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March 2015 FAQs

Questions

What are the new guidelines for the pharmacological management of obesity?

What information is available on the use of peramivir for treatment of influenza?

What data supports the use of new oral anticoagulants in special populations (hepatic impairment, obesity, pregnancy, lactation, and pediatrics)?

Answers

What are the new guidelines for the pharmacological management of obesity?

Introduction

Obesity remains a prevalent, serious health issue in the United States. According to the Centers for Disease Control and Prevention (CDC), approximately 78.6 million American adults and 12.7 million children and adolescents (2 to 19 years of age) are obese.1,2 Obesity plays a significant role in some of the leading causes of preventable death including heart disease, stroke, type 2 diabetes, and certain cancers.1 In addition, the annual medical cost of obesity is considerable - $147 billion (2008 dollars) - with obese individuals experiencing significantly higher medical costs than those of normal weight.

In 2013, the American Heart Association (AHA), American College of Cardiology (ACC), and The Obesity Society released a guideline for the management of overweight and obesity in adults.3 This guideline focused on identifying patients who need to lose weight, matching treatment benefits with risk profiles, dietary and lifestyle interventions, and selecting patients for bariatric surgical treatment; pharmacological management of obesity was not a focus. In 2015, The Endocrine Society addressed the issue of pharmacological management in a new guideline that was co-sponsored by the European Society of Endocrinology and The Obesity Society.4

Pharmacologic Agents for Obesity

In the 1960s, the Food and Drug Administration (FDA) approved the first agents for short-term (few weeks) adjunctive therapy of obesity in combination with exercise, behavioral modification, and caloric restriction – phentermine and diethylpropion.4-6 For almost 4 decades, these were the only approved agents for obesity management until the approval of orlistat, a gastrointestinal lipase inhibitor, in 1999.4,7 In 2012, lorcaserin and the combination of phentermine/topiramate were approved.8,9 Finally, in 2014, liraglutide and naltrexone/bupropion became available for chronic weight management.4,10,11 Table 1 summarizes general information regarding the available pharmacologic agents for obesity. The advantages and disadvantages associated with each weight loss medication including cost, degree of weight loss, long-term efficacy data, and safety profile were evaluated in the guideline.

Table 1. Pharmacologic Agents for Obesity.4,5-11

Generic

(Brand)

Mechanism of action

Usual adult dose

Common side effects

Phentermine

Norepinephrine-release agent

37.5 mg capsule or tablet orally once daily given before breakfast or 1 to 2 hours after breakfast

Headache, elevated blood pressure and heart rate, insomnia, dry mouth, constipation, anxiety, palpitations, ischemic events

Diethylpropion

Norepinephrine-releasing agent

25 mg tablet orally three times daily, one hour before meals, and in midevening if desired to overcome night hunger

Similar to phentermine

Orlistat (Xenical; Alli)*

Pancreatic and gastric lipase inhibitor

Xenical: 120 mg capsule orally three times daily with each main meal containing fat (during or up to 1 hour after the meal)

Alli: 60 mg capsule orally three times daily with each main meal containing fat

Decreased absorption of fat-soluble vitamins, steatorrhea, oily spotting, flatulence with discharge, fecal urgency, oily evacuation, increased defecation, fecal incontinence

Lorcaserin (Belviq)

5HT2c receptor agonist

10 mg tablet twice daily orally with or without food

Headache, nausea, dry mouth, dizziness, fatigue, constipation

Phentermine/ topiramate (Qsymia)

GABA receptor modulation plus norepinephrine-releasing agent

3.75 mg phentermine/23 mg topiramate capsule orally once daily in the morning for 14 days; then increase to 7.5 mg phentermine/46 mg topiramate orally once daily

The dose may be increased further if sufficient weight loss does not occur. The maximum available dose is 15 mg phentermine/92 mg topiramate.

Insomnia, dry mouth, constipation, paresthesia, dizziness, dysgeusia

Naltrexone/ bupropion (Contrave)

Reuptake inhibitor of dopamine and norepinephrine and opioid antagonist

The usual dose should be escalated according to the following schedule:

Week 1: 8 mg naltrexone/90 mg bupropion tablet orally once daily in the morning

Week 2: One tablet in the morning and one tablet in the evening

Week 3: Two tablets in the morning and one tablet in the evening

Week 4 - onward: Two tablets in the morning and two tablets in the evening

Nausea, constipation, headache, vomiting, dizziness

Liraglutide (Saxenda)

GLP-1 agonist

The usual dose should be escalated according to the following schedule:

Week 1: 0.6 mg SC once daily without regard to timing of meals

Week 2: 1.2 mg SC once daily

Week 3: 1.8 mg SC once daily

Week 4: 2.4 mg SC once daily

Week 5 – onward: 3 mg SC once daily

Nausea, vomiting, pancreatitis

*Alli is the over-the counter brand name for orlistat; Xenical is the prescription brand name. SC = subcutaneous.

Guideline Recommendations

The Endocrine Society-appointed Task Force of experts developed the guideline using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe the strength of recommendations and the quality of evidence.4 A summary of recommendations made by the Task Force is presented in Table 2.

Table 2. Summary of Endocrine Society Clinical Practice Guideline Recommendations.4

Guideline recommendation

Strength of recommendation/
evidence

Diet, exercise, and behavioral modification should be included in all approaches to obesity management for individuals with a BMI ≥ 25 kg/m 2 and other tools such as pharmacotherapy (BMI ≥ 27 kg/m2 with comorbidity or BMI > 30 kg/m2) and bariatric surgery (BMI ≥ 35 kg/m2with comorbidity or BMI > 40 kg/m2) be used as adjunctive therapy. Pharmacologic therapy may increase adherence to behavior modification and improve physical functioning so that exercise becomes easier with time. Candidates for obesity medications include patients who have a history of being unable to successfully lose and maintain weight and who meet label indications.

Strong recommendation; high quality evidence

The administration of approved weight loss medications is suggested (versus no therapy) to ameliorate comorbidities and increase adherence to behavior modification in certain obese patients.

Weak recommendation; low quality evidence

Phentermine and diethylpropion are not recommended for use in patients with uncontrolled hypertension or a history of heart disease.

Strong recommendation; moderate quality evidence

For any patient prescribed pharmacologic therapy for obesity, efficacy and safety monitoring should occur at least monthly for the initial 3 months and then at least every 3 months thereafter.

Weak recommendation; low quality evidence

If a patient’s response to pharmacologic therapy is effective (i.e., weight loss ≥ 5% of body weight after 3 months) and safe, treatment should be continued. If there is a lack of response or safety issues occur, therapy should be discontinued and an alternative treatment approach undertaken.

Strong recommendation; high quality evidence

If pharmacologic therapy for chronic weight management is undertaken, dosing should be initiated at the lowest dose and escalated based on efficacy and tolerability to the recommended dose. Administering doses above the maximum approved dose is not recommended.

Weak recommendation; low quality evidence

For obese patients with type 2 diabetes, administration of a GLP-1 analog or SGLT2 inhibitor is recommended to promote weight loss in addition to the recommended first line agent, metformin.

Weak recommendation; moderate quality evidence

Lorcaserin and/or orlistat are recommended weight loss agents for patients with cardiovascular disease.

Weak recommendation; Very low quality evidence

BMI = body mass index.

Beyond the recommendations in Table 2, the guideline discusses the need to consider alternatives to medications that cause weight gain for various disease states and conditions including type 2 diabetes, hypertension, depression, epilepsy, schizophrenia, human immunodeficiency virus (HIV) infection, chronic inflammatory diseases such as rheumatoid arthritis, and contraception.4 Examples include recommendations to use weight-neutral antipsychotics and oral contraceptives over injectable formulations if possible. Finally, the guideline suggests against the off-label use of medications approved for other disease states for the sole purpose of weight loss.

Summary

Obesity continues to be a serious health concern for millions of American adults and children. The cornerstone of obesity management includes increased physical activity and reduced caloric intake; however, other approaches such as surgery and drug therapy also play a role. A recent Endocrine Society evidence-based practice guideline emphasizes that the appropriate adjunctive use of pharmacologic therapy may increase adherence to behavior modifications and improve physical functioning in obese patients.

References

1. Adult obesity facts. Centers for Disease Control and Prevention.http://www.cdc.gov/obesity/data/adult.html. Accessed February 9, 2015.

2. Childhood obesity facts. Centers for Disease Control and Prevention.http://www.cdc.gov/obesity/data/childhood.html. Accessed February 9, 2015.

3. Jensen MD, Ryan DH, Apovian CM, et al. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. Circulation. 2014;129(25 Suppl 2):S102-S138.

4. Apovian CM, Aronne LJ, Bessesen DH, et al. Pharmacological management of obesity: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2015;100(2):342-362.

5. Phentermine [package insert]. Phoenix, AZ: Apotheca; 2010.

6. Diethylpropion [package insert]. Philadelphia, PA: Lannett Company, Inc.; 2011.

7. Xenical [package insert]. South San Francisco, CA: Genentech; 2013.

8. Belviq [package insert]. Woodcliff Lake, NJ: Eisai; 2014.

9. Qsymia [package insert]. Mountain View, CA: Vivus, Inc.; 2014.

10. Contrave [package insert]. La Jolla, CA; Orexigen Therapeutics, Inc.; 2014.

11. Saxenda [package insert]. Plainsboro, NJ: Novo Nordisk, Inc.; 2015.

Return to Top

What information is available on the use of peramivir for treatment of influenza?

Introduction

Influenza is a common vaccine-preventable disease responsible for substantial morbidity and mortality. Between 1993 and 2008, the average hospitalization rate due to influenza was 63.5 per 100,000 person-years and over 25,000 deaths occurred in the US each year due to seasonal influenza between 1976 and 2003.1,2 In a recent study, it was estimated that about 28,000 adults are hospitalized annually in the intensive care unit (ICU) for influenza-associated critical illness.3 Of these patients with severe sepsis or acute respiratory failure, about one-third do not survive. The demographic with the highest risk of hospitalization were patients < 1 year or 65 years and older.1

There are 3 types of seasonal influenza viruses – A, B and C.4,5 Type A influenza viruses are classified into subtypes according to the combination of the surface proteins, hemagglutinin and neuraminidase. Currently, the subtypes influenza A (H1N1) and A (H3N2) are found in humans. Influenza B is classified by lineages and strains, including B/Yamagata and B/Victoria. It is less common but causes significant morbidity. Type C influenza occurs much less frequently than A and B and causes only mild upper respiratory tract illness; therefore, it is not included in seasonal influenza vaccines.

Prior to December 2014, 4 prescription influenza antiviral agents were approved by the US Food and Drug Administration (FDA): oral oseltamivir (Tamiflu®), inhaled zanamivir (Relenza®), amantadine (Symmetrel®), and rimantadine (Flumadine®).6 Oseltamivir and zanamavir are neuraminidase inhibitors that have activity against both influenza A and B viruses. Amantadine and rimantadine are adamantanes that are only active against influenza A viruses. During the past influenza seasons, there has continued to be high levels of resistance (>99%) to adamantanes among common influenza A strains. As a result of increasing resistance and lack of activity against the influenza B virus, amantadine and rimantadine are not recommended by the Center for Disease Control (CDC) for antiviral treatment or chemoprophylaxis.

Oral or inhaled administration of the recommended antivirals to patients with severe symptoms or patients who require respiratory therapy can be difficult. The development of an anti-influenza medication in an injectable form could be beneficial for critically ill influenza patients with severe or life-threatening symptoms for whom oral or inhalation administration would be challenging. In 2009, the FDA granted an emergency use authorization to use IV peramivir, which was commercially available in Japan at the time, for the influenza A (H1N1) pandemic.

On December 19, 2014, the FDA approved intravenous (IV) peramivir (Rapivab®), a third neuraminidase inhibitor with activity against influenza A and B, to treat influenza in adults for the 2014-2015 influenza season. Table 1 summarizes the current FDA indications and the CDC and American Academy of Pediatrics (AAP) recommendations for use of antiviral medications for the treatment of influenza.

Table 1. Antiviral Medications Recommended for Treatment of Influenza.6-10

Antiviral Agent

Active Against

Age

Contraindications

Oseltamivir

Influenza A and B

14 days and oldera

N/A

Zanamivir

7 years and older

People with underlying respiratory disease (i.e., asthma, COPD)b

Peramivir

Influenza A and Bc

18 years and older

N/A

aOral oseltamivir is FDA approved for the treatment of acute uncomplicated influenza in patients 14 days and older and for chemoprophylaxis in persons 1 year and older. However, use of oral oseltamivir for treatment of influenza in patients younger than 14 days old, including preterm infants, is recommended by the CDC and the AAP bZanamivir is contraindicated in patients with history of allergy to milk protein. cPeramivir efficacy is based on clinical trials in which the predominant influenza virus type was influenza A.

Abbreviations: COPD=chronic obstructive pulmonary disease; N/A=not applicable.

Literature Review

Adults

The safety and efficacy of peramivir in adult patients has been evaluated in multiple clinical trials.11-16 A majority of these studies occurred in Japan and other Asian countries due to the approved use of peramivir for influenza since 2010. Table 2 summarizes select published clinical trials of peramivir in adults. In an effort to determine utility of IV peramivir in high-risk hospitalized patients, de Jong and colleagues compared the time to symptom resolution in 338 patients who received a single peramivir dose to patients who received standard of care with or without use of another neuraminidase inhibitor.11 At interim analysis, no significant difference in outcome was observed between the groups and due to the need to recruit a greater number of patients, the trial was terminated.

A multinational, Phase II randomized, double-blind trial evaluated the efficacy and safety of IV peramivir 200 mg and 400 mg compared to oral oseltamivir in 137 hospitalized patients.12Peramivir at both doses demonstrated similar efficacy (clinical stability) to oseltamivir; however, the study did not include critically ill patients and did not meet the prespecified power to detect a difference between groups. Furthermore, the doses used in this Phase II trial are lower than the currently FDA-approved dose.

In 2 trials of outpatients with confirmed influenza, a single dose of 300 mg or 600 mg peramivir demonstrated noninferiority to a 5-day treatment course of oseltamivir 75 mg twice daily in over 1000 outpatients and superiority compared to placebo in close to 300 outpatients in time to alleviation of symptoms.13,15 These studies did not include high-risk patients who required hospitalization.

In a smaller study of 37 patients, the efficacy and safety of multiple doses of IV 300 mg and 600 mg peramivir was evaluated in those at high-risk requiring hospitalization.14 Over 60% received treatment for 2 days and 27% of patients received treatment for 1 day. The higher dose of peramivir demonstrated a shorter duration of illness and a shorter time to normalization of body temperature. Due to the small sample size of this study and lack of a comparator agent, this study demonstrated potential, but not proven, efficacy of multiple doses of peramivir in high-risk influenza patients requiring hospitalization. Gastrointestinal symptoms such as nausea and diarrhea were the most common adverse drug reactions reported in these trials.

Efficacy and safety outcomes of adult and pediatric patients with confirmed influenza between October 2010 and February 2012 who received peramivir in Japan were obtained in a post-marketing observational study.16 Adults received 300 mg or 600 mg (for severe symptoms or complications) IV peramivir infused over at least 15 minutes. Children received 10 mg/kg/day as a single dose up to a maximum of 600 mg. Of the 1174 patients, 83% were adults (defined as 15 to 64 years of age), 5.9% were younger than 15 years and 11.1% were 65 years or older. Only 3.2% were inpatients. Fever and symptom resolution occurred at a median time of 3 days in over 65% of patients. Diarrhea (1.87%), vomiting (0.85%), and nausea (0.68%) were the most common adverse drug reactions. Adverse drug reactions occurred within 3 days of treatment and resolved within one week of onset.

Pediatrics

Although peramivir is not FDA-approved for pediatric use, a multi-center, open-label study evaluated its efficacy and safety in children with pH1N1 virus infection.17 A study in 115 pediatric patients ages 28 days to 16 years examined the time to alleviation of influenza symptoms. Peramivir 10 mg/kg IV (maximum dose 600 mg) was administered over 15 to 60 minutes once daily for up to 5 days if body temperature was ≥38°C or if the patient was symptomatic. Of the pH1N1 population (n=106), 105 patients (91.3%) were treated for 1 day and 10 patients (8.7%) were treated for 2 days. The median time to alleviation of influenza symptoms was 29.1 hours (95% confidence interval [CI], 22.1 to 32.4) in the pH1N1 population and 27.9 hours (95% CI, 21.7 to 31.7) in the intent-to-treat infected population. The median time to resolution of fever was 20.6 hours (95% CI, 19.4 to 21.1.) in the pH1N1 population and 20.4 hours (19.1 to 20.9) in the intent-to-treat infected population. The most common adverse events were diarrhea (16.2%) and a decrease in neutrophil count (21.4%). A higher incidence of adverse events tended to be observed in younger children.

In a single-center, non-randomized study in Japan conducted between February and April 2011, 223 pediatric patients under the age of 18 years with confirmed influenza received one of 4 antiviral drugs (laninamivir 20 mg inhalation for patients < 10 years and 40 mg inhalation for patients 10 years or older, peramivir 10 mg/kg IV with a maximum of 300 mg as a single dose infused over 15 minutes, oseltamivir 4 mg/kg/day in 2 divided doses with a maximum of 150 mg/day for 5 days, zanamivir 20 mg/day in 2 divided doses for 5 days).18 The median age (range) of patients who received the antivirals were laninamivir, 132.5 months (80 to 164); oseltamivir, 56.5 months (3 to 135); peramivir, 76 months (2 to 219); and zanamivir, 124.5 months (59 to 198). For patients between ages 0 and 9 years who received oseltamivir or peramivir, the median duration of fever was not significantly different: 2 days (range 0 to 6 days) and 1.5 days (range 1 to 3 days), respectively (p=0.4499). When compared to zanamivir and laninamivir in patients between 5 and 18 years, peramivir reduced fever duration by 1 to 2 days which was considered to be statistically significant. No adverse events were reported in this study.

A post-marketing observational study in over 1100 Japanese children 15 years of age or younger evaluated the safety and efficacy of peramivir in patients who received the antiviral between October 2010 and February 2012.19 In terms of age range, slightly over 4% of the patients were between 4 weeks and 1 year of age, 44% were between 1 and 7 years, and 51.4% were between 7 and 15 years. Slightly over 11% of the patients were inpatient. Over 96% of patients received treatment for 1 day. Approximately 60% of patients had alleviation of symptoms in 3 days and close to 80% of patients had resolution of fever in 3 days. Incidences of some common adverse events were diarrhea (3.1%), abnormal behavior (3%), vomiting (1.5%), and decreased neutrophil count (1.5%). A majority of these adverse events occurred within 3 days of treatment and resolved within 7 days of occurrence. Patients with underlying conditions, severe influenza symptoms, on concomitant medications, and who received 2 or more doses of peramivir were more likely to experience an adverse event.

The results of these studies are promising; however, due to the open-label, unblinded, observational, and non-randomized design of these studies, the efficacy and safety of peramivir in children needs to be further demonstrated in larger, randomized, comparative trials.

Table 2. Clinical efficacy of peramivir for seasonal influenza in adult patients11-14

Study, Design and Duration

Population and Interventions

Endpoints

Outcomes

De Jong112014

DB, PC, RCT, Phase III

September 2009 to November 2012

Study was stopped at interim analysis due to futility and inability to recruit more patients

N=338 high-risk patients ≥ 6 years with confirmed influenza requiring hospital-ization

Over 75% of patients had influenza A

Peramivir IV 10 mg/kg once daily for children up to a maximum of 600 mg in adults once daily for 5 days plus standard of care (n=222)

Standard of care, with no antiviral (n=43)

Standard of care with either oseltamivir or zanamivir (n=73)

Primary:

· Time to clinical resolution (defined as time from treatment to resolution of at least 4 of the 5 vital sign abnormalities for 24 h)

Secondary:

· Changes in viral titer within 48 h

· Time to hospital discharge

· Influenza-related complications

· Incidence and duration of ICU stay during treatment

· Mortality

Safety:

· AEs

Primary:

· Time to clinical resolution in patients receiving peramivir plus standard of care compared to patients who received standard of care alone was 42.5 h (95% CI 40.0 to 61.9) vs. 49.5 h, respectively (95% CI 34.0 to 57.9; p=0.97).

· Time to clinical resolution in patients receiving peramivir plus standard of care compared to patients who received another neuraminidase inhibitor plus standard of care was 41.8 h (95% CI 30.9 to 56.8) vs. 48.9 (95% CI 31.0 to 65.8, p=0.74).

Secondary:

· No statistically significant differences in the secondary endpoints were observed between the treatment groups.

· Common adverse events related to medication included GI effects and were similar between treatment groups.

· Serious adverse events of pneumonia, COPD, septic shock, acute respiratory distress were attributed to influenza complications.

Ison 201312

MC, DB, RCT, Phase II

July 2007 to September 2008

N=122 hospitalized patients with confirmed influenza

Over 65% of patients had influenza A

Peramivir 400 mg IV once daily

Peramivir 200 mg IV once daily

Oseltamivir 75 mg PO twice daily

Treatment duration was 5 days

All patients received IV and PO treatment (1 active and 1 placebo to maintain blinding)

Primary:

· Composite of clinical stability (the following for ≥24 h: normal temperature, oxygen saturation ≥92% on room air, and ≥2 of the 3 following findings: respiratory rate ≤24/min, heart rate ≤100 bpm and systolic blood pressure ≥90mmHg)

Secondary:

· Changes in presence and severity of symptoms of influenza

· Clinical relapse defined as regression of ≥2 of the components of the primary end point for ˃12 h after achieving clinical stability

· Time to hospital discharge

· Mortality

· Time to resumption of usual activities (0 to 10 VAS recorded by the subjects once daily on days 1 to 5, 10 and 14; resumption of usual activities occurred when the score was recorded as 10)

Safety:

· AEs

· Routine hematological and laboratory results during treatment and up to 30 days after treatment initiation

Primary:

· Clinical stability by treatment with peramivir 400 mg, peramivir 200 mg, or oseltamivir was 37 h (22 to 48.7), 23 h (16 to 38.9) and 28 h (22 to 37), respectively (p=0.306).

Secondary:

· No significant differences were present for alleviation of influenza symptoms during treatment, 89.5 h (49.6 to 204.4), 70.3 h (60.5 to 97), and 73 h (48.1 to 96.5) for peramivir 400 mg, peramivir 200 mg and oseltamivir, respectively (p=0.783).

· Five (4%) patients required ICU admission during the first days of study treatment.

· There were no significant differences in time to hospital discharge, 3.8 h (2.7 to 4.8), 4 h (3 to 4.7), 4 h (2.9 to 4.6) for peramivir 400 mg, peramivir 200 mg and oseltamivir, respectively (p=0.994).

· None of the patients with confirmed influenza died during the study period.

· Patients treated with peramivir had a shorter median times to resumption of usual activities: 9 days, 8.8 days, and 13.7 days for peramivir 400 mg, peramivir 200 mg and oseltamivir, respectively (p=0.276).

Safety:

· A higher proportion of patients who received peramivir experienced ≥1 AE than those who received oseltamivir.

· Gastrointestinal AEs (mainly due to higher frequency of diarrhea) were reported in 33% of subjects for peramivir 200 mg, 28% for peramivir 400 mg, and 15% for oseltamivir.

· Serious AEs occurred in 8 patients treated with peramivir 400 mg, in 2 patients treated with peramivir 200 mg and in 4 treated with oseltamivir.

· There were no adverse changes in routine hematology or chemistry values.

Kohno 201113

MC, DB, DD, NI, RCT

November 2008 to April 2009

N=1091 outpatients with confirmed influenza

90% of patients had influenza A

Peramivir 300 mg single IV infusion

Peramivir 600 mg single IV infusion

Oseltamivir 75 mg PO twice daily for 5 days

Treatment duration was 5 days.

The concomitant use of acetamino-phen was allowed, but other antipyretics, antivirals, and antimicro-bials were not permitted.

Primary:

· Time to alleviation of influenza symptoms, considered to occur the first time all 7 influenza symptoms (cough, sore throat, headache, nasal stuffiness, feverishness or chills, muscle or joint pain, and fatigue) were rated as 0 (none) or 1 (mild) for at least 21.5h in the ITTI population

Secondary:

· Change from baseline in composite symptom score

· Proportion of patients whose body temperature returned to normal (<37°C)

· Time to resumption of usual activities

· Incidence of influenza-related complications (sinusitis, otitis media, bronchitis, and pneumonia

· Time-weighted change from baseline in the virus titer

Safety:

· Incidence of ADRs

Primary:

· The median times to alleviation of symptoms were 78 h (95% CI 68.4 to 88.6), 81 h (95% CI 72.7 to 91.5), and 81.8 h (95% CI 73.2 to 91.1) in peramivir 300 mg, peramivir 600 mg, and oseltamivir groups, respectively.

· The HR for time to alleviation of symptoms for the peramivir 300 mg and 600 mg groups compared to the oseltamivir group were 0.946 (97.5% CI 0.793 to 1.129) and 0.97 (97.5% CI 0.814 to 1.157), respectively.

· Both peramivir groups demonstrated noninferiority to oseltamivir (97.5% CI <1.17).

Secondary:

· The proportion of patients whose body temperatures returned to normal 24 h after treatment was significantly higher in the peramivir 300 mg and 600 mg groups (59.3%, p=0.0272 and 57.9%, p=0.0326, respectively) than in the oseltamivir group (49.7%).

· The median times to resumption of usual activity were 155.7 h, 195.5 h, and 171.3 h in the peramivir 300 mg, peramivir 600 mg, and oseltamivir groups, respectively.

· The incidence of influenza-related complications for the peramivir 300 mg group was 1 case (0.3%) of sinusitis, 6 cases (1.6%) of bronchitis, 3 cases (0.8%) of pneumonia; for the peramivir 600 mg group there was 1 case (0.3%) of sinusitis, 1 case (0.3%) of otitis media, 6 cases (1.7%) of bronchitis, and 1 case (0.3%) of pneumonia; for the oseltamivir group there were 4 cases (1.1%) of sinusitis, 6 cases (1.6%) of bronchitis, and 2 cases (0.5%) of pneumonia.

· The time-weighted change from baseline in the A/H3N3 infected subpopulation in the peramivir 300 mg was greater than the oseltamivir group (p=0.0386 at day 2 and p=0.0218 at day 3).

Safety:

· The incidence of ADRs (14%, 18.1%, and 20% in the peramivir 300 mg, peramivir 600 mg, and oseltamivir groups, respectively) was significantly lower in the peramivir 300 mg group (p=0.0382) and nonsignificantly lower in the peramivir 600 mg group (p=0.5718) than in the oseltamivir group.

· The common ADRs in the 3 treatment groups included diarrhea, nausea and a reduced neutrophil count. Compared to peramivir 600 mg, only nausea was numerically more frequent with oseltamivir. (1.9% vs. 4.4%).

· Prolonged QT interval and reduced neutrophil count was observed in the peramivir groups.

Kohno 201114

MC, DB, R

January 2009 to May 2009

N=37 high-risk patients with confirmed influenza who had diabetes, chronic respiratory tract disease or immune-suppressive treatment

Over 65% of patients had influenza A

Peramivir 300 mg IV single daily dose

Peramivir 600 mg IV single daily dose

Doses were administered IV over a period of 15 to 60 min for 1 to 5 days according to the repeated dosing criteria (temperature ≥37.5⁰C or clinical judgment).

Use of aceta-minophen was permitted.

Primary:

· Duration of influenza illness in the per-protocol population (the point at which all 7 influenza symptoms had become "0" (none) or "1" (mild) and remained at that level for ≥ 21.5 h

Secondary:

· Duration until body temperature normalized (temperature of ˂37⁰C for ≥12 h)

· Influenza virus titer

· Proportion of patients who were influenza virus positive after administration

· Incidence of influenza-associated complications (pneumonia, bronchitis, otitis media, and paranasal sinusitis)

Safety:

· ADRs

Primary:

· The median duration of influenza illness was 68.6 h in all patients (90% CI 41.5 to 113.4) , 114.4 h (90% CI 40.2 to 235.3) in the peramivir 300 mg group, and 42.3 h (90% CI 30 to 82.7) in the peramivir 600 mg group.

· 62% of patients received treatment for 2 days and 27% received 1 day treatment.

· HR for duration of illness for the 600 mg group compared to 300 mg was 0.497 (90% CI 0.251 to 0.984).

· The median duration of influenza illness was 92 h (90% CI 14.6 to 235.3; n=10) in the single dose patients and 64.1 h (90% CI 41.5 to 111.2; n=27) in multiple dose patients.

Secondary:

· The median time until body temperature normalized (˂37⁰C) was 40.2 h (90% CI, 34.2 to 53.8) for the total group, 57.1 h (90% CI, 34.2 to 75.1) for the 300 mg group, and 37.6 h (90% CI, 22.3 to 46.8) for the 600 mg group. The time to temperature normalization for the peramivir 600 mg group was also significantly shorter than that for the peramivir 300 mg group (HR 0.375, 90% CI 0.182 to 0.770).

· The mean influenza virus titers on day 2 in patients with positive virus titers at the time of enrollment were 1.9±1.88 overall, 2.29±2.52 in the peramivir 300 mg group, and 1.59±1.12 in the peramivir 600 mg group. The titers on day 3 were 1.9±1.88 overall, 2.09±2.42 in the peramivir 300 mg group, and 0.69±0.65 in the peramivir 600 mg group. The titers on day 6 were below the limit of detection (0.5) in both groups.

· The proportion of influenza virus-positive patients overall was 71% on day 2 (71.4% peramivir 300 mg, 70.6% peramivir 600 mg) after the start of administration, 31.3% on day 3 (46.7% peramivir 300 mg, 17.6% peramivir 600 mg), and 0% on day 6.

· The incidence of influenza-associated complications was 10.8%. The most common influenza-associated complication was pneumonia in 8.1% of patients.

Safety:

· The incidence of ADRs was 33.3%. 11 ADRs occurred in 28.6% of pts in the peramivir 300 mg group and 10 ADRs occurred in 38.1% of pts in the peramivir 600 mg group.

· The major events (≥3 instances of either an AE or ADR) were abnormal changes in clinical test values, including increased blood glucose levels and decreased neutrophil counts, in addition to diarrhea, pneumonia, and oral herpes infection.

Kohno 201015

MC, DB, PC, RCT

December 2007 to April 2008

N=296 patients with confirmed influenza and moderate to severe symptoms

Over 95% of patients had influenza A.

Single dose of peramivir 600 mg IV (n=97)

Single dose of peramivir 300 mg IV (n=99)

Single dose of placebo (n=100)

The study drug was infused over 30 to 60 min.

Use of aceta-minophen was allowed.

Primary:

· Time to alleviation of symptoms defined as the time from start of treatment to recovery (when all 7 influenza symptoms scores had been at “0” or “1” for at least 21.5 h)

Secondary:

· Baseline change in composite symptom scores at 24, 36, 48, and 96 h after the start of treatment

· Proportion of afebrile subjects (temperature ˂37°C)

· Change in influenza virus titer from baseline

· Time to resumption of usual activities

· Incidence of influenza related complications (otitis media, bronchitis, sinusitis, and pneumonia)

Safety:

· AEs

· Physical findings

· Vital signs

· Laboratory data

Primary:

· The median time to alleviation of symptoms was significantly reduced in the peramivir treatment groups compared to placebo (peramivir 300 mg 59.1 h, 95% CI 50.9 to 72.4; peramivir 600 mg 59.9 h, 95% CI 54.4 to 68.1; placebo 81.8 h, 95% CI 68 to 101.5). The HR of treatment to placebo for the time to alleviation of symptoms was 0.681 (95% CI, 0.511 to 0.909, adjusted p=0.0092) in the 300 mg group and 0.666 (95% CI 0.499 to 0.89, adjusted p=0.0092) in the 600 mg group.

Secondary:

· The efficacy of peramivir was apparent as early as 24 h after the start of treatment.

· The proportion of afebrile subjects was increased by treatment, and a reduction in fever was evident within 24 h of therapy.

· At baseline, the viral titers were similar for all 3 groups; however, on day 3, the proportions of virus-positive subjects were significantly decreased in the 300 mg (36.8%, p=0.0485) and 600 mg (25.8%, p=0.0003) groups compared to placebo (51.5%).

· Virus was not detected in most subjects on day 9 (300 mg, 0%; 600 mg, 1.1%; placebo 0%).

· Peramivir recipients reported shorter times to resumption of their usual activities (43.6 h and 41.7 h earlier in the 300 mg and 600 mg groups, respectively; 300 mg median duration 125.6 h (95% CI 103.8 to 148.5, p=0.0367), 600 mg 127.4 h (95% CI 122.1 to 153.1], p=0.0152), and placebo 169.1 h [95% CI, 142 to 180]).

· Physician-diagnosed secondary complications (pneumonia, bronchitis, sinusitis, and otitis media) occurred in 3 recipients (3%) of 300 mg peramivir (bronchitis), 1 recipient (1%) of 600 mg peramivir (otitis media), and 3 (3%) placebo recipients (bronchitis).

Safety:

· Most AEs were mild to moderate and were GI-related (diarrhea occurred in 14.1%, 15.2%, and 17% and nausea occurred in 3%, 6.1%, and 1% in the 300 mg, 600 mg and placebo groups, respectively).

· Severe AEs occurred in 2 subjects (2%) in the 300 mg group (3 – prolonged QT interval, 3 subjects (3%) in the 600 mg group (1 – prolonged QT interval, 1 – increased blood glucose, and 1 – increased blood creatinine), and 5 subjects (5%) in the placebo group (3 – prolonged QT interval, 1 – increased BP, 1 – increased blood glucose).

· The other severe AEs were attributed to influenza virus infection or its complications.

Abbreviations: AE(s)=adverse event(s); ADR(s)=adverse drug reaction(s); BP=blood pressure; CI=confidence interval; COPD=chronic obstructive pulmonary disease; DB=double-blind; DD=double-dummy; GI=gastrointestinal; HR=hazard ratio; ICU=intensive care unit; ITTI, intent-to-treat infected; IV=intravenously; MC= multicenter; NI= non-inferiority; PC=placebo controlled; PO=orally; R=randomized; RCT=randomized controlled trial; VAS=visual analog scale.

Clinical Use of Peramivir

Peramivir is a cyclopentane analogue neuraminidase inhibitor that selectively inhibits the influenza virus neuraminidase enzyme preventing the release of viral particles from infected cells.10 Peramivir is indicated for the treatment of acute, uncomplicated influenza in patients 18 years and older as a 600 mg single dose IV infusion over 15 to 30 minutes within 2 days of symptom onset. Peramivir can be prepared in 0.9% or 0.45% NaCl, 5% dextrose, or lactated ringers (maximum volume of 100 mL) and should be administered immediately or refrigerated for up to 24 hours. The manufacturer does not recommend mixing or co-infusing peramivir with other IV medications.

Peramivir does not undergo metabolism and is excreted via the kidney primarily as unchanged drug.10 It has an elimination half-life of about 20 hours. Dose adjustment is not required for a single administration of peramivir for patients with creatinine clearance 50 mL/min or higher. A reduced dose of peramivir 200 mg and 100 mg is recommended for patients with creatinine clearance below 50 mL/min and 30 mL/min, respectively. In patients requiring hemodialysis, peramivir should be administered after dialysis at a dose adjusted based on intrinsic renal function. In critically ill patients requiring continuous renal replacement therapy, 2 case studies report the use of IV peramivir 600 mg daily for 4 to 5 days for patients on daily continuous or prolonged hemodialysis based on plasma peramivir concentrations.20,21

In controlled clinical trials including patients with influenza, diarrhea and other gastrointestinal adverse effects were reported with peramivir, but the incidence was similar to that with placebo.11-19 Neutropenia has occurred in patients receiving peramivir. Serious skin reactions, including erythema multiforme and Stevens-Johnson syndrome, have occurred rarely.10 Neuropsychiatric events, including self-injury and delirium, which can be a complication of influenza illness, have been reported in patients with influenza taking neuraminidase inhibitors, including peramivir. Administration of peramivir within 48 hours before or less than 2 weeks after administration of the intranasal live attenuated influenza vaccine (FluMist Quadrivalent®) may reduce the vaccine’s efficacy and should be avoided. Inactivated influenza vaccine can be administered at any time relative to use of peramivir.

Influenza virus A and B isolates with neuraminidase amino acid substitutions associated with reduced susceptibility to peramivir and oseltamivir have been recovered in clinical trials.22Neuraminidase inhibition assays have found that some influenza A/H1N1 strains that are resistant to oseltamivir and peramivir remain susceptible to zanamivir.

Conclusion

Neuraminidase inhibitors are currently the drugs of choice for treatment of patients with influenza and are most effective when started within 48 hours of symptoms onset.4,6Currently, none of the neuraminidase inhibitors is approved for use in hospitalized or critically ill patients. Although approved by the FDA only for treatment of uncomplicated influenza in outpatients, the off-label use of peramivir, an IV drug, to treat hospitalized patients may be needed. Given the high mortality among the critically ill, the World Health Organization (WHO) and CDC recommend that all critically ill patients receive oseltamivir orally or via nasogastric tube. In patients unable to take oseltamavir, IV peramivir or investigational IV zanamivir should be considered.

Peramivir is the first neuraminidase inhibitor to be FDA-approved for IV administration and shows efficacy for the treatment of seasonal and pH1N1 influenza. Peramivir has demonstrated non-inferior efficacy to oral oseltamivir for treatment of adults with uncomplicated influenza. Additionally, efficacy and safety in children has been suggested in small, uncontrolled trials. The availability of an IV antiviral influenza agent is promising and its efficacy in hospitalized, critically ill adults and children remains to be established.

References

1. Zhou H, Thompson WW, Viboud CG et al. Hospitalizations associated with influenza and respiratory syncytial virus in the United States, 1993-2008. Clin Infect Dis. 2012;54(10):1427-1436.

2. Thompson WW, Weintraub E, Dhakher P et al. Estimated of US influenza-associated deaths made using four different methods. Influenza Other Respi Viruses. 2009;3(1):37-49.

3. Ortiz JR, Neuzil KM, Shay DK et al. The burden of influenza-associated critical illness hospitalizations. Crit Care Med. 2014;42(11):2325-2332.

4. World Health Organization. Influenza (Seasonal). http://www.who.int/mediacentre/factsheets/fs211/en/. Updated March 2014. Accessed January 30, 2015.

5. Centers for Disease Control and Prevention. Types of influenza viruses. http://www.cdc.gov/flu/about/viruses/types.htm. Updated August 19, 2014. Accessed February 19, 2015.

6. Centers for Disease Control and Prevention. Influenza antiviral medications: summary for clinicians. http://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm. Updated January 9, 2015. Accessed January 30, 2015.

7. American Academy of Pediatrics Committee on Infectious Diseases. Recommendations for prevention and control of influenza in children, 2013-2014. Pediatrics. 2013;132(4):e1089-e1104.

8. Tamiflu [package insert]. San Francisco, CA: Genetech, Inc.; 2014.

9. Relenza [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2013.

10. Rapivab [package insert]. Durham, NC: BioCryst Pharmaceuticals, Inc.; 2014.

11. de Jong MDIson MGMonto AS, et al. Evaluation of intravenous peramivir for treatment of influenza in hospitalized patients. Clin Infect Dis. 2014;59(12):e172-e185.

12. Ison MG, Hui DS, Clezy K et al. A clinical trial of intravenous peramivir compared with oral oseltamivir for the treatment of seasonal influenza in hospitalized adults. Antivir Ther. 2013;18(5):651-661.

13. Kohno S, Yen MY, Cheong HJ et al. Phase III randomized, double-blind study comparing single-dose intravenous peramivir with oral oseltamivir in patients with seasonal influenza virus infection. Antimicrob Agents Chemother. 2011;55(11):5267-5276.

14. Kohno S, Kida H, Mizuguchi M et al. Intravenous peramivir for treatment of influenza A and B virus infection in high-risk patients. Antimicrob Agents Chemother. 2011;55(6):2803-2812.

15. Kohno S, Kida H, Mizuguchi M et al. Efficacy and safety of intravenous peramivir for treatment of seasonal influenza virus infection. Antimicrob Agents Chemother. 2010;54(11):4568-4574.

16. Komeda T, Ishii S, Itoh Y, et al. Post-marketing safety and effectiveness evaluation of the intravenous anti-influenza neuraminidase inhibitor peramivir (I): a drug use investigation.

J Infect Chemother. 2014;20(11):689-695.

17. Sugaya N, Kohno S, Ishibashi T et al. Efficacy, safety, and pharmacokinetics of intravenous peramivir in children with 2009 pandemic H1N1 influenza A virus infection.Antimicrob Agents Chemother. 2012;56(1):369-377.

18. Hikita THikita HHikita F, et al. Clinical effectiveness of peramivir in comparison with other neuraminidase inhibitors in pediatric influenza patients.Int J Pediatr. 2012;2012:834181. doi: 10.1155/2012/834181.

19. Komeda TIshii SItoh Y, et al. Post-marketing safety and effectiveness evaluation of the intravenous anti-influenza neuraminidase inhibitor peramivir (II): A pediatric drug use investigation.J Infect Chemother. 2015;21(3):194-201.

20. Thomas B, Hollister AS, Muczynski KA. Peramivir clearance in continuous renal replacement therapy. Hemodial Int. 2010;14(3):339-340.

21. Scheetz MH, Griffith MM, Ghossein C et al. Pharmacokinetic assessment of peramivir in a hospitalized adult undergoing continuous venovenous hemofiltration. Ann Pharmacother. 2011;45(12):e64.

22. Nguyen HT, Sheu TG, Mishin VP et al. Assessment of pandemic and seasonal influenza A (H1N1) virus susceptibility to neuraminidase inhibitors in three enzyme activity inhibition assays. Antimicrob Agents Chemother. 2010:54(9):3671-3677.

Prepared by:

Clarissa M. Sema, PharmD

PGY1 Pharmacy Resident

January 2015

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What data supports the use of new oral anticoagulants in special populations (hepatic impairment, obesity, pregnancy, lactation, and pediatrics)?

Introduction

In recent years, several new oral anticoagulants (NOACs) have been approved by the US Food and Drug Administration (FDA) for various disease states including stroke prophylaxis in atrial fibrillation (AF), venous thromboembolism (VTE) prophylaxis in major orthopedic surgery, and treatment and prevention of VTE.1-4 The efficacy and safety of these agents, and their therapeutic advantages compared to warfarin, have garnered interest among clinicians. However, there is little clinical experience with these medications in special populations. This article summarizes the available published evidence for apixaban, dabigatran, edoxaban, and rivaroxaban in the following populations: hepatic impairment, obesity, pregnancy, lactation, and pediatrics.

Hepatic impairment

The liver plays only a minor role in the metabolism and elimination of all NOACs.1-4 Apixaban undergoes some cytochrome (CYP)-mediated elimination via 1A2, 2C8, 2C9, 2C19, and 2J2 enzymes and rivaroxaban is oxidatively metabolized by CYP 3A4/5 and 2J2.1,4 Dabigatran and edoxaban are not metabolized in the liver and undergo primarily renal elimination.2,3Although their pharmacokinetic properties do not make it likely that use in patients with hepatic impairment would lead to any major safety concerns, data supporting their safe use in this population is limited.5 In particular, patients with cirrhosis and/or impaired hepatic production of coagulation factors, or those with hepatorenal syndrome, may be at an increased risk of bleeding.

In patients with mild hepatic impairment (Child-Pugh Class A), all NOAC manufacturers endorse their use without dose adjustment. 1-5 In the setting of moderate impairment (Child-Pugh Class B), there are no dose recommendations for apixaban or dabigatran but their use is not discouraged. 1,3 Edoxaban and rivaroxaban should not be used in patients with moderate hepatic impairment due to the risk of increased bleeding risk and coagulopathy.2,4Data with dabigatran is lacking in patients with severe hepatic impairment (Child-Pugh Class C); apixaban, edoxaban, and rivaroxaban are not recommended with severe impairment.1-4

The primary literature provides little additional clinical information regarding use of these agents in patients with hepatic impairment. All NOACs have some pharmacokinetic data in patients with hepatic impairment (either published or provided to the FDA to support their approval) but the studies used single doses (not steady state) and had small sample sizes.5

Recently, some data has been published regarding the use of NOACs in patients with cirrhosis. An in vitro study found that plasma from 14 patients with cirrhosis (n=9 Child-Pugh Class B, n=5 Child-Pugh Class C) demonstrated decreased total (51% and 55%) and mean (32% and 30%) thrombin generation in comparison to 11 control patients, after apixaban 25 ng/mL or 50 ng/mL, respectively, was added to each sample.6 This study suggests that patients with cirrhosis may be at increased risk of bleeding with apixaban use, and potentially other NOACs. However, 2 recent case reports/series describe effective use of apixaban and rivaroxaban in patients with cirrhosis for the treatment of portal vein thrombosis (PVT), without any bleeding complications. 7,8 In the first case, a 50 year-old male with Child-Pugh Class A cirrhosis due to nonalcoholic steatohepatitis, esophageal varices, and PVT received heparin followed by transition to rivaroxaban 20 mg daily.7 Baseline serum creatinine was normal (0.6 mg/dL) and the international normalized ratio was 1.1. The thrombus had completely resolved by 6 months of follow-up and the patient did not report any bleeding complications. The second article was a case series (n=5) of patients with Child-Pugh Class A cirrhosis who received either apixaban 2.5 mg twice daily or rivaroxaban 10 to 20 mg daily for treatment of PVT.8 During follow-up (durations ranging from 1 to 7 months), the authors reported that therapy was well-tolerated and no patients experienced bleeding complications. These promising results now need to be confirmed in larger, prospective settings before widespread use of NOACs in patients with cirrhosis can be recommended.

Although some postmarketing reports describe drug-induced liver injury caused by dabigatran and rivaroxaban, a 2014 meta-analysis/systematic review of 29 randomized controlled trials (n=152,116 patients) did not identify an increased risk of liver injury with NOACs overall (relative risk 0.90, 95% confidence interval 0.72 to 1.13) or with individual agents.9-13

Obesity

Anticoagulant dosing in obesity is challenging due to the potential for unpredictable or decreased anticoagulant effects. Also, therapeutic monitoring is not available for NOACs so it is not possible to confirm the degree of anticoagulation. Formal dosing recommendations regarding use of NOACs in obese patients are lacking; however, there are a few published literature reports in this population with apixaban, dabigatran, and rivaroxaban. 1-4,14-20

A Phase I pharmacokinetic study with apixaban included 18 healthy subjects with mean body weight 137 kg (range 120 to 175 kg) and mean body mass index (BMI) ≥ 42.6 kg/m(range 32 to 54 kg/m2).14 Following a single dose of apixaban 10 mg, the mean apixaban maximum concentration (Cmax) and area under the curve (AUC) were 31% and 23% lower, respectively, compared to subjects with more normal body weight (65 to 85 kg). The apparent volume of distribution was 24% larger and the half-life was 3 hours shorter in obese subjects compared to subjects with normal body weight. There was a trend toward lower plasma anti-factor Xa activity with increasing body weight. Overall, the authors concluded that the differences in apixaban exposure with obesity were modest and not likely to be clinically significant; therefore, no dose adjustment based on body weight was recommended.

Two published reports describe use of dabigatran in obese patients.15,16 The first article is a post-hoc pooled analysis of dabigatran 220 mg daily in 896 patients with BMI >30 kg/m2 for the prevention of VTE following major orthopedic surgery.16 Data were obtained from 3 major clinical trials (RE-MODEL, RE-NOVATE, and RE-NOVATE II).21-23 Among all patients who received dabigatran in these trials, 22.6% had BMI >30 to 35 kg/m2, 6.9% had BMI >35 to 40 kg/m2, and 2% had BMI >40 kg/m2. The composite primary endpoint of major VTE and VTE-related mortality occurred at a similar rate in obese and non-obese patients (2.7% vs 2.1%). Obese patients also had a similar rate of the primary endpoint compared to patients who received enoxaparin 40 mg daily (2.9%, p=0.797). There were no differences in bleeding between groups. The 220 mg dose cannot be achieved with the dabigatran formulations currently available in the US (75 and 150 mg capsules), but these results do provide some reassurance regarding the safety and efficacy of dabigatran in obese patients. The other published report with dabigatran is a case report describing an acute ischemic stroke in a 48 year-old obese patient (153 kg, BMI 44.7 kg/m2) who had been taking dabigatran 150 mg twice daily for the prior 4 weeks for paroxysmal AF with purportedly good compliance.15 The dabigatran plasma level at presentation (patient-reported 9 hours after the most recent dose), as assessed by the Hemoclot thrombin inhibitor assay, was undetectable. Dabigatran therapy was continued following thrombolysis and plasma level monitoring demonstrated a peak plasma level of 50 ng/mL 4 hours post-dose at steady state. The authors report that this peak level was less than the 25th percentile of the therapeutic trough level. In response to the potentially sub-therapeutic dabigatran dose, therapy was switched to a coumarin anticoagulant. Further prospective data regarding the efficacy of dabigatran in patients with obesity are needed.

Among the NOACs, rivaroxaban has the largest number of published reports describing its use in obese patients.17,18,20 Similar to the apixaban study described previously, a single-center, randomized, single-blind, placebo-controlled study was conducted to evaluate the pharmacokinetics of rivaroxaban in healthy subjects.17 A total of 12 obese subjects (mean weight 132.2 kg, mean BMI 43.5 kg/m2 ) received a single 10 mg dose of rivaroxaban. There were no differences in Cmax, AUC, time to maximum concentration (tmax) or half-life between obese and non-obese subjects. Pharmacokinetic data for rivaroxaban were also published in a case report of a 67 year-old obese patient with acute ischemic stroke due to previously undiagnosed nonvalvular AF.20 Ten days after the stroke, the patient was started on dabigatran 150 mg twice daily. Hemoclot assay results after 1 week of therapy indicated that the patient did not reach the interquartile range for Cmax and most readings were below the interquartile range of trough concentration (Ctrough). In response, the patient was switched to rivaroxaban 20 mg daily; DiXal direct factor Xa inhibitor assay peak and trough results suggested effective anticoagulation.

One report of rivaroxaban use following bariatric surgery is available.18 A 27 year-old patient (145 kg) with a prior history of gastric bypass surgery and recurrent VTE was switched from warfarin to rivaroxaban 20 mg daily due to extreme difficulty achieving stable INR levels. Anti-Xa levels were monitored but these results were not provided. The authors concluded that the patient’s rivaroxaban peak plasma levels were within the expected range, suggesting that rivaroxaban is sufficiently absorbed following bariatric surgery to achieve therapeutic levels. However, the absorption of rivaroxaban in the early postoperative period following bariatric surgery may be reduced since food enhances absorption but some patients are placed on calorie-restricted diets immediately after certain bariatric procedures.19

In summary, apixaban and rivaroxaban have fairly predictable pharmacokinetic profiles in obese patients but no data are available regarding therapeutic efficacy in this population. Dabigatran does have some clinical outcome data in obese patients but the case reports suggesting lack of efficacy are concerning. No conclusion can be made regarding edoxaban since published data in obese patients is lacking.

Pregnancy

There is limited information regarding the safe use of NOACs in pregnant patients. Apixaban is FDA pregnancy category B, while dabigatran, edoxaban, and rivaroxaban are pregnancy category C. 1-4 The product labeling for rivaroxaban contains a warning regarding the risk of pregnancy-related hemorrhage but this seems to be a general risk of all anticoagulants rather than a specific risk of rivaroxaban.4 Rivaroxaban is the only agent with a published case report of its use in pregnancy.24 A 24 year-old woman with a history of recurrent VTE, including upper and lower extremities and pulmonary embolism, received rivaroxaban 15 mg daily for 19 weeks until her pregnancy was discovered. Rivaroxaban was switched to enoxaparin for the remainder of the pregnancy. The baby was born spontaneously at 40 weeks gestation without complication, and no abnormalities were observed on any routine physical examinations or screenings up to 13 weeks of age. Although there are no clinical data in pregnancy with dabigatran, an in vitro pharmacokinetic placental transfer study observed a fetal/maternal ratio of 0.33 for dabigatran and 0.17 for the dabigatran etexilate mesylate prodrug after 3 hours, suggesting limited transfer of the prodrug across the placenta.25 The study authors recommended that dabigatran crosses the placenta to some extent and should not be used in pregnant women due to the risk of fetal coagulation abnormalities with in utero exposure.

Lactation

The manufacturers of all NOACs state that it is unknown whether these agents are excreted in human milk.1-4 The apixaban manufacturer refers to 12% excretion of the maternal dose in the milk of lactating rats, but it is unclear whether this can be extrapolated to humans.1 No published reports of NOAC use in lactating patients were found.

Pediatrics

According to the product labeling for all NOACs, safety and effectiveness in pediatric patients have not been established.1-4 However, many children require anticoagulant therapy and NOACs may be desirable alternative therapies in patients with contraindications or intolerance to warfarin due to their ease of administration compared to parenteral therapies. One limitation to the use of NOACs in children is the availability of recipes and stability data for compounding liquid oral formulations for children who cannot swallow tablets. The apixaban and rivaroxaban package inserts contain instructions for crushing and mixing the tablets with appropriate media (e.g., fluids, applesauce) for enteral tube administration, but no clinical data are available with this approach and it is unclear whether these preparations could also be given orally to children.1,4

The only agent with published reports of use in pediatric patients is rivaroxaban.26,27 In the first case, a 6 year-old girl (21 kg) received rivaroxaban for the prevention of skin necrosis in the setting of severe protein S deficiency.27 The patient had previously been on warfarin since day 6 of life, but 5 episodes of skin necrosis during the prior year prompted a trial of rivaroxaban. Skin necrosis developed with the initial dose of rivaroxaban 5 mg, so the dose was titrated over a period of 8 weeks to 40 mg daily given as 10 mg every 6 hours. The more frequent dosing scheme was based on the patient’s pharmacokinetic/pharmacodynamic profile. Pharmacokinetic evaluations demonstrated rapid absorption with a mean half-life of 3.5 hours and anti-factor Xa activity correlated with plasma rivaroxaban concentration; therefore, a frequent dosing interval was warranted. At 1 year of follow-up, the patient had not experienced any episodes of skin necrosis or bleeding complications. The second case was a 15 year-old adolescent girl who received rivaroxaban 20 mg for treatment of deep vein thrombosis possibly triggered by hormonal contraceptive therapy.26 A pharmacokinetic evaluation demonstrated fast absorption, lower peak plasma concentrations than in adults, and markedly decreased plasma concentrations within 6 hours. At 6-month follow-up, the patient had not experienced any bleeding complications and no further thrombosis had developed. At present, studies with all NOACs are ongoing in pediatric patients, including safety/tolerability, pharmacokinetic, and efficacy studies depending on the agent.28

Conclusion

Clinical experience with NOACs is fairly limited in special populations, including liver impairment, obesity, pregnancy, lactation, and pediatrics. Clinicians are urged to limit their use of these agents to clinical situations with published data supporting their efficacy and safety, which may include specific situations in special populations.

References

1. Eliquis [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2014.

2. Savaysa [package insert]. Parsippany, NJ: Daiichi Sankyo, Inc; 2015.

3. Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; 2014.

4. Xarelto [package insert]. Titusville, NJ: Janssen Pharmacueticals, Inc; 2014.

5. Graff J, Harder S. Anticoagulant therapy with the oral direct factor Xa inhibitors rivaroxaban, apixaban and edoxaban and the thrombin inhibitor dabigatran etexilate in patients with hepatic impairment. Clin Pharmacokinet. 2013;52(4):243-254.

6. Potze W, Adelmeijer J, Lisman T. Decreased in vitro anticoagulant potency of rivaroxaban and apixaban in plasma from patients with cirrhosis. Hepatology. 2014. doi: 10.1002/hep.27350.

7. Martinez M, Tandra A, Vuppalanchi R. Treatment of acute portal vein thrombosis by nontraditional anticoagulation. Hepatology. 2014;60(1):425-426.

8. Intagliata NM, Maitland H, Northup PG, Caldwell SH. Treating thrombosis in cirrhosis patients with new oral agents: ready or not? Hepatology. 2015;61(2):738-739.

9. Caldeira D, Barra M, Santos AT, et al. Risk of drug-induced liver injury with the new oral anticoagulants: systematic review and meta-analysis. Heart. 2014;100(7):550-556.

10. Rochwerg B, Xenodemetropoulos T, Crowther M, Spyropoulos A. Dabigatran-induced acute hepatitis. Clin Appl Thromb Hemost. 2012;18(5):549-550.

11. Barrett P, Vuppalanchi R, Masuoka H, Chalasani N. Severe drug-induced skin and liver injury from rivaroxaban. Dig Dis Sci. 2015 Feb 13. [Epub ahead of print]

12. Russmann S, Niedrig DF, Budmiger M, et al. Rivaroxaban postmarketing risk of liver injury. J Hepatol. 2014;61(2):293-300.

13. Liakoni E, Ratz Bravo AE, Terracciano L, Heim M, Krahenbuhl S. Symptomatic hepatocellular liver injury with hyperbilirubinemia in two patients treated with rivaroxaban.JAMA Intern Med. 2014;174(10):1683-1686.

14. Upreti VV, Wang J, Barrett YC, et al. Effect of extremes of body weight on the pharmacokinetics, pharmacodynamics, safety and tolerability of apixaban in healthy subjects.Br J Clin Pharmacol. 2013;76(6):908-916.

15. Breuer L, Ringwald J, Schwab S, Kohrmann M. Ischemic stroke in an obese patient receiving dabigatran. N Engl J Med. 2013;368(25):2440-2442.

16. Eriksson BI, Dahl OE, Feuring M, et al. Dabigatran is effective with a favourable safety profile in normal and overweight patients undergoing major orthopaedic surgery: a pooled analysis. Thromb Res. 2012;130(5):818-820.

17. Kubitza D, Becka M, Zuehlsdorf M, Mueck W. Body weight has limited influence on the safety, tolerability, pharmacokinetics, or pharmacodynamics of rivaroxaban (BAY 59-7939) in healthy subjects. J Clin Pharmacol. 2007;47(2):218-226.

18. Mahlmann A, Gehrisch S, Beyer-Westendorf J. Pharmacokinetics of rivaroxaban after bariatric surgery: a case report. J Thromb Thrombolysis. 2013;36(4):533-535.

19. Thomas Z, Bareket Y, Bennett W. Rivaroxaban use following bariatric surgery. J Thromb Thrombolysis. 2014;38(1):90-91.

20. Safouris A, Demulder A, Triantafyllou N, Tsivgoulis G. Rivaroxaban presents a better pharmacokinetic profile than dabigatran in an obese non-diabetic stroke patient. J Neurol Sci.2014;346(1-2):366-367.

21. Eriksson BI, Dahl OE, Rosencher N, et al. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. Lancet. 2007;370(9591):949-956.

22. Eriksson BI, Dahl OE, Rosencher N, et al. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost. 2007;5(11):2178-2185.

23. Eriksson BI, Dahl OE, Huo MH, et al. Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II). A randomised, double-blind, non-inferiority trial. Thromb Haemost. 2011;105(4):721-729.

24. Konigsbrugge O, Langer M, Hayde M, Ay C, Pabinger I. Oral anticoagulation with rivaroxaban during pregnancy: a case report. Thromb Haemost. 2014;112(6):1323-1324.

25. Bapat P, Kedar R, Lubetsky A, et al. Transfer of dabigatran and dabigatran etexilate mesylate across the dually perfused human placenta. Obstet Gynecol. 2014;123(6):1256-1261.

26. Beyer-Westendorf J, Gehrisch S. Phamacokinetics of rivaroxaban in adolescents.Hamostaseologie. 2014;34(1):85-87.

27. Martinelli I, Bucciarelli P, Artoni A, et al. Anticoagulant treatment with rivaroxaban in severe protein S deficiency. Pediatrics. 2013;132(5):e1435-1439.

28. US National Institutes of Health. Clinicaltrials.gov website. https://clinicaltrials.gov/. Accessed February 13, 2015.

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