). In addition, the change in the secondary endpoint of Clinical Global Impression Change-TD (CGI-TD) score was significant for valbenazine vs. placebo (-0.8, 95% CI -1.2 to -0.5; P<0.0001). The most common adverse events were fatigue (9.8%) and headache (9.8%). There were no treatment-related deaths.

The KINECT 3 trial was a 6-week, phase 3, fixed-dose study of valbenazine 40 mg and 80 mg once daily in 234 patients aged 18 to 85 years old with schizophrenia, schizoaffective disorder, or mood disorder and dopamine receptor blocker-induced moderate to severe TD for ≥ 3 months.⁸ The primary endpoint was change at week 6 from baseline AIMS score with valbenazine 80 mg compared to placebo and the secondary endpoint was change in CGI-TD score from baseline at week 6. Valbenazine 80 mg showed an AIMS score reduction of -3.2 compared to -0.1 with placebo, P<0.001. The AIMS score also improved with the valbenazine 40 mg dose compared to placebo, -1.9 vs. -0.1, respectively; P=0.002. The intent-to-treat population did not show significant differences with either the 40 mg or 80 mg doses of valbenazine compared to placebo for the CGI-TD score at week 6; however, the per-protocol population did show significant differences in favor of valbenazine. The most common adverse events were somnolence, akathisia, and dry mouth. Five out of 7 patients withdrawn from the study were from the valbenazine groups due to hostility/altered mental status, suicidal attempt/ideation, and worsening schizoaffective disorder, which were unlikely due to valbenazine, except reactivation of hepatitis, which was considered possibly related to valbenazine.

Dosage and administration

Valbenazine is available as both 40 mg and 80 mg capsules.⁶ The initial dose is 40 mg once daily with or without food, and can be titrated up to 80 mg after 1 week. For patients with hepatic impairment (Child-Pugh score 7 to 15), the recommended dose is 40 mg once daily. Dose adjustments are recommended for poor metabolizers of CYP2D6, and concomitant use with strong CYP3A4 or CYP2D6 inhibitors. Valbenazine is not recommended for use with strong CYP3A4 inducers.

Conclusion

Tardive dyskinesia is a movement disorder that can occur because of exposure to dopamine receptor blockers.¹^,² Valbenazine is one of two VMAT2 inhibitors FDA-approved for the treatment of TD; the other drug is deutetrabenazine (Austedo). Valbenazine can be considered a treatment option for patients who develop TD because of chronic antipsychotic use. Valbenazine has shown reductions in the AIMS score, a rating scale that measures involuntary movement, compared to placebo.⁷^,⁸ Deutetrabenazine (Austedo) has a similar pharmacokinetic profile and is also approved for Huntington disease chorea, but unlike valbenazine it should be taken with food.⁹ Tetrabenazine, also a VMAT2 inhibitor, is used off-label for TD, but it is associated with frequent dosing and side effects, such as Parkinsonism with long-term use.⁹^,10 Currently, there are no head-to-head trials comparing VMAT2 inhibitors.¹¹ Although VMAT2 inhibitors are not curative for TD, both FDA-approved agents are efficacious and tolerable for use.¹² As long as antipsychotics are prescribed, it is likely that TD will be encountered in clinical practice. Currently, the FDA-approved VMAT2 inhibitors are relatively expensive and require prescribing through specialty pharmacies.

References

1. Frei K, Truong DD, Fahn S, Jankovic J, Hauser RA. The nosology of tardive syndromes [published online ahead of print February 6, 2018]. J Neurol Sci. doi: 10.1016/j.jns.2018.02.008.

2. D’Abreu A, Akbar U, Friedman JH. Tardive dyskinesia: epidemiology [published online ahead of print February 5, 2018]. J Neurol Sci. doi: 10.1016/j.jns.2018.02.007.

3. Solmi M, Pigato G, Kane JM, Correll CU. Clinical risk factors for the development of tardive dyskinesia. [published ahead of print February 5, 2018]. J Neurol Sci. doi: 10.1016/j.jns.2018.02.012.

4. Uhlyar S, Rey JA. Valbenazine (Ingrezza). The first FDA-approved treatment for tardive dyskinesia. P&T.43(6):328-331.

5. Bhidayasiri R, Fahn S, Weiner WJ, et al; American Academy of Neurology. Evidence-based guideline: Treatment of tardive syndromes. Neurology. 2013;81(5):463-469.

6. Ingrezza [package insert]. San Diego, CA; Neurocrine Biosciences, Inc.; 2017.

7. O’Brien CF, Jimenez R, Hauser RA, et al. NBI-98854, a selective monoamine transport inhibitor for the treatment of tardive dyskinesia: a randomized, double-blind, placebo-controlled study. Mov Disrd. 2015;30(12):1681-1687.

8. Hausner RA, Factor SA, Marder SR, et al. KINECT 3: A phase 3 randomized, double-blind, placebo-controlled trial of valbenazine for tardive dyskinesia. Am J Psychiatry. 2017;174(5):476-484.

9. Niemann N, Jankovic J. Treatment of tardive dyskinesia: A general overview with focus on the vesicular monoamine transporter 2 inhibitors. Drugs. 2018;78(5):525-541.

10. Kim AP, Baker DE, Levien TL. VMAT2 inhibitors: new drugs for the treatment of tardive dyskinesia. Consult Pharm. 2018;33:201-209.

11. Solmi M, Pigato G, Kane JM, Correll CU. Treatment of tardive dyskinesia with VMAT-2 inhibitors: a systematic review and meta-analysis of randomized controlled trials. Drug Des Devel Ther. 2018;12:1215-1238.

12. Citrome L. Tardive dyskinesia: placing vesicular monoamine transporter 2 (VMAT2) inhibitors into clinical perspective. Expert Rev Neurother. 2018;18(4):323-332.

Prepared by:

Yesha Patel, PharmD, BCPS

Clinical Assistant Professor

July 2018

The information presented is current as of June 18, 2018. This information is intended as an educational piece and show not be used as the sole source for clinical decision-making.

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Drug Information Group

Retzky College of Pharmacy - Chicago | Rockford

July 2018 FAQs

July 2018 FAQs

What is the efficacy and safety of IV acetaminophen when compared to oral acetaminophen?

What is the clinical efficacy of fish-oil containing lipid emulsion products compared to soybean oil-based lipid emulsion products for parenteral nutrition?

What is the evidence on the use of valbenazine (Ingrezza) for tardive dyskinesia?

Drug Information Group, Deparment of Pharmacy Practice