The medical letter on drugs and therapeutics janurary 2 2017

1511 on Drugs and Therapeutics Antiviral Drugs for Seasonal Influenza 2016-2017 ...p 1 Another Insulin Glargine Basaglar for Diabetes ...p 3 Ustekinumab Stelara for Crohn’s Disease ...p

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IN THIS ISSUE

ISSUE

1433

Volume 56

Published by The Medical Letter, Inc • A Nonprofi t Organization

ISSUE No

1511

on Drugs and Therapeutics

Antiviral Drugs for Seasonal Influenza 2016-2017 p 1

Another Insulin Glargine (Basaglar) for Diabetes p 3

Ustekinumab (Stelara) for Crohn’s Disease p 5

Tenofovir Alafenamide (Vemlidy) for Hepatitis B p 6

1

on Drugs and Therapeutics

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Published by The Medical Letter, Inc • A Nonprofi t Organization

ISSUE

1433

Volume 56

ISSUE No

1511 Another Insulin Glargine (Basaglar) for Diabetes Ustekinumab (Stelara) for Crohn’s Disease p 3p 5

Tenofovir Alafenamide (Vemlidy) for Hepatitis B p 6

ALSO IN THIS ISSUE

Antiviral Drugs for Seasonal

Influenza 2016-2017

▶

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Recommendations for Treatment of Seasonal Influenza

▶ Antiviral treatment should be started as soon as possible after illness onset, without waiting for the results of influenza testing

▶ Treatment is indicated for persons with influenza who are at high risk for complications (including pregnant women), have severe illness, or are hospitalized.

▶ Treatment can be considered for previously healthy persons with uncomplicated influenza if it can be started within 48 hours of illness onset.

▶ Neuraminidase inhibitors (oral oseltamivir, inhaled zanamivir,

or IV peramivir) are the drugs of choice.

▶ These drugs are most effective when started within 48 hours

of illness onset.

▶ Oseltamivir is preferred for treatment of pregnant women and hospitalized patients.

Antiviral drugs can be used for prophylaxis and treatment

of influenza Frequently updated information on influenza

activity, testing for influenza, and antiviral resistance is

available from the CDC at www.cdc.gov/flu

INDICATIONS FOR TREATMENT — The CDC

recommends starting antiviral treatment as soon as

possible after illness onset, without waiting for the

results of influenza testing Antiviral treatment is

indicated for all persons with suspected or confi rmed

influenza who are at high risk for complications,

including children <2 years old, persons <19 years

old receiving long-term aspirin therapy, adults ≥65

years old, morbidly obese persons (BMI ≥40), women

who are pregnant or ≤2 weeks postpartum, persons

of Ameri can Indian/Alaska Native heritage, residents

of nursing homes or other chronic care facilities, and

persons who are immunosuppressed or have certain

chronic medical conditions (including pulmonary,

cardiovascular, renal, hepatic, hematological,

metabolic, neurologic, or neurodevelopmental

disorders) Antiviral treatment is recommended for

all patients with suspected or confi rmed influenza

who have severe, complicated, or progressive illness,

develop symptoms of lower respiratory tract infection,

or require hospitalization Antiviral treatment can

be considered for previously healthy persons with

uncomplicated influenza if it can be started within 48

hours of illness onset.1

INDICATIONS FOR CHEMOPROPHYLAXIS — Antiviral

prophy laxis is not recommended for healthy persons exposed to influenza It can be considered for persons at high risk for complications who have not been vaccinated against influenza this season, have received the vaccine within the last 2 weeks or are unlikely to respond to vaccination, for unvaccinated healthcare workers who are exposed to influenza, and to help control outbreaks

in nursing homes

NEURAMINIDASE INHIBITORS — Neuraminidase

inhibitors remain the drugs of choice for treatment

and prophylaxis of influenza Oseltamivir (Tamiflu,

and generic), which is taken orally, and zanamivir

(Relenza), which is inhaled, are approved by the FDA

for treatment of acute, uncomplicated influenza in children and adults; both drugs are also approved for influenza prophylaxis A single intravenous dose of

peramivir (Rapivab) is FDA-approved for treatment of

acute uncomplicated influenza in adults.2

Effectiveness – When used for prophylaxis against

susceptible strains of seasonal influenza A or B

viruses, neuraminidase inhibitors have generally been

about 70-90% effective.3

Use of neuraminidase inhibitors for treatment of influenza

can shorten the duration of symptoms by about one

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day.4,5 Although most controlled trials of these drugs have

not been powered to assess their effi cacy in preventing

serious influenza complications, expert clinicians have

generally interpreted the combined results of controlled

trials, observational studies, and meta-analyses as

showing that early antiviral treatment of high-risk patients

with influenza may reduce the risk of complications.6

Timing and Duration – When indicated, prophylaxis

with oseltamivir or zanamivir should be started within

48 hours after exposure to the influenza virus and

continued for 7 days after the last known exposure

Longer durations of prophylaxis are often recommended

for institutional and community outbreaks (see Table 1)

Treatment of influenza with a neuraminidase inhibitor

is most effective when started within 48 hours after

illness onset; however, the results of some

observa-tional studies in hospitalized and critically ill patients

suggest that treatment started as late as 4-5 days

af-ter illness onset may reduce the risk of complications

such as pneumonia, respiratory failure, and death.7-9

The usual duration of treatment for patients with uncomplicated influenza is 5 days with oseltamivir

or zanamivir and 1 day with peramivir For hospital-ized, critically ill, or immunocompromised patients,

in whom viral replication may be protracted, a longer treatment course of oseltamivir (e.g., 10 days) is often used IV peramivir (for at least 5 days) or investiga-tional IV zanamivir may be considered for those who cannot take oseltamivir.1

Pregnancy — Pregnant women are at high risk for

complications of influenza, including death.10 Prompt antiviral treatment is recommended for women with suspected or confi rmed influenza who are pregnant or

≤2 weeks postpartum Oseltamivir and zanamivir appear

to be safe for use during pregnancy, but oseltamivir is preferred for treatment.11-13 Antiviral prophylaxis can be considered for pregnant women who have had close contact with someone likely to have been infected with influenza Zanamivir may be preferred for prophylaxis because of its limited systemic absorption, but oseltamivir is a reasonable alternative

Table 1 Antiviral Drugs for Prophylaxis and Treatment of Seasonal Influenza 2016-2017

Drug Oseltamivir (Tamiflu, and generic) Zanamivir (Relenza)1 Peramivir (Rapivab)

Formulations 30, 45, 75 mg caps; 5 mg/blister for inhalation 2 200 mg/20 mL single-use

6 mg/mL oral susp (Tamiflu only) vials

Cost 3 generic: $127.50 4 $59.00 $950.00

Tamiflu: 143.00

Prophylaxis of Influenza

Adult Dosage 75 mg PO once daily x 7 days 5 2 inhalations once daily x 7 days 5 Not FDA-approved for prophylaxis

Adult Dosage CrCl 30-60 mL/min: 30 mg once daily No dosage adjustment required Not FDA-approved for prophylaxis

for Renal CrCl >10-30 mL/min: 30 mg every other day for renal impairment

Impairment HD: 30 mg after every other HD 6

CAPD: 30 mg once/week after exchange

ESRD not on HD: not recommended

Pediatric Dosage 30-75 mg 7 PO once daily x 7 days 5 ≥5 yrs: 2 inhalations once daily Not FDA-approved for prophylaxis

Treatment of Uncomplicated Influenza

Adult Dosage 75 mg PO bid x 5 days 8 2 inhalations bid x 5 days 600 mg IV once 8

Adult Dosage CrCl 30-60 mL/min: 30 mg bid No dosage adjustment CrCl 30-49 mL/min: 200 mg once

for Renal CrCl >10-30 mL/min: 30 mg once daily required for renal impairment CrCl 10-29 mL/min: 100 mg once Impairment HD: 30 mg after every HD HD: administer dose (based

CAPD: 30 mg after exchange on CrCl) after HD

ESRD not on HD: not recommended

Pediatric Dosage 30-75 mg 7 PO bid x 5 days 8 ≥7 yrs: 2 inhalations bid x 5 days Not FDA-approved for use in children

CAPD = continuous ambulatory peritoneal dialysis; ESRD = end-stage renal disease; HD = hemodialysis

1 Inhaled zanamivir is not recommended for use in patients with underlying respiratory disease such as asthma or COPD or in patients with severe influenza, including hospitalized patients Contraindicated in patients with a history of allergy to milk protein.

2 Available in a carton containing 5 rotadisks (each rotadisk contains four 5-mg blisters of the active drug in a lactose carrier) and a Diskhaler inhalation device

Zanamivir should not be used in a nebulizer

3 Approximate WAC for 5 days’ treatment with oseltamivir or zanamivir, or a single dose of peramivir at the adult dosage WAC = wholesaler acquisition cost or manufac-turer’s published price to wholesalers; WAC represents a published catalogue or list price and may not represent an actual transactional price Source: AnalySource® Monthly December 5, 2016 Reprinted with permission by First Databank, Inc All rights reserved ©2016 www.fdbhealth.com/policies/drug-pricing-policy

4 Cost at www.healthwarehouse.com Accessed December 20, 2016.

5 After the last known exposure For prophylaxis of exposures in institutions, the drug should be taken for at least 2 weeks and continued for 1 week after the end

of the outbreak For prophylaxis during community outbreaks, oseltamivir has been shown to be effective and safe when taken for up to 42 days, and zanamivir for up to 28 days Some expert clinicians would use twice-daily therapeutic doses for post-exposure prophylaxis in highly immunocompromised persons.

6 Initial dose can be administered before start of HD.

7 Dose for children 1-12 yrs old: ≤15 kg: 30 mg; 15.1-23 kg: 45 mg; 23.1-40 kg: 60 mg; ≥40.1 kg: 75 mg The FDA-approved dosage for treatment of infants

≥2 weeks to <1 year old is 3 mg/kg bid; the CDC recommends the same dosage for treatment of children <2 weeks old Although not FDA-approved for prophy-laxis in children <1 year old, the ACIP and CDC recommend that children 3-11 months old receive 3 mg/kg once/d For treatment of premature infants, refer to CDC recommendations (www.cdc.gov/flu).

8 In hospitalized, critically ill, or immunocompromised patients a longer treatment course of oseltamivir (e.g., 10 days) is often used Oseltamivir can be ad-ministered by oro/nasogastric tube to patients who are unable to swallow capsules IV peramivir (for at least 5 days) or investigational IV zanamivir may be considered for those who cannot take oseltamivir IV zanamivir is available under an emergency investigational new drug request to the manufacturer (GSK 877-626-8019) for hospitalized patients with severe influenza.

1 CDC Influenza antiviral medications: summary for

clini-cians Available at: www.cdc.gov/flu/professionals/antivirals/

summary- clinicians.htm Accessed December 20, 2016.

2 Peramivir (Rapivab): an IV neuraminidase inhibitor for

treat-ment of influenza Med Lett Drugs Ther 2015; 57:17

3 AE Fiore et al Antiviral agents for the treatment and

chemopro-phylaxis of influenza – recommendations of the Advisory

Com-mittee on Immunization Practices (ACIP) MMWR Recomm Rep

2011; 60:1

4 J Dobson et al Oseltamivir treatment for influenza in adults:

a meta-analysis of randomised controlled trials Lancet 2015;

385:1729

5 IDSA Statement by the Infectious Disease Society of America

(IDSA) on the recent publication on "Neuraminidase inhibitors

for preventing and treating influenza in healthy adults and

chil-dren." April 2014 Available at: www.idsociety.org/influenza_

statement.aspx Accessed December 20, 2016

6 In brief: Concerns about oseltamivir (Tamiflu) Med Lett Drugs

Ther 2015; 57:14.

7 JK Louie et al Neuraminidase inhibitors for critically ill children

with influenza Pediatrics 2013; 132:e1539

Another Insulin Glargine

(Basaglar) for Diabetes

▶

The FDA has approved Basaglar (Lilly/Boehringer

Ingelheim), a “follow-on” 100 units/mL insulin glargine

product similar to Lantus (Sanofi ), which recently

went off patent A 300 units/mL formulation of insulin

glargine (Toujeo) was approved in 2015.1

Pronunciation Key

Basaglar: baze' uh glar

Resistance – Most of the recently circulating virus

strains tested by the CDC have been susceptible

to neuraminidase inhibitors.14 Resistance of some

influenza virus strains (particularly influenza A

[H1N1]) to oseltamivir or peramivir can emerge during

or after treatment, especially in immunocompromised

patients with prolonged viral shedding.15,16 Resistant

isolates have generally remained susceptible to

zanamivir, but reduced susceptibility to zanamivir has

been reported.17

Adverse Effects – Nausea, vomiting, and headache

are the most common adverse effects of oseltamivir;

taking the drug with food may minimize

gastro-intestinal adverse effects Diarrhea, nausea, sinusitis,

fever, and arthralgia have been reported with zanamivir

Inhalation of zanamivir can cause bronchospasm; the

drug should not be used in patients with underlying

airway disease Diarrhea and neutropenia have

occurred with peramivir Neuropsychiatric events,

including self-injury and delirium, have been reported in

patients taking neuraminidase inhibitors, but a

cause-and-effect relationship has not been established, and

neuropsychiatric dysfunction is a known complication

of influenza illness.18

Neuraminidase inhibitors administered within 48

hours before or <2 weeks after administration of the

intranasal live-attenuated influenza vaccine (FluMist

Quadrivalent) may interfere with the vaccine’s effi cacy

The live-attenuated vaccine is not recommended for

use during the 2016-2017 influenza season because

it has been less effective than the inactivated vaccine

in recent seasons.19 Inactivated influenza vaccine can

be given at any time relative to use of a neuraminidase

inhibitor ■

8 SG Muthuri et al Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influ-enza A H1N1pdm09 virus infection: a meta-analysis of indi-vidual participant data Lancet Respir Med 2014; 2:395

9 JK Louie et al Treatment with neuraminidase inhibitors for critically ill patients with influenza A (H1N1)pdm09 Clin Infect Dis 2012; 55:1198

10 MH Yudin Risk management of seasonal influenza during preg-nancy: current perspectives Int J Womens Health 2014; 6:681

11 IK Oboho et al Benefi t of early initiation of influenza antiviral treatment to pregnant women hospitalized with laboratory-confi rmed influenza J Infect Dis 2016; 214:507.

12 LM Ghulmiyyah et al Influenza and its treatment during preg-nancy: a review J Neonatal Perinatal Med 2015; 8:297.

13 CDC Recommendations for obstetric health care providers re-lated to use of antiviral medications in the treatment and preven-tion of influenza Available at: www.cdc.gov/flu/ professionals/ antivirals/avrec_ob.htm Accessed December 20, 2016

14 AC Hurt et al Global update on the susceptibility of human influenza viruses to neuraminidase inhibitors, 2014-2015 An-tiviral Res 2016; 132:178.

15 QM Le et al A community cluster of oseltamivir-resistant cases of 2009 H1N1 influenza N Engl J Med 2010; 362:86.

16 C Renaud et al H275Y mutant pandemic (H1N1) 2009 virus

in immunocompromised patients Emerg Infect Dis 2011; 17:653.

17 E Takashita et al Influenza A(H1N1)pdm09 virus exhibiting enhanced cross-resistance to oseltamivir and peramivir due

to a dual H275Y/G147R substitution, Japan, March 2016 Euro Surveill 2016; 21(24): Article 2.

18 S Toovey et al Post-marketing assessment of neuropsychiat-ric adverse events in influenza patients treated with oseltami-vir: an updated review Adv Ther 2012; 29:826

19 Influenza vaccine for 2016-2017 Med Lett Drugs Ther 2016; 58:127

INSULIN GLARGINE — A recombinant DNA analog of

human insulin, insulin glargine forms microprecipitates

in subcutaneous tissue, prolonging its duration of action to a mean of about 24 hours.2 It has less peak-to-trough variation and causes less nocturnal hypoglycemia than NPH insulin

CLINICAL STUDIES — Approval of Basaglar was

based on data demonstrating the clinical effi cacy and

safety of Lantus.3 Comparative studies have found

no signifi cant differences in the pharmacokinetics,

toxicity, or immunogenicity of Lantus and Basaglar.4,5

Revised 1/20/17: See page 4

Basaglar was compared to Lantus in two noninferiority

trials in adults with type 1 or type 2 diabetes In an

open-label trial, 535 patients with type 1 diabetes

were randomized to receive Basaglar or Lantus, both

in combination with mealtime insulin lispro.6 In a

double-blind, controlled trial, 756 patients with type 2

diabetes who were taking ≥2 oral antihyperglycemic

drugs were randomized to receive Basaglar or Lantus

in addition to their oral medications.7 In both studies,

decreases in mean HbA1c values from baseline to 24

weeks, the primary endpoint, were similar with the two

insulin glargine products

ADVERSE EFFECTS — In clinical trials, the incidence of

adverse effects, including nocturnal hypoglycemia and

weight gain, was similar with Basaglar and Lantus

Both drugs can cause injection-site reactions

REGULATORY STATUS — Even though Basaglar is highly

similar to Lantus in composition, strength, presentation,

and in its physicochemical, structural, and biological

properties, and appears to produce the same clinical

results, it was not designated as a biosimilar or an

interchangeable biologic product by the FDA because

of a regulatory technicality: insulin is classifi ed as a

chemical, not a biological, entity, so there is no biologic

reference product for insulin glargine Pharmacists

generally cannot substitute Basaglar for Lantus without

the permission of the prescriber

PREGNANCY AND LACTATION — There are no

well-controlled studies of insulin glargine use in pregnant

women In rats and rabbits given up to 7 times the

recommended human starting dose of an insulin

glargine product before and during mating and

throughout pregnancy, no adverse effects on the fetus

were detected Endogenous insulin is present in breast

milk, but whether insulin glargine is excreted in human

milk is not known

DOSAGE AND ADMINISTRATION — Basaglar is

available in packages of fi ve multi-dose KwikPens,

each prefi lled with 3 mL of insulin glargine 100 units/

mL A pen can deliver 1 to 80 units per injection It

should be primed with 2 units of insulin glargine before

each injection

1 Concentrated insulin glargine (Toujeo) for diabetes Med Lett Drugs Ther 2015; 57:69.

2 Drugs for diabetes Med Lett Drugs Ther 2017; 59:9 (in press)

3 Center for Drug Evaluation and Research Basaglar Summary Review Available at: www.accessdata.fda.gov/drugsatfda_ docs/nda/2015/205692Orig1s000SumR.pdf Accessed De-cember 20, 2016.

4 H Linnebjerg et al Comparison of the pharmacokinetics and pharmacodynamics of LY2963016 insulin glargine and EU- and US-approved versions of Lantus insulin glargine in healthy subjects: three randomized euglycemic clamp studies Diabe-tes Care 2015; 38:2226.

5 LL Ilag et al Evaluation of immunogenicity of LY2963016 insu-lin glargine compared with Lantus insuinsu-lin glargine in patients with type 1 or type 2 diabetes mellitus Diabetes Obes Metab 2016; 18:159.

6 TC Blevins et al Effi cacy and safety of LY2963016 insulin glargine compared with insulin glargine (Lantus) in patients with type 1 diabetes in a randomized controlled trial: the ELE-MENT 1 study Diabetes Obes Metab 2015; 17:726.

7 J Rosenstock et al Similar effi cacy and safety of LY2963016 in-sulin glargine and inin-sulin glargine (Lantus) in patients with type

2 diabetes who were insulin-nạve or previously treated with insulin glargine: a randomized, double-blind controlled trial (the ELEMENT 2 study) Diabetes Obes Metab 2015; 17:734.

Table 1 Insulin Glargine Products

Basaglar (Lilly/Boehringer Ingelheim) 100 units/mL 3 mL KwikPen 1-4 hrs ~24 hrs 2 $63.40

Lantus (Sanofi) 100 units/mL 3 mL SoloStar pen; 10 mL vial 1-4 hrs 22-26 hrs 74.60

Toujeo (Sanofi) 300 units/mL 1.5 mL SoloStar pen 1-6 hrs 24-36 hrs 111.80

1 Approximate WAC for one prefi lled pen WAC = wholesaler acquisition cost or manufacturer’s published price to wholesalers; WAC represents a published catalogue

or list price and may not represent an actual transactional price Source: AnalySource® Monthly December 5, 2016 Reprinted with permission by First Databank, Inc All rights reserved ©2016 www.fdbhealth.com/policies/drug-pricing-policy.

2 H Linnebjerg et al Diabetes Obes Metab 2016 Aug 3 (epub).

Basaglar should be injected subcutaneously once

daily at the same time each day Insulin-naive patients

with type 1 diabetes should start Basaglar therapy at

about one-third of their estimated total daily insulin requirement, with the remaining requirement fulfi lled

by short- or rapid-acting pre-meal insulin In patients

with type 2 diabetes, the recommended starting

dosage of Basaglar is 0.2 units/kg or up to 10 units once daily Patients on Lantus can switch to Basaglar

at the same daily dosage In patients switching from

Toujeo or from a twice-daily NPH insulin, the dosage

of Basaglar should be 80% of the previous total insulin dosage Patients switching to Toujeo from Lantus

or Basaglar may require about 10-15% more basal

insulin per day

Patients previously controlled on an intermediate- or long-acting insulin (other than insulin glargine) who

switch to Basaglar may need to adjust the dosage

of their basal insulin, short-acting insulin, or other antihyperglycemic drugs

CONCLUSION — Basaglar is similar to Lantus in

effi cacy and safety Patients could use either one ■

Revised 1/20/17: In the Dosage and Administration paragraph, we removed the word “syringe” in describing Basaglar’s KwikPen device Basaglar is not available as a prefi lled

syringe; it is only available as a KwikPen

Ustekinumab (Stelara) for

Crohn’s Disease

▶

The FDA has approved the human interleukin (IL)-12

and -23 antagonist ustekinumab (Stelara – Janssen

Biotech) for treatment of moderately to severely active

Crohn’s disease in adults who were intolerant of or

whose disease was unresponsive to treatment with

im-munomodulators or corticosteroids, or a tumor necrosis

factor (TNF) inhibitor Ustekinumab was approved

ear-lier for treatment of psoriasis and psoriatic arthritis.1,2

In the maintenance trial (IM-UNITI), 397 patients who had responded to ustekinumab in the 8-week trials were randomized to receive maintenance treatment with ustekinumab 90 mg SC every 8 or 12 weeks or switch to placebo Signifi cantly more patients who received ustekinumab were in clinical remission after

44 weeks compared to those who received placebo.6

ADVERSE EFFECTS — The most common adverse

effects reported with ustekinumab in Crohn’s disease clinical trials were vomiting with induction treatment and injection site erythema, pruritis, nasopharyngitis, bronchitis, sinusitis, urinary tract infection, and vulvovaginal candidiasis with maintenance treatment

Ustekinumab has been associated with serious infections, including tuberculosis; screening for tuberculosis is recommended before starting the drug

Hypersensitivity reactions and reversible posterior leukoencephalopathy syndrome have also occurred

Development of autoantibodies has been reported;

whether they reduce treatment response remains to

be determined

The incidence of non-melanoma skin cancer (0.2%) was similar in patients with Crohn's disease treated with ustekinumab or placebo for one year Other malignancies occurred in 0.2% of patients treated with ustekinumab and in none of those who received placebo In one safety analysis that included 3117 patients with psoriasis treated with ustekinumab for 1-5 years, the incidence of malignancies other than non-melanoma skin cancer was similar to that expected in the general US population.7

Table 1 Some Clinical Trials of Ustekinumab for Treatment

of Crohn’s Disease

Induction

UNITI-1 3 (n=741) Ustekinumab ~6 mg/kg 4 34% 21%

Ustekinumab 130 mg 34% 16%

Placebo 22% 7%

UNITI-2 3 (n=628) Ustekinumab ~6 mg/kg 4 56% 40%

Ustekinumab 130 mg 52% 31%

IM-UNITI 3 (n=388) Ustekinumab 90 mg q8 wks 59% 53%

Ustekinumab 90 mg q12 wks 58% 49%

*All differences between ustekinumab and placebo are statistically signifi cant.

1 Primary endpoint for UNITI-1 and UNITI-2 Clinical response was defi ned

as a decrease from baseline in the Crohn’s Disease Activity Index (CDAI) score of ≥100 points or a total CDAI score <150 at week 6 for UNITI-1 and UNITI-2 and at week 44 for IM-UNITI

2 Primary endpoint for IM-UNITI Clinical remission was defi ned as a CDAI score <150 at week 8 in UNITI-1 and UNITI-2 and at week 44 in IM-UNITI

3 B Feagan et al N Engl J Med 2016; 375:1946.

4 Patients who weighed ≤55 kg received 260 mg, those >55-85 kg received

390 mg, and those >85 kg received 520 mg.

Pronunciation Key

Ustekinumab: us" te kin' ue mab Stelara: ste lar' uh

STANDARD TREATMENT — Corticosteroids are used

to induce remission of Crohn's disease Azathioprine

or 6-mercaptopurine (6-MP) can be used for

maintenance of remission A TNF inhibitor alone or in

combination with azathioprine or 6-MP can be used

for both induction and maintenance of remission in

patients with moderate to severe disease.3 The integrin

receptor antagonist vedolizumab (Entyvio) can be used

in patients who do not respond to or cannot tolerate

standard treatments, including TNF inhibitors.4 Use

of natalizumab (Tysabri), another integrin receptor

antagonist, has been limited by rare occurrences of

progressive multifocal leukoencephalopathy (PML)

MECHANISM OF ACTION — Ustekinumab is a fully

human IgG1 antibody that binds to the common

p40 protein subunit of both IL-12 and -23 cytokines,

preventing activation of inflammatory and immune

responses thought to be involved in the pathogenesis

of Crohn’s disease.5

CLINICAL STUDIES — Approval of ustekinumab for

treatment of Crohn's disease was based on the results

of two 8-week induction trials (UNITI-1 and UNITI-2)

and one 44-week maintenance trial (IM-UNITI); results

of these trials are summarized in Table 1.6 Patients in

all three trials were allowed to remain on stable doses

of immunosuppressants, mesalamine, antibiotics,

and/or oral corticosteroids

The two induction trials included a total of 1369

patients with moderately to severely active Crohn’s

disease who could not tolerate or had not adequately

responded to treatment with either ≥1 TNF inhibitor

(UNITI-1) or immunomodulators or corticosteroids

(UNITI-2) In both trials, signifi cantly more patients

treated with ustekinumab than with placebo had a

clinical response at week 6 (the primary endpoint) and

were in clinical remission at week 8.6

PREGNANCY AND LACTATION — There are no

ade-quate studies of ustekinumab use in preg nant women

No teratogenic or other adverse developmental effects

were observed in the fetuses of pregnant monkeys who

were given high doses of ustekinumab In one study in

which 40 pregnant monkeys were given high doses of

ustekinumab and 20 were given placebo, there were

2 neonatal deaths in the ustekinumab group and no

deaths in the placebo group Ustekinumab has been

detected in the milk of lactating monkeys

DRUG INTERACTIONS — Patients should not receive

live vaccines during treatment with ustekinumab

Proinflammatory cytokines can alter the formation of

CYP enzymes Starting treatment with ustekinumab

may normalize CYP enzyme formation and could

alter the metabolism of CYP substrates; dosage

adjustment of substrates with narrow therapeutic

indices such as warfarin or cyclosporine may be

needed Ustekinumab may decrease the protective

effect of allergen immunotherapy

DOSAGE AND ADMINISTRATION — The recommended

induction dosage of ustekinumab for treatment of

Crohn’s disease is 260 mg in patients who weigh

≤55 kg, 390 mg in those >55-85 kg, and 520 mg

in those >85 kg The induction dose should be

administered as a single IV infusion over at least

1 Drugs for psoriasis Med Lett Drugs Ther 2015; 57:81.

2 Drugs for psoriatic arthritis Med Lett Drugs Ther 2015; 57:e88.

3 Drugs for inflammatory bowel disease Med Lett Drugs Ther 2014; 56:65.

4 Vedolizumab (Entyvio) for inflammatory bowel disease Med Lett Drugs Ther 2014; 56:86.

5 W Strober et al Proinflammatory cytokines underlying the in-flammation of Crohn’s disease Curr Opin Gastroenterol 2010; 26:310.

6 B Feagan et al Ustekinumab as induction and maintenance therapy for Crohn’s disease N Engl J Med 2016; 375:1946.

7 KA Papp et al Long-term safety of ustekinumab in patients with moderate-to-severe psoriasis: fi nal results from 5 years of follow-up Br J Dermatol 2013; 168:844.

one hour The recommended maintenance dosage

is 90 mg injected subcutaneously every 8 weeks

Stelara is available for IV infusion in single-dose

vials containing 130 mg/26 mL It is also available for SC injection in single-dose prefi lled syringes containing 90 mg/mL and single-dose vials and prefi lled syringes containing 45 mg/0.5 mL Patients may use the syringes to self-inject after receiving proper training

CONCLUSION — Ustekinumab (Stelara), an interleukin

(IL)-12 and -23 antagonist, is effective for treatment

of moderately to severely active Crohn’s disease in adults who have had an inadequate response to or could not tolerate standard therapies, including tumor necrosis factor (TNF) inhibitors How it compares to the other biologic agents for treatment of Crohn’s disease remains to be determined ■

Tenofovir Alafenamide (Vemlidy)

for Hepatitis B

▶

The FDA has approved tenofovir alafenamide

(Vemlidy – Gilead) for treatment of chronic hepatitis

B virus (HBV) infection in adults with compensated liver disease It is the fi rst single-drug product containing tenofovir alafenamide (TAF), a prodrug of the nucleotide reverse transcriptase inhibitor tenofovir,

to become available; several combination products containing TAF are approved for treatment of HIV-1

infection Tenofovir disoproxil fumarate (TDF; Viread –

Gilead), another tenofovir prodrug, has been used for many years for treatment of chronic HBV infection;

a generic formulation of TDF is expected to become available in December 2017

Pronunciation Key

Tenofovir alafenamide: ten of' oh veer al" a fen' a mide

Vemlidy: vem li' dee

Table 2 Some Biologics for Treatment of Crohn’s Disease

Integrin Receptor Antagonists

Natalizumab ― Tysabri 300 mg IV q4 wks $11,594.00

(Biogen)

Vedolizumab ― Entyvio 300 mg IV at wks 0, 5212.20

(Takeda) 2, and 6, then

300 mg IV q8 wks

Interleukin (IL)-12 and -23 Antagonist

Ustekinumab ― Stelara One IV weight-based 2 17,680.40

(Janssen Biotech) dose at wk 0, then

90 mg SC q8 wks

Tumor Necrosis Factor (TNF) Inhibitors

Adalimumab ― Humira 160 mg SC at wk 0, then 8194.10

(Abbvie) 80 mg SC at wk 2, followed

by 40 mg SC every other wk starting at wk 4

Certolizumab ― Cimzia 400 mg SC at wks 0, 2, 7020.30

(UCB) and 4, then 400 mg SC q4 wks

Infliximab ― Remicade 5 mg/kg IV at wks 0, 2, 4453.10 3

(Janssen Biotech) and 6, then 5-10 mg/kg

Inflectra4 (Celltrion) IV q8 wks 3785.10 3

1 Approximate WAC for 8 weeks’ treatment at the lowest maintenance

dos-age WAC = wholesaler acquisition cost or manufacturer’s published price

to wholesalers; WAC represents a published catalogue or list price and may

not represent an actual transactional price Source: AnalySource® Monthly

December 5, 2016 Reprinted with permission by First Databank, Inc All

rights reserved ©2016 www.fdbhealth.com/policies/drug-pricing-policy

2 Recommended weight-based induction dose at week 0: ≤55 kg: 260 mg;

>55-85 kg: 390 mg; >85 kg: 520 mg.

3 Cost based on a 75-kg patient.

4 Infliximab-dyyb (Inflectra) is a Remicade biosimilar.

TDF, those taking TAF had signifi cantly smaller mean decreases in hip and spine BMD in both trials, and a signifi cantly smaller mean increase in serum creatinine in the study of HBeAg-positive patients (see Table 1) In a pooled analysis of the two trials, the median decrease in eGFR was 1.2 mL/min with TAF and 5.4 mL/min with TDF

ADVERSE EFFECTS — In the two double-blind trials, the

most common adverse effects of TAF and TDF were headache, abdominal pain, fatigue, cough, nausea, and back pain Patients taking TAF were more likely than those taking TDF to have glycosuria (5% vs 1%) and an LDL-cholesterol level >190 mg/dL (4% vs <1%) Seven subjects treated with TAF developed symptomatic increases in amylase levels Fatal lactic acidosis with severe hepatomegaly and steatosis has been reported with use of nucleotide analogs, including TDF Acute exacerbation of HBV infection can occur if tenofovir is discontinued; patients should be monitored for at least several months after stopping treatment

PREGNANCY AND LACTATION — TAF has not

been studied in pregnant or lactating women Supratherapeutic doses of TAF in pregnant animals did not cause adverse developmental effects In

a study of 50 healthy African women taking TDF

300 mg/day and their breastfed infants, tenofovir plasma levels were undetectable in 94% of the infants and not clinically signifi cant in the others.9

DRUG INTERACTIONS — Like TDF, TAF is a substrate

of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); inducers and inhibitors of these transporters can alter TAF exposure.8 In pharmacokinetic studies summarized in the package insert, TAF exposure was 55% lower with coadministration of the P-gp inducer carbamazepine and 165% greater with coadministration of the P-gp inhibitor cobicistat

Coadministration of TAF or TDF with drugs that reduce renal function or compete for active tubular secretion,

STANDARD TREATMENT — The goal of chronic HBV

treatment is to reduce the risk of cirrhosis, hepatic

failure, and hepatocellular carcinoma Effective therapy

can reduce the viral load and promote HBV e-antigen

seroconversion (loss of HBeAg with development of

HBe antibodies); loss of HBV surface antigen (HBsAg) is

uncommon Peginterferon alfa-2a (PEG-IFN; Pegasys),

entecavir (Baraclude, and generics), and tenofovir are

considered preferred options for initial treatment of

chronic HBV infection in treatment-naive adults

PEG-IFN is injected once weekly for 48 weeks, but it can cause

intolerable adverse effects, has many contraindications,

and is expensive Entecavir and tenofovir have lower

rates of resistance than other nucleoside/tide analogs

and are more likely to induce virologic suppression

These drugs may need to be taken indefi nitely.1-3

TAF vs TDF — Systemic exposure to tenofovir may

cause nephrotoxicity and reduce bone mineral density

(BMD).4 TAF is delivered effi ciently to hepatocytes,5 and

unlike TDF, which is extensively converted to tenofovir

in plasma, TAF activation predominantly occurs

intracellularly In a pharmacokinetic analysis, TAF

25 mg once daily produced circulating tenofovir levels

that were 86% lower and intracellular tenofovir levels

that were 7 times higher than those achieved with TDF

300 mg once daily.6

CLINICAL STUDIES — Approval of TAF for treatment

of chronic HBV infection was based on the results

of two double-blind noninferiority trials, one in 425

patients with HBeAg-negative infection and the other

in 873 patients with HBeAg-positive infection In both

trials, patients were randomized to receive once-daily

treatment with TAF 25 mg or TDF 300 mg The primary

endpoint was the rate of virologic suppression (HBV

DNA <29 IU/mL) at week 48; changes from baseline in

serum creatinine level and hip and spine BMD at week

48 were secondary endpoints.7,8

TDF and TAF produced similar virologic suppression

rates in both trials Compared to patients taking

Table 1 48-Week Results of Vemlidy Clinical Trials

Treatment Virologic Change in Change in Change in HBeAg Status Arms Suppression Rate 1 Serum Creatinine Hip BMD Spine BMD

Negative (n=425) 2 TAF 25 mg/d 94% +0.01 mg/dL -0.29%* -0.88%*

TDF 300 mg/d 93% +0.02 mg/dL -2.16% -2.51%

Positive (n=873) 3 TAF 25 mg/d 64% +0.01 mg/dL* -0.10%* -0.42%*

TDF 300 mg/d 67% +0.03 mg/dL -1.72% -2.29%

*p<0.05 vs TDF

BMD = bone mineral density; HBeAg = hepatitis B e-antigen; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate

1 Defi ned as an HBV viral load <29 IU/mL at week 48 (the primary endpoint) TAF was found to be noninferior to TDF in both trials.

2 M Buti et al Lancet Gastroenterol Hepatol 2016; 1:196.

3 HLY Chan et al Lancet Gastroenterol Hepatol 2016; 1:185.

such as antiherpetic drugs, aminoglycosides, or

high-dose NSAIDs, can increase tenofovir exposure

and toxicity

DOSAGE AND ADMINISTRATION — The recommended

dosage of Vemlidy is 25 mg once daily with food The

dosage should be increased to 50 mg once daily in

patients also taking carbamazepine Coadministration

of Vemlidy with other P-gp inducers,10 including

anticonvulsants, rifamycin derivatives, and St John’s

wort, is not recommended

Serum creatinine and phosphorus levels, estimated

CrCl, and urine glucose and protein levels should be

assessed before and periodically during treatment

with TAF The drug is not recommended for use in

patients with end-stage renal disease (CrCl <15 mL/

min) or decompensated hepatic impairment

(Child-Pugh B/C) Patients should be screened for HIV-1

infection before starting TAF; those co-infected with

HBV and HIV-1 should not receive TAF alone

CONCLUSION — Tenofovir alafenamide (Vemlidy) is

an effective fi rst-line treatment for chronic hepatitis

B virus infection in adults with compensated liver

disease In short-term trials, it was less likely than

tenofovir disoproxil fumarate (Viread) to decrease

bone mineral density Whether it is also less likely to

cause renal dysfunction in patients with hepatitis B

infection remains to be established ■

1 P Martin et al A treatment algorithm for the management of chronic hepatitis B virus infection in the United States: 2015 update Clin Gastroenterol Hepatol 2015; 13:2071.

2 NA Terrault et al AASLD guidelines for treatment of chronic hepatitis B Hepatology 2016; 63:261.

3 AS Lok et al Antiviral therapy for chronic hepatitis B viral infec-tion in adults: a systematic review and meta-analysis Hepatol-ogy 2016; 63:284.

4 Antiviral drugs Treat Guidel Med Lett 2013; 11:19.

5 E Murakami et al Implications of effi cient hepatic delivery by tenofovir alafenamide (GS-7340) for hepatitis B virus therapy Antimicrob Agents Chemother 2015; 59:3563.

6 PJ Ruane et al Antiviral activity, safety, and pharmacokinetics/ pharmacodynamics of tenofovir alafenamide as 10-day mono-therapy in HIV-1-positive adults J Acquir Immune Defi c Syndr 2013; 63:449.

7 M Buti et al Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of patients with HBeAg-negative chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial Lancet Gastroenterol Hepatol 2016; 1:196

8 HLY Chan et al Tenofovir alafenamide versus tenofovir diso-proxil fumarate for the treatment of HBeAg-positive chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial Lancet Gastroenterol Hepatol 2016; 1:185.

9 KK Mugwanya et al Pre-exposure prophylaxis use by breast-feeding HIV-uninfected women: a prospective short-term study

of antiretroviral excretion in breast milk and infant absorption PLoS Med 2016 September 27 (epub).

10 Inhibitors and inducers of CYP enzymes and P-glycoprotein Med Lett Drugs Ther 2016 Aug 2 (epub) Available at: secure medicalletter.org/downloads/CYP_PGP_Tables.pdf Accessed December 20, 2016.

Table 2 Some Drugs for Chronic Hepatitis B Virus Infection

Nucleoside/Nucleotide Analogs

Adefovir dipivoxil – generic 10 mg tabs 10 mg PO once/d $895.00

Emtricitabine – Emtriva (Gilead) 200 mg caps; 10 mg/mL oral soln 200 mg PO once/d 2 536.50 Entecavir 3 – generic 0.5, 1 mg tabs; 0.05 mg/mL oral soln 0.5 mg PO once/d 4 737.60

Lamivudine HBV 5 – generic 100 mg tabs 100 mg PO once/d 351.50

Epivir-HBV (GSK) 100 mg tabs; 25 mg/5 mL oral soln 447.50

Telbivudine – Tyzeka (Novartis) 600 mg tabs 600 mg PO once/d 1071.10 Tenofovir alafenamide 3 – Vemlidy (Gilead) 25 mg tabs 25 mg PO once/d 7 997.80 Tenofovir disoproxil fumarate 3 – Viread (Gilead) 150, 200, 250, 300 mg tabs 300 mg PO once/d 997.80

Interferon

Peginterferon alfa-2a 3,8 – Pegasys (Genentech) 180 mcg/1 mL single-use vials; 180 mcg SC once/wk 3778.00

180 mcg/0.5 mL prefilled syringes; x 48 wks

135, 180 mcg/0.5 mL single-use autoinjectors

1 Approximate WAC for 30 tablets or capsules or 4 injections WAC = wholesaler acquisition cost or manufacturer’s published price to wholesalers; WAC represents a published catalogue or list price and may not represent an actual transactional price Source: AnalySource® Monthly December 5, 2016 Reprinted with permission by First Databank, Inc All rights reserved ©2016 www.fdbhealth.com/policies/drug-pricing-policy.

2 Dosage of oral solution is 240 mg (24 mL) once/d.

3 Preferred option for initial treatment of adults with immune-active chronic HBV infection

4 Dosage for nucleoside/nucleotide analog-naive patients Entecavir is no longer recommended for use in patients with lamivudine-resistant HBV infection; if used in such patients, the dosage should be increased to 1 mg once/d.

5 Cannot be substituted for lamivudine (Epivir, and generics) in HIV treatment regimens Lamivudine 150 mg bid or 300 mg once/d should be used in patients

with HBV/HIV coinfection.

7 The dosage should be increased to 50 mg once/d in patients taking carbamazepine Coadministration of other P-glycoprotein inducers, including anticonvul-sants, rifamycin derivatives, and St John’s wort, is not recommended.

8 Contraindicated in patients with autoimmune disease, uncontrolled psychiatric disease, uncontrolled seizures, severe cardiac disease, or cytopenias

Peginterferon alfa-2a is more likely to induce HBV e-antigen seroconversion in patients with HBV genotype A or B than in those with other genotypes.

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1 Discuss the 2016-2017 recommendations for use of antiviral drugs for prophylaxis and treatment of seasonal influenza.

2 Review the effi cacy and safety of Basaglar, the new "follow-on" insulin glargine product, for treatment of diabetes and discuss how it compares to Lantus.

3 Review the effi cacy and safety of ustekinumab (Stelara) for treatment of Crohn’s disease

4 Review the effi cacy and safety of tenofovir alafenamide (Vemlidy) for treatment of chronic hepatitis B infection.

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