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Mar 2019 FAQs

What is the available literature regarding use of KCentra® (Four Factor Prothrombin Complex Concentrate) (4F-PCC) for the treatment of coagulopathies and acute hemorrhage in patients with liver disease who are not receiving concomitant anticoagulation therapy?

What data exist for the use of tolvaptan beyond 30 days in the setting of hyponatremia?

What are anesthesia safety considerations related to patients taking cannabis?

Answers

What is the available literature regarding use of KCentra® (Four Factor Prothrombin Complex Concentrate) (4F-PCC) for the treatment of coagulopathies and acute hemorrhage in patients with liver disease who are not receiving concomitant anticoagulation therapy?

Background

Patients with cirrhosis and portal hypertension are at high risk for decompensation and variceal hemorrhage. When this occurs, patients are estimated to have a 5-year mortality rate ranging from 20 to 80% depending on other complications.1 Patients presenting with acute esophageal variceal hemorrhage along with ascites or encephalopathy have a 5-year mortality rate closer to 80%.

In patients presenting with acute variceal hemorrhage, the main goals are to control bleeding and prevent recurrence.2 Initially, volume resuscitation should be initiated to maintain hemodynamic stability. Vasoactive drugs, such as octreotide, given by intravenous infusion have been shown to lower 7-day all-cause mortality and lower transfusion requirements in patients with acute variceal hemorrhage.  The 2016 American Association for the Study of Liver Disease (AASLD) Guidelines also recommend that an endoscopy should be performed within 12 hours of presentation. If a variceal source is found, an endoscopic variceal ligation (EVL) should be performed. Procedures such as transjugular intrahepatic portosystemic shunt (TIPS), and balloon tamponade are alternative options that may be performed if bleeding recurs or is uncontrollable.

Liver disease has traditionally been associated with a higher risk of bleeding. However, there is also evidence to suggest that patients with cirrhosis who are hospitalized may be at a high risk for thrombosis as well.3 This fragile state is commonly referred to as “rebalanced” hemostasis.4 The relative balance or imbalance of bleeding and thrombosis may be different for each patient.

Patients with liver disease who are actively using alcohol or are malnourished may have low levels of Vitamin K. Since Vitamin K is responsible for modification of coagulation factors within the liver, these patients may have a decreased production of Factors II, VII, IX, and X as well as Proteins C and S, similar to if they were taking a vitamin K antagonist such as warfarin. However, supplementation with vitamin K has only been shown to result in slight improvements in coagulation parameters.5  

Other treatment options that have been explored for restoring hemostasis in patients with liver disease include fresh frozen plasma, cryoprecipitate, platelets, recombinant factor VIIa, antifibrinolytic agents, desmopressin, red blood cells, and prothrombin concentrate complexes.6  The 2016 AASLD Guidelines state that randomized controlled trials studying the use of recombinant factor VIIa have not shown a clear benefit in this population and that the use of fresh frozen plasma or factor VIIa are not recommended.2 Guidelines also discuss that the International Normalized Ratio (INR) is not a reliable indicator of coagulation status in this patient population. The 2016 AASLD Guidelines are silent on the use of 4F-PCC.

Four factor prothrombin complex concentrate (4F-PCC) is currently approved under the brand name KCentra® in the United States for emergent reversal of oral vitamin K antagonists in the setting of acute life-threatening bleeding or need for invasive life-saving procedures.7 There have been case reports on the use of 4F-PCC to reverse coagulopathy in patients with liver cirrhosis for similar indications. 4F-PCC has many potential appeals including a smaller infusion volume than most other blood products and a rapid onset of action. However, current guidelines are silent on its use and there is no clearly defined dosing strategy in this patient population. The purpose of this FAQ is to review the currently available literature regarding the use of 4F-PCC in patients with liver disease for the management of coagulopathies and bleeding.

Four Factor Prothrombin Complex Concentrate (4F-PCC)

Four factor prothrombin complex concentrate contains four clotting factors – Factor II (prothrombin), Factor VII, Factor IX, and Factor X as well as proteins C and S. 7 Dosing of 4F-PCC for the treatment of urgent reversal of acquired coagulation factor deficiency induced by warfarin therapy with acute major bleeding or the need for an urgent surgery or invasive procedure is based on units of Factor IX and is guided by INR value and body weight.

Table 1. FDA-approved Dosing of Four Factor Prothrombin Complex Concentrate 7

Pre-treatment INR

2-3.9

4-6

>6

Dose (units of Factor IX per kg body weight)

25

35

50

Maximum dose (by units of Factor IX)

2500

3500

5000

Abbreviations: FDA=Food and Drug Administration; INR=international normalized ratio.

When used for approved indications, it is recommended that 4F-PCC is given concurrently with Vitamin K to maintain factor levels once the effects of 4F-PCC have diminished.7 Repeat dosing is not currently recommended in the prescribing information. 4F-PCC was not studied in patients with a history of thromboembolic events in 3 months prior to administration and its use is contraindicated in patients with disseminated intravascular coagulation (DIC) or known heparin-induced thrombocytopenia. Table 2 provides a summary of the currently available literature on use of 4F-PCC for treatment of coagulopathies or bleeding in patients with liver disease.

Table 2. Summary of the use of 4F-PPC in patients with liver disease. 8-14

Study Design and Duration

Subjects

Intervention&

Results

Authors’ Conclusions

Prospective Trials

Lorenz 20038

Open-label, non-controlled, prospective, multicenter

N=22

Adults with hemostatic defects due to severe LD requiring rapid hemostasis (acute hemorrhage, urgent surgery, invasive intervention)

4F-PCC* dose and duration determined by intensity of coagulopathy (1 unit 4F-PCC/kg to increase Quick’s value by ~1%) (median dose 1500 IU); could receive second dose if necessary

  • Clinical efficacy assessed by clinician: very good (76%), satisfactory (24%)
  • No thromboembolic events occurred
  • 1 adverse event occurred thought to be related to the study drug (vomiting)
  • 5 patients received a second dose (median dose 2000 IU)
  • 4F-PCC is an effective, well-tolerated method of correcting coagulopathy in patients with severe LD with acute hemorrhage, prior to urgent surgery or invasive intervention

Retrospective Trials

Larson 20189

Retrospective, single-center

N=30 patients with LD who received 4F-PCC

26.7% on concomitant warfarin therapy

4F-PCC dosing not discussed

  • Average reduction in INR: 0.9 in non-warfarin group
  • Resolution of bleeding in non-warfarin group: 47.1%
  • 2 thromboembolic events (9%) occurred in non-warfarin group
  • Suboptimal response to 4F-PCC in patients with LD

Huang 201710

Single-center, retrospective, observational

N=85

Adults with or without LD who received at least 1 dose of 4F-PCC

LD: 36%

No LD: 64%

4F-PCC 25 to 50 units/kg per package insert based on INR or fixed low dose of 500 units if planned procedure

Median dose

LD: 23 units/kg (1638 units)

Non-LD: 27 units/kg (2146 units)

  • Primary outcome: coagulopathy reversal (post-INR ≤ 1.5, 30 min after 4F-PCC administration): 19.4% LD vs 81.5% non-LD group (p<0.01)
  • Hemostasis 48-hours post 4F-PCC administration: 19.4% LD vs. 42.6% non-LD (p=0.03)
  • Thromboembolic events: 3.2% in LD group vs 14.8% in non-LD group
  • ICU LOS was significantly longer in the LD group than non-LD (11 vs 3 days, P<0.01) as well as overall hospital stay (20 vs 8 days, P<0.01)
  • Subgroup analysis excluding patients who received fixed doses prior to procedures found inferior coagulopathy reversal, longer hospitalizations, and higher mortality in the LD group
  • Majority of LD patients did not reverse their coagulopathy
  • Hemostasis achieved in LD patients was less optimal compared to non-LD patients
  • PT/INR is a poor predictor of bleeding risk in the LD population but was used due to lack of other readily available and validated biomarkers at the time of this study
  • High mortality rate observed in LD patients may be due to the nature of the disease state rather than the administration of 4F-PCC
  • 4F-PCC resulted in poor coagulopathy reversal and hemostasis corrections in LD patients with a major bleed or necessitating coagulopathy reversal prior to a procedure

Young 201711

Retrospective, cohort, single-center

N=70 patients with various conditions received 4F-PCC for intracranial hemorrhage, GI bleed, pre-procedural, or as a transfusion protocol for significant bleeding

Indication:

Warfarin:  47 administrations to 44 patients

LD: 32 administrations to 44 patients

CAS: 11 administrations to 11 patients

4F-PCC dosing stratified by groups of dosing ranges

  • 20 to 30 IU/kg
  • 30 to 40 IU/kg
  • 45 to 55 IU/kg

  • Primary outcome: change in INR: decrease by 0.7 in LD patients (p=0.09)
  • Secondary outcome: change in RBC following 4F-PCC administration: no significant difference in LD patients
  • Trend towards significant INR reduction in LD
  • 4F-PCC for treatment of coagulopathy is well tolerated and effective
  • Adequately powered prospective trials are needed

Richard-Carpentier

201312

Retrospective, single-center

N=51 adults with LD who received 4F-PCC+

Indication:

Bleeding: 55%,

Invasive procedure: 39%

10 patients noted to be taking warfarin

4F-PCC dosing based on INR

  • INR <3: 1000 IU
  • INR 3-5: 2000 IU
  • INR >5: 3000 IU
  • Controlled bleeding (cessation of bleeding, absence of rebleeding or surgical intervention for hemostasis or decrease in Hgb >1g/dL 24h post 4F-PCC): 32%
  • INR corrected to ≤ 1.3: 10%
  • INR corrected to ≤ 1.8: 61%
  • Thromboembolic events: 6%
  • Low percentage of bleeding events were controlled with 4F-PCC
  • No association between correction of INR and efficacy of 4F-PCC to control bleeding
  • 4F-PCC is possibly less effective in patients with Child-Pugh C cirrhosis and acute liver failure

Carvalho 201213

Retrospective, non-randomized, non-controlled, observational, open-label, multi-center

N=1152 patients who received 4F-PCC at

17 hospitals in Portugal

Indication:

Reversal of oral anticoagulant: 69.2%,

Liver dysfunction: 17.3%, Uncontrolled bleeding: 10.2%

4F-PCC dosing based on INR

  • INR<5: 15 IU/kg
  • INR >5: 30 IU/kg

Mean dose in LD: 21.99 IU/kg

  • Efficacy assessed by reduction in INR
  • 95 patients in LD group had evaluable INR data
  • Statistically significant changes in INR reported for patients with LD
  • Efficacious in a majority of bleeding episodes in patients with liver dysfunction
  • Limited information on safety data reported

Drebes 201114

Retrospective, single-center

N=69 patients with LD who received 4F-PCC+ for bleeding, invasive procedures, or correction of coagulopathy after bleeding episode

Chronic LD: 46%

Acute liver failure: 13%

Undergoing liver transplant: 26%

Related conditions: 14%

4F-PCC dose ranged from 6 to 50 IU/kg (median: 20 IU/kg)

Co-administered with other blood factor products in some patients

  • 127 total administration events observed
  • No excessive bleeding observed in invasive procedures
  • 1 thrombotic event identified
  • Fibrinogen concentrate co-administered (n=43)
  • Recombinant factor VIIa concentrate co-administered (n=2)
  • Only preliminary data reported

& Unless otherwise noted, KCentra (United States Trade Name for 4F-PCC) used as 4F-PCC; *Beriplex (European Trade Name for 4F-PCC); +Octaplex and Beriplex (European Trade Names for 4F-PCC); Octaplex

Abbreviations: CAS=coagulopathy of acute sepsis; CCLD=coagulopathy of chronic liver disease; Hgb=hemoglobin level; LD=liver disease.

Summary of the Literature

Strong literature is currently lacking to support the use of 4F-PCC in patients with liver disease and acute hemorrhage. Although the study by Lorenz and colleagues does provide prospective data, many limitations exist including no formal determination of sample size and use of descriptive statistics.8 Dosing in this study was based on the authors’ previous experience and it was estimated that one standardized unit of 4F-PCC per kg of body weight would increase Quick’s value by about 1%. The authors define Quick’s value as “a function of the reciprocal value of the prothrombin time of the test sample compared with that of standard normal plasma, expressed as a percentage”.  Quick’s value may not be commonly used at all institutions and the standardized unit of 4F-PCC used for dosing differs from typical dosing by units of Factor IX.

Many of the currently available studies are retrospective in nature and have failed to show a clear benefit with the use of 4F-PCC.9-14 One main limitation of many of these studies is that 4F-PCC dosing was either unclear or based on INR values. However, the 2016 AASLD Guidelines clearly state that INR is not a reliable indicator of coagulation status in cirrhosis.2 Therefore, it is difficult to assess the findings of these studies in patients with liver disease.

Economic and Cost Data

A study by DeAngelo and colleagues assessed the use of prothrombin complex concentrates (PCCs) used for off-label indications and compared blood product use and cost information.15 This retrospective cohort study was conducted across two tertiary care institutions in the United States. Patients included were those that received a PCC for an un-approved indication and were not being treated with warfarin. The primary outcome assessed was blood product use during hospitalization such as plasma, platelets, cryoprecipitate, and packed red blood cells. Secondary endpoints included drug costs as well as total hemostasis costs, length of stay, and in-hospital mortality. This study included 182 patients total, 64 who received 4F-PCC. Fourteen patients in the study received PCC for the indication of coagulopathy of liver disease. There was no significant difference found between 3F-PCC and 4F-PCC groups with regards to blood product use, length of stay, or in-hospital mortality. Drug and total hemostatic costs were found to be higher in the 4F-PCC group. Although this study included a wide variety of patients, no significant difference in clinical outcomes was found between groups. The authors of this trial suggest that hospitals may want to consider having both 3F and 4F-PCCs on formulary, using 4F-PCC for warfarin reversal and having a 3F-PCC available to use for other indications.

Since this study only contained a small number of patients with liver disease, evidence is lacking regarding economic benefit of 4F-PCC in this particular patient population.

Conclusion

Since INR is not a reliable indicator of coagulation status in patients with liver disease, it is difficult to interpret much of the currently available data. Newer laboratory tests such as thromboelastography (TEG) and thromboelastometry possibly provide a better predictor of coagulation status in patients with liver disease and may be an area of interest for future studies.16  The currently available literature is unclear on whether 4F-PCC provides benefit when used for acute hemorrhage in patients with liver disease. Larger, prospective studies with alternative dosing strategies that use methods other than INR are needed to support its use in this population.

References

  1. D’Amico G, Pasta L, Morabito A, et al. Competing risks and prognostic stages of cirrhosis: a 25-year inception cohort study of 494 patients. Aliment Phamacol Ther. 2014;39(10):1180-1193.
  2. Garcia-Tsao G, Abraldes JG, Berzigotti A, Bosch J. Portal hypertensive bleeding in cirrhosis: Risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the Study of Liver Diseases. Hepatology. 2017;65(1):310-335.
  3. Northup P, McMahon M, Ruhl AP, et al. Coagulopathy does not fully protect hospitalized cirrhosis patients from peripheral venous thromboembolism. Am J Gastroenterol. 2006;101(7):1524-1528.
  4. Intagliata NM, Argo CK, Stine JG, Lisman T, Caldwell SH, Violi F. Concepts and controversies in haemostasis and thrombosis associated with liver disease: proceedings of the 7th international coagulation in liver disease conference. Thromb Haemost. 2018;118(8):1491-1506.
  5. Saja MF, Abdo AA, Sanai FM, Saikh SA, Abdel Gader AGM. The coagulopathy of liver disease: does vitamin K help? Blood Coagul Fibrinolysis. 2013;24(1):10-16.
  6. Shah NL, Intagliata NM, Norhtup PG, Argo Ck, Caldwell SH. Procoagulant therapeutics in liver disease: a critique and clinical rationale. Nat Rev Gastroenterol Hepatol. 2014;11(11):675-682.
  7. KCentra [package insert]. Marburg, Germany: CSL Behring GmbH; 2018.
  8. Lorenz R, Kienast J, Otto U, et al. Efficacy and safety of a prothrombin complex concentrate with two virus-inactivation steps in patients with severe liver damage. Eur J Gastroenterol Hepatol. 2003;15(1):15-20.
  9. Larson J, Coler E, Vakayil V, et al. Use of four-factor prothrombin complex concentrate in patients with liver disease. Poster presented at: 2018 47th Society of Critical Care Congress; February, 2018; San Antonio, TX.
  10. Huang WT, Cang WC, Derry KL, Lane JR, von Drygalski A. Four-factor prothrombin complex concentrate for coagulopathy reversal in patients with liver disease. Clin Appl Thromb Hemost. 2017;23(8):1028-1035.
  11. Young H, Holzmacher JL, Amdur R, Gondek S, Sarani B, Schroeder ME. Use of four-factor prothrombin complex concentrate in the reversal of warfarin-induced and nonvitamin K antagonist-related coagulopathy. Blood Coagul Fibrinolysis. 2017;28(7):564-569.
  12. Richard-Carpentier G, Blais N, Rioux-Masse B. Use of prothrombin complex concentrates in patients with hepatic coagulopathy: a single center retrospective [abstract]. Blood. 2013;122(21):2400.
  13. Carvalho MC, Rodrigues AG, Conceicao LM, Galvao ML, Ribeiro LC. Prothrombin complex concentrate (Octaplex): a Portuguese experience in 1152 patients. Blood Coagul Fibrinolysis. 2012;23(3):222-228.
  14. Drebes AB, Burroughs A, Gatt A, Mallett S, Tuddenham EGD, Ghowdary P. Use of prothrombin complex concentrate in patients with acute or chronic liver disease – A single centre retrospective audit [abstract]. J Thromb Haemost. 2011;9(Suppl 2):231.
  15. DeAngelo J, Jarrell DH, Cosgrove R, Camamo J, Edwards CJ, Patanwala AE. Comparison of blood product use and costs with use of 3-factor versus 4-factor prothrombin complex concentrate for off-label indications. Am J Health-Syst Pharm. 2018;75(15):1103-1109.
  16. Dumitrescu G, Januszkiewicz A, Agren A, Magnusson M, Wahlin S, Wernerman J. Thromboelastometry relation to the severity of liver cirrhosis in patients considered for liver transplantation. Medicine. 2019;96(23):1-8.

Prepared by:

Elizabeth Madrzyk, PharmD

PGY1-Pharmacy Resident

Loyola University Medical Center

March 2019

Reviewed by:

Rita Soni, PharmD, BCPS

College of Pharmacy

University of Illinois at Chicago

The information presented is current as of January 25, 2019. 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 data exist for the use of tolvaptan beyond 30 days in the setting of hyponatremia?

Introduction

Hyponatremia, typically defined as a serum sodium level less than 135 mEq/L, is a common electrolyte disorder, occurring in 15 to 30% of hospitalized patients.1 It is particularly common among women and elderly patients. The prevalence of hyponatremia among nursing home patients is estimated at 18%.2 Hyponatremia may result from a variety of underlying disease processes, and may be categorized as hypotonic, isotonic, or hypertonic.1 Only hypotonic hyponatremia typically requires treatment. Treatment for hypotonic hyponatremia depends on whether the patient is hypovolemic, euvolemic, or hypervolemic. Hypovolemic hyponatremia may be caused by gastrointestinal disease, diuretic therapy, cerebral salt wasting, or mineralocorticoid deficiency. Euvolemic hyponatremia is most commonly caused by syndrome of inappropriate antidiuretic hormone secretion (SIADH), which may be idiopathic or secondary to other factors, such as medication therapy, central nervous system disorders, or cancer.1,3,4 Other causes of euvolemic hyponatremia include glucocorticoid deficiency, primary polydipsia, and vigorous endurance exercise.1 Common causes of hypervolemic hyponatremia are heart failure, cirrhosis, and kidney disease.

Tolvaptan is an oral selective vasopressin V2 receptor antagonist that may be used in the treatment of hyponatremia.5 It works to correct euvolemic and hypervolemic hyponatremia by blocking the action of arginine vasopressin at the V2 receptors in the kidneys; this increases water excretion without increasing electrolyte losses, effectively increasing the serum sodium concentration.1 The U.S. Food and Drug Administration (FDA) labeling specifies that tolvaptan should not be used for longer than 30 days in the setting of hyponatremia: however, because serum sodium levels tend to decrease once tolvaptan is stopped, it may be necessary to consider continuing tolvaptan therapy on a long-term basis.4 This article will explore the reasons for this treatment duration limitation, and discuss evidence for the safety of tolvaptan when used to treat hyponatremia for longer than 30 days.

Tolvaptan Products and Indications

Tolvaptan is available under 2 brand names, Samsca and Jynarque.5 Each brand has a specific indication and recommended dosing (Table 1). Samsca is indicated for use in clinically significant euvolemic and hypervolemic hyponatremia (ie, serum sodium less than 125 mEq/L or symptomatic hyponatremia that cannot be corrected with fluid restriction).5,6 This drug must be initiated in the hospital setting, so that serum sodium can be monitored; if serum sodium correction occurs too rapidly, osmotic demyelination may occur, resulting in serious adverse events or death.6 However, once the drug is initiated, it may be taken on an outpatient basis.

Jynarque is indicated to slow kidney function decline in patients at risk of rapidly-progressing autosomal dominant polycystic kidney disease (ADPKD).7 Jynarque is used at higher doses than Samsca, and does not have a restriction on treatment duration.6,7 However, the distribution of Jynarque is restricted under a Risk Evaluation and Mitigation Strategy (REMS) program due to risk of liver injury.7 As part of this program, liver function tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], and bilirubin) must be monitored prior to initiation, at 2 and 4 weeks after initiation, monthly for the first 18 months, then every 3 months thereafter.

Table 1. Comparison of Tolvaptan Products.5-7

Brand Name

Indication

Usual Dosing

Treatment Duration

Samsca

Clinically significant euvolemic and hypervolemic hyponatremia*, including patients with HF and SIADH

Initial: 15 mg daily

Maximum: 60 mg daily

≤30 days

Jynarque

Slow kidney function decline in patients at risk of rapidly progressing ADPKD

Initial: 60 mg/day (divided as 45 mg once, then 15 mg 8 hours later)

Target dose: 120 mg/day (divided as 90 mg once, then 30 mg 8 hours later)

None, but LFT monitoring required

*Defined as serum sodium less than 125 mEq/L or symptomatic hyponatremia that has resisted correction with fluid restriction

Abbreviations: ADPKD=autosomal dominant polycystic kidney disease; HF=heart failure; LFT=liver function test; SIADH=syndrome of inappropriate antidiuretic hormone

FDA Labeling of Tolvaptan for Hyponatremia: Why 30 Days?

When tolvaptan (Samsca) was initially approved for hyponatremia in 2009, no treatment duration limitation was specified in the prescribing information: however, in April 2013, the FDA required the addition of new restrictions and warnings to the drug’s labeling.8 At that time, tolvaptan was being studied for use in ADPKD; in the clinical trials for ADPKD, 3 cases of serious liver injury were reported, and 4.4% of patients on tolvaptan experienced elevated alanine aminotransferase (ALT) levels more than 3 times the upper limit of normal (versus 1.0% of patients receiving placebo). These hepatic adverse events were generally reversible, resolving gradually over 1 to 4 months following drug discontinuation.9

An in vitro study investigated the mechanisms of tolvaptan hepatotoxicity and found that tolvaptan may delay cell cycle progression, damage DNA, and induce apoptosis in human liver cells.10 This damage occurred in a concentration- and time-dependent manner; while the cytotoxic concentrations in this study were substantially higher than plasma concentrations typically seen with hyponatremia treatment doses in humans, it is unknown whether higher concentrations may be reached in the liver.

Hepatic adverse events were not noted in clinical trials for hyponatremia; however, these trials only lasted for 30 days, and the earliest reports of severe liver injury in ADPKD trials occurred 3 months after tolvaptan initiation.8 Based on these data, the FDA recommended a maximum tolvaptan treatment duration of 30 days in the setting of hyponatremia. Additionally, the FDA recommended avoiding tolvaptan use in patients with symptoms of liver injury or underlying liver disease (ie, cirrhosis).

Safety of Longer Treatment Durations

Although the FDA recommends a maximum of 30 days’ treatment with tolvaptan in the setting of hyponatremia, two studies have provided some safety data for tolvaptan use over longer periods of time (Table 2). The SALTWATER trial was an open label continuation of the SALT-1 and SALT-2 trials, which examined the efficacy and safety of tolvaptan in patients with hyponatremia secondary to heart failure, cirrhosis, and SIADH.11 Patients who continued in the SALTWATER study received tolvaptan for a mean of 701 days, resulting in a total exposure of 77,369 patient-days. Tolvaptan, at a mean dose of 30 mg/day, maintained serum sodium levels over time; the drug-related adverse events reported in this study were not related to hepatic injury, with the exception of one patient with pre-existing cirrhosis who developed hepatorenal syndrome (this adverse event was rated as “possibly related” to tolvaptan exposure). The EVEREST trial compared tolvaptan to placebo for reduction of mortality in hospitalized heart failure patients.12 While this trial did not focus specifically on the treatment of hyponatremia (only 8% of patients in the study had serum sodium less than 134 mEq/L at baseline), the doses used were similar to those used in hyponatremia. Over a median treatment duration of 8 months, tolvaptan’s safety profile was similar to that of placebo, with the exception of increased thirst and dry mouth vs. placebo. No hepatic adverse events were reported for either group.

In addition to these larger studies, several case reports and smaller retrospective studies have examined the safety of prolonged tolvaptan treatment in specific patient populations that may be more prone to hyponatremia. In 1 retrospective study (conducted in China), 7 hyponatremic patients aged >90 years received tolvaptan treatment for >12 months at maintenance doses that ranged from 7.5 mg every other day to 30 mg daily.13 Correction of serum sodium was maintained over 12 months of tolvaptan treatment, and adverse events were generally mild. No increases in ALT were seen over the 12-month period, and no hepatic adverse events were reported. An additional case report describes an 80-year-old female with idiopathic SIADH who received tolvaptan 15 mg/day for 6 years.14 Her serum sodium levels were successfully maintained on this dose, and she did not experience any adverse events related to tolvaptan therapy. Her liver enzymes and liver synthesis parameters consistently remained within normal range throughout the treatment period. Finally, a case of long-term tolvaptan use was reported in a patient with SIADH secondary to small cell lung cancer.15 The 59-year-old woman in this case received tolvaptan at doses ranging from 7.5 to 22.5 mg daily for about 1 year (October 2012 through October 2013). Tolvaptan was discontinued in October 2013 after complete remission and stable serum sodium levels were achieved; a week after tolvaptan discontinuation, she was readmitted for symptomatic hyponatremia and reinitiated on tolvaptan 7.5 mg daily, which she continued for a subsequent 6 months. No serious adverse events were reported.

Table 2. Summary of evidence for long-term use of tolvaptan in hyponatremia.11,12

Study Design

Subjects

Interventions

Endpoints

Conclusion

Berl 201011

SALTWATER

4-year sequential OL extension study of SALT-1 and SALT-2

N=111 patients who had hyponatremia and completed the SALT-1 or SALT-2 trial

Mean follow-up time: 701 days

Tolvaptan, mean dose of 30 mg/day

Dose was initiated at 15 mg/day and titrated based on serum sodium response

Safety:

Most common drug-related AEs were pollakiuria (9.9%), thirst (9.0%), fatigue (5.4%), dry mouth, polydipsia, polyuria, hypotension, hypernatremia, dizziness, headache, peripheral edema, and acute renal failure (3.6% each)

6 patients had drug-related AEs leading to discontinuation (1 each due to ventricular tachycardia, irritability, blood sodium increase, anorexia, blood creatinine increase, and pruritis)

Efficacy:

After the initial 14 days of treatment, mean serum sodium levels remained in normal range throughout the rest of the 4-year follow-up period.

By week 4, more than 60% and 45% of patients with mild or marked hyponatremia, respectively, had achieved normalization of serum sodium concentrations. Correction rates were somewhat lower among patients with cirrhosis, compared to patients with CHF or SIADH

Tolvaptan maintained efficacy over the long-term, with an acceptable safety profile.

Konstam 200712

MC, DB, PC, NI, RCT

N=4133 adults with LVEF≤40%, NYHA III/IV symptoms, and hospitalization for exacerbation of chronic heart failure no more than 48 hours prior to enrollment

Median follow-up time: 9.9 months

Tolvaptan 30 mg daily (n=2072)

Placebo (n=2061)

Treatment continued for a minimum of 60 days (median treatment duration, 8.0 months)

Primary:

All-cause mortality: no significant difference between groups (25.9% vs. 26.3% for tolvaptan vs. placebo; HR, 0.98; 95% CI, 0.87 to 1.11; p<0.001 for noninferiority [upper bound of 96% CI≤1.25]; p=NS for superiority)

Cardiovascular death or hospitalization for heart failure: no significant difference between groups (42.0% vs. 40.2% for tolvaptan vs. placebo; HR, 1.04; 95% CI, 0.95 to 1.14; p=NS for superiority)

Secondary:

Improvements in dyspnea scores and reductions in mean body weight at day 1 were significantly greater in the tolvaptan group vs. the placebo group (p<0.001)

Patients with low serum sodium at baseline exhibited greater increases in serum sodium at day 7 or discharge when treated with tolvaptan vs. placebo (p<0.001); effects on sodium were maintained through 40 weeks of treatment

Safety:

AEs resulting in drug discontinuation occurred in 6.5% of tolvaptan patients and 5.5% of placebo patients; of these, only thirst occurred more often with tolvaptan vs. placebo (n=7 vs. n=0; p=0.02)

Thirst and dry mouth occurred more frequently with tolvaptan vs. placebo; all other adverse events were similar between groups

Tolvaptan had no effect on long-term mortality or heart failure-related morbidity in patients with heart failure; the long-term safety profile was similar to that of placebo, with the exception of increased thirst and dry mouth.

Abbreviations: AE=adverse event; CHF=congestive heart failure; CI=confidence interval; DB=double blind; HR=hazard ratio; LVEF=left ventricular ejection fraction; MC=multicenter; NI=noninferiority; NS=not significant; NYHA=New York Heart Association; OL=open label; PC=placebo-controlled; RCT=randomized controlled trial; SIADH=syndrome of inappropriate antidiuretic hormone.

Conclusion

The FDA-approved labeling for tolvaptan states that it should not be used for longer than 30 days in the setting of hyponatremia. This limitation was added to the labeling after hepatic safety concerns were reported in ADPKD trials. Doses used in the treatment of hyponatremia are lower than those used in ADPKD, and some limited data exist to support the long-term safety of tolvaptan when used at doses relevant to hyponatremia treatment. While treatment duration should be limited when possible, long-term therapy may be necessary in some patients to maintain adequate serum sodium levels. If long-term tolvaptan therapy is deemed necessary, liver function should be monitored frequently; if changes in liver function are observed, tolvaptan should be discontinued immediately, as liver damage associated with tolvaptan is typically reversible upon drug discontinuation.

References

1.         Verbalis JG, Goldsmith SR, Greenberg A, et al. Diagnosis, evaluation, and treatment of hyponatremia: expert panel recommendations. Am J Med. 2013;126(10 Suppl 1):S1-42.

2.         Wehling M, Ashton C, Ekpo E, et al. Filling the gap - improving awareness and practice in hyponatraemia and the syndrome of inappropriate antidiuretic hormone secretion (SIADH) in the older patient: a European consensus view. Drug Res (Stuttg). 2017;67(1):5-12.

3.         Else T, Hammer GD. Disorders of the hypothalamus and pituitary gland. In: Hammer GD, McPhee SJ, eds. Pathophysiology of Disease: An Introduction to Clinical Medicine. 8th ed. New York, NY: McGraw-Hill; 2019. http://accesspharmacy.mhmedical.com/content.aspx?bookid=2468&sectionid=198223896. Accessed February 22, 2019.

4.         Cuesta M, Thompson CJ. The syndrome of inappropriate antidiuresis (SIAD). Best Pract Res Clin Endocrinol Metab. 2016;30(2):175-187.

5.         Clinical Pharmacology [database online]. Tampa, FL: 2019. http://clinicalpharmacology.com/. Accessed February 22, 2019.

6.         Samsca [package insert]. Rockville, MD: Otsuka America Pharmaceutical Inc; 2018.

7.         Jynarque [package insert]. Rockville, MD: Otsuka America Pharmaceutical Inc; 2018.

8.         FDA drug safety communication: FDA limits duration and usage of Samsca (tolvaptan) due to possible liver injury leading to organ transplant or death. U.S. Food and Drug Administration website. https://www.fda.gov/Drugs/DrugSafety/ucm350062.htm. Published April 30, 2013. Updated May 12, 2017. Accessed February 22, 2019.

9.         Watkins PB, Lewis JH, Kaplowitz N, et al. Clinical pattern of tolvaptan-associated liver injury in subjects with autosomal dominant polycystic kidney disease: analysis of clinical trials database. Drug Saf. 2015;38(11):1103-1113.

10.       Wu Y, Beland FA, Chen S, Liu F, Guo L, Fang JL. Mechanisms of tolvaptan-induced toxicity in HepG2 cells. Biochem Pharmacol. 2015;95(4):324-336.

11.       Berl T, Quittnat-Pelletier F, Verbalis JG, et al. Oral tolvaptan is safe and effective in chronic hyponatremia. J Am Soc Nephrol. 2010;21(4):705-712.

12.       Konstam MA, Gheorghiade M, Burnett JC, Jr., et al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial. Jama. 2007;297(12):1319-1331.

13.       Liu YH, Han XB, Fei YH, Xu HT. Long-term low-dose tolvaptan treatment in hospitalized male patients aged >90 years with hyponatremia: Report on safety and effectiveness. Medicine (Baltimore). 2017;96(52):e9539.

14.       Buttner S, Bachmann J, Geiger H, Obermuller N. Long-term vaptan treatment of idiopathic SIADH in an octogenarian. J Clin Med. 2017;6(3).

15.       Bordi P, Tiseo M, Buti S, Regolisti G, Ardizzoni A. Efficacy and safety of long-term tolvaptan treatment in a patient with SCLC and SIADH. Tumori. 2015;101(2):e51-53.

Prepared by:

Laura Koppen, PharmD, BCPS

Clinical Assistant Professor, Drug Information Specialist

University of Illinois at Chicago College of Pharmacy

March 2019

The information presented is current as of February 5, 2019. 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 are anesthesia safety considerations related to patients taking cannabis?

Background

Recreational or medical cannabis comes from the plant genus Cannabis sativa.1 Cannabis sativa can yield up to over 100 distinct phytocannabinoids. The primary psychoactive component of cannabis is ∆9-tetrahydrocannabinol (THC), which affects cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2 (CB2). The CB1 receptors are primarily present in the central nervous system, smooth muscle, myocardium, adipocytes, and preganglionic sympathetic neurons. The CB2 receptors are found in peripheral blood mononuclear cells (eg, macrophages, B cells, and natural killer cells), central nervous system, myocardium, vascular endothelium, and smooth muscle. Consumption of THC leads to activation of CB1 receptors causing a reduction in neurotransmission. As a result, providers can observe impairment in learning, memory, spatial orientation, and attention, especially in acute intoxication cases. Cannabidiol, another component of cannabis, has weak affinity for CB1 and CB2 receptors and lacks psychoactive properties of THC.

Cannabis is typically smoked or ingested orally.2 Psychoactive effects may last up to 24 hours post-consumption regardless of the route. Cannabis is lipid soluble, leading to a single dose of cannabis being present in the system for up to 30 days. The elimination half-life is 56 h in occasional users and 28 h in chronic users.3

Federally, the use of cannabis is prohibited, but about 30 states allow medical use of cannabis.1 Approved medical indications for cannabis vary by state, and prescribing providers must be certified with the state as a protection against federal law. For-profit dispensaries usually supply medical cannabis to patients, and “good manufacturing practices” for compounding cannabis are lacking. According to the 2017 data of the National Institute on Drug Abuse, about 47.5% of adults ages 26 years and older in the United States have used cannabis in their lifetime.4 A 2003 survey among surgical patients found a prevalence of 14% for recreational cannabis use in the previous 6 months.5 This article reviews anesthesia safety considerations in patients using medical or recreational cannabis.

Effects of cannabis on anesthesia: physiologic effects

The use of inhaled cannabis has been associated with isolated uvulitis and uvular edema that may lead to respiratory distress.2 Therefore, recent use of cannabis may lead to airway obstruction during anesthesia. Elective procedures may need to be postponed if cannabis inhalation occurred 4 hours prior to the procedure because uvular edema and airway obstruction may lead to bronchospasm, asphyxia, brain damage, and/or tracheal intubation. If necessary, administration of dexamethasone 1 mg/kg every 6 to 12 h over 1 to 2 days may relieve airway obstruction.

The use of cannabis also affects the cardiovascular system.6 Cannabis may cause tachycardia and hypertension at low doses because it increases activity of the sympathetic system and reduces the activity of the parasympathetic system.3,6 At high doses, cannabis inhibits the sympathetic but not the parasympathetic system, and thus, bradycardia and orthostatic hypotension may occur. The risk for myocardial infarction, supraventricular and ventricular ectopic activities, or reversible ST-segment and T-wave abnormalities is present.

Effects of cannabis on anesthesia: drug interactions

The evidence on drug interactions between cannabis and anesthesia agents comes mainly from small case reports or theoretical assumptions based on mechanisms of action. Due to effects on the cardiovascular system, cannabis may interact with agents used during anesthesia affecting blood pressure and heart rate.3 For example, a potential exists for profound myocardial depression when cannabis is combined with potent inhalational anesthesia agents. On the other hand, patients with acute marijuana abuse are at risk for severe tachycardia when receiving ketamine, pancuronium, atropine, and epinephrine. Such agents should be avoided in patients with acute marijuana abuse.

Cannabis may interact with several medications used as part of anesthesia.2 A prospective, single-blinded, randomized study found that patients using cannabis more than once weekly required higher doses of propofol for clinical induction to insert a laryngeal mask.7 The authors proposed that the levels of THC affect the response to propofol. A case report described the need for increased doses of propofol, thiopental, and sevoflurane and the addition of nitrous oxide in a 37-year old patient with regular cannabis consumption to induce and maintain anesthesia.8 The author of this case report proposed that CB1 receptor and gamma-aminobutyric acid type A (GABA-A) receptor form a receptor complex resulting in reduced GABA transmission. Therefore, anesthetics mediated through GABA-A receptor could not maintain anesthesia, and only after the addition of nitrous oxide, an inhibitor of the N-methyl-D-aspartate (NMDA) receptor, could anesthesia be successfully maintained. The authors recommended patients avoid consumption of cannabis as long as possible before a surgical procedure. Another case report described a 34-year old patient requiring repetitive doses of propofol, midazolam, and ketorolac, and high doses of isoflurane and nitrous oxide to maintain anesthesia who smoked cannabis the night prior to the tooth extraction.9 A more recent experimental study in mice revealed that THC may have synergistic properties with pentobarbital.10

Cannabis is mainly metabolized via CYP3A4 and CYP2C9 and thus may interact with agents such as fentanyl, codeine, and oxycodone that are also metabolized through CYP3A4.6 The combination of cannabis with sedative agents such as alcohol, hypnotics, or benzodiazepines may lead to increased fatigue due to depression of the central nervous system.3,6 

Murray and colleagues proposed that cannabis may have caused alveolar hemorrhage in a 31-year-old male patient undergoing perirectal pilonidal cyst excision and receiving sevoflurane.11 The original case report suggested that sevoflurane caused diffuse alveolar hemorrhage, but previous case reports with this adverse reaction from sevoflurane are extremely limited. Cannabis has anticoagulation effects via inhibition of thrombin-driven clot formation. Therefore, cannabis possibly was the agent that caused antecedent lung injury and hemorrhage leading to negative pressure pulmonary edema.

Conclusion

Close to 50% of adults aged 26 years and older in the United States have used cannabis in their lifetime, and about 14% of the surgical population have used recreational cannabis within 6 months.4,5 Physiologically, cannabis may have effects on the cardiovascular and respiratory systems during anesthesia. The evidence on drug interactions between cannabis and anesthesia agents comes mainly from small case reports or theoretical assumptions based on mechanisms of action. Higher doses of agents such as propofol, thiopental, sevoflurane, midazolam, ketorolac, and isoflurane and the addition of nitrous oxide may be necessary in some cases to induce and/or maintain anesthesia in patients who use cannabis. The use of ketamine, pancuronium, atropine, and epinephrine should be avoided in patients who acutely abuse cannabis due to the risk of severe tachycardia. Finally, caution is necessary when co-administering agents metabolized through CYP3A4 such as fentanyl, codeine, and oxycodone because cannabis is also metabolized through this enzyme. Overall, the evidence regarding physiologic and drug interactions between cannabis and anesthesia agents remains limited, and more high-quality research is required to determine potential outcomes of anesthesia in patients taking cannabis.

References

1.         Ebbert JO, Scharf EL, Hurt RT. Medical cannabis. Mayo Clin Proc. 2018;93(12):1842-1847.

2.         Huson HB, Granados TM, Rasko Y. Surgical considerations of marijuana use in elective procedures. Heliyon. 2018;4(9):e00779.

3.         Hernandez M, Birnbach DJ, Van Zundert AA. Anesthetic management of the illicit-substance-using patient. Curr Opin Anaesthesiol. 2005;18(3):315-324.

4.         Marijuana. National Institute on Drug Abuse website. https://www.drugabuse.gov/drugs-abuse/marijuana. Accessed February 22, 2019.

5.         Mills PM, Penfold N. Cannabis abuse and anaesthesia. Anaesthesia. 2003;58(11):1125.

6.         Beaulieu P. Anesthetic implications of recreational drug use. Can J Anaesth. 2017;64(12):1236-1264.

7.         Flisberg P, Paech MJ, Shah T, Ledowski T, Kurowski I, Parsons R. Induction dose of propofol in patients using cannabis. Eur J Anaesthesiol. 2009;26(3):192-195.

8.         Richtig G, Bosse G, Arlt F, von Heymann C. Cannabis consumption before surgery may be associated with increased tolerance of anesthetic drugs: a case report. Int J Case Rep Images. 2015;6(7):436-439.

9.         Symons IE. Cannabis smoking and anaesthesia. Anaesthesia. 2002;57:1142-1143.

10.       Kimura T, Takaya M, Usami N, Watanabe K, Yamamoto I. (9)-Tetrahydrocannabinol, a major marijuana component, enhances the anesthetic effect of pentobarbital through the CB1 receptor. Forensic Toxicol. 2019;37(1):207-214.

11.       Murray AW, Smith JD, Ibinson JW. Diffuse alveolar hemorrhage, anesthesia, and cannabis. Ann Am Thorac Soc. 2014;11(8):1338-1339.

Prepared by:

Janna Afanasjeva, PharmD, BCPS

Clinical Assistant Professor, Drug Information Specialist

University of Illinois at Chicago College of Pharmacy

March 2019

The information presented is current as February 22, 2019. 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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