The medical letter on drugs and therapeutics february 1 2016

1487 on Drugs and Therapeutics Drugs for Acne ...p 13 Drugs for Rosacea ...p 16 Rolapitant Varubi for Prevention of Delayed Chemotherapy-Induced Nausea and Vomiting ...p 17 Addendum:

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IN THIS ISSUE

ISSUE

1433

Volume 56

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

ISSUE No

1487

on Drugs and Therapeutics

Drugs for Acne p 13

Drugs for Rosacea p 16

Rolapitant (Varubi) for Prevention of Delayed Chemotherapy-Induced Nausea

and Vomiting p 17

Addendum: Timing of Levothyroxine p 18

13

The Medical Letter

on Drugs and Therapeutics

ISSUE

1433

Volume 56

ISSUE No

1487 Drugs for Rosacea

p 16

Rolapitant (Varubi) for Prevention of Delayed Chemotherapy-Induced Nausea

and Vomiting p 17

Addendum: Timing of Levothyroxine p 18

ALSO IN THIS ISSUE

Drugs for Acne

▶

The pathogenesis of acne is multifactorial: follicular

hyperkeratinization, bacteria, sebum production,

androgens, and inflammation all play a role The

gram-positive microaerophilic bacteria Propionibacterium

acnes promotes development of acne lesions by

secreting chemotactic factors that attract leukocytes to

the follicle, causing inflammation

TOPICAL THERAPY — Salicylic Acid – Widely available

over the counter (OTC), topical salicylic acid is a

well-tolerated keratolytic agent that can be used alone or in

combination with other drugs such as benzoyl peroxide

Benzoyl Peroxide – The oxidizing agent benzoyl peroxide

is available in a wide variety of OTC and prescription

preparations for treatment of mild to moderate acne Its

effect is primarily due to its antibacterial activity against

P acnes Benzoyl peroxide is often used in combination

with topical or oral antibiotics It can also be used with a

retinoid Benzoyl peroxide can cause skin irritation and

bleaching of skin and fabric Contact dermatitis can also

occur Unlike other topical antimicrobials, benzoyl peroxide

has not been shown to promote bacterial resistance

Antibiotics – Topical clindamycin and erythromycin are

also commonly used to treat mild to moderate acne Both

have antibacterial and anti-inflammatory properties

Products containing sulfur and/or sulfacetamide are

sometimes used as well, but clinical data supporting

their effi cacy are limited

Topical antibiotics are generally safe and well tolerated

Skin irritation can occur, but is typically milder than with

retinoids Bacterial resistance can develop, especially

to erythromycin; concurrent use of topical antibiotics

and benzoyl peroxide protects against development

of resistance The combination may also be effective

against resistant P acnes.

Dapsone, an antimicrobial drug used orally to treat

leprosy, Pneumocystis pneumonia, and toxoplasmosis, is

available in a 5% gel formulation (Aczone) that is effective

for treatment of both inflammed and noninflammed

acne lesions Concurrent application of dapsone and benzoyl peroxide can cause temporary yellow or orange discoloration of the skin and facial hair

Azelaic Acid – An anti-keratinizing agent with

antibacterial and anti-inflammatory activity, azelaic

acid (Azelex for acne; Finacea for rosacea) is less

irritating than benzoyl peroxide Hypopigmentation can occur, particularly in people with dark skin

Retinoids – Topical retinoids such as tretinoin, adapalene, and tazarotene can be used alone or in

combination with antibiotics to treat both inflamed and noninflamed acne lesions, or for maintenance treatment Many dermatologists now use them for

fi rst-line treatment of acne All topical retinoids normalize keratinization and appear to have anti-inflammatory effects Whether any one of these agents is more effective than any other is not clear Retinoid/antimicrobial combinations are more effective than either component alone, particularly for patients with inflammatory lesions (papules and pustules) Concurrent application of tretinoin and benzoyl peroxide is not recommended because it can cause oxidation of tretinoin and loss of its effectiveness Patients are generally instructed to apply topical retinoids

at night because tretinoin is photolabile; adapalene, tazarotene, and the microsphere formu-lation of tretinoin appear to be more stable when exposed to light

Adverse effects typically associated with topical retinoids, including dry skin, scaling, photosensitivity,

Recommendations for Treatment of Acne

▶ Topical salicylic acid and benzoyl peroxide, both available OTC, are often used for initial treatment of acne

▶ A topical antibiotic, often in combination with benzoyl peroxide, is commonly used to treat mild to moderate acne

▶ Many dermatologists now prescribe a topical retinoid for

fi rst-line treatment of acne

▶ Retinoid/antimicrobial combinations are more effective than either component alone, particularly for patients with inflammatory lesions

▶ Oral antibiotics are generally prescribed for moderate to severe acne unresponsive to topical drugs

▶ The most effective drug available for treatment of inflammatory acne is isotretinoin; it can clear severe recalcitrant nodular acne, but it has many adverse effects.

Note: An addendum to this article has been published

Related article(s) since publication

oxidation of tretinoin and loss of its effectiveness

Patients are generally instructed to apply topical

retinoids at night because tretinoin is photolabile;

adapalene, tazarotene, and the microsphere

formu-lation of tretinoin appear to be more stable when

exposed to light

Adverse effects typically associated with topical

retinoids, including dry skin, scaling, photosensitivity,

erythema, burning, and pruritus, vary with the

formulation, concentration, and frequency of

application Tazarotene gel may be more irritating

than adapalene Retinoids are teratogenic; even

though only small amounts are absorbed systemically,

tretinoin and adapalene are classifi ed as category C

(teratogenic in rats; no adequate studies in pregnant

women) for use during pregnancy Tazarotene is

contraindicated during pregnancy (category X)

SYSTEMIC THERAPY — Oral Antibiotics – Tetracyclines such as doxycycline and minocycline

are generally prescribed for moderate to severe inflammatory acne unresponsive to topical drugs In addition to their antibacterial activity, they may have anti-inflammatory effects

When oral antibiotics are used for treatment of acne they are usually taken for months, which can lead

to development of bacterial resistance Resistance

is reported more frequently with erythromycin than with other oral antibiotics, and the drug can cause intolerable GI adverse effects Trimethoprim/ sulfamethoxazole should only be used in patients who

do not tolerate or respond to other oral antibiotics

Adverse Effects of Tetracyclines – Tetracyclines can

cause mild GI upset and vaginal candidiasis Doxycycline can cause photosensitivity, and hyperpigmentation

Table 1 Some Topical Drugs for Acne

Antimicrobials

Azelaic acid – Azelex (Allergan) 20% cream bid $344.70/30 g Clindamycin – generic 1% gel, soln, lotion, pads bid 69.10/30 g

Clindamycin/benzoyl peroxide –

Erythromycin – generic 2% gel, soln, pads bid 201.00/60 g

Erythromycin/benzoyl peroxide –

Retinoids

Adapalene – generic 0.1%, 0.3% gel, cream, lotion once/d at bedtime 157.30/45 g

Differin (Galderma) 0.1% gel, cream, lotion; 0.3% gel 529.70/45 g

Tazarotene – Tazorac (Allergan) 0.05%, 0.1% gel, cream once/d in the evening 310.60/30 g

Fabior (Stiefel) 0.1% foam once/d in the evening 415.20/50 g Tretinoin – generic 0.01%, 0.025% gel once/d at bedtime 128.00/45 g

Atralin (Valeant) 0.05% gel once/d at bedtime 562.40/45 g

Avita (Mylan) 0.025% gel, cream once/d in the evening 192.90/45 g

Retin-A (Valeant) 0.025%, 0.01% gel once/d at bedtime 249.20/45 g

Tretinoin microspheres – generic 0.04% gel once/d in the evening 451.70/45 g

Retin-A Micro (Valeant) 0.04%, 0.08%, 0.1% gel 722.50/45 g

Retinoid/Antimicrobial Combinations

Epiduo (Galderma) 0.1% adapalene/2.5% benzoyl peroxide gel once/d 398.10/45 g

Veltin (Stiefel) 0.025% tretinoin/1.2% clindamycin phosphate gel once/d in the evening 243.10/30 g

Ziana (Valeant) 0.025% tretinoin/1.2% clindamycin phosphate gel once/d at bedtime 367.00/30 g

1 Approximate WAC for one tube or bottle of the listed size in the lowest available strength When multiple formulations are listed, the cost of the gel is provided 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 January 5, 2016 Reprinted with permission by First Databank, Inc All rights reserved ©2016 www.fdbhealth.com/policies/drug-pricing-policy.

and vertigo can occur with minocycline

Extended-release minocycline (Solodyn, and generics) is available

for once-daily treatment of acne; whether it is less

likely than standard minocycline to cause vertigo

remains to be established.1 Drug-induced lupus and

autoimmune hepatitis can occur with long-term use of

minocycline.Minocycline may also have a deleterious

effect on spermatogenesis; it should not be used by

men or women who are attempting to conceive a child

Because of their adverse effects on tooth and bone

development, none of the tetracyclines should be used

during pregnancy or in children <8 years old

Isotretinoin – The oral retinoid isotretinoin is the

most effective drug available for treatment of severe

nodulocystic acne It inhibits P acnes colonization by

reducing sebum production and has keratolytic and

anti-inflammatory effects Isotretinoin can completely

clear severe nodulocystic lesions, in many cases

leading to long-term remission One isotretinoin

product, Absorica, can be taken with or without food;

other formulations should be taken with a meal

Mucocutaneous adverse effects of isotretinoin

in-clude cheilitis, epistaxis, dry skin, alopecia, eczema,

skin fragility, and photosensitivity Depression, suicidal

ideation, myalgia, hypertriglyceridemia, hepatitis,

pancreatitis, and pseudotumor cerebri can occur

Isotretinoin is a potent human teratogen (pregnancy

category X); its use is regulated by iPLEDGE, a risk

management program (www.ipledgeprogram.com)

Oral Contraceptives – Women with acne are often

treated with oral contraceptives Estrogen decreases

formation of ovarian and adrenal androgens and

suppresses sebum secretion Products approved by the FDA for this indication include certain formulations combining ethinyl estradiol with norgestimate, norethindrone, or drospirenone, but any low-dose combination oral contraceptive can be used.2,3

Spironolactone – The anti-androgen aldosterone

receptor antagonist spironolactone (Aldactone,

and generics), which has been shown to inhibit sebaceous gland activity, has been used off-label

to treat acne in women.4 It may be useful in pa-tients with resistant disease.5 Hyperkalemia and menstrual irregularities can occur Spironolactone

is classified as category C (embryofetal toxicity in animals; no adequate studies in pregnant women) for use during pregnancy

PHOTOTHERAPY — Blue light, infrared lasers,

photodynamic therapy, and other light-based therapies may be effective for short-term treatment of acne, but their long-term effi cacy and how they compare with conventional acne therapies are unclear.6 ■

Antibiotics

Doxycycline – generic 20, 50, 100 mg caps, tabs 20-100 mg bid $108.20 2,3 delayed-release – generic 75, 100, 150 mg tabs 150 mg once/d 422.40

Minocycline – generic 50, 75, 100 mg caps, tabs 50-100 mg bid 15.90

extended-release – generic 45, 90, 135 mg tabs 1 mg/kg once/d 338.70 4

Solodyn (Valeant) 55, 65, 80, 105, 115 mg tabs 1040.40 4

Retinoids

Isotretinoin –

Absorica5 (Ranbaxy) 10, 20, 25, 30, 35, 40 mg caps 0.5-1 mg/kg/d in 2 divided doses 1802.10 6

Amnesteem (Mylan) 10, 20, 40 mg caps for 15-20 weeks 551.30 6

1 Approximate WAC for 30 days’ treatment with the lowest usual 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 January 5, 2016 Reprinted with permission by First Databank, Inc All rights reserved ©2016 www.fdbhealth.com/policies/drug-pricing-policy

2 May be available at some large discount pharmacies for $4.00.

3 Cost for 50 mg twice daily.

4 Cost is the same for all strengths.

5 Absorica is not therapeutically equivalent to other isotretinoin products.

6 Cost of 30 days’ treatment at 60 mg/day.

1 SE Garner et al Minocycline for acne vulgaris: effi cacy and safety Cochrane Database Syst Rev 2012; 8:CD002086.

2 AO Arowojolu et al Combined oral contraceptive pills for treatment of acne Cochrane Database Syst Rev 2012; 7:CD004425.

3 EA Arrington et al Combined oral contraceptives for the treat-ment of acne: a practical guide Cutis 2012; 90:83.

4 GK Kim and JQ Del Rosso Oral spironolactone in post-teen-age female patients with acne vulgaris: practical consider-ations for the clinician based on current data and clinical ex-perience J Clin Aesthet Dermatol 2012; 5:37.

5 CB Turowski and WD James The effi cacy and safety of amoxi-cillin, trimethoprim-sulfamethoxazole, and spironolactone for treatment-resistant acne vulgaris Adv Dermatol 2007; 23:155.

6 HC Williams et al Acne vulgaris Lancet 2012; 379:361.

Table 1 Some Topical Drugs for Rosacea

Some Available Usual Drug Formulations Dosage 1 Cost/Size 2

Azelaic acid –

Finacea (Bayer) 15% gel bid $275.40/50 g

Brimonidine –

Mirvaso (Galderma) 0.33% gel once/d 360.00/30 g

Ivermectin –

Soolantra (Galderma) 1% cream once/d 275.00/30 g

Metronidazole –

generic 0.75% gel, cream, once/d 157.40/45 g 3

lotion; 1% gel

Metrocream 0.75% cream 569.10/45 g

(Galderma)

Metrogel 1% gel 342.60/55 g

Metrolotion 0.75% lotion 654.20/59 mL

1 A pea-sized amount should be applied in a thin layer to each affected area

of the face.

2 Approximate WAC for the size listed WAC = wholesaler acquisition cost, or

manufacturer’s published price to wholesalers; WAC represents a published

catalogue or list price and may not represent actual transactional prices

Source: AnalySource® Monthly January 5, 2016 Reprinted with permission

by First Databank, Inc All rights reserved ©2015

www.fdbhealth.com/poli-cies/drug-pricing-policy.

3 Cost of a 45-g tube of 0.75% cream.

Recommendations for Treatment of Rosacea

▶ Topical antimicrobials such as metronidazole and azelaic acid are generally tried fi rst for treatment of rosacea, sometimes in combination with oral antimicrobials

▶ Oral antibiotics such as low-dose doxycycline are effective for treatment of papules, pustules, and erythema, but prolonged courses of treatment are needed

▶ Ivermectin cream appears to be more effective than metro-nidazole cream for treatment of papulopustular rosacea.

▶ Topical retinoids are sometimes used for patients who do not respond to topical antimicrobials

▶ Isotretinoin is generally reserved for patients with severe inflammatory disease who have not responded to other treatments

Drugs for Rosacea

▶

This common, chronic inflammatory facial eruption

of unknown cause is more prevalent in women

than in men Rosacea is characterized by erythema

and telangiectasia, and sometimes by recurrent,

progressive crops of acneiform papules and pustules,

usually on the central part of the face Some patients

develop granulomas and tissue hypertrophy, which

may lead to rhinophyma (a bulbous nose), particularly

in men Blepharitis and conjunctivitis are common

Keratitis and corneal scarring occur rarely

TOPICAL THERAPY — After starting treatment with

topical drugs, it may take 4-6 weeks for improvement

to become visible Metronidazole (Metrogel, and

others) and azelaic acid (Finacea for rosacea; Azelex

for acne) are the standard topical antimicrobials used

to treat the papules and pustules of rosacea; they

appear to be about equally effective, but few

well-controlled comparative trials have been published

Benzoyl peroxide, erythromycin, clindamycin, and

sulfacetamide/sulfur have also been used.1 The topical

retinoids used to treat acne are also sometimes used

(off-label) to treat rosacea

Brimonidine tartrate 0.33% (Mirvaso), an

alpha-adrenergic receptor agonist, is approved for topical

treatment of persistent facial erythema of rosacea in

adults.2 It is not indicated for treatment of inflammatory

lesions (papules and pustules) Brimonidine constricts

dilated facial blood vessels to reduce the redness of

rosacea It has a rapid onset of action, with effects occurring as soon as 30 minutes after application and lasting for up to 12 hours Rebound erythema worse than baseline and skin burning sensation occurring several hours after application have been reported.3,4

Demodex mites have been implicated in the

pathogenesis of the inflammatory facial eruptions of

rosacea Ivermectin 1% cream (Soolantra) was recently

approved for once-daily treatment of inflammatory lesions of rosacea.5 Ivermectin has both anti-inflammatory and antiparasitic activity In a 16-week trial in patients with moderate to severe papulopustular rosacea, ivermectin cream was more effective and better tolerated than metronidazole cream.6

SYSTEMIC THERAPY — Oral Antimicrobials –

Systemic antibiotic therapy is effective for treatment

of papules, pustules, and erythema, but not for telangiectasia, rhinophyma, or the flushing that nearly always accompanies rosacea It is generally used for symptoms that are moderate to severe or have not responded to topical therapy Effective treatment often requires a prolonged course (months

or sometimes years) of an oral antibiotic such as doxycycline A once-daily subantimicrobial-dose

(40 mg) formulation of doxycycline (Oracea, and

generics) is FDA-approved for treatment of papulo-pustular rosacea.7 Use of generic immediate-release doxycycline 20 mg twice daily is a cheaper alternative

Oral metronidazole (Flagyl, and generics) is also

effective for rosacea, but it has some unpleasant side effects such as metallic taste Oral ivermectin

(Stromectol, and generics), often in combination with

topical permethrin, has been used in patients with

facial proliferation of Demodex mites.8

Isotretinoin – Patients with severe papulopustular

rosacea can be treated (off-label) with low doses

of isotretinoin (0.1-0.5 mg/kg/day) for 6-8 months

Rolapitant (Varubi) for Prevention

of Delayed Chemotherapy-Induced

Nausea and Vomiting

▶

The FDA has approved rolapitant (Varubi – Tesaro),

an oral substance P/neurokinin 1 (NK1) receptor

antagonist, for use with other antiemetics to prevent

delayed nausea and vomiting associated with cancer

chemotherapy in adults It is the third substance P/

NK1 receptor antagonist to be approved in the US;

aprepitant (Emend) and netupitant (only available

in combination with the 5-HT3 receptor antagonist

palonosetron as Akynzeo) were approved earlier for

prevention of both acute and delayed

chemotherapy-induced nausea and vomiting.1,2

Table 2 Rolapitant Clinical Trials

Complete Response 1

Rolapitant 2,3 Placebo 3

Highly Emetogenic Chemotherapy

1 Defi ned as no emesis and no use of rescue medication in the delayed phase (>24-120 hours after initiation of chemotherapy) in cycle 1.

2 Patients received rolapitant 180 mg 1-2 hours before administration of chemotherapy on day 1.

3 All patients also received granisetron and dexamethasone (dosage and schedule varied between studies).

4 Patients received moderately emetogenic chemotherapy or regimens containing an anthracycline and cyclophosphamide.

5 LS Schwartzberg et al Lancet Oncol 2015; 16:1071.

6 BL Rapoport et al Lancet Oncol 2015; 16:1079.

Pronunciation Key Rolapitant: roe la' pi tant Varubi: va rue' bee

Table 1 Pharmacology

Class Substance P/NK 1 receptor antagonist Formulation 90 mg tablets

Route Oral Tmax ~4 hours (rolapitant);

~120 hours (active metabolite) Metabolism Primarily by CYP3A4 to active metabolite Elimination Feces (73%); urine (14.2%)

Half-life 169-183 hours (rolapitant);

158 hours (active metabolite)

MECHANISM OF ACTION — Chemotherapy-induced

emesis is mediated by neurotransmitters such as serotonin, dopamine, and substance P, a neuropeptide that binds to NK1 receptors in the gut, brainstem, and area postrema, all of which are involved in the emetic response Rolapitant selectively inhibits NK1 receptors and blocks the action of substance P.5

CLINICAL STUDIES — Approval of rolapitant was

based on the results of three randomized, double-blind trials in patients receiving moderately or

1 LK Oge' et al Rosacea: diagnosis and treatment Am Fam

Phy-sician 2015; 92:187

2 Brimonidine gel (Mirvaso) for rosacea Med Lett Drugs Ther

2013; 55:82.

STANDARD TREATMENT — Patients receiving

moderately emetogenic chemotherapy should be

treated with dexamethasone (Decadron, and

palonosetron (Aloxi); granisetron (Kytril, and

others) or ondansetron (Zofran, and others) may

be substituted if palonosetron is not available

Used with dexamethasone, palonosetron is more

effective than the other 5-HT3 receptor antagonists

in preventing delayed nausea and vomiting.3 Patients

who receive highly emetogenic chemotherapy should

be treated with a three-drug regimen consisting of

a substance P/NK1 receptor antagonist, a 5-HT3

receptor antagonist (ondansetron, granisetron, or

palonosetron), and dexamethasone for prevention of

acute and delayed nausea and vomiting.4

tion from a new topical brimonidine tartrate gel 0.33% J Am Acad Dermatol 2014; 70:e37.

4 D Ilkovitch and RG Pomerantz Brimonidine effective but may lead to signifi cant rebound erythema J Am Acad Dermatol 2014; 70:e109.

5 Ivermectin cream (Soolantra) for rosacea Med Lett Drugs Ther 2015; 57:51.

6 A Taieb et al Superiority of ivermectin 1% cream over metnidazole 0.75% cream in treating inflammatory lesions of ro-sacea: a randomized, investigator-blinded trial Br J Dermatol 2015; 172:1103.

7 A low-dose doxycycline (Oracea) for rosacea Med Lett Drugs Ther 2007; 49:5.

8 JQ Del Rosso et al Consensus recommendations from the Ameri-can Acne & Rosacea Society on the management of rosacea, part 3: a status report on systemic therapies Cutis 2014; 93:18.

9 E Tanghetti et al Consensus recommendations from the Ameri-can Acne & Rosacea Society on the management of rosacea, part 4: a status report on physical modalities and devices Cutis 2014; 93:71.

category X); careful monitoring is necessary in

women of childbearing age Signifi cant reductions

in erythema, papules, and telangiectasia occur

after about 2 months of treatment No other

pharmacologic treatment has been reported to

reduce telangiectasia

LIGHT-BASED THERAPY — In small clinical trials, light

and laser therapies have decreased the severity of

telangiectasia and erythema in patients with rosacea,

but long-term studies are lacking.9 Adverse effects

have included purpura and hyperpigmentation ■

Table 3 Substance P/NK 1 Receptor Antagonists for Prevention of Delayed Chemotherapy-Induced Nausea and Vomiting

Aprepitant – Emend (Merck)3 80, 125 mg caps PO : 125 mg on day 1 (1 hr before chemotherapy), $543.10 5

then 80 mg on days 2-3 4

Fosaprepitant – Emend for Injection (Merck)3 150 mg vials IV : 150 mg on day 1 (~30 mins before chemotherapy) 6 268.50

Rolapitant – Varubi (Tesaro) 90 mg tabs PO : 180 mg on day 1 (~1-2 hrs before chemotherapy) 530.00

Netupitant/palonosetron – Akynzeo 300 mg/0.5 mg caps PO : 300 mg/0.5 mg on day 1 (~1 hr before chemotherapy) 549.00

1 For highly emetogenic chemotherapy

2 Approximate WAC for one dose 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 January 5, 2016 Reprinted with permission by First Databank, Inc All rights reserved ©2016 www.fdbhealth.com/policies/drug-pricing-policy.

3 Also approved for prevention of acute nausea and vomiting associated with cancer chemotherapy.

4 If no chemotherapy is administered on days 2 and 3, aprepitant should be taken in the morning.

5 Cost for one 125-mg capsule and two 80-mg capsules.

6 Or 115 mg on day 1, followed by 80 mg of aprepitant PO on days 2 and 3.

1 Aprepitant (Emend) for prevention of nausea and vomiting due to cancer chemotherapy Med Lett Drugs Ther 2003; 45:62.

2 Netupitant/palonosetron (Akynzeo) for chemotherapy-induced nausea and vomiting Med Lett Drugs Ther 2015; 57:61.

3 E Basch et al Antiemetics: American Society of Clinical Oncology clinical practice guideline update J Clin Oncol 2011; 29:4189.

4 PJ Hesketh et al Antiemetics: American Society of Clinical

Oncolo-gy focused guideline update J Clin Oncol 2015 November 2 (epub).

5 C Rojas and BS Slusher Mechanisms and latest clinical studies of new NK1 receptor antagonists for chemotherapy-induced nausea and vomiting: rolapitant and NEPA (netupitant/palonosetron) Can-cer Treat Rev 2015; 41:904.

6 LS Schwartzberg et al Safety and effi cacy of rolapitant for preven-tion of chemotherapy-induced nausea and vomiting after admin-istration of moderately emetogenic chemotherapy or anthracy-cline and cyclophosphamide regimens in patients with cancer: a randomised, active-controlled, double-blind, phase 3 trial Lancet Oncol 2015; 16:1071

7 BL Rapoport et al Safety and effi cacy of rolapitant for prevention of chemotherapy-induced nausea and vomiting after administration

of cisplatin-based highly emetogenic chemotherapy in patients with cancer: two randomised, active-controlled, double-blind, phase 3 trials Lancet Oncol 2015; 16:1079.

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

highly emetogenic chemotherapy In all three trials,

signifi cantly more patients taking rolapitant in

addition to granisetron and dexamethasone had a

complete response (no emesis and no use of rescue

medication in the delayed phase in cycle 1) than those

receiving granisetron and dexamethasone alone.6,7

The results of these trials are summarized in table

2 No studies are available comparing rolapitant with

aprepitant or netupitant for delayed

chemotherapy-induced nausea and vomiting

ADVERSE EFFECTS — The most common adverse

effects reported with rolapitant in clinical trials

(occurring in ≥5% of patients) were neutropenia,

hiccups, decreased appetite, and dizziness

PREGNANCY AND LACTATION — Rolapitant has not

been studied in pregnant women No teratogenic or

embryofetal effects were detected in rats and rabbits

given doses up to 1.2 and 2.9 times, respectively, the

maximum recommended human dose Rolapitant has

been detected in the milk of lactating rats

DRUG INTERACTIONS — Rolapitant is a moderate

inhibitor of CYP2D6 and an inhibitor of breast cancer

resistance protein (BCRP) and P-glycoprotein (P-gp)

The inhibitory effect on CYP2D6 lasts at least 7 days

Unlike aprepitant and netupitant, rolapitant is not an

inhibitor of CYP3A4 and does not increase serum

concentrations of drugs metabolized by this pathway,

such as dexamethasone Rolapitant is a substrate of

CYP3A4; concurrent administration of strong CYP3A4

inducers can reduce its effectiveness and should

be avoided.8

DOSAGE AND ADMINISTRATION — The recommended

dosage of rolapitant is 180 mg (2 tablets) taken 1-2

hours before each cycle of moderately or highly

emetogenic chemotherapy Rolapitant should not be

taken more than once every 2 weeks

Addendum: Timing of Levothyroxine

In our October 26, 2015 article on drugs for hypothyroidism (Med Lett Drugs Ther 2015; 57:147), we said that levothyroxine should be taken on an empty stomach with a full glass of water 30-60 minutes (60 is preferable) before breakfast We should have added that taking the drug consistently at bedtime, at least

3 hours after the last meal, is an alternative that some patients may fi nd more convenient.

CONCLUSION — Addition of the oral substance P/

neurokinin 1 (NK1) receptor antagonist rolapitant (Varubi)

to a regimen including dexamethasone and the 5-HT3

receptor antagonist granisetron was more effective than dexamethasone plus granisetron alone in preventing delayed nausea and vomiting in adults undergoing moderately or highly emetogenic chemotherapy How rolapitant compares to aprepitant or netupitant for this indication remains to be determined Unlike the other substance P/NK1 antagonists, rolapitant is not approved for prevention of acute nausea and vomiting associated with cancer chemotherapy ■

102

The Medical Letter

on Drugs and Therapeutics

Addendum: Depression and Suicidality with Isotretinoin

(Med Lett Drugs Ther 2016; 58:13)

that the oral retinoid isotretinoin (Accutane, and others)

is the most effective drug available for patients with

severe nodulocystic acne, but warned that depression,

suicidality, myalgia, hypertriglyceridemia, and other

adverse effects can occur One of our readers objected

to our listing depression and suicidality, which are the

subject of a prominent warning in the package insert, in

the same sentence as indisputable side effects such as

hyperlipidemia and myalgia.

Depression and suicidal ideation have been reported in

patients with severe acne after starting treatment with

isotretinoin, including some cases in which symptoms

resolved after discontinuation of the drug and reappeared

after rechallenge 2 A cause-and-effect relationship has not

been established, however, and acne itself is associated

with symptoms of anxiety and depression

Two large population-based cohort studies conducted in

Canada and the UK found no evidence that treatment of

acne with isotretinoin was associated with an increased

risk of depression, suicide, or other psychiatric adverse

effects 3 In a small US cohort study in 132 patients 12-19

years old with moderate to severe acne, use of isotretinoin

did not increase depressive symptoms compared to use

of topical drugs and oral antibiotics, and treatment of

A prospective, observational study in 346 patients ≥16

years old with moderate acne found that treatment with

isotretinoin for 30 weeks reduced symptoms of anxiety

conclusions ■

1 Drugs for acne Med Lett Drugs Ther 2016; 58:13.

2 JD Bremner et al Retinoic acid and affective disorders: the

evi-dence for an association J Clin Psychiatry 2012; 73:37.

3 SS Jick et al Isotretinoin use and risk of depression, psychotic

symptoms, suicide, and attempted suicide Arch Dermatol 2000;

136:1231.

4 CY Chia et al Isotretinoin therapy and mood changes in

adoles-cents with moderate to severe acne: a cohort study Arch

Derma-tol 2005; 141:557.

5 SE Marron et al Anxiety, depression, quality of life and patient

satisfaction in acne patients treated with oral isotretinoin Acta

Derm Venereol 2013; 93:701.

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1 Discuss the pharmacologic options available for treatment of acne and rosacea and compare them based on their effi cacy, dosage and administration, and potential adverse effects.

2 Determine the most appropriate therapy given the clinical presentation of an individual patient with acne or rosacea.

3 Review the effi cacy and safety of rolapitant (Varubi) for prevention of delayed chemotherapy-induced nausea and vomiting.

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Issue 1487 Questions

(Correspond to questions #21-30 in Comprehensive Exam #74, available July 2016)

Drugs for Rosacea

6 Topical brimonidine is effective for treating which of the following symptoms of rosacea?

a telangiectasia

b erythema

c rhinophyma

d all of the above

7 A 49-year-old man with rosacea is beginning treatment with oral metronidazole Which of the following could you tell him to expect?

a improvement in rhinophyma

b relief from flushing

c a metallic taste in his mouth

d all of the above

8 Ivermectin 1% cream:

a was more effective than topical metronidazole cream in a clinical trial in patients with papulopustular rosacea

b has anti-inflammatory activity

c has antiparasitic activity and may be effective in treating

Demodex mites

d all of the above

Rolapitant (Varubi) for Prevention of Delayed

Chemotherapy-Induced Nausea and Vomiting

9 Patients receiving highly emetogenic chemotherapy should receive which of the following to prevent delayed nausea and vomiting?

a a substance P/NK1 receptor antagonist

b a 5-HT3 receptor antagonist

c dexamethasone

d all of the above

10 In the trial comparing addition of rolapitant or placebo to granisetron and dexamethasone in patients receiving moderately emetogenic chemotherapy, the absolute difference in the percentage of patients who had a complete response was approximately :

a 5%

b 10%

c 20%

d 30%

Drugs for Acne

1 Benzoyl peroxide:

a has antibacterial activity

b can reduce development of bacterial resistance when used

with topical antibiotics

c can bleach skin and fabric

d all of the above

2 Topical retinoids:

a are teratogenic

b can cause photosensitivity

c are more effective for treatment of acne when used with a

topical antimicrobial

d all of the above

3 An 18-year-old girl has moderate inflammatory acne despite

treatment with a topical antimicrobial/retinoid combination

Which of the following oral antibiotics would be reasonable to

try fi rst in this patient?

a minocycline

b erythromycin

c trimethoprim/sulfamethoxazole

d metronidazole

4 The most effective drug available for treatment of inflammatory

acne is:

a minocycline

b erythromycin

c isotretinoin

d azelaic acid

5 Isotretinoin can cause:

a pancreatitis

b depression

c fetal malformations

d all of the above

ACPE UPN: Per Issue Exam: 0379-0000-16-487-H01-P; Release: February 1, 2016, Expire: February 1, 2017 Comprehensive Exam 74: 0379-0000-16-074-H01-P; Release: July 2016, Expire: July 2017

PRESIDENT: Mark Abramowicz, M.D.; VICE PRESIDENT/EXECUTIVE EDITOR: Gianna Zuccotti, M.D., M.P.H., F.A.C.P., Harvard Medical School; EDITOR-IN-CHIEF: 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; David N Juurlink, BPhm, M.D., Ph.D.,

Sunnybrook Health Sciences Centre; Richard B Kim, M.D., University of Western Ontario; Franco M Muggia, M.D., New York University Medical Center; 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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Valentino; VICE PRESIDENT AND PUBLISHER: Yosef Wissner-Levy

Founded in 1959 by Arthur Kallet and Harold Aaron, M.D.

Copyright and Disclaimer: The Medical Letter, Inc is an independent nonprofi t organization that provides healthcare professionals with unbiased drug prescribing recommendations The editorial

process used for its publications relies on a review of published and unpublished literature, with an emphasis on controlled clinical trials, and on the opinions of its consultants The Medical Letter, Inc is supported solely by subscription fees and accepts no advertising, grants, or donations No part of the material may be reproduced or transmitted by any process in whole or in part without prior permission in writing The editors do not warrant that all the material in this publication is accurate and complete in every respect The editors shall not be held responsible for any damage resulting from any error, inaccuracy, or omission.

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