1489 Drugs for Tobacco Dependence ...Sonidegib Odomzo for Basal Cell Carcinoma ...p 27p 31 Clarifi cation: Half-Life of Heroin ...p 32 Olaparib Lynparza for Advanced Ovarian Cancer ...o
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IN THIS ISSUE
ISSUE
1433
Volume 56
Published by The Medical Letter, Inc • A Nonprofi t Organization
ISSUE No
1489
on Drugs and Therapeutics
Elbasvir/Grazoprevir (Zepatier) for Hepatitis C p 25
Drugs for Tobacco Dependence p 27
Sonidegib (Odomzo) for Basal Cell Carcinoma p 31
Clarifi cation: Half-Life of Heroin p 32
Olaparib (Lynparza) for Advanced Ovarian Cancer online only
Trang 2
25
on Drugs and Therapeutics
ISSUE
1433
Volume 56
ISSUE No
1489 Drugs for Tobacco Dependence Sonidegib (Odomzo) for Basal Cell Carcinoma p 27p 31
Clarifi cation: Half-Life of Heroin p 32
Olaparib (Lynparza) for Advanced Ovarian Cancer online only
ALSO IN THIS ISSUE
Elbasvir/Grazoprevir (Zepatier)
for Hepatitis C
▶
The FDA has approved Zepatier (Merck), a fi
xed-dose combination of two direct-acting antiviral
agents — elbasvir, an NS5A inhibitor, and grazoprevir,
an NS3/4A protease inhibitor — for oral treatment
of chronic hepatitis C virus (HCV) genotype 1 or 4
infection
Pronunciation Key Elbasvir : elb' as veer Zepatier : zep' ah teer
Grazoprevir : graz oh' pre veer
HCV GENOTYPES — Genotype 1 is responsible for
70-80% of HCV infections in the US Genotype 4
is uncommon in the US and Canada; it is the most
prevalent strain of HCV in Central sub-Saharan Africa,
North Africa, and the Middle East.1
FIXED-DOSE COMBINATIONS — Zepatier is the third
all-oral, interferon-free, fi xed-dose combination to
be approved for treatment of infections with HCV genotypes 1 and 4 The combination of ledipasvir/
sofosbuvir (Harvoni) was approved for HCV genotype
1 infection in 20142 and for genotypes 4, 5, and 6 in
paritaprevir/ritonavir copackaged with dasabuvir
(Viekira Pak) was approved for HCV genotype 1
infection in 2014.4 Ombitasvir/paritaprevir/ritonavir
(Technivie) coadministered with ribavirin was
approved for genotype 4 the following year.5
TREATMENT OF HCV GENOTYPE 1 — Current
guidelines recommend that patients with chronic HCV
genotype 1 infection receive either Harvoni, Viekira
Pak, sofosbuvir (Sovaldi) plus simeprevir (Olysio),
or daclatasvir (Daklinza) plus sofosbuvir, all with or
Table 1 Oral Regimens for HCV Genotype 1 Infection
Brand Name Formulation Usual Dosage Tablets Cost 1
Harvoni (Gilead) 90/400 mg ledipasvir/sofosbuvir tabs 1 tab once/day x 12 wks 2,3 1/day 4 $94,500
Sovaldi (Gilead) 400 mg sofosbuvir tabs 1 sofosbuvir 3 tab and 1 daclatasvir 2/day 4 147,000
+ Daklinza (BMS) + 60 mg daclatasvir tabs tab once/day x 12 wks 5
Sovaldi (Gilead) 400 mg sofosbuvir tabs 1 sofosbuvir 3 tab and 1 simeprevir 6 2/day 4 150,360
+ Olysio (Janssen) + 150 mg simeprevir caps cap once/day x 12 wks 7
(Abbvie) ombitasvir/paritaprevir/ritonavir tabs tabs qAM and 1 dasabuvir
+ 250 mg dasabuvir tabs tab bid x 12 wks 8,9
Zepatier (Merck) 50/100 mg elbasvir/grazoprevir tabs 1 tab once/day x 12 wks 9,10 1/day 4 54,600
1 Approximate WAC for 12 weeks’ 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 February 5, 2016 Reprinted with permission by First Databank, Inc All rights reserved ©2016 www.fdbhealth.com/policies/drug-pricing-policy.
2 24 weeks for treatment-experienced patients with compensated cirrhosis 8 weeks may be considered for treatment-naive patients without cirrhosis with baseline HCV RNA <6 million IU/mL Patients with decompensated cirrhosis should also receive ribavirin 1000 mg/day (1200 mg/day for those weighing ≥75 kg).
3 Not recommended for use in patients with severe or end-stage renal disease.
4 Patients requiring ribavirin would also take 4-7 tablets or capsules of ribavirin 200 mg each day A 12-week supply of ribavirin for a 70-kg patient costs about $500.
5 Patients with decompensated cirrhosis or post-transplant should also receive ribavirin 1000 mg/day
6 Not recommended for use in patients with moderate or severe hepatic impairment.
7 24 weeks for patients with cirrhosis Whether treatment-experienced patients or those with HCV genotype 1a should also receive ribavirin 1000 mg/day (1200 mg/day for those weighing ≥75 kg) in two divided doses is unclear
8 24 weeks for patients with HCV genotype 1a and cirrhosis (12 weeks may be considered in this population, except in prior non-responders to peginterferon/ribavi-rin) All patients with HCV genotype 1a or cirrhosis should also receive ribavirin 1000 mg/day (1200 mg/day for those weighing ≥75 kg) in two divided doses.
9 Contraindicated for use in patients with moderate or severe hepatic impairment.
10 Patients with HCV genotype 1a with baseline NS5A polymorphisms should also take ribavirin and should be treated for 16 weeks Patients who have failed
to respond to peginterferon, ribavirin and a protease inhibitor should also receive ribavirin, but can be treated for 12 weeks Ribavirin should be given in two divided doses (for those with CrCl >50 mL/min; <66 kg = 800 mg/day, 66-80 kg = 1000 mg/day, 81-105 kg = 1200 mg/day, >105 kg = 1400 mg/day).
Trang 3without ribavirin.6 Harvoni has produced sustained
virologic response (SVR) rates >90% in various patient
populations, with minimal adverse effects Viekira Pak
with or without ribavirin for 12 or 24 weeks appears
to be similar in effi cacy to Harvoni, but has a higher
pill burden and has a greater potential for adverse
drug interactions The level of evidence supporting
use of simeprevir plus sofosbuvir is the same as that
for Harvoni and Viekira Pak for treatment-naive
pa-tients, but lower for treatment-experienced patients
Daclatasvir plus sofosbuvir was recently approved by
the FDA for treatment of HCV genotype 1 infection; the
level of evidence supporting its use is lower than that
for the other three regimens in both treatment-naive
and treatment-experienced patients
Harvoni, simeprevir plus sofosbuvir, and daclatasvir
plus sofosbuvir are not recommended for patients
with severe or end-stage renal disease because serum
concentrations of sofosbuvir and its metabolite are
signifi cantly increased in these patients
CLINICAL STUDIES — Approval of elbasvir/grazoprevir
was based on the results of trials in both
treatment-naive and treatment-experienced patients infected
with HCV genotype 1, 4, or 6
In one double-blind trial (C-EDGE) in 306
treatment-naive patients with HCV genotype 1 or 4 infection with
or without cirrhosis, 95% of patients (273/288) with
genotype 1 and 100% (18/18) of those with genotype
4 who were treated with elbasvir/grazoprevir achieved
a sustained virologic response 12 weeks after stopping
treatment (SVR12); there were no signifi cant differences
between cirrhotic and non-cirrhotic patients.7
In a single-arm trial in 218 treatment-naive
patients co-infected with HCV and HIV (C-EDGE
CO-INFECTION), 210 (96%), including all 35 patients
with cirrhosis, achieved an SVR12.8
In an unpublished, 4-arm, open-label trial (C-EDGE
TE), 420 patients with HCV genotype 1, 4, or 6
infection that had previously failed to respond to
peginterferon and ribavirin were randomized to
receive elbasvir/grazoprevir for 12 or 16 weeks, with
or without ribavirin Patients treated with ribavirin
in addition to elbasvir/grazoprevir for 16 weeks had
slightly higher SVR12 response rates (97%) than
those treated with the combination alone for 12 or 16
weeks (92%) or with the combination plus ribavirin
for only 12 weeks (94%).9
In an open-label trial in 79 patients with HCV genotype
1 infection that did not respond to previous treatment
with peginterferon and ribavirin in combination with boceprevir, telaprevir, or simeprevir (C-SALVAGE), 96% of patients treated with elbasvir/grazoprevir in combination with ribavirin for 12 weeks achieved an SVR12.10 Virologic response rates were maintained 24 weeks after stopping treatment.11
In a trial in 122 naive and treatment-experienced patients with HCV genotype 1 infection and stage 4-5 chronic kidney disease, including 92 patients
on hemodialysis (C-SURFER), 94% of patients treated with elbasvir/grazoprevir achieved an SVR12.12
In a small cohort of patients with HCV genotype 1a infection who had a pre-existing NS5A resistance-associated polymorphism, an SVR12 occurred in only 70% of patients (39/56) treated with elbasvir/ grazoprevir for 12 weeks compared to 100% (6/6) with
a 16-week course of elbasvir/grazoprevir plus ribavirin
ADVERSE EFFECTS — Fatigue, headache, and nausea
were the most frequent adverse effects reported in clinical trials in patients treated with elbasvir/grazoprevir for 12 weeks; similar adverse event rates were reported
in patients taking placebo Anemia has developed in patients treated for 16 weeks with elbasvir/grazoprevir and ribavirin ALT elevations to >5 times the upper limit of normal occurred in 1% of patients in clinical trials In non-HCV-infected subjects with severe hepatic impairment, grazoprevir levels rose to 12 times the levels found in
those with no hepatic impairment Like Viekira Pak,
Table 2 Results of Some Zepatier Clinical Trials
Treatment-Naive Patients with or without Cirrhosis
C-EDGE (double-blind; 316 patients with genotype 1, 4, or 6)
Zepatier x 12 weeks 95%
C-EDGE CO-INFECTION (open-label; 218 patients with genotype 1,
4, or 6 and HIV)
Zepatier x 12 weeks 96%
Treatment-Experienced Patients with or without Cirrhosis
C-EDGE TE (open-label; 420 patients with genotype 1, 4, or 6 with
or without HIV) 1
Zepatier x 12 weeks 92%
Zepatier x 16 weeks 92%
Zepatier + ribavirin x 12 weeks 94%
Zepatier + ribavirin x 16 weeks 97%
C-SALVAGE (open-label; 79 patients with genotype 1) 2
Zepatier + ribavirin x 12 weeks 96%
Patients with Severe Renal Impairment including Hemodialysis 3
C-SURFER (double-blind; 122 patients with genotype 1)
Zepatier x 12 weeks 94%
SVR12 = HCV RNA <15 or <25 IU/mL 12 weeks after stopping treatment
1 Previously failed to respond to peginterferon and ribavirin
2 Previously failed to respond to boceprevir, simeprevir, or telaprevir in combination with peginterferon and ribavirin
3 Treatment-naive or treatment-experienced patients with or without cir-rhosis
Trang 4elbasvir/grazoprevir is contraindicated in patients with
moderate or severe hepatic impairment
PREGNANCY — Use of elbasvir/grazoprevir in
pregnant women has not been studied Studies in
animals using large doses have demonstrated no
adverse effects on fetal development
DRUG INTERACTIONS — Both elbasvir and grazoprevir
are substrates of CYP3A; concomitant use with the
strong CYP3A inhibitor ketoconazole (Nizoral, and
others) increased their serum concentrations and
coadministration with the CYP3A inducer efavirenz
(Sustiva) decreased them Zepatier is contraindicated
for use with efavirenz and strong inducers of CYP3A,
such as rifampin, because of the potential for loss
of effi cacy Grazoprevir is a substrate of organic
anion transporting polypeptide (OATP) 1B1 and 1B3;
coadministration with inhibitors of these transporters
such as cyclosporine (Neoral, and others) can
increase serum concentrations of grazoprevir and
is contraindicated
Grazoprevir is a weak inhibitor of CYP3A; it has
been shown to increase serum concentrations of
midazolam (Versed, and generics) Elbasvir and
grazoprevir are both inhibitors of the drug transporter
breast cancer resistance protein (BCRP) and may
increase plasma concentrations of drugs that are
substrates of this transporter
DOSAGE — Zepatier tablets contain 50 mg of elbasvir
and 100 mg of grazoprevir The recommended dosage
for most patients is one tablet once daily for 12 weeks
Patients with genotype 1a infection who have
high-level NS5A resistance-associated polymorphisms
at baseline should also receive ribavirin and should
be treated for 16 weeks Patients with genotype 1a
or 1b infection previously treated with peginterferon,
ribavirin, and a protease inhibitor should also receive
ribavirin, but can be treated for 12 weeks In patients
with genotype 4 infection previously treated with
peginterferon and ribavirin, addition of ribavirin
is recommended, and their treatment should be
continued for 16 weeks
CONCLUSION — The oral fi xed-dose combination
of the direct-acting antiviral agents elbasvir and
grazoprevir (Zepatier) appears to be highly effective
and well tolerated in patients infected with HCV
genotype 1 or 4 It is less expensive than Harvoni and
may be safer in patients with severe renal impairment
Zepatier, like Viekira Pak, is contraindicated in
patients with moderate or severe hepatic impairment;
Harvoni is not ■
1 JP Messina et al Global distribution and prevalence of hepatitis
C virus genotypes Hepatology 2015; 61:77.
2 A combination of ledipasvir and sofosbuvir (Harvoni) for hepa-titis C Med Lett Drugs Ther 2014; 56:111.
3 In brief: new indications for Harvoni Med Lett Drugs Ther 2016; 58:6.
4 A 4-drug combination (Viekira Pak) for hepatitis C Med Lett Drugs Ther 2015; 57:15.
5 In brief: Technivie for HCV genotype 4 infection Med Lett Drugs Ther 2015; 57: e162.
6 American Association for the Study of Liver Diseases/Infec-tious Disease Society of America/International Antiviral So-ciety–USA Recommendations for testing, managing, and treating hepatitis C December 11, 2015 Available at www hcvguidelines.org Accessed February 18, 2016.
7 S Zeuzem et al Grazoprevir-elbasvir combination therapy for treatment-naive cirrhotic and noncirrhotic patients with
chron-ic hepatitis C virus genotype 1, 4, or 6 infection: a randomized trial Ann Intern Med 2015; 163:1.
8 JK Rockstroh et al Effi cacy and safety of grazoprevir (MK-5172) and elbasvir (MK-8742) in patients with hepatitis C virus and HIV co-infection (C-EDGE CO-INFECTION): a non-randomised, open-label trial Lancet HIV 2015; 2:e319.
9 P Kwo et al Effi cacy and safety of grazoprevir/elbasvir +/- RBV for 12 or 16 weeks in patients with HCV G1, G4 or G6 infection who previously failed peginterferon/RBV : C-EDGE treatment-experienced EASL - The International Liver Congress 2015 50th Annual Meeting of the European Association for the Study
of the Liver; Vienna, Austria; April 22-26 Available at www.nat-ap.org/2015/EASL/EASL_04.htm Accessed February 18, 2016
10 X Forns et al Grazoprevir and elbasvir plus ribavirin for chronic HCV genotype-1 infection after failure of combination therapy containing a direct-acting antiviral agent J Hepatol 2015; 63:564.
11 M Buti et al Grazoprevir, elbasvir, and ribavirin for chronic hepa-titis C virus genotype 1 infection after failure of pegylated
interfer-on and ribavirin with an earlier-generatiinterfer-on protease inhibitor: fi nal 24-week results from C-SALVAGE Clin Infect Dis 2016; 62:32.
12 D Roth et al Grazoprevir plus elbasvir in treatment-naive and treatment-experienced patients with hepatitis C virus geno-type 1 infection and stage 4-5 chronic kidney disease (the C-SURFER study): a combination phase 3 study Lancet 2015; 386:1537.
Drugs for Tobacco Dependence
▶ Tobacco dependence remains the primary preventable cause of death in the United States It is a chronic disorder that often requires pharmacologic therapy, but counseling may be equally effective and can add to the effectiveness of any treatment for this indication.1,2 Abrupt cessation of smoking appears to be as effective
as gradual reduction.3
NICOTINE — All FDA-approved nicotine replacement
therapies (NRTs) deliver nicotine to nicotinic receptors
in the central nervous system (CNS) in a lower dose and
at a sub stantially slower rate than tobacco cigarettes They increase smoking cessation rates by 50-70% and,
in the short term, may decrease weight gain associated with smoking cessation.4,5 Nicotine undergoes fi rst-pass metabolism, which limits its effectiveness in oral
Trang 5pill formulations Nicotine gum, lozenges, and patches
are available without a prescription in the US for
persons ≥18 years old; these products appear to be as
effective as those that require a prescription (nicotine
oral inhaler and nasal spray).Used as monotherapy, a
rapid-onset NRT such as a gum, lozenge, nasal spray,
or oral inhaler should be taken on a regular schedule
to prevent nicotine withdrawal symptoms Combining
the nicotine patch with a rapid-onset formulation
(combination NRT) is more effective than monotherapy
Transdermal – Nicotine patches require 6-8 hours
to achieve peak serum concentrations They deliver
nicotine to the CNS more slowly than any other NRT
Oral – Nicotine from a gum, lozenge, or oral inhaler is
absorbed through the buccal mucosa Serum nicotine
concentrations peak in 20-60 minutes If oral nicotine
is swallowed, fi rst-pass metabolism decreases its
bioavailability
Nasal Spray – Nicotine from nasal spray, the
fastest-acting of all NRTs (but still much slower than
cigarettes), achieves a peak CNS concentration in
5-20 min utes Patients report that relief of nicotine
withdrawal symptoms is faster with the nasal spray
than with other NRT formulations Because it can
irritate the throat and nasal mucosa, the nasal spray
should not be used for more than 3 months
Adverse Effects – The transdermal nicotine patch is
generally well tolerated, but some patients discontinue
it because of insomnia, vivid dreams, or pruritus at the
application site Removing the patch at bedtime can
minimize or eliminate vivid dreams and other sleep
disturbances The nico tine oral inhaler can cause minor
mouth and throat irri tation and cough; tolerance to the
irritating effects usually develops within one or two days
Nicotine gum can cause flatulence, indigestion, nausea,
unpleasant taste, hiccups, and a sore mouth, throat,
and jaw Nicotine lozenges can cause mouth irritation, heartburn, hiccups, and nausea Nicotine nasal spray
causes transient burning and stinging of the nasal mucosa, throat irritation, flushing, coughing, sneezing, lacrima tion, rhinorrhea, and nausea; these symptoms are a common cause of drug discontinuation
Drug Interactions – NRTs are metabolized by CYP2A6,
but do not inhibit or induce CYP enzymes to a clinically signifi cant extent Tobacco smoke, not nicotine itself, induces CYP1A2, CYP2E1, and some uridine diphosphate-glucuronosyltransferases (UGTs); it may increase the metab olism and decrease the effi cacy of drugs that are substrates of these pathways such as
clozapine (Clozaril, and others), theophylline
(Theo-Dur, and others), and propranolol.6,7 Dosages of these drugs may need to be reduced when patients stop smoking
BUPROPION — Used mainly for treatment of
depression, bupropion also has some nicotinic-receptor-blocking activity A sustained-release (SR) formulation of bupropion is FDA-approved for
treat-ment of tobacco dependence (marketed as Zyban)
Bupropion SR should be started 7-14 days before the target quit date to allow for adequate steady-state serum concentrations Immediate-release bupropion
(Wellbutrin, and generics) has also been used
(off-label) to treat tobacco dependence
Effectiveness — Bupropion has doubled smoking
cessation rates compared to placebo in short-term trials It has been as effective as NRT in increasing smoking cessation rates and decreasing weight gain.8
Adverse Effects – Bupropion is generally well tolerated
The most common adverse effects in clinical trials were insomnia and dry mouth Headache, nausea, and anxiety can also occur.9 Bupropion SR has been associated with a seizure incidence of 0.1%; patients with a history of seizure, stroke, brain tumor, brain sur-gery, or severe head injury should not take bupropion
Drug Interactions – Bupropion is primarily metabolized
by CYP2B6 to hydroxybupropion, its most active metabolite Drugs that are inhibitors or inducers of CYP2B6 may interact with bupropion Bupropion and hydroxybupropion inhibit CYP2D6; many antidepres-sants, antipsychotics, beta-blockers, and type 1C antiarrhythmics are CYP2D6 substrates and should be used with caution in patients taking bupropion.6 Use of bupropion with a monoamine oxidase (MAO) inhibitor
or within 2 weeks of stopping one is contraindicated
Recommendations for Treatment of Tobacco Dependence
▶ Tobacco dependence can be safely and effectively
treated with counseling and pharmacotherapy.
▶ All of the nicotine replacement therapies (NRTs) appear
to be about equally effective, but a combination of a
patch and a rapid-onset formulation is generally more
effective than monotherapy
▶ Bupropion has been as effective as NRT
▶ Varenicline appears to be the most effective drug for
treatment of tobacco dependence.
▶ Use of ≥2 medications has been more effective than
monotherapy.
▶ The optimal duration of treatment is not clear; 3-6
months is probably the minimum, and some patients may
need longer treatment
▶ The effi cacy of electronic cigarettes for smoking
cessation remains to be established.
Trang 6Table 1 Some Drugs for Treatment of Tobacco Dependence
Some Available Usual Adult
Nicotinic Receptor Agonists
Nicotine transdermal patch 3 – generic 7, 14, 21 mg/24 hr patches 1 patch/d 4 $40.70 5
NicoDerm CQ (Sanofi ) 84.10 5
Nicotine nasal spray – Nicotrol NS (Pfi zer) 200 sprays/10 mL bottle 1 dose (2 sprays) 8-40x/d 304.90 7
(0.5 mg/spray) (max 5 doses/hr) 4,6
Nicotine oral inhaler – Nicotrol (Pfi zer) 10 mg cartridges 4-16 cartridges/d 290.40 8
(max 16 cartridges/d) 4
Nicotine polacrilex gum 3 – generic 2, 4 mg/piece 8-24 pieces/d 4,9 77.20
Nicorette Gum (GSK) 84.00
Nicotine polacrilex lozenge 3 – generic 2, 4 mg/lozenge 8-20 lozenges/d 4,10 72.00
Nicorette Lozenge(GSK) 11 103.00
Dopaminergic-Noradrenergic Reuptake Inhibitors
Bupropion SR – generic 100, 150, 200 mg SR tabs 12 150 mg bid 13 27.00
Wellbutrin SR (GSK)14 377.20
Zyban (GSK) 150 mg SR tabs 236.00
Nicotinic Receptor Partial Agonist
Varenicline tartrate – Chantix (Pfi zer) 0.5, 1 mg tabs 1 mg bid 15 157.50
1 Dosage reduction may be needed for hepatic or renal impairment.
2 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 February
5, 2016 Reprinted with permission by First Databank, Inc All rights reserved ©2016 www.fdbhealth.com/policies/drug-pricing-policy.
3 Available over the counter (OTC) for persons ≥18 years old Patients should not eat or drink within 15 minutes of using a gum or lozenge.
4 See specifi c label for instructions for dose titration.
5 Cost for 28 transdermal patches.
6 One spray per nostril Maximum of 40 doses/day Should not be used for >3 months
7 Cost of 4 10-mL bottles.
8 Cost of 168 10-mg cartridges; each cartridge delivers 4 mg of nicotine.
9 A second piece of gum can be used within one hour Continuously chewing one piece after another is not recommended.
10 Maximum of 5 lozenges in 6 hours or 20 lozenges/day Do not use more than one lozenge at a time or continuously use one after another.
11 Also available in a mini-lozenge.
12 Only the generic 150-mg SR tablets are FDA-approved for this indication.
13 Initial dosage is 150 mg once/d for 3 days.
14 Not FDA-approved for this indication.
15 Initial dosage is 0.5 mg once/d for 3 days, then bid for 4-7 days.
VARENICLINE — Varenicline tartrate (Chantix), a
nicotinic receptor partial agonist, is FDA-approved
for smoking cessation.10 It binds selectively to 4β2
nicotinic acetylcholine receptors, relieving cravings
and withdrawal symptoms during abstinence
Varenicline binds to the 4β2 receptor with greater
smoking Varenicline should be started 7 days before
the target quit date to allow for adequate
steady-state serum concentrations
Effectiveness – Randomized controlled trials,
including both short-term trials and some for up to
one year, have found varenicline to be more effective
than NRT monotherapy or bupropion and as effective
as combination NRT (nicotine patch plus a
rapid-onset NRT) in increasing smoking cessation rates.11,12
In one randomized, open-label trial in 1086 smokers,
smoking cessation rates with varenicline, combination
NRT, and a nicotine patch alone were similar at 26
and 52 weeks, possibly due to a relatively low level of
Adverse Effects – Varenicline was generally well
tolerated in clinical trials The most common
ad-verse effects were nausea, sleep disturbances, abnormal dreams, headache, constipation, vomiting, flatulence, and xerostomia Neuropsychiatric symp-toms, exacerbations of pre-existing psychiatric illness, suicidal behavior, and an increased rate
of cardiovascular events have been associated with varenicline use in observational studies, but a retrospective cohort study in almost 165,000 patients found no increased risk of any cardiovascular or neuropsychiatric event with varenicline compared
smoking cessation rates in patients with psychiatric illnesses, with no signifi cant psychiatric adverse effects.15,16 Recent analyses of clinical trials have found no increase in suicidal behavior in patients treated with varenicline compared to those treated with NRT, bupropion, or placebo.17
Drug Interactions – Varenicline has no clinically
signifi cant drug interactions Coadministration of varenicline and transdermal nicotine does not affect nicotine pharmacokinetics, but nausea, headache, vomiting, dizziness, dyspepsia, and fatigue may occur more frequently with combined use than with transdermal nicotine alone
Trang 7COMBINATIONS — Use of ≥2 medications has
generally been more effective than monotherapy in
treating tobacco dependence In one trial, 127 smokers
with comorbid conditions were randomly assigned to
receive a nicotine patch alone or in combination with
a nicotine oral inhaler and bupropion for 10 weeks;
abstinence rates at 26 weeks were 35% with the
combination compared to 19% with the patch alone.18
A randomized, placebo-controlled trial in 446 smokers
that included a week treatment period and a
12-week follow-up found that varenicline plus a nicotine
patch was signifi cantly more effective than varenicline
alone in achieving continuous abstinence at 12 weeks
(55.4% vs 40.9%) and 24 weeks (49.0% vs 32.6%) and
point-prevalence abstinence at 6 months (65.1% vs
46.7%).19 In another trial, a combination of varenicline
and bupropion SR was signifi cantly more effective than
varenicline alone in achieving prolonged abstinence
among 506 smokers at 12 weeks (53.0% vs 43.2%) and
26 weeks (36.6% vs 27.6%), but not at 52 weeks.20
DURATION OF TREATMENT — Longer-duration
pharmacotherapy may improve smoking cessation
of 3-6 months of effective therapy In general, the
dosage of NRTs should be tapered at the end of
treatment; bupropion SR and varenicline can usually
be discontinued without a gradual dosage reduction,
but some clinicians recommend a taper
ELECTRONIC CIGARETTES — Electronic cigarettes,
also called e-cigarettes, are advertised as a safer,
more convenient, and socially acceptable alternative
to tobacco cigarettes They have not been approved
by the FDA as smoking cessation aids E-cigarettes
are battery-operated devices that typically contain a
heating element (atomizer) and a reservoir of liquid
(usually nicotine dissolved in propylene glycol and/or
glycerin) When the user inhales or activates the
device with a button, the liquid nicotine is vaporized
into a visible mist
Clinical Studies – In a clinical trial in adult smokers not
intending to quit, 300 participants were randomized to
e-cigarettes containing 5.4 or 7.2 mg of nicotine or
no nicotine At 12 weeks, complete abstinence from
tobacco cigarettes had occurred in 14% of participants
using a nicotine-containing e-cigarette and in 4% of
those using the nicotine-free device.22
A randomized trial in 657 smokers who wanted to
quit compared a 16-mg nicotine e-cigarette, a
21-mg nicotine patch, and a placebo e-cigarette The
percentage of patients who achieved abstinence from
tobacco cigarettes at 6 months was not signifi cantly higher with the nicotine e-cigarette (7.3%) than with the nicotine patch (5.8%) or placebo device (4.1%).23
A meta-analysis of 38 trials of smokers who used e-cigarettes, including some in smokers who wanted
to quit and others in smokers in general, found that those who used e-cigarettes were actually 28% less likely to quit smoking tobacco cigarettes than smokers who did not use e-cigarettes.24
Adverse Effects – There is no evidence to date that
short-term use of e-cigarettes has serious adverse effects.25 The most common adverse effects reported during clinical trials of e-cigarettes were mouth and throat irritation and dry cough Lipoid pneumonia has been reported.26 In non-smokers, repeated exposure
to nicotine in e-cigarettes could lead to nicotine dependence
Toxic Substances – An FDA analysis of 2 different
brands of e-cigarette cartridges found that they contained a number of impurities including polycyclic aromatic hydrocarbons and tobacco-specifi c
e-cigarettes has been found to contain levels of potentially toxic and carcinogenic substances that are lower than those found in cigarette smoke, but higher than those in ambient air.28,29
PREGNANCY — Counseling is the preferred treatment
for pregnant women who smoke Nicotine is classifi ed
as category D (positive evidence of risk) for use during pregnancy However, using NRT during preg-nancy is probably safer for the fetus than smoking, which increases the incidence of low birth weight deliveries and is associated with peri- and post-natal complications NRT can increase smoking cessation rates in late pregnancy by about 40% and,
in one trial that followed infants after birth, it improved developmental outcomes.30 Bupropion and varenicline are classifi ed as category C (no adequate studies in pregnant women; fetal toxicity in animals) for use during pregnancy ■
1 MC Fiore et al Treating tobacco use and dependence: 2008 update U.S Public Health Service Clinical Practice Guideline executive summary Respir Care 2008; 53:1217.
2 AL Siu et al Behavioral and pharmacotherpy interventions for tobacco smoking cessation in adults, including pregnant wom-en: U.S Preventive Services Task Force recommendation state-ment Ann Intern Med 2015; 163:622.
3 N Lindson-Hawley et al Gradual reduction vs abrupt cessation
as a smoking cessation strategy in smokers who want to quit JAMA 2013; 310:91.
4 LF Stead et al Nicotine replacement therapy for smoking ces-sation Cochrane Database Syst Rev 2012; 11:CD000146.
Trang 8Sonidegib (Odomzo) for Basal Cell
Carcinoma
▶
Pronunciation Key Sonidegib: soe' ni deg' ib Odomzo: oh dom' zoe
The FDA has approved the hedgehog pathway
inhibitor sonidegib (Odomzo – Novartis) for oral
treatment of locally advanced basal cell carcinoma that cannot be treated with surgery or radiation or has recurred following such treatment Vismodegib
(Erivedge), another oral hedgehog pathway inhibitor,
was approved earlier for the same indication and also for treatment of metastatic basal cell carcinoma.1
STANDARD TREATMENT — Basal cell carcinomas that
cannot be treated effectively with surgery or radiation because of their size or invasion of other organs are uncommon Topical therapies such as 5-fluorouracil, imiquimod, or photodynamic therapy have been used to treat superfi cial lesions Vismodegib is modestly effective for treatment of locally advanced or metastatic basal cell carcinoma.1
MECHANISM OF ACTION — The hedgehog signaling
pathway is important in embryofetal development and
in the regulation of adult stem cells; alterations in the pathway have been implicated in the development
smoothened homolog (SMO) activates the pathway SMO prevalence on the cell surface is regulated by the cell surface receptor patched homolog 1 (PTCH1) Hedgehog ligands inhibit PTCH1, permitting SMO proliferation and activity Mutations in SMO or PTCH1
Table 1 Hedgehog Pathway Inhibitors
Sonidegib (Odomzo) Vismodegib (Erivedge)
Formulation 200 mg capsules 150 mg capsules Route Oral Oral
Metabolism Primarily hepatic by Minimal; 98%
CYP3A4; 36% unchanged unchanged
Elimination Feces (70%); urine (30%) Feces (82%); urine (4%) Half-life 28 days 12 days
Dosage 200 mg once/day 150 mg once/day with
on an empty stomach or without food Cost 1 $335.30 $352.10
1 Approximate wholesale acquisition cost (WAC) for 1 capsule WAC = whole-saler acquisition cost or manufacturer's published price to wholewhole-salers; WAC represents a published catalogue or list price and may not represent an actual transactional price Source: AnalySource® Monthly February 5, 2016 Reprinted with permission by First Databank, Inc All rights reserved ©2016 www.fdbhealth.com/policies/drug-pricing-policy.
5 AC Farley et al Interventions for preventing weight gain
af-ter smoking cessation Cochrane Database Syst Rev 2012;
1:CD006219.
6 Inhibitors and inducers of CYP enzymes and P-glycoprotein
Med Lett Drugs Ther 2013; 55:e44.
7 LA Kroon Drug interactions with smoking Am J Health Syst
Pharm 2007; 64:1917.
8 JR Hughes et al Antidepressants for smoking cessation
Co-chrane Database Syst Rev 2014; 1:CD000031.
9 JT Hays and JO Ebbert Bupropion for the treatment of tobacco
dependence: guidelines for balancing risks and benefi ts CNS
Drugs 2003; 17:71.
10 Varenicline (Chantix) for tobacco dependence Med Lett Drugs
Ther 2006; 48:66.
11 EJ Mills et al Comparisons of high-dose and combination
nicotine replacement therapy, varenicline, and bupropion for
smoking cessation: a systematic review and multiple treatment
meta-analysis Ann Med 2012; 44:588.
12 K Cahill et al Pharmacological interventions for smoking
ces-sation: an overview and network meta-analysis Cochrane
Da-tabase Syst Rev 2013; 5:CD009329.
13 TB Baker et al Effects of nicotine patch vs varenicline vs
com-bination nicotine replacement therapy on smoking cessation at
26 weeks: a randomized clinical trial JAMA 2016; 315:371.
14 D Kotz et al Cardiovascular and neuropsychiatric risks of
var-enicline: a retrospective cohort study Lancet Respir Med 2015;
3:761.
15 RM Anthenelli et al Effects of varenicline on smoking cessation
in adults with stably treated current or past major depression: a
randomized trial Ann Intern Med 2013; 159:390.
16 AE Evins et al Maintenance treatment with varenicline for
smoking cessation in patients with schizophrenia and bipolar
disorder: a randomized clinical trial JAMA 2014; 311:145.
17 JR Hughes Varenicline as a cause of suicidal outcomes
Nico-tine Tob Res 2016; 18:2.
18 MB Steinberg et al Triple-combination pharmocotherapy for
medically ill smokers: a randomized trial Ann Intern Med 2009;
150:447.
19 CF Koegelenberg et al Effi cacy of varenicline combined with
nicotine replacement therapy vs varenicline alone for smoking
cessation: a randomized clinical trial JAMA 2014; 312:155.
20 JO Ebbert et al Combination varenicline and bupropion SR for
tobacco-dependence treatment in cigarette smokers: a
ran-domized trial JAMA 2014; 311:155.
21 M Siahpush et al Association between duration of use of
phar-macotherapy and smoking cessation: fi ndings from a national
survey BMJ Open 2015; 5:e006229.
22 P Caponnetto et al Effi ciency and safety of an electronic
ciga-rette (ECLAT) as tobacco cigaciga-rettes substitute: a prospective
12-month randomized control design study PLoS One 2013;
8:e66317.
23 C Bullen et al Electronic cigarettes for smoking cessation: a
randomised controlled trial Lancet 2013; 382:1629.
24 S Kalkhoran and SA Glantz E-cigarettes and smoking
cessa-tion in real-world and clinical settings: a systematic review and
meta-analysis Lancet Respir Med 2016; 4:116.
25 H McRobbie et al Electronic cigarettes for smoking
ces-sation and reduction Cochrane Database Syst Rev 2014;
12:CD010216.
26 L McCauley et al An unexpected consequence of electronic
cigarette use Chest 2012; 141:1110.
27 FDA Summary of results: laboratory analysis of electronic
cigarettes conducted by FDA April 22, 2014 Available at www.
fda.gov/NewsEvents/PublicHealthFocus/ucm173146.htm
Ac-cessed February 18, 2016.
28 ML Goniewicz et al Levels of selected carcinogens and
toxi-cants in vapour from electronic cigarettes Tob Control 2014;
23:133.
29 R Goel et al Highly reactive free radicals in electronic cigarette
aerosols Chem Res Toxicol 2015; 28:1675.
30 T Coleman et al Pharmacological interventions for promoting smoking cessation during pregnancy Cochrane Database Syst Rev 2015; 12:CD010078.
Trang 91 Vismodegib (Erivedge) for basal cell carcinoma Med Lett Drugs Ther 2012; 54:53.
2 J Rodon et al A phase I, multicenter, open-label, fi rst-in-human, dose-escalation study of the oral smoothened inhibi-tor sonidegib (LDE225) in patients with advanced solid tumors Clin Cancer Res 2014; 20:1900.
3 MR Migden et al Treatment with two different doses of sonidegib in patients with locally advanced or metastatic basal cell carcinoma (BOLT): a multicentre, randomised, double-blind phase 2 trial Lancet Oncol 2015; 16:716.
4 FDA Medical review - sonidegib Available at: www.accessdata fda.gov/drugsatfda_docs/nda/2015/205266Orig1s000MedR pdf Accessed February 18, 2016.
5 C Danial et al An investigator-initiated open-label trial of sonidegib in advanced basal cell carcinoma patients resistant
to vismodegib Clin Cancer Res 2015 Nov 6 (epub).
can cause unchecked hedgehog pathway activity and
have been found in ~10% and >85%, respectively, of
basal cell carcinomas.3 Like vismodegib, sonidegib
binds to and inhibits the signaling activity of SMO
CLINICAL STUDIES — Approval of sonidegib was
based on the results of a double-blind trial (BOLT)
that included 194 patients with locally advanced
basal cell carcinoma who were not candidates for
surgery or radiation Patients were randomized
to receive once-daily treatment with sonidegib
200 mg or 800 mg.3 A 12-month effi cacy analysis
(summarized in FDA review documents) found that
an objective (complete or partial) response occurred
in 58% (38/66) of patients taking 200 mg/day and in
44% (56/128) of those taking 800 mg/day.4
ADVERSE EFFECTS — In an 18-month safety analysis
that included 79 patients who received sonidegib
200 mg/day in the clinical trial, muscle spasms,
alopecia, dysgeusia, fatigue, nausea, diarrhea, and
weight loss were reported at rates >30%, but were
usually mild to moderate (grade 1-2) in severity
Severe (grade 3-4) musculoskeletal adverse effects
and increases in serum creatine kinase levels
occurred in 9% and 8% of patients, respectively Lipase
elevations were severe in 13% of patients Sonidegib
treatment was discontinued in 34% of patients
and interrupted in 20% because of adverse effects
Amenorrhea of ≥18 months’ duration occurred in 2 of
14 premenopausal women who were taking the drug
PREGNANCY — Sonidegib is teratogenic and
embryotoxic, and exposure can occur through seminal
fluid Effective contraception is recommended for
both women and men taking the drug, including men
who have had a vasectomy Women should avoid
pregnancy during treatment and for at least 20 months
following the last dose; men should use condoms
during treatment and for at least 8 months after the
last dose Patients taking sonidegib should not donate
blood or blood products for at least 20 months after
their last dose
DRUG INTERACTIONS — Sonidegib is a substrate of
CYP3A4; the mean AUC of the drug increased 2.2-fold
when it was administered with ketoconazole (Nizoral,
and others), a strong CYP3A inhibitor Use of sonidegib
with strong or moderate CYP3A inhibitors should be
avoided; patients who must take a moderate CYP3A
inhibitor such as fluconazole (Diflucan, and generics)
concurrently should do so for <14 days and should
be monitored for adverse effects Coadministration
of rifampin (Rifadin, and generics), a strong CYP3A
inducer, decreased sonidegib exposure by 72%; use
of sonidegib with strong or moderate CYP3A inducers should be avoided
RESISTANCE — In a single-arm trial, 9 patients
with advanced basal cell carcinoma that had not responded to vismodegib were treated with sonidegib
800 mg/day No objective responses occurred In vitro
analyses identifi ed the presence of SMO mutations conveying resistance against hedgehog pathway inhibition in 5 patients, all of whom experienced disease progression.5
DOSAGE AND ADMINISTRATION — The recom-mended dosage of sonidegib is 200 mg once daily
at least 1 hour before or 2 hours after a meal Serum creatine kinase and creatinine levels should
be measured before and during treatment If severe musculoskeletal reactions occur, treatment interruption or discontinuation may be necessary
CONCLUSION — Sonidegib (Odomzo), the second
oral hedgehog pathway inhibitor to be approved by the FDA, is modestly effective for treatment of locally advanced basal cell carcinoma It does not appear to
offer any advantages over vismodegib (Erivedge) and
has not been effective in treating cancers that have not responded to vismodegib ■
Clarifi cation: Half-Life of Heroin
A reader expressed concern that a statement in our article
Naloxone (Narcan) Nasal Spray for Opioid Overdose (Med
Lett Drugs Ther 2016; 58:1) might be misleading We stated that heroin has a half-life of 2-6 minutes, which is correct, but heroin is a prodrug that is rapidly metabolized
to 6-acetylmorphine and morphine The risk of respiratory depression is related to those active metabolites, and it may persist well beyond the clearance of heroin from the blood.
Online Only Article
Olaparib (Lynparza) for Advanced Ovarian Cancer
www.medicalletter.org/TML-article-1489e
Trang 10
e32
The Medical Letter
on Drugs and Therapeutics
The FDA has approved the oral poly (ADP-ribose)
poly-merase (PARP) inhibitor olaparib (Lynparza –
Astra-Zeneca) as monotherapy for treatment of women with
advanced ovarian cancer who have BRCA1/2 germline
mutations and have received at least 3 prior lines of
chemotherapy Olaparib is the fi rst PARP inhibitor to
be approved in the US It is approved outside the US
for maintenance treatment of relapsed BRCA-mutated
ovarian cancer
therapy for treatment of breast cancer and other cancers with defi ciencies in DNA repair mechanisms, including endometrial, prostate, and pancreatic cancers.5
ADVERSE EFFECTS — Olaparib appears to be better
tolerated than other drugs used to treat advanced cancer Nausea, vomiting, fatigue, and anemia are common, but generally have only been mild to moderate (grade 1-2) in severity Fatal pneumonitis has been reported with olaparib; treatment should be interrupted if new or worsening respiratory symptoms occur According to olaparib labeling, myelodysplastic syndrome/acute myeloid leukemia occurred in 22 of 2,618 patients treated with the drug; 17 of these cases were fatal
DRUG INTERACTIONS — Lynparza is primarily
metabolized by CYP3A; concomitant use of strong
or moderate CYP3A inhibitors or inducers should be avoided.6
DOSAGE AND COST — Olaparib is available in
50-mg capsules The recommended dosage is 400 50-mg (8 capsules) twice daily A bottle containing 112 capsules (a 7-day supply) costs $2996.00.7
CONCLUSION — Oral treatment with olaparib
(Lynparza), a poly (ADP-ribose) polymerase (PARP)
inhibitor, can produce a response in some women with advanced ovarian cancer, particularly those with BRCA-mutated cancers, and it is generally well tolerated Whether it improves overall survival is unknown Its effi cacy in the treatment of other cancers remains to be established ■
Olaparib (Lynparza) for Advanced
Ovarian Cancer
▶
1 CC Gunderson and KN Moore Olaparib: an oral PARP-1 and PARP-2 inhibitor with promising activity in ovarian cancer Fu-ture Oncol 2015; 11:747.
2 SM Domchek et al Effi cacy and safety of olaparib monotherapy
in germline BRCA1/2 mutation carriers with advanced ovarian cancer and three or more lines of prior therapy Gynecol Oncol 2016; 140:199.
3 J Ledermann et al Olaparib maintenance therapy in plati-num-sensitive relapsed ovarian cancer N Engl J Med 2012; 366:1382.
4 J Ledermann et al Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a pre-planned retrospective analysis of outcomes by BRCA status in
a randomised phase 2 trial Lancet Oncol 2014; 15:852.
Pronunciation Key Olaparib: oh lap' a rib Lynparza: lin par' zah
MECHANISM OF ACTION — PARP enzymes are involved
in many cellular functions, including DNA
transcrip-tion and repair PARP inhibitranscrip-tion causes breaks in
double-stranded DNA Olaparib is most active against
tumors with a defi ciency in homologous recombination
(DNA repair), such as those with BRCA1/2 mutations,
because it activates an ineffective repair mechanism,
a process known as synthetic lethality It is cytotoxic
for ovarian cancer cells in general, but especially for
those that are BRCA1/2-defi cient.1
CLINICAL STUDIES — FDA approval of olaparib
was based on the results of a single-arm trial that
included 137 women with germline BRCA1/2-mutated
advanced ovarian cancer who had previously received
at least 3 lines of chemotherapy The objective
response rate with olaparib monotherapy was 34%
(partial response 32%; complete response 2%) and the
median duration of response was 7.9 months.2
A randomized, double-blind, placebo-controlled trial
evaluated the effi cacy of olaparib maintenance therapy
in 265 women with platinum-sensitive relapsed
ovarian cancer with or without BRCA1/2 mutations;
progression-free survival was signifi cantly longer with
olaparib than with placebo (8.4 vs 4.8 months).3 In a
subset analysis of 136 women with a BRCA mutation,
progression-free survival was 11.2 months with
olaparib versus 4.3 months with placebo.4
Olaparib and other (investigational) PARP inhibitors
are being tried for use alone and as part of combination