The medical letter on drugs and therapeutics july 4 2016

Improvement can occur within the fi rst two weeks of drug therapy, but it may take 4-8 weeks to achieve a substantial benefi t.1 Fewer than 50% of patients with depression respond to

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ISSUE No.

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on Drugs and Therapeutics

Insect Repellents p 83

Drugs for Depression p 85

In Brief: Uridine Triacetate (Vistogard) for Fluorouracil Overdose p 90

83

on Drugs and Therapeutics

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ISSUE

1433

Volume 56

ISSUE No.

1498 Drugs for Depression In Brief: Uridine Triacetate (Vistogard) for Fluorouracil Overdose p 85p 90

ALSO IN THIS ISSUE

Use of insect repellents is strongly recommended by

the CDC and the EPA to prevent Zika virus infection1,2

and other mosquito- and tickborne diseases.3

Mosqui-toes can transmit chikungunya, dengue, West Nile, and

yellow fever viruses, and malaria Ticks can transmit

Lyme disease and rickettsial diseases such as Rocky

Mountain spotted fever

DEET — The topical insect repellent with the best

documented effectiveness against mosquitoes is

N, N-diethyl-m-toluamide (DEET).4,5 Applied on exposed

skin, DEET also repels ticks, chiggers, fleas, gnats,

and some flies DEET is available in concentrations of

5-100% In general, higher concentrations provide

Insect Repellents

concen-tration above 50% has not been shown to improve effi cacy Long-acting polymer-based or liposomal DEET formulations containing concentrations of 30-34% have been shown to protect against mosquitoes for up to

12 hours The CDC recommends using concentrations

≥20% for protection against ticks.

Adverse Effects – Toxic and allergic reactions to DEET

have been uncommon, and serious adverse effects are rare Rashes ranging from mild irritation to urticaria and bullous eruptions have been reported Patients

fi nd that some DEET formulations feel uncomfortably oily or sticky on their skin DEET can damage clothes made from synthetic fi bers and plastics on eyeglass frames and watch crystals

Table 1 Some Insect Repellents

Duration of Protection 1

DEET Cutter Skinsations 7% pump spray 1-3 hrs3 6 hrs3 $6.40 (7.5 oz)

Repel Scented Family 15% aerosol spray 5-8 hrs3 8.5 hrs3 6.86 (6.5 oz)

Off Deep Woods VIII 25% aerosol spray 8 hrs3 5 hrs3 7.38 (6 oz)

Sawyer Ultra 30 Liposome 30% lotion 11 hrs N.A 8.49 (4 oz)

Controlled Release Ultrathon4 34% lotion 12 hrs N.A 6.99 (2 oz) Picaridin Cutter Advanced 5.75% wipes 8 hrs 5 hrs 5.99 (18 wipes)

Avon Skin So Soft 10% aerosol spray 8 hrs 12 hrs 6.99 (4 oz) Bug Guard Plus Picaridin

Natrapel 8 hour 20% pump spray 8 hrs 8 hrs 5.59 (3.4 oz) IR3535 Avon Skin So Soft 7.5% lotion 2 hrs 2 hrs 10.89 (4 oz) Bug Guard Plus IR3535 5

Coleman Skin Smart 20% pump spray 8 hrs 8 hrs 4.99 (5 oz) Oil of lemon Coleman Botanicals 30% pump spray 6 hrs N.A 8.94 (4 oz) eucalyptus Repel Lemon Eucalyptus 30% pump spray 7-8 hrs3 7 hrs3 4.99 (4 oz) Permethrin Sawyer Premium 0.5% pump spray — — 14.99 (24 oz) Permethrin Clothing

Repel Permethrin 0.5% aerosol spray — — 7.42 (6.5 oz) Clothing and Gear

N.A = not available

1 For repellents applied to exposed skin, according to protection times approved by the EPA for product labels Available at: www.epa.gov/insect-repellents/

fi nd-insect-repellent-right-you Accessed June 23, 2016 Duration of protection may be affected by ambient temperature, activity level, amount of perspiration, exposure to water, and other factors.

2 Cost at amazon.com (June 23, 2016).

3 Duration of protection against Aedes and Culex mosquitoes and deer ticks according to the results of laboratory tests performed by Consumer Reports Available

at: www.consumerreports.org/cro/health/beauty-personal-care/insect-repellent/insect-repellent-ratings/ratings-overview.htm Accessed June 23, 2016

4 Long-acting polymer-based formulation developed for the US military.

5 Contains IR3535 combined with sunscreen; products that contain both an insect repellent and a sunscreen are not recommended because the sunscreen may need to be reapplied more often and in greater amounts than the repellent.

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Forwarding, copying or any other distribution of this material is strictly prohibited.

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Children – According to the CDC, DEET is safe for

children and infants >2 months old; the American

Academy of Pediatrics recommends using

formu-lations containing concentrations of 10-30% in

children Toxic encephalopathy has occurred, usually

with prolonged or excessive use in infants and children

that sometimes included ingestion of the product

PICARIDIN — Picaridin provides protection against

mosquitoes, ticks, flies, fleas, and chiggers It is

avail-able in concentrations of 5-20%; higher concentrations

typically provide longer durations of protection.7 In a

controlled fi eld trial, picaridin 19.2% prevented

mos-quito bites as effectively as a long-acting 33% DEET

formulation used by the US military.8 Picaridin 20% can

provide 8-10 hours of protection against tick bites.9

Adverse Effects – Picaridin can cause skin and eye

ir-ritation, but it appears to be better tolerated on the skin

than DEET It is odorless, non-greasy, and does not

dam-age fabric or plastic; it can discolor leather and vinyl

Children – According to the American Academy

of Pediatrics, formulations of picaridin containing

concentrations of 5-10% can be used on children as

an alternative to DEET

IR3535 — IR3535 repels mosquitoes, deer ticks, and

flies It is available in concentrations of 7.5% and

20% in the US Concentrations ≥10% have been found

to be effective against mosquito bites for several

hours.10 Two studies found the 7.5% concentration to

be ineffective.6,11

OIL OF LEMON EUCALYPTUS (OLE) — OLE

(p-men-thane-3,8-diol [PMD]), which repels mosquitoes, flies,

and gnats, occurs naturally in the lemon eucalyptus

plant It is chemically synthesized for commercial

use In fi eld studies against malaria-transmitting

mosquitoes, OLE provided up to 6 hours of protection

against mosquito bites.10 It is less effective than DEET or

picaridin against ticks.9 OLE can be irritating to the eyes

Children – OLE products should not be used on

children <3 years old.

CITRONELLA — Citronella oil-based insect repellents

provide short-term protection against mosquitoes,

but they are probably not effective against ticks In

laboratory studies, various concentrations of citronella

oil were much less effective than DEET against

mosquito bites; the protection times for citronella oil

ranged from 1.5 to 5 hours.12

ESSENTIAL OILS — Essential oils obtained from raw

botanical material, including clove, geraniol, and

1 LH Chen and DH Hamer Zika virus: rapid spread in the Western Hemisphere Ann Intern Med 2016; 164:613

2 E Dirlikov et al Update: Ongoing Zika virus transmission – Puerto Rico, November 1, 2015-April 14, 2016 MMWR Morb Mortal Wkly Rep 2016; 65:451

3 CDC/EPA Joint statement on insect repellents from the Envi-ronmental Protection Agency and the Centers for Disease Con-trol and Prevention July 17, 2014 Available at: https://www epa.gov/sites/production/files/2014-07/documents/joint-epa-cdc-stmnt_3.pdf Accessed June 23, 2016

4 E Lupi et al The effi cacy of repellents against Aedes, Anoph-eles, Culex and Ixodes spp – a literature review Travel Med Infect Dis 2013; 11:374

patchouli, provide limited and variable protection against mosquitoes High concentrations may be more effective, but can be irritating to the skin.13

SUNSCREEN AND INSECT REPELLENTS — Insect

repellents can be used with sunscreens; the repellent should be applied after the sunscreen Applying DEET after sunscreen has been shown to reduce the SPF

of the sunscreen, but applying sunscreen second may increase absorption of DEET The CDC does not recommend use of products that combine a sunscreen with an insect repellent because the sunscreen may need to be reapplied more often and in greater amounts than the repellent.

PERMETHRIN — A synthetic pyrethroid contact

insecticide, permethrin is used on clothing, mosquito nets, tents, and sleeping bags to repel and kill mosquitoes and ticks Sprayed on clothing, it remains active for several weeks through multiple launderings with minimal transfer to the skin An indoor laboratory study found that subjects wearing permethrin-treated sneakers and socks were 73.6 times less likely to be bit-ten by a tick than those wearing untreated foot wear.14

Studies in outdoor workers in North Carolina wearing commercially available permethrin-impregnated uni-forms found that the clothing protected against mosquito and tick bites for at least 1 year.15,16

PREGNANCY — The CDC considers EPA-registered

formulations of DEET, picaridin, IR3535, and OLE safe

for use during pregnancy.3 According to the EPA, there

is no evidence that exposure to permethrin results in reproductive effects in pregnant or nursing women or developmental adverse effects in their children.17

CONCLUSION — DEET-containing insect repellents

can prevent mosquito and tick bites and are generally safe Picaridin appears to be as effective as equivalent concentrations of DEET and may be better tolerated Wearing protective clothing treated with the insecticide permethrin in addition to using DEET or picaridin on exposed skin may provide the best protection ■

The Medical Letter ® Vol 58 (1498) July 4, 2016

5 Advice for travelers Med Lett Drugs Ther 2015; 57:52

6 MS Fradin and JF Day Comparative effi cacy of insect repellents

against mosquito bites N Engl J Med 2002; 347:13

7 Picaridin – a new insect repellent Med Lett Drugs Ther 2005;

47:46

8 SP Frances et al Field evaluation of repellent formulations

against daytime and nighttime biting mosquitoes in a tropical

rainforest in northern Australia J Med Entomol 2002; 39:541

9 F Pages et al Tick repellents for human use: prevention of tick

bites and tick-borne diseases Vector Borne Zoonotic Dis 2014;

14:85

10 LI Goodyer et al Expert review of the evidence base for

arthro-pod bite avoidance J Travel Med 2010; 17:182

11 SP Frances et al Comparative fi eld evaluation of repellent

for-mulations containing deet and IR3535 against mosquitoes in

Queensland, Australia J Am Mosq Control Assoc 2009; 25:511

12 C Kongkaew et al Effectiveness of citronella preparations in

pre-venting mosquito bites: systematic review of controlled

labora-tory experimental studies Trop Med Int Health 2011; 16:802

13 Y Trongtokit et al Comparative repellency of 38 essential oils

against mosquito bites Phytother Res 2005; 19:303

14 NJ Miller et al Tick bite protection with permethrin-treated

summer-weight clothing J Med Entomol 2011; 48:327

15 MF Vaughn et al Long-lasting permethrin impregnated

uni-forms: a randomized-controlled trial for tick bite prevention Am

J Prev Med 2014; 46:473

16 B Londono-Renteria et al Long-lasting

permethrin-impregnat-ed clothing protects against mosquito bites in outdoor workers

Am J Trop Med Hyg 2015; 93:869

17 US Environmental Protection Agency Repellent-treated

clothing Last updated March 29, 2016 Available at: https://

www.epa.gov/insect-repellents/repellent-treated-clothing

Accessed June 23, 2016

▶ Drugs for Depression

Complete remission of symptoms is the goal of

antidepressant therapy; partial response is associated

with an increased risk of relapse Improvement can

occur within the fi rst two weeks of drug therapy,

but it may take 4-8 weeks to achieve a substantial

benefi t.1 Fewer than 50% of patients with depression

respond to fi rst-line pharmacotherapy, and the rate of

response decreases with each subsequent drug trial.2

Following remission after a fi rst episode of depression,

many experts recommend continuing antidepressant

treatment at the same dose for at least 6-12 months

to consolidate recovery For patients with recurrent

depressive episodes, long-term maintenance therapy

can reduce the risk of recurrence.

SSRIs – Selective serotonin reuptake inhibitors

(SSRIs) are generally recommended for fi rst-line

treatment of major depression There is no convincing

evidence that any one SSRI is more effective than any

other Fluoxetine has been shown to be effective and

is the only SSRI approved by the FDA for treatment

of major depressive disorder in children.3 Fluoxetine

and escitalopram are both approved for treatment of

major depressive disorder in adolescents.

Adverse Effects – Restlessness and sleep disturbances,

particularly vivid dreams, can occur with SSRI treat-ment Nausea, diarrhea, headache, dizziness, fatigue, and sexual dysfunction, which can include decreased libido, impaired arousal, delayed orgasm, or anorgasmia, can also occur.4 An increase in motor activity is common

in children The long-term effects of these drugs on the growth, personality development, and behavior of children are unknown, but after >25 years of use, no clear signal for problems has been detected.

Some patients gain signifi cant amounts of weight with continued use of an SSRI SSRIs can cause hyponatremia, particularly in elderly patients They have been associated with a possible increase in the risk of nonvertebral fractures in older women.5 SSRIs can also increase the risk of bleeding by inhibiting serotonin uptake by platelets SSRIs vary in their effects

on CYP isoenzymes and interact with many other drugs; some of these interactions are summarized in Table 2 (see p 88) Citalopram and escitalopram can prolong the QT interval.6

When SSRIs are stopped abruptly, discontinuation symptoms including nervousness, anxiety, irritability, electric-shock sensations, bouts of tearfulness or cry-ing, dizziness, lightheadedness, insomnia, confusion, trouble concentrating, nausea, and vomiting can occur; these effects are most severe with paroxetine, possibly because of its potent serotonergic effects, and least likely to occur with fluoxetine because of its long half-life.

Pregnancy – The risk of congenital malformations

after taking an SSRI during pregnancy appears to

be very low, and no increase in perinatal mortality

Recommendations for Treatment of Depression

▶ An SSRI, an SNRI, bupropion, or mirtazapine could be used for fi rst-line treatment of major depression, but most expert clinicians begin with an SSRI

▶ The choice among SSRIs may be determined by adverse effects and potential drug interactions, as well as accessibility and cost

▶ Generic sertraline or escitalopram would be a reasonable choice for fi rst-line treatment of depression in adults

▶ Generic fluoxetine would be a good choice for treatment of depressed children, adolescents, or young adults, or patients

of any age who are not taking medications metabolized by CYP2D6 or 2C19 and who would benefi t from a longer half-life, such as those who miss doses

▶ When patients show little to no response to an adequate trial of an SSRI (4-8 weeks), many expert clinicians switch to another SSRI or try an antidepressant from a different class Combining two antidepressants from different classes, such as bupropion and an SSRI, or adding another drug for augmentation, such as an antipsychotic, are additional alternatives

has been demonstrated.7 An increased risk of

cardiovascular and other malformations has been

reported in infants born to mothers who took

paroxetine in the fi rst trimester.8 Both untreated

maternal depression and SSRI use during pregnancy

have been associated with delayed fetal development,

preterm birth, and low birth weight.9 Taking SSRIs in

the third trimester has been associated with a

self-limited neonatal behavioral syndrome, treatment

in a neonatal intensive care unit, and a possible

risk of persistent pulmonary hypertension in the

newborn.10,11

SNRIs — Serotonin and norepinephrine reuptake

inhibitors (SNRIs) are also considered fi rst-line

options for treatment of major depression It is not

clear that they offer any advantage in effi cacy over

SSRIs, and they cause more adverse effects.

Adverse Effects – The adverse effects of venlafaxine,

desvenlafaxine, duloxetine, and levomilnacipran are similar to those of SSRIs, but can also include increased sweating, tachycardia, and urinary retention Severe discontinuation symptoms can occur when these drugs are stopped, especially with venlafaxine and desvenlafaxine because of their short half-lives SNRIs can cause a dose-dependent increase in blood pressure; blood pressure should be controlled before starting an SNRI and monitored during treatment False-positive urine immunoassay screening tests for phencyclidine (PCP) and amphetamine have been reported in patients taking venlafaxine or desvenlafaxine.

Pregnancy – Pregnancy studies with SNRIs are

limit-ed; fetal malformations are uncommon, but increased risks of neonatal behavioral syndrome and perinatal

Table 1 Some Drugs for Depression

SSRIs

Citalopram – generic 10, 20, 40 mg tabs; 20 mg once/d 40 mg once/d3 $4.004

40 mg ODT; 10 mg/5 mL soln

Escitalopram – generic 5, 10, 20 mg tabs; 10 mg once/d 10-20 mg once/d 6.60

Fluoxetine – generic 10, 20, 40 mg caps; 10, 20 mg 10-20 mg once/d 20 mg once/d 4.004

tabs; 20 mg/5 mL soln

delayed-release – generic 90 mg caps 90 mg once/wk 90 mg once/wk 130.70

Paroxetine hydrochloride – generic 10, 20, 30, 40 mg tabs; 20 mg once/d 20 mg once/d 4.004

extended-release – generic 12.5, 25, 37.5 mg tabs 12.5-25 mg once/d 25 mg once/d 139.60

Paroxetine mesylate – Pexeva (Noven) 10, 20, 30, 40 mg tabs 20 mg once/d 20-50 mg once/d 322.50 Sertraline–generic 25, 50, 100 mg tabs; 50 mg once/d 50-200 mg once/d 2.90

SNRIs

Desvenlafaxine succinate – generic 25, 50, 100 mg ER tabs 50 mg once/d 50 mg once/d 161.00

Desvenlafaxine – generic 50, 100 mg ER tabs 50 mg once/d 50 mg once/d 139.30

Desvenlafaxine base – Khedezla 50, 100 mg ER tabs 50 mg once/d 50 mg once/d 365.30 (Osmotica)

Duloxetine – generic 20, 30, 60 mg delayed-release 30-60 mg once/d 60 mg once/d or 40.80

Venlafaxine – generic 25, 37.5, 50, 75, 100 mg tabs 25 mg tid 75 mg tid 31.50 extended-release – generic 37.5, 75, 150 mg caps; 37.5, 75, 37.5 mg once/d 75-225 mg once/d 9.305

150, 225 mg tabs

Levomilnacipran – Fetzima (Allergan) 20, 40, 80, 120 mg ER caps 20 mg once/d x 2d, 40-120 mg once/d 299.20

then 40 mg once/d

ODT = orally disintegrating tablet; soln = solution; susp = suspension; ER = extended-release

1 Dosage may need to be adjusted for renal or hepatic impairment or for drug interactions.

2 Approximate WAC for 30 days’ treatment at the lowest usual adult daily 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 June 5,

2016 Reprinted with permission by First Databank, Inc All rights reserved ©2016 www.fdbhealth.com/policies/drug-pricing-policy

3 According to the FDA, the daily dose should not exceed 40 mg (20 mg in patients >60 years old, patients with hepatic impairment, CYP2C19 poor metabolizers,

or those taking a CYP2C19 inhibitor).

4 Cost of generics at some large discount pharmacies.

The Medical Letter ® Vol 58 (1498) July 4, 2016

complications have been reported with use of SNRIs

during pregnancy.12

BUPROPION — Bupropion can be used as an

alternative to an SSRI for depressed patients who

do not have severe anxiety or a primary anxiety

disorder Bupropion may improve hypoactive sexual

desire disorder and antidepressant-induced sexual

dysfunction.13 It is not sedating and has not been

associated with weight gain, sexual dysfunction, or

an increased risk of bleeding

Adverse Effects – Bupropion can cause agitation,

anxiety, insomnia, headache, nausea, anorexia, and

hypersensitivity reactions Dose-related seizures may

occur; the drug is contraindicated in patients with

seizure disorders It is also contraindicated in patients

with eating disorders because these patients have had

a higher incidence of seizures when treated with high

doses of bupropion The safety of bupropion during pregnancy has not been established.14

MIRTAZAPINE — Mirtazapine may be useful when

insomnia is prominent, and its appetite-stimulating and weight-gain-promoting properties may be helpful

in depressed patients with marked anorexia

Adverse Effects – Mirtazapine can cause sedation,

increased appetite, weight gain, dizziness, dry mouth, and constipation; neutropenic fevers have occurred rarely Pregnancy studies with mirtazapine are limited; the risk of congenital malformations appears

to be low.15

OTHER DRUGS — Trazodone, which is also sedating,

is seldom used as monotherapy, but is commonly used in low doses as an adjunct to an SSRI in patients with insomnia.16 Trazodone can cause drowsiness,

orthostatic hypotension, myocardial irritability,

Table 1 Some Drugs for Depression (continued)

TCAs6

Amitriptyline – generic 10, 25, 50, 75, 100, 150 mg tabs 25-100 mg at bedtime 100-300 mg once/d $34.30

Desipramine – generic 10, 25, 50, 75, 100, 150 mg tabs 25-100 mg once/d 100-300 mg once/d 115.10

Imipramine – generic 10, 25, 50 mg tabs 25-100 mg once/d 100-300 mg once/d 32.20

Imipramine pamoate – generic 75, 100, 125, 150 mg caps 75 mg once/d 150 mg once/d 672.60 Nortriptyline – generic 10, 25, 50, 75 mg caps 50-100 mg once/d 50-150 mg once/d 7.10

MAOIs

Isocarboxazid – Marplan (Validus) 10 mg tabs 10 mg bid 30-40 mg/d divided 354.60

Selegiline – Emsam (Somerset) 6, 9, 12 mg/24 hr patches 6 mg/24 hr 6, 9, 12 mg/24 hr 1513.40 Tranylcypromine – generic 10 mg tabs 10 mg once/d 20-30 mg bid 323.00

Other

Bupropion – generic 75, 100 mg tabs 100 mg bid 100 mg tid 63.00 extended-release (12 hour) – generic 100, 150, 200 mg tabs 150 mg once/d 150 mg bid 19.00

Aplenzin (Valeant) 174, 348, 522 mg ER tabs 174 mg once/d 348 mg once/d 1444.20 extended-release (24 hour) – generic 150, 300 mg tabs 150 mg once/d 300 mg once/d 78.30

Forfi vo XL (Edgemont) 450 mg ER tabs See footnote 7 450 mg once/d 360.00 Mirtazapine – generic 7.5, 15, 30, 45 mg tabs 15 mg once/d at hs 30-45 mg once/d 11.30

orally disintegrating – generic 15, 30, 45 mg ODT 60.20

Nefazodone8 – generic 50, 100, 150, 200, 250 mg tabs 100 mg bid 200 mg bid 82.30 Trazodone – generic 50, 100, 150, 300 mg tabs 75 mg bid 300 mg divided bid 10.80

extended-release – Oleptro (Labopharm) 150, 300 mg tabs 150 mg once/d 150-375 mg once/d 96.00

Vilazodone – Viibryd (Allergan) 10, 20, 40 mg tabs 10 mg once/d 40 mg once/d 208.30

Vortioxetine – Trintellix (Takeda/Lundbeck) 5, 10, 20 mg tabs 10 mg once/d 10-20 mg once/d 318.20

5 Cost of capsules The cost for tablets is $115.30

6 Therapeutic serum concentrations are: amitriptyline 100-250 ng/mL; desipramine 150-300 ng/mL; imipramine 150-300 ng/mL; nortriptyline 50-150 ng/mL.

7 Initiate treatment with another bupropion formulation.

8 Brand name nefazodone was withdrawn from the market due to hepatotoxicity.

and priapism Nefazodone, which is structurally

similar to trazodone, has been withdrawn from the

market in some countries because of rare severe

hepatotoxicity.

Vilazodone is an SSRI and partial serotonin 1a receptor

agonist; it appears to be an effective antidepressant,

but there is no acceptable evidence for claims that

it acts more rapidly than SSRIs.17 Vilazodone has an

adverse effect profi le similar to that of SSRIs; limited

data exist to support claims that it causes less sexual

dysfunction or weight gain than SSRIs.18

Vortioxetine, which inhibits reuptake of serotonin and

acts as an agonist or antagonist at various serotonin

receptors, is FDA-approved for treatment of major

depressive disorder.19 Vortioxetine has an adverse

effect profi le similar to that of SSRIs

Tricyclic antidepressants (TCAs) and monoamine

oxidase inhibitors (MAOIs) remain valuable

alternatives for patients with moderate to severe

treatment-resistant depression TCAs have a narrow

therapeutic index and serum levels should be

monitored TCAs commonly cause anticholinergic

effects (urinary retention, constipation, dry mouth,

blurred vision, memory impairment, confusion),

orthostatic hypotension, weight gain, sedation,

and sexual dysfunction They can cause cardiac

conduction delays which can lead to arrhythmias and

death when taken in overdose TCAs must be used

with caution in patients with ischemic heart disease

TCA use during pregnancy has been associated with

jitteriness and convulsions in newborns

MAOIs are contraindicated for use with serotonergic

drugs (SSRIs) or other drugs that increase monoamines (noradrenergic, dopaminergic), and their use requires strict adherence to a low tyramine diet to avoid life-threatening drug interactions Interactions with serotonergic drugs, sympathomimetics, and tyramine-rich foods can result in serotonin syndrome or a hypertensive crisis, either of which can be fatal These interactions have not been reported with transdermal selegiline 6 mg/day.20 The enzyme-inhibiting effects of MAOIs can persist for up to 2 weeks after the drug is stopped (during which period of time other serotonergic medications are contraindicated) Adverse effects

of MAOIs include sleep disturbances, orthostatic hypotension, sexual dysfunction, and weight gain Some expert clinicians do not recommend use of MAOIs during pregnancy because of the risk of drug or food interactions causing a hypertensive crisis

A single IV infusion of the anesthetic agent ketamine,

which can have hallucinogenic effects, has been found

to be effective for treatment of depression in several trials, but it is not recommended because it lacks FDA approval for use in depression and has a potential for abuse.21

OTHER ADVERSE EFFECTS – Suicidality – All

FDA-approved antidepressants have a boxed warning in their labels regarding an increased risk of suicidal thinking and behavior in children, adolescents, and young adults

An FDA analysis of placebo-controlled antidepressant studies found an increased risk of suicidal thinking or behavior in patients ≤24 years old being treated with

Table 2 Some SSRI and SNRI Drug Interactions

Citalopram Metabolized by 2C191 and 3A4 Maximum dose of 20 mg/day in 2C19 poor metabolizers or with inhibitors of 2C19;

higher serum concentrations increase the risk of QT prolongation; avoid use with other drugs that prolong the QT Interval

Desvenlafaxine Metabolized by 3A4 Low potential for interactions; reduce dose of 2D6 substrates if administered with

Weak inhibitor of 2D6 400 mg of desvenlafaxine Duloxetine Metabolized by 1A21 and 2D6 Avoid strong inhibitors of 1A2; 2D6 inhibitors can increase duloxetine concentrations;

Moderate inhibitor of 2D6 duloxetine increases concentrations of drugs that are substrates of 2D6 Escitalopram Metabolized by 2C191 and3A4 Low potential for interactions; dose adjustments may be needed with 2C19

inhibitors; may prolong the QT interval Fluoxetine Metabolized by 2D61 and 2C9 May decrease effi cacy of tamoxifen; may increase concentrations of 2D6 sub strates;

Strong inhibitor of 2D6 long half-life is a problem when interactions occur Moderate inhibitor of 2C19

Levomilnacipran Metabolized by 3A41 Dose adjustment needed when administered with strong 3A4 inhibitors

Paroxetine Metabolized by 2D6 May decrease effi cacy of tamoxifen; may increase concentrations of 2D6 substrates;

Strong inhibitor of 2D6 lower doses of paroxetine may be needed with 2D6 inhibitors Sertraline Metabolized by 2C19 Low potential for interactions

Moderate inhibitor of 2D6 Venlafaxine Metabolized by 2D61 and 3A4 Low potential for interactions; serum concentrations may be increased by 3A4

inhibitors

1 Primary pathway

The Medical Letter ® Vol 58 (1498) July 4, 2016

1 American Psychiatric Association, 2010 Treating major depressive disorder: a quick reference guide Practice guideline for the treatment of patients with major depressive disorder, third edition Available at psychiatryonline.org/pb/assets/ raw/sitewide/practice_guidelines/guidelines/mdd-guide.pdf Accessed June 23, 2016

2 D Warden et al The STAR*D Project results: a comprehensive review of fi ndings Curr Psychiatry Rep 2007; 9:449

3 A Cipriani et al Comparative effi cacy and tolerability of antide-pressants for major depressive disorder in children and adoles-cents: a network meta-analysis Lancet 2016 Jun 7 (epub)

4 MD Waldinger Psychiatric disorders and sexual dysfunction Handb Clin Neurol 2015; 130:469

5 V Rabenda et al Risk of nonvertebral fractures among elderly postmenopausal women taking antidepressants Bone 2012; 51:674

6 Citalopram, escitalopram and the QT interval Med Lett Drugs Ther 2013; 55:59

7 O Stephansson et al Selective serotonin reuptake inhibitors during pregnancy and risk of stillbirth and infant mortality JAMA 2013; 309:48

8 A Bérard et al Paroxetine use during pregnancy and perinatal outcomes including types of cardiac malformations in Quebec and France: a short communication Curr Drug Saf 2012; 7:207

9 H Malm et al Pregnancy complications following prenatal exposure

to SSRIs or maternal psychiatric disorders: results from population-based national register data Am J Psychiatry 2015; 172:1224

10 S Gentile On categorizing gestational, birth, and neonatal com-plications following late pregnancy exposure to antidepres-sants: the prenatal antidepressant exposure syndrome CNS Spectr 2010; 15:167

an antidepressant and a decreased risk in those ≥65

years old Several other reviews have also suggested

that antidepressant use can increase the risk of

aggression and suicidality in children, adolescents,

and young adults.22,23 No increase in completed

suicide was documented among patients treated with

antidepressants In one randomized controlled trial in

adolescents with depression, fluoxetine signifi cantly

improved suicidal thinking, compared to placebo.24

One study of early adolescent suicide found that more

SSRI prescriptions were associated with lower suicide

rates.25 All depressed children, adolescents, and adults

should be monitored for suicidal ideation and behavior.

Mania – All antidepressants can induce mania, most

often in patients with undetected or undiagnosed

bipolar disorder Patients should be screened for

personal or fi rst-degree-relative history of mania,

hypomania, or other evidence of bipolar disorder

before starting antidepressant therapy Patients

starting antidepressant therapy should be followed

closely in the fi rst weeks to months of treatment.

Serotonin Syndrome – All serotonergic drugs can cause

serotonin syndrome, a rare but potentially life-threatening

condition characterized by altered mental status, fever,

tachycardia, hypertension, agitation, tremor, myoclonus,

hyperreflexia, ataxia, incoordination, diaphoresis,

shivering, and gastrointestinal symptoms.26 It occurs

only very rarely with SSRI monotherapy at recommended

doses Serotonin syndrome occurs most commonly as a

result of interactions with other drugs Serotonergic drugs

and MAOIs should not be used concurrently or within 2

weeks of each other; up to 5 weeks may be required with

fluoxetine Some drugs with MAOI activity, such as the

antimicrobial agent linezolid (Zyvox, and generics), and

some drugs that may not be recognized as serotonergic,

such as dextromethorphan, sumatriptan (Imitrex, and

generics), tramadol (Ultram, and generics), methadone,

and St John’s wort, can cause serotonin syndrome when

taken concurrently with an SSRI or SNRI.27

SECOND-LINE TREATMENT — When patients show

little to no response to an adequate trial of an SSRI

(4-8 weeks), many expert clinicians switch to another

SSRI or try an antidepressant from a different class

Combining two antidepressants from different classes,

such as bupropion and an SSRI, or adding another

drug for augmentation are additional alternatives.1,28,29

Augmentation with second-generation antipsychotic

drugs has been effective, but it can cause weight gain,

metabolic adverse effects, and akathisia.30,31

Extended-release quetiapine, aripiprazole, and brexpiprazole32

are FDA-approved for adjunctive treatment of major

depressive disorder A fi xed-dose combination of

olanzapine and fluoxetine (Symbyax) is FDA-approved

for treatment-resistant depression Augmentation

with liothyronine has been reported to be effective, but

thyroid function must be monitored.33 Augmentation

with low doses of lithium has been reported to be

effective with both TCAs and newer antidepressants.34

Augmentation with the anti-anxiety agent buspirone,

once widely used, appears to be ineffective.28,29,35

NON-DRUG THERAPY — Psychotherapy, particularly cognitive-behavioral therapy (CBT) and interpersonal therapy, is an effective treatment for mild to moderately

severe, nonpsychotic depression Electroconvulsive

therapy (ECT) is highly effective for severe depression,

depression with psychosis, bipolar depression, and depression refractory to medications.36 Transcranial

magnetic stimulation (TMS) and vagus nerve stimulation

(VNS) are FDA-approved for treatment-resistant depression TMS, unlike ECT, does not require anesthesia and does not appear to have cognitive side effects Studies

of TMS have demonstrated response and remission rates similar to those with antidepressants37; it may be

a reasonable treatment option when patients are unable

to tolerate or do not respond to antidepressants Deep

brain stimulation has been effective in a small number of

patients with treatment-resistant depression,38 but was not found to be superior compared to sham treatment in clinical trials.39 ■

11 CD Chambers et al Selective serotonin-reuptake inhibitors and

risk of persistent pulmonary hypertension of the newborn N

Engl J Med 2006; 354:579

12 C Bellantuono et al The safety of serotonin-noradrenaline

reuptake inhibitors (SNRIs) in pregnancy and breastfeeding: a

comprehensive review Hum Psychopharmacol 2015; 30:143

13 VM Pereira et al Bupropion in the depression-related sexual

dysfunction: a systematic review CNS Neurol Disord Drug

Tar-gets 2014; 13:1079

14 NE De Long et al Is it safe to use smoking cessation

therapeu-tics during pregnancy? Expert Opin Drug Saf 2014; 13:1721

15 U Winterfeld et al Pregnancy outcome following maternal

ex-posure to mirtazapine: a multicenter, prospective study J Clin

Psychopharmacol 2015; 35:250

16 Extended-release trazodone (Oleptro) for depression Med Lett

Drugs Ther 2010; 52:91

17 Vilazodone (Viibryd) – a new antidepressant Med Lett Drugs

Ther 2011; 53:53

18 AH Clayton et al Sexual dysfunction during treatment of

ma-jor depressive disorder with vilazodone, citalopram, or placebo:

results from a phase IV clinical trial Int Clin Psychopharmacol

2015; 30:216

19 Vortioxetine (Brintellix/Trintellix) for depression Med Lett

Drugs Ther 2013; 55:93

20 Transdermal selegiline (Emsam) Med Lett Drugs Ther 2006;

48:41

21 C Caddy et al Ketamine and other glutamate receptor

modu-lators for depression in adults Cochrane Database Syst Rev

2015; 9:CD011612

22 SE Hetrick et al Newer generation antidepressants for

depres-sive disorders in children and adolescents Cochrane Database

Syst Rev 2012; 11:CD004851

23 T Sharma et al Suicidality and aggression during

antidepres-sant treatment: systematic review and meta-analyses based

on clinical study reports BMJ 2016 Jan 27 (epub)

24 J March et al Fluoxetine, cognitive-behavioral therapy, and

their combination for adolescents with depression: Treatment

for Adolescents With Depression Study (TADS) randomized

controlled trial JAMA 2004; 292:807

25 RD Gibbons et al The relationship between antidepressant

prescription rates and rate of early adolescent suicide Am J

Psychiatry 2006; 163:1898

26 NA Buckley et al Serotonin syndrome BMJ 2014 Feb 19 (epub)

27 EW Boyer and M Shannon The serotonin syndrome N Engl J

Med 2005; 352:1112

28 KR Connolly and ME Thase If at fi rst you don’t succeed: a

re-view of the evidence for antidepressant augmentation,

combi-nation and switching strategies Drugs 2011; 71:43

29 MH Trivedi et al Medication augmentation after the failure of

SSRIs for depression N Engl J Med 2006; 354:1243

30 Adjunctive antipsychotics for major depression Med Lett

Drugs Ther 2011; 53:74

31 BM Wright et al Augmentation with atypical antipsychotics for

depression: a review of evidence-based support from the

medi-cal literature Pharmacotherapy 2013; 33:344

32 Brexpiprazole (Rexulti) for schizophrenia and depression Med

Lett Drugs Ther 2015; 57:116

33 R Cooper-Kazaz and B Lerer Effi cacy and safety of

triiodothy-ronine supplementation in patients with major depressive

dis-order treated with specifi c serotonin reuptake inhibitors Int J

Neuropsychopharmacol 2008; 11:685

34 JC Nelson et al A systematic review and meta-analysis of

lith-ium augmentation of tricyclic and second generation

antide-pressants in major depression J Affect Disord 2014; 168:269

35 MH Trivedi et al Clinical results for patients with major

depres-sive disorder in the Texas Medication Algorithm Project Arch

Gen Psychiatry 2004; 61:669

36 PE Holtzheimer and HS Mayberg Neuromodulation for

treat-ment-resistant depression F1000 Med Rep 2012; 4:22

IN BRIEF

Uridine Triacetate (Vistogard) for

Fluorouracil Overdose

The FDA has approved the pyrimidine analog uridine

triacetate (Vistogard – Wellstat Therapeutics) for

emergency treatment of a fluorouracil (5-FU) or

capecitabine (Xeloda, and generics) overdose or

severe toxicity that occurs within 96 hours following administration of one of these drugs Fluorouracil is a cytotoxic antimetabolite used to treat breast, colorectal, and other cancers; capecitabine is an oral prodrug of fluorouracil

Uridine triacetate, a prodrug, is deacetylated to uridine after oral administration Excess circulating uridine

is converted into uridine triphosphate, which inhibits the cytotoxic activity of 5-fluorouridine triphosphate,

a fluorouracil metabolite, by competing with it for incorporation into RNA.

FDA approval was based on two unpublished open-label studies (summarized in the package insert) in a total of

135 adults and children with overdoses of fluorouracil

or capecitabine (n=117) or severe or life-threatening toxicities within 96 hours after their administration (n=18) The overall survival rate at 30 days was 96%

In retrospective case reports that included 25 patients who received only supportive care after a fluorouracil overdose, the survival rate was 16%.

Vistogard is supplied as orange-flavored oral

granules in single-dose packets containing 10 grams

of uridine triacetate The granules should be mixed with 3-4 ounces of soft food and taken every 6 hours for 20 doses The recommended

dose is 10 grams for adults and 6.2 grams/m2 (10 grams maximum) for children Mild to moderate nausea, vomiting, and diarrhea have been reported The cost for one course of treatment is $75,000.1 ■

1 Approximate WAC WAC = wholesaler acquisition cost or man-ufacturer’s published price to wholesalers; WAC represents a published catalogue or list price and may not represent an ac-tual transactional price Source: AnalySource® Monthly June

5, 2016 Reprinted with permission by First Databank, Inc All rights reserved ©2016 www.fdbhealth.com/policies/drug-pricing-policy

37 Health Quality Ontario Repetitive transcranial magnetic stimu-lation for treatment-resistant depression: A systematic review and meta-analysis of randomized controlled trials Ont Health Technol Assess Ser 2016; 16:1

38 IO Bergfeld Deep brain stimulation of the ventral anterior limb

of the internal capsule for treatment-resistant depression: a randomized clinical trial JAMA Psychiatry 2016; 73:456

39 DD Dougherty A randomized sham-controlled trial of deep brain stimulation of the ventral capsule/ventral striatum for chronic treatment-resistant depression Biol Psychiatry 2015; 78:240

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