The medical letter on drugs and therapeutics november 10 2014

1455 Two New GLP-1 Receptor Agonists for Diabetes ...A Combination of Ledipasvir and Sofosbuvir Harvoni for Hepatitis C ...p 109p 111 Contrave – A Combination of Bupropion and Naltrexone

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1455 Two New GLP-1 Receptor Agonists for Diabetes A Combination of Ledipasvir and Sofosbuvir (Harvoni) for Hepatitis C p 109p 111

Contrave – A Combination of Bupropion and Naltrexone for Weight Loss p 112

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1455 A Combination of Ledipasvir and Sofosbuvir (Harvoni) for Hepatitis C Contrave – A Combination of Bupropion and Naltrexone for Weight Loss .p 111p 112

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Two new injectable GLP-1 (glucagon-like peptide-1)

receptor agonists, dulaglutide (Trulicity [trū li si tee] –

Lilly) and albiglutide (Tanzeum [tan' zee um] – GSK),

have been approved by the FDA for once-weekly

treatment of type 2 diabetes Other available GLP-1

receptor agonists include exenatide, which is approved

for injection twice daily (Byetta) or once weekly

(Bydureon), and liraglutide (Victoza), which is injected

once daily

GLP-1 RECEPTOR AGONISTS — When metformin alone

fails to control hyperglycemia, addition of a GLP-1

receptor agonist is an option These drugs are less likely

than sulfonylureas or insulin to cause hypoglycemia

and usually cause weight loss, but they are expensive

and long-term safety data are lacking.1

Mechanism of Action – Released by cells in the

gastro-intestinal tract in response to food, GLP-1 activates

receptors in pancreatic beta cells, resulting in increased

levels of cyclic AMP and potentiation of insulin secretion GLP-1 receptor agonists also lower serum glucagon concentrations, slow gastric emptying, and promote satiety

Class Adverse Effects – Gastrointestinal effects and

injection-site reactions are the most common adverse effects of GLP-1 receptor agonists; the rates, severity,

and duration of these effects vary within the class

GLP-1 receptor agonists have been shown to cause thyroid C-cell tumors in animals, and thyroid C-cell hyperplasia has been reported in humans; they are contraindicated for use in patients with a personal or family history of medullary thyroid carcinoma and in those with Multiple Endocrine Neoplasia syndrome type 2 These drugs have rarely been associated with acute pancreatitis GLP-1 receptor agonists are classifi ed as category C (developmental toxicity

in animals; no adequate studies in women) for use during pregnancy

Drug Interactions – Since they slow gastric

empty-ing, GLP-1 receptor agonists may decrease the rate

Two New GLP-1 Receptor Agonists

for Diabetes

▶

Table 1 GLP-1 Receptor Agonists

Drug Formulations Usual Maintenance Dosage Cost 1

Dulaglutide – Trulicity (Lilly) 0.75 mg/0.5 mL, 1.5 mg/0.5 mL 0.75 or 1.5 mg SC once/wk 3 488.30

single-dose pen or syringe Exenatide –

immediate-release

(1.2, 2.4 mL prefi lled pen) extended-release

for injectable suspension 2

Liraglutide – Victoza (Novo Nordisk) 6 mg/mL (3 mL prefi lled pen) 1.2 or 1.8 mg SC once/d 3 392.40

1 Approximate WAC for 30 days’ treatment at the lowest usual maintenance dosage 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 October

2 Requires reconstitution before injection.

3 Can be given at any time of day, with or without food.

4 Should be given within 60 minutes before morning and evening meals (or before the two main meals of the day, approximately 6 hours or more apart).

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and extent of absorption of oral medications taken

concomitantly The risk of hypoglycemia increases

when these drugs are used in combination with insulin

secretagogues, such as sulfonylureas, or insulin

DULAGLUTIDE CLINICAL STUDIES — In randomized, controlled trials

in patients with type 2 diabetes, use of dulaglutide,

alone and in combination with metformin, a

sul-fonylurea, pioglitazone, or insulin, lowered HbA1c

(A1C) and reduced weight (Table 2)

upper arm, which can be increased to a maximum

of 1.5 mg once weekly Dulaglutide does not require reconstitution prior to administration It should be stored in a refrigerator in its original carton to keep the drug protected from light (it can be stored at room temperature for up to 14 days)

ALBIGLUTIDE CLINICAL STUDIES — In randomized, controlled trials,

use of albiglutide alone and in combination with other antihyperglycemic drugs led to modest reductions

in A1C and weight in patients with type 2 diabetes (Table 3)

Table 2 Some Dulaglutide Clinical Trials

Study Drug Regimen (%) 1 (kg) 1

Monotherapy

G Umpierrez et al 2 Dulaglutide 0.75 mg/wk -0.7 -2.3

26 weeks Dulaglutide 1.5 mg/wk -0.8 -2.3

(n=807) Metformin 1500-2000 mg/d -0.6 -2.2

Add-on Therapy

M Nauck et al 3 Metformin

52 weeks + Dulaglutide 0.75 mg/wk -0.9 -2.6

(n=1098) + Dulaglutide 1.5 mg/wk -1.1 -3.0

+ Sitagliptin 100 mg/d -0.4 -1.5

C Wysham et al 4 Metformin + pioglitazone

26 weeks + Dulaglutide 0.75 mg/wk -1.3 +0.2

+ Exenatide 10 mcg bid -1.0 -1.1

52 weeks 5 Metformin + glimepiride

+ Dulaglutide 1.5 mg/wk -1.1 -1.9 + Insulin glargine -0.6 +1.4

26 weeks 5 Insulin lispro ± metformin

(n=884) + Dulaglutide 0.75 mg/wk -1.6 +0.2

+ Dulaglutide 1.5 mg/wk -1.6 -0.9

+ Insulin glargine -1.4 +2.3

KM Dungan et al 6 Metformin

26 weeks + Dulaglutide 1.5 mg/wk -1.4 -2.9

(n=599) + Liraglutide 1.8 mg/d -1.4 -3.6

1 Mean change from baseline.

2 G Umpierrez et al Diabetes Care 2014; 37:2168.

3 M Nauck et al Diabetes Care 2014; 37:2149.

4 C Wysham et al Diabetes Care 2014; 37:2159.

5 Summarized in the package insert.

6 KM Dungan et al Lancet 2014; 384:1349.

ADVERSE EFFECTS — According to pooled data from

placebo-controlled trials, the most common adverse

effects of dulaglutide 1.5 mg were nausea (21%),

diarrhea (13%), vomiting (13%), abdominal pain (9%),

decreased appetite (9%), dyspepsia (6%), and fatigue

(6%); these effects were considered mild in 48% of

patients, moderate in 43%, and severe in 11%, and

occurred more frequently than with the 0.75-mg

dose Injection-site reactions occurred in only 0.5% of

patients treated with the drug

DOSAGE AND ADMINISTRATION — The recommended

dosage of dulaglutide is 0.75 mg once weekly,

injected subcutaneously in the abdomen, thigh, or

Table 3 Some Albiglutide Clinical Trials

A1C Weight

Study Drug Regimen (%) 1 (kg) 1

Monotherapy

52 weeks 2 Albiglutide 30 mg/wk -0.7 -0.4 to -0.9 (n=296) Albiglutide 50 mg/wk -0.9 -0.4 to -0.9

Add-on Therapy

B Ahrén et al 3 Metformin

104 weeks + Albiglutide 30 mg/wk 4 -0.6 -1.2 (n=999) + Sitagliptin 100 mg/d -0.3 -0.9

+ Glimepiride 2-4 mg/d -0.4 +1.2

J Reusch et al 5 Metformin ± pioglitazone

52 weeks + Albiglutide 30 mg/wk -0.8 +0.3 (n=299) + Placebo -0.1 +0.5

52 weeks 2 Metformin + glimepiride (n=657) + Albiglutide 30 mg/wk 4 -0.6 -0.4 + Pioglitazone 30-45 mg/d -0.8 +4.4

RE Pratley et al 6 Current oral antihyper-

32 weeks glycemic therapy (n=805) + Albiglutide 30 mg/wk 4 -0.8 -0.6

+ Liraglutide 1.8 mg/d -1.0 -2.2

PN Weissman et al 7 Metformin ± sulfonylurea

52 weeks + Albiglutide 30 mg/wk 4 -0.7 -1.1 (n=735) + Insulin glargine -0.8 +1.6

J Rosenstock et al 8 Insulin glargine

26 weeks + Albiglutide 30 mg/wk 4 -0.8 -0.7 (n=563) + Insulin lispro -0.7 +0.8

LA Leiter et al 9 Current oral antihyper-

26 weeks glycemic therapy (n=486) + Albiglutide 30 mg/wk 4 -0.8 -0.8

+ Sitagliptin 25-100 mg/d -0.5 -0.2

1 Mean change from baseline.

2 Summarized in the package insert.

3 B Ahrén et al Diabetes Care 2014; 37:2141.

4 Dose could be increased to 50 mg/week.

5 J Reusch et al Diabetes Obes Metab 2014 August 23 (epub).

6 RE Pratley et al Lancet Diabetes Endocrinol 2014; 2:289.

7 PN Weissman et al Diabetologia 2014 September 11 (epub).

8 J Rosenstock et al Diabetes Care 2014; 37:2317.

9 In patients with renal impairment LA Leiter et al Diabetes Care 2014; 37:2723.

ADVERSE EFFECTS — According to pooled data from

placebo-controlled trials, diarrhea (13%) and nausea (11%) were the most common gastrointestinal adverse effects of albiglutide Injection-site reactions occurred

in 11% of patients treated with the drug

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DOSAGE AND ADMINISTRATION — The rec ommended

dosage of albiglutide is 30 mg once weekly, injected

subcutaneously in the abdomen, thigh, or upper

arm, which can be increased to 50 mg once weekly

Albiglutide should be stored in a refrigerator in its

original carton, but it can be stored at room temperature

for up to 4 weeks before use Before injecting the drug,

the patient must twist the cartridge on the pen to mix

the lyophilized albiglutide powder with the diluent

and then gently rock the pen side-to-side 5 times To

ensure that the reconstituted solution is mixed, the

patient must wait for 15 minutes before injecting a

30-mg dose and for 30 minutes before a 50-mg dose

CONCLUSION — The two new once-weekly GLP-1

receptor agonists dulaglutide (Trulicity) and albiglutide

(Tanzeum) are both effective in lowering A1C, but

dulaglutide appears to be superior in reducing weight

and less likely to cause injection-site reactions The

ready-to-use formulation of dulaglutide is more

convenient than albiglutide or once-weekly exenatide

(Bydureon), which must be reconstituted before

use Once-daily liraglutide (Victoza) and twice-daily

exenatide (Byetta) are also ready to use ■

A Combination of Ledipasvir and

Sofosbuvir (Harvoni) for Hepatitis C

▶

Table 1 Pharmacokinetics

Ledipasvir Sofosbuvir

Metabolism Oxidation via Hepatic activation via hydrolysis

unknown and phosphoramidate cleavage, mechanism followed by phosphorylation;

inactivated by dephosphorylation Elimination Feces (~86%); Urine (~80%); feces (~14%);

urine (~1%) expired air (~2.5%) Half-life 47 hours 0.5 hours

The FDA has approved a fixed-dose combination

(Harvoni [har voe' nee] – Gilead) of sofosbuvir and

ledipasvir (led’ i pas’ vir), two oral direct-acting

antiviral agents, for treatment of chronic hepatitis

C virus (HCV) genotype 1 infection Genotype 1 is

responsible for 70-80% of HCV infections in the US

Sofosbuvir (Sovaldi) was approved earlier for use in

combination with other antiviral drugs for treatment

of HCV infection Ledipasvir is a new drug

DRUGS FOR HCV INFECTION — Sofosbuvir is the

most effective drug available to date for treatment

of chronic HCV infection, and it appears to have a

high genetic barrier to resistance.1 In combination

with pegylated interferon and/or ribavirin, or

with the protease inhibitor simeprevir (Olysio),2

sofosbuvir has produced higher sustained virologic

response (SVR) rates with shorter treatment

durations than the previous standard regimen of

peginterferon, ribavirin, and a protease inhibitor,

and it is better tolerated.3

1 Drugs for type 2 diabetes Treat Guidel Med Lett 2014; 12:17.

MECHANISM OF ACTION — Sofosbuvir is a uridine

nucleotide analog that is converted to an active metabolite in the liver It inhibits the HCV NS5B RNA-dependent RNA polymerase, which is essential for viral replication Ledipasvir inhibits the HCV NS5A protein, which is also essential for viral replication

CLINICAL STUDIES — A randomized, open-label trial

(ION-1) in 865 treatment-naive patients with HCV

genotype 1 infection compared use of the fi xed-dose combination of ledipasvir and sofosbuvir with

or without ribavirin for 12 or 24 weeks; 16% of these patients had cirrhosis and 67% had genotype 1a infection, 2 features that have been associated with less successful treatment outcomes An SVR was achieved in 99% of patients treated for 12 weeks and in 98% of those treated for 24 weeks with the combination alone The addition of ribavirin had little effect on SVR rates (97% with 12 weeks of treatment and 99% with

24 weeks) Among patients with cirrhosis, SVR rates ranged from 94% to 100% in the 4 treatment groups.4

A similar trial (ION-2) compared use of the fi xed-dose combination of ledipasvir and sofosbuvir with

or without ribavirin for 12 or 24 weeks in 440 patients

with previously treated HCV genotype 1 infection; 20%

of these patients had cirrhosis and 79% had genotype 1a infection An SVR was achieved in 94% of patients treated for 12 weeks and in 99% of those treated for

24 weeks with the combination alone The addition of ribavirin had little or no effect on SVR rates (96% with

12 weeks of treatment and 99% with 24 weeks) Among patients with cirrhosis, those treated for 12 weeks had SVR rates of 86% with the combination alone and 82% with addition of ribavirin; with 24 weeks of treatment, the SVR rate for patients with cirrhosis was 99% with

or without ribavirin.5

In a randomized, open-label trial (ION-3) in 647 treatment-naive patients with chronic HCV infection

without cirrhosis, SVR rates were 94% with 8 weeks

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of treatment and 95% with 12 weeks of treatment with

ledipasvir and sofosbuvir alone.6

ADVERSE EFFECTS — The most common adverse

effects of ledipasvir and sofosbuvir have been

headache, fatigue, nausea, diarrhea, and insomnia In

all 3 of the clinical trials, the percentages of patients

who permanently discontinued treatment because of

adverse effects were 0%, <1%, and 1% with 8, 12, and 24

weeks of treatment, respectively Harvoni is classifi ed

as category B (no evidence of harm in animals; no

adequate human studies) for use during pregnancy

DRUG INTERACTIONS — The absorption of ledipasvir

is pH-dependent; administration of antacids within

4 hours of Harvoni should be avoided Under fasting

conditions, usual doses of proton pump inhibitors can

be taken simultaneously with ledipasvir H2-receptor

antagonists at usual doses and ledipasvir can be

taken simultaneously or 12 hours apart

Ledipasvir and sofosbuvir are substrates of the

drug transporters P-glycoprotein (P-gp) and breast

cancer resistance protein (BCRP), and ledipasvir

is an inhibitor of P-gp and BCRP Coadministration

with P-gp inducers such as rifampin, St John’s wort,

carbamazepine, or tipranavir/ritonavir may decrease

serum concentrations of ledipasvir and sofosbuvir and

is not recommended.7 Concurrent use of the protease

inhibitor simeprevir, which is a substrate and inhibitor

of P-gp, and ledipasvir has been shown to increase

serum concentrations of both drugs and is also not

recommended Harvoni may markedly increase serum

concentrations of rosuvastatin (Crestor), a BCRP

substrate, and could increase the risk of myopathy

and rhabdomyolysis Harvoni also increases serum

concentrations of tenofovir, a substrate of P-gp and

BCRP, and could increase concentrations of digoxin, a

P-gp substrate

DOSAGE, ADMINISTRATION, AND COST — The fi

xed-dose combination of ledipasvir 90 mg and sofosbuvir

400 mg should be taken orally once daily, with or

without food for 8, 12, or 24 weeks The labeling

recommends a treatment duration of 8 weeks for

patients without cirrhosis who have a baseline

HCV RNA <6 million IU/mL Treatment-experienced

patients with cirrhosis should take the drug for 24

weeks The cost of 12 weeks’ treatment with Harvoni

is $94,500, compared to about $150,000 for the

combination of sofosbuvir and simeprevir.8

CONCLUSION — The fi xed-dose combination of

ledipasvir and sofosbuvir (Harvoni) taken orally for

8, 12, or 24 weeks can achieve sustained virologic responses in more than 95% of patients with chronic hepatitis C virus genotype 1 infection, with minimal adverse effects It should become the standard of care for treatment of this infection ■

1 TJ Liang and MG Ghany Therapy of hepatitis C – back to the future N Engl J Med 2014; 370:2043.

2 E Lawitz et al Simeprevir plus sofosbuvir, with or without riba-virin, to treat chronic infection with hepatitis C virus genotype

1 in non-responders to pegylated interferon and ribavirin and treatment-naive patients: the COSMOS randomised study Lan-cet 2014 July 26 (epub).

3 Sofosbuvir (Sovaldi) for chronic hepatitis C Med Lett Drugs Ther 2014; 56:5.

4 N Afdhal et al Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection N Engl J Med 2014; 370:1889.

5 N Afdhal et al Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection N Engl J Med 2014; 370:1483.

6 KV Kowdley et al Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis N Engl J Med 2014; 370:1879.

7 Inhibitors and inducers of CYP enzymes and P-glycoprotein Med Lett Drugs Ther 2013; 55:e44.

8 Approximate WAC WAC = wholesaler acquisition cost, or manufacturer’s published price to wholesalers; WAC represents published catalogue or list prices and may not represent actual transactional prices Source: AnalySource® Monthly October

Contrave – A Combination of

Bupropion and Naltrexone for

Weight Loss

▶

The FDA has approved a fi xed-dose combination of

the opioid receptor antagonist naltrexone (ReVia, and

others) and the antidepressant and smoking cessation

agent bupropion (Wellbutrin SR, Zyban, and others),

as Contrave (Orexigen/Takeda) for weight loss The

combination was approved for use as an adjunct to diet and increased physical activity in patients with a body mass index (BMI) ≥30 kg/m2 or a BMI ≥27 kg/m2

and one or more weight-related comorbidities such as hypertension, diabetes, or dyslipidemia Naltrexone/ bupropion is not a controlled substance

Table 1 Pharmacology of Naltrexone/Bupropion

Formulation 8/90 mg extended-release tablets

Metabolism Naltrexone: extensive, not by CYP enzymes

Bupropion: extensive, primarily by CYP2B6 Half-life, mean Naltrexone: 5 hours

Bupropion: 21 hours Elimination Primarily renal

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DRUGS FOR WEIGHT LOSS — None of the drugs

available for this indication in the US have proven to be

both effective and tolerable for continued use Lorcaserin

(Belviq) and phentermine/topiramate (Qsymia) have

been effective in the fi rst year of use, but much less

so thereafter; they are both schedule IV controlled

substances.1 The lipase inhibitor orlistat (Xenical, Alli)

is modestly effective (over 1-4 years, patients have

lost 2.5-3.2 kg more than with placebo), but it causes

unpleasant adverse effects such as flatulence with

discharge, oily spotting, and fecal urgency

The sympathomimetic amines, which are approved

by the FDA only for short-term use to initiate

diet-induced weight loss, are all controlled substances;

methamphetamine has a high abuse potential and

probably should not be used All sympathomimetics

can increase heart rate, raise blood pressure, and cause

nervousness and insomnia.2

The GLP-1 receptor agonist liraglutide, which is

approved for treatment of type 2 diabetes as Victoza,

is currently under review by the FDA (as Saxenda) for

treatment of obesity

MECHANISM OF ACTION — Bupropion stimulates

neu-rons in the hypothalamus associated with regulation

of appetite to produce an anorexigenic effect These

neurons also release beta-endorphin, which decreases

the anorexigenic effect Naltrexone blocks the effect of

beta-endorphin.3

CLINICAL STUDIES — The effi cacy of the naltrexone/

bupropion combination in conjunction with lifestyle

modifi cations was evaluated in four randomized, double-blind, placebo-controlled trials in overweight

or obese patients; the overweight patients also had

at least one comorbidity (hypertension, dyslipidemia,

or type 2 diabetes) Naltrexone/bupropion was signifi cantly more effective than placebo after

56 weeks for percentage change from baseline

in body weight and percentage of patients with a

≥5% reduction in body weight (Table 3) Markers of cardiovascular risk, such as waist circumference, LDL-C, HDL-C, triglycerides, and insulin resistance also improved signifi cantly with the combination compared to placebo In patients with type 2 diabetes, HbA1c was reduced by 0.6% versus 0.1% with placebo

As is common in obesity trials, the completion rate in all of these trials was only about 50%.4-7

ADVERSE EFFECTS — Nausea, the most common

adverse effect of the naltrexone/bupropion combi-nation, occurred in about 30% of patients in clinical trials Headache, constipation, dizziness, vomiting, and dry mouth also occurred frequently and more often with the active drug than with placebo Increases

in resting heart rate and in blood pressure have been reported An interim analysis of an ongoing cardiovascular outcomes trial in overweight and obese adults with cardiovascular risk factors found that naltrexone/bupropion did not increase the risk

of major adverse cardiovascular events.8 Used in about the same dosage for treatment of depression, bupropion has caused agitation, anxiety, insomnia, and (rarely) seizures; a seizure episode was reported

Table 2 Some FDA-Approved Drugs for Treatment of Obesity 1

Some Available

(Orexigen/Takeda)

Lipase Inhibitor

Sympathomimetic Amines

Phentermine/topiramate ER – Qsymia (Vivus) 7.5/46, 15/92 mg ER caps 4 7.5/46-15/92 mg once/d 170.70

ER = extended-release; ODT = orally disintegrating tablets.

1 Weight loss drugs, including over-the-counter medications, are not recommended for use during pregnancy.

2 Approximate WAC for 30 days’ treatment with the lowest strength available 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 October 5, 2014 Reprinted

3 Available over the counter.

4 Also available in 3.75/23 and 11.25/69 mg capsules which are intended for use only during titration.

Trang 7

in one patient treated with Contrave in a clinical trial

(COR-II).The package insert includes a boxed warning

about suicidal thoughts and behavior associated with

use of antidepressants and serious neuropsychiatric

reactions reported with use of bupropion for smoking

cessation9; clinical trials of naltrexone/bupropion

sought, but did not fi nd, associations with suicidality

Aminotransferase elevations and hepatotoxicity have

been reported in patients taking naltrexone

DRUG INTERACTIONS — Drugs that are inhibitors of

CYP2B6, such as ticlopidine and clopidogrel (Plavix),

may increase serum concentrations of bupropion; the

maximum dose of Contrave is 2 tablets daily when used

concomitantly with either of these drugs Concurrent

use of bupropion and the CYP2B6 inducers ritonavir,

lopinavir/ritonavir (Kaletra), or efavirenz (Sustiva) is

not recommended Bupropion is a strong inhibitor of

CYP2D6; many antidepressants, antipsychotics,

beta-blockers, and type 1C antiarrhythmics are substrates

of 2D6 and should be used with caution in patients

taking bupropion

Neurotoxicity has occurred with concurrent use of

bupropion and amantadine or levodopa, probably

caused by additive dopaminergic effects Bupropion

may lower the seizure threshold and can cause

CNS depression; additive effects could occur when

bupropion is used concomitantly with any other drug

that increases seizure risk or causes CNS depression

Adverse neuropsychiatric events have been reported

in patients who consumed alcohol during bupropion

treatment Use of bupropion with, or within 2 weeks of

stopping, an MAO inhibitor is contraindicated

Bupropion inhibits the renal organic cation transporter

OCT2 in vitro; systemic concentrations of drugs

transported by OCT2 such as metformin (Glucophage,

and others) and varenicline (Chantix) may increase

when coadministered with the combination The effi cacy of opioid-containing medications may be

reduced if taken with naltrexone; use of Contrave is

contraindicated in patients on chronic opioid therapy

DOSAGE AND ADMINISTRATION — The recommended

dosage of Contrave is 1 tablet in the AM in week 1, 1

in the AM and another in the PM in week 2, 2 in the

AM and 1 in the PM in week 3, and 2 in both the AM and PM (naltrexone 32 mg/bupropion 360 mg/day) in week 4 and thereafter The maximum recommended daily dose is one tablet twice daily in patients with moderate or severe renal impairment, and one tablet

in the morning in patients with hepatic impairment

Contrave should not be taken with a high-fat meal

If the patient has not lost at least 5% of their body weight after 12 weeks of treatment at the maintenance dosage, the drug should be discontinued

CONCLUSION – The combination of naltrexone and

bupropion (Contrave) taken as an adjunct to diet and

exercise resulted in weight loss of about 5-9% in the

fi rst year of use in the manufacturer’s clinical trials As with other drugs for this indication, its effectiveness may wane in the second year and thereafter Nausea is common, and constipation, headache, insomnia, and (rarely) seizures can occur ■

Table 3 Some Contrave Clinical Trials

Study Drug Weight Weight

Design Regimen Loss (%) Loss (%)

FL Greenway et al 4 Naltrexone 16 mg/ -5.0 39

56 weeks bupropion 360 mg

(n=1742) Naltrexone 32 mg/ -6.1 48

bupropion 360 mg

CM Apovian et al 5 Naltrexone 32 mg/ -6.4 50.5

(n=1496) Placebo -1.2 17.1

TA Wadden et al 6 Naltrexone 32 mg/ -9.3 66.4

(n=793) Placebo -5.1 42.5

P Hollander et al 7 Naltrexone 32 mg/ -5.0 44.5

(n=505) Placebo -1.8 18.9

1 Two drugs for weight loss Med Lett Drugs Ther 2012; 54:69.

2 SZ Yanovski and JA Yanovski Long-term drug treatment for obesity: a systematic and clinical review JAMA 2014; 311:74.

3 A Caixàs et al Naltrexone sustained-release/bupropion sus-tained-release for the management of obesity: review of the data to date Drug Des Devel Ther 2014; 8:1419.

4 FL Greenway et al Effect of naltrexone plus bupropion on weight loss in overweight and obese adults (COR-I): a multi-centre, randomised, double-blind, placebo-controlled, phase 3 trial Lancet 2010; 376:595.

5 CM Apovian et al A randomized, phase 3 trial of naltrexone SR/ bupropion SR on weight and obesity-related risk factors (COR-II) Obesity (Silver Spring) 2013; 21:935.

6 TA Wadden et al Weight loss with naltrexone SR/bupropion SR combination therapy as an adjunct to behavior modifi cation: the COR-BMOD trial Obesity (Silver Spring) 2011; 19:110.

7 P Hollander et al Effects of naltrexone sustained-release/bu-propion sustained-release combination therapy on body weight and glycemic parameters in overweight and obese patients with type 2 diabetes Diabetes Care 2013; 36:4022.

8 Press Release Orexigen announces successful interim analy-sis of Contrave Light Study November 25, 2013 Available at http://ir.orexigen.com/phoenix.zhtml?c=207034&p=irol-news Article&ID=1879629 Accessed October 30, 2014.

9 Safety of smoking cessation drugs Med Lett Drugs Ther 2009; 51:65.

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Obinutuzumab (Gazyva) for Chronic Lymphocytic Leukemia

www.medicalletter.org/TML-article-1455d

Pembrolizumab (Keytruda) for Metastatic Melanoma

www.medicalletter.org/TML-article-1455e

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Obinutuzumab (Gazyva) for Chronic

Lymphocytic Leukemia

▶

Obinutuzumab (Gazyva – Genentech), a humanized

anti-CD20 monoclonal antibody, has been approved

by the FDA for use in combination with chlorambucil

(Leukeran) in patients with previously untreated

chronic lymphocytic leukemia (CLL) Two other

anti-CD20 antibodies, rituximab (Rituxan) and

ofatumumab (Arzerra),1 were previously approved for

treatment of CLL

STANDARD TREATMENT — Initial treatment of

advanced or symptomatic CLL usually includes

fludarabine, rituximab, and cyclophosphamide

(Cytoxan, and others).2 Combining rituximab or

ofatumumab with the alkylating agent chlorambucil

has been effective in elderly patients and in those

with coexisting medical conditions, who often have

diffi culty tolerating chemotherapy

Ibrutinib (Imbruvica), an oral inhibitor of Bruton's

tyrosine kinase approved for second-line treatment of

CLL, has also been effective as initial monotherapy in elderly patients with CLL.3 Idelalisib (Zydelig), another

oral kinase inhibitor, was recently approved by the FDA for use in combination with rituximab for treatment of patients with relapsed CLL

MECHANISM OF ACTION — CD20 antibodies bind to the

CD20 antigen on B-cell lymphocytes and cause B-cell lysis Obinutuzumab has enhanced activity, compared

to rituximab or ofatumumab, in inducing antibody-dependent cell-mediated cytotoxicity and apoptosis

In preclinical studies in animals, obinutuzumab had greater antitumor activity than rituximab or ofatumumab.4

CLINICAL STUDIES — In an open-label randomized

clinical trial in 663 patients (median age 73 years) with previously untreated CLL and coexisting medical conditions or reduced renal function, median progression-free survival was signifi cantly longer with obinutuzumab plus chlorambucil (26.7 months) than with rituximab plus chlorambucil (15.2 months).5

Obinutuzumab has not been compared directly with ofatumumab In an unpublished trial (summarized in

Table 1 Anti-CD20 Monoclonal Antibodies for Initial Treatment of CLL

Gazyva (Genentech) vial (25 mg/mL) 900 mg on day 2, 1000 mg on days 8 and 15

Cycles 2-6: 1000 mg IV on day 1

Cycles 2-12: 1000 mg IV on day 1 4

Rituxan (Genentech) vials (10 mg/mL) Cycles 2-6: 500 mg/m 2 IV on day 1

1 Obinutuzumab is approved for use only in previously untreated patients The dosage listed for ofatumumab is for treatment of previously untreated CLL; ofatumumab dosage for previously treated patients with CLL would be higher The dosage of rituximab is the same for previously untreated and treated CLL.

2 Each treatment cycle is 28 days.

3 Approximate wholesale acquisition cost (WAC) for 1 cycle of treatment (excluding cycle 1) Source: Analy$ource® Monthly (Selected from FDB MedKnowledge™) October 5, 2014 Reprinted with permission by FDB, Inc All rights reserved ©2014 www.fdbhealth.com/policies/drug-pricing-policy Actual retail prices may be higher

4 For a minimum of 3 cycles until best response or a maximum of 12 cycles.

5 Cost calculated for a patient with a body surface area of 1.6 m 2

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the Arzerra package insert) comparing ofatumumab

plus chlorambucil to chlorambucil alone in 447

patients with previously untreated CLL (median age

69 years), median progression-free survival was 22.4

months with ofatumumab plus chlorambucil and 13.1

months with chlorambucil alone

ADVERSE EFFECTS — Adverse effects of obinutuzumab

plus chlorambucil have included infusion reactions

(some life-threatening), grade 3 or 4 neutropenia, and

tumor lysis syndrome The labeling of obinutuzumab

includes a boxed warning about the risk of potentially

fatal progressive multifocal leukoencephalopathy

(PML) and hepatitis B virus (HBV) reactivation Serious

infections and fatal cardiac events have also been

reported

ADMINISTRATION — Obinutuzumab is administered

for six 28-day treatment cycles Premedication with a

glucocorticoid, acetaminophen, and an antihistamine

is recommended to reduce the risk of an infusion-

related reaction on days 1 and 2 of cycle 1 For

subsequent infusions, premedication with

acetamino-phen alone is recommended for patients who have not

experienced a reaction

CONCLUSION — The combination of obinutuzumab

1 Ofatumumab (Arzerra) for CLL Med Lett Drugs Ther 2010; 52:51.

2 M Hallek Chronic lymphocytic leukemia: 2013 update on diagnosis, risk stratifi cation, and treatment Am J Hematol 2013; 88:803.

3 Ibrutinib (Imbruvica) for chronic lymphocytic leukemia Med Lett Drugs Ther 2014; 56:29.

4 S Herter et al Preclinical activity of the type II CD20 antibody GA101 (obinutuzumab) compared with rituximab and ofatumumab in vitro and in xenograft models Mol Cancer Ther 2013; 12:2031.

5 V Goede et al Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions N Engl J Med 2014; 370:1101.

(Gazyva) plus chlorambucil (Leukeran) is more

effective than rituximab (Rituxan) plus

chloram-bucil in previously untreated elderly patients with chronic lymphocytic leukemia and coexisting medical conditions Serious adverse effects including life-threatening infusion reactions, grade 3 or 4 neutropenia, and progressive multifocal leukoenceph-alopathy can occur ■

EDITOR IN CHIEF: Mark Abramowicz, M.D.; EXECUTIVE EDITOR: Gianna Zuccotti, M.D., M.P.H., F.A.C.P., Harvard Medical School; EDITOR: Jean-Marie Pflomm, Pharm.D.; ASSISTANT EDITORS, DRUG INFORMATION: Susan M Daron, Pharm.D., Corinne Z Morrison, Pharm.D., Michael P Viscusi, Pharm.D.; CONSULTING EDITORS: Brinda M Shah, Pharm.D.,

F Peter Swanson, M.D; SENIOR ASSOCIATE EDITOR: Amy Faucard

CONTRIBUTING EDITORS: Carl W Bazil, M.D., Ph.D., Columbia University College of Physicians and Surgeons; Vanessa K Dalton, M.D., M.P.H., University of Michigan Medical

School; Eric J Epstein, M.D., Albert Einstein College of Medicine; Jane P Gagliardi, M.D., M.H.S., F.A.C.P., Duke University School of Medicine; Jules Hirsch, M.D., Rockefeller University; David N Juurlink, BPhm, M.D., Ph.D., Sunnybrook Health Sciences Centre; Richard B Kim, M.D., University of Western Ontario; Hans Meinertz, M.D., University Hospital, Copenhagen; Sandip K Mukherjee, M.D., F.A.C.C., Yale School of Medicine; Dan M Roden, M.D., Vanderbilt University School of Medicine; Esperance A.K Schaefer, M.D., M.P.H., Harvard Medical School; F Estelle R Simons, M.D., University of Manitoba; Neal H Steigbigel, M.D., New York University School of Medicine; Arthur M F Yee, M.D., Ph.D., F.A.C.R.,

Weill Medical College of Cornell University

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Pembrolizumab (Keytruda) for

Metastatic Melanoma

▶

The FDA has approved pembrolizumab (Keytruda –

Merck), a human programmed death receptor-1 (PD-1)

blocking antibody, for treatment of unresectable or

metastatic melanoma that has progressed following

treatment with ipilimumab (Yervoy) and, if the patient

is BRAF V600 mutation positive, a BRAF inhibitor It

is the fi rst PD-1 inhibitor to be marketed in the US

Nivolumab, another PD-1 inhibitor, is available in

Japan Pembrolizumab was previously known as

lambrolizumab

STANDARD TREATMENT — Metastatic melanoma has

traditionally been treated with the cytotoxic agent

dacarbazine (DTIC), which has not been shown to

improve survival Other therapies have included

high-dose interleukin-2 (aldesleukin, Proleukin), which

has produced responses in 16% of patients, but can cause severe toxicity and requires hospitalization for treatment The anti-CTLA4 monoclonal antibody ipilimumab has produced response rates similar to those with high-dose interleukin-2.1 Three drugs have become available for treatment of metastatic melanoma with BRAF V600 mutations, which are found in about 50% of melanomas.2,3

MECHANISM OF ACTION — The programmed death

receptor-1 (PD-1) is an inhibitory receptor expressed

by T-cells during long-term antigen exposure, such

as in chronic viral infections or cancer.4 Activation of PD-1 by its ligands, PD-L1 and PD-L2, inhibits T-cell proliferation and cytokine production Upregulation of these ligands occurs in some tumors Pembrolizumab binds to the PD-1 receptor, blocking the interaction

Table 1 Some Drugs for Metastatic Melanoma

Drug Mechanism Indication 1 Effi cacy Dosage Cost 2

Pembrolizumab – Programmed Disease progression OS rate (1 yr estimated): 58% 2 mg/kg IV $58,266.00 4

Keytruda (Merck) death receptor-1 after ipilimumab and, PFS: 22 weeks (~5.1 mos) 3 q3wks

Ipilimumab – Yervoy Cytotoxic T- Melanoma regardless OS: 10.1 mos vs 6.4 mos 3 mg/kg IV 129,274.00 4

(BMS) lymphocyte- of BRAF mutation with gp100 vaccine q3wks x 4 doses

associated antigen 4 status, before or after OS rate (1 yr): 45.6%

(CTLA-4) blocker other therapies PFS: 2.86 mos vs 2.76 mos

with gp100 vaccine 5 Vemurafenib – BRAF kinase Melanoma with PFS: 5.3 mos vs 1.6 mos 960 mg (4 tabs) 65,104.80

Dabrafenib – BRAF kinase Melanoma with PFS: 5.1 mos vs 2.7 mos 150 mg PO bid 10 50,274.00

Trametinib – MEK kinase Melanoma with PFS: 4.8 mos vs 1.5 mos 2 mg PO once/d 57,550.50

Mekinist (GSK) inhibitor BRAF V600E or with dacarbazine or

V600K mutations 8,11 paclitaxel 12

OS = overall survival, PFS = progression-free survival

1 All of these drugs are only approved for use in patients with unresectable or metastatic melanoma.

2 Approximate WAC for 6 months’ treatment 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 October 5, 2014 Reprinted with permission by

3 C Robert et al Lancet 2014; 384:1109.

4 Cost calculated for a patient weighing 75 kg.

5 FS Hodi et al N Engl J Med 2010; 363:711.

6 PB Chapman et al N Engl J Med 2011; 364:2507.

7 Not indicated for treatment of patients with wild-type BRAF (BRAF-negative) melanoma

8 The combination of dabrafenib and trametinib is FDA-approved for treatment of BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma.

9 A Hauschild et al Lancet 2012; 380:358.

10 Taken at least 1 hour before or at least 2 hours after a meal

11 Trametinib monotherapy is not recommended for patients who have previously been treated with a BRAF inhibitor.

12 KT Flaherty et al N Engl J Med 2012; 367:107.

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