The medical letter on drugs and therapeutics august 15 2016

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Drugs for Bipolar Disorder .................................................................................................. p 97
Sofosbuvir/Velpatasvir (Epclusa) for Hepatitis C ............................................................. p 101

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The Medical Letter

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on Drugs and Therapeutics
Volume 58

August 15, 2016
Take CME Exams

ISSUE

ISSUE No.

1433
1501

ALSO IN THIS ISSUE

Sofosbuvir/Velpatasvir (Epclusa) for Hepatitis C ............................................................. p 107

Volume 56

▶

Drugs for Bipolar Disorder

Recommendations for Treatment of Bipolar Disorder

▶ Second-generation antipsychotics, lithium, and

Bipolar disorder is characterized by intermittent
episodes of mania and/or depression.1 Even with
maintenance treatment, recurrences of manic or (more
frequently) depressive episodes are common. Some of
the drugs and dosages recommended here have not
been approved by the FDA for use in bipolar disorder.
TREATMENT OF MANIA — Second-generation antipsychotics, lithium, and valproate are effective for
treatment of acute manic episodes.2 Both lithium
and valproate may take days to weeks to have a
full therapeutic effect; treatment of an acute manic
episode with these agents generally requires addition
of an antipsychotic drug.
TREATMENT OF DEPRESSION — The secondgeneration antipsychotics quetiapine and lurasidone
and the combination of olanzapine and fluoxetine
have been shown to be effective in treating bipolar
depression.3-6 Antidepressant drugs such as selective
serotonin reuptake inhibitors (SSRIs) or bupropion
can be effective for treatment of bipolar depression,

but they can precipitate mania and generally should
be used only as an adjunct to mood-stabilizing drugs
such as lithium.7 Lithium has been shown to have
protective effects against suicide and self-harm when
used for treatment of bipolar depression.8 Lamotrigine
may be modestly effective for this indication, but its
usefulness in treating an acute episode is limited by
the amount of time required for safe titration to an
effective dose.9
MAINTENANCE — Lithium remains the drug of choice
for maintenance treatment of bipolar disorder,
especially for prevention of manic episodes.10,11 The
anticonvulsant lamotrigine is effective for prevention
of recurrent depressive episodes. Antiepileptic
drugs such as valproate and carbamazepine are also

valproate are effective for treatment of acute episodes
of mania; treatment of an acute manic episode with
lithium or valproate generally requires addition of an
antipsychotic drug.
▶ Lithium, quetiapine, lurasidone, and a combination
of olanzapine and fluoxetine have been shown to be
effective for treatment of bipolar depression.
▶ Lithium is generally the drug of choice for maintenance
treatment of bipolar disorder.
▶ Lamotrigine is effective in preventing recurrent depressive
episodes.

widely used for maintenance treatment, but they are
generally less effective than lithium. Maintenance

therapy with lithium alone or in combination with
valproate, carbamazepine, or lamotrigine decreases
the risk of recurrent manic and depressive episodes.
Second-generation antipsychotics may also be
effective in preventing recurrences of manic and
depressive episodes, especially when taken in
combination with lithium.
ADVERSE EFFECTS — Lithium – Nausea and fatigue
may occur in the first days to weeks of lithium
treatment, even when serum concentrations are within
the recommended range. Tremor, thirst, polyuria,
edema, and weight gain may persist for the duration
of treatment. Lithium-induced tremor can be managed
by reducing the dosage or adding a beta blocker such
as propranolol.
Toxic renal effects, including tubular lesions, interstitial fibrosis, and decreased creatinine clearance,
have been reported with long-term use of lithium.
Nephrogenic diabetes insipidus can occur; it further
increases the risk of lithium toxicity and may be
irreversible. Hypothyroidism can occur with long-term
lithium treatment and can contribute to exacerbations
of bipolar disorder. Confusion and ataxia can occur
with high serum lithium concentrations. Lithium
103

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The Medical Letter

®

Vol. 58 (1501)

August 15, 2016

Table 1. Some Oral Drugs for Bipolar Disorder
Drug

Some Available
Formulations

Initial Adult
Dosage1

Usual Adult
Dosage1

150, 300, 600 mg caps; 300 mg tabs;
8 mEq/5 mL soln5
300, 450 mg tabs
300 mg tabs

900-1800 mg
divided tid or qid
900-1800 mg
divided bid or tid

900-1200 mg
divided tid or qid

900-1200 mg
divided bid or tid

200 mg tabs; 100 mg chewable
tabs
200 mg tabs; 100 mg/5 mL susp7
100, 200, 400 mg tabs;
100, 200, 300 mg caps
100, 200, 300 mg caps
100, 200, 400 mg tabs
100, 200, 300 mg caps

200-600 mg
divided tid or qid

600-1200 mg
divided bid or tid

200-600 mg
divided bid

600-1200 mg
divided bid

25, 100, 150, 200 mg tabs;
5, 25 mg chewable tabs9
25, 50, 100, 200 mg ODT

25 mg once/d10

200 mg once/d

8.10
442.80
270.90
372.50
332.10
652.80

250 mg caps; 250 mg/5 mL soln11

250 mg tid

1500-2000 mg
divided bid

125, 250, 500 mg tabs

750 mg/d divided

72.00
797.40
59.40
530.40
322.20
576.00
256.20
531.90

Cost2

Antimanic Agent
Lithium carbonate3,4 – generic
extended release – generic
Lithobid (Ani)

$7.10
25.80
669.60

Anticonvulsants
Carbamazepine – generic6
Tegretol (Novartis)6
extended release – generic6
Carbatrol (Shire)6
Tegretol XR (Novartis)6
Equetro (Validus)3,8
Lamotrigine – generic4
Lamictal (GSK)4
orally disintegrating – generic4
Lamictal ODT4
extended release – generic6
Lamictal XR6
Valproate
Valproic acid – generic6
Depakene (Abbvie)6
Divalproex sodium – generic3
Depakote (Abbvie)3
delayed release – generic6
Depakote Sprinkle6

extended release – generic3,8
Depakote ER3,8

200 mg bid

125 mg caps
25 mg/kg once/d12

171.50
172.30
212.40
182.40
211.00

25, 50, 100, 200, 250, 300 mg tabs

250, 500 mg tabs

111.60

25-40 mg/kg once/d12

soln = solution; susp = suspension; ODT = orally disintegrating tablet
1. Dosage for maintenance treatment. Dosage may need to be adjusted for serum concentrations, renal or hepatic impairment, or drug interactions (see Table
2 on p. 106).
2. Approximate WAC for 30 days’ treatment with tablets or capsules for a 70-kg patient at the lowest usual 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. July 5, 2016. Reprinted with permission by First Databank, Inc. All rights reserved. ©2016. www.fdbhealth.com/policies/
drug-pricing-policy.
3. FDA-approved for acute treatment of manic episodes.

4. FDA-approved for maintenance treatment of bipolar disorder.
5. Available as lithium citrate.

may cause mild leukocytosis, hypercalcemia, or
hyperparathyroidism. It can also cause severe acne,
folliculitis, hair loss, and other skin reactions, and
induce or exacerbate psoriasis.
Lithium has a narrow therapeutic window and
requires careful monitoring. Serum lithium
concentrations should be monitored every 6-12
months in stable patients (every 3 months in unstable
patients). Concentrations should be measured about
12 hours after the last dose. For acute treatment,
target serum concentrations are 0.8-1.2 mEq/L.
For maintenance treatment, serum concentrations
should be 0.6-1.0 mEq/L. Thyroid and renal function
should be monitored before starting lithium and
every six months during treatment. Patients should
also be monitored for signs of toxicity such as
vomiting, diarrhea, tremor, lethargy, slurred speech,
and weakness.
104

Valproate – Adverse effects of valproate include
somnolence, fatigue, weight gain, nausea, and
diarrhea; tremor has been reported, but it is less
common than with lithium. Reversible hair loss can
occur. Thrombocytopenia may occur and appears
to be dose-related. Transient elevations of hepatic
transaminases are common; fatal hepatotoxicity has

occurred rarely, particularly in young children and
with use of multiple anticonvulsants. Polycystic ovary
syndrome has occurred. Rare idiosyncratic reactions
include hemorrhagic pancreatitis, hyperammonemic
encephalopathy, and agranulocytosis.
Carbamazepine — Adverse effects of carbamazepine
include rash, dizziness, diplopia, nausea, somnolence,
headache, hyponatremia, elevated transaminases and,
rarely, Stevens-Johnson syndrome, agranulocytosis,
and aplastic anemia. Han Chinese may have a tenfold increased risk of Stevens-Johnson syndrome.12


The Medical Letter

Vol. 58 (1501)

®

August 15, 2016

Table 1. Some Oral Drugs for Bipolar Disorder (continued)
Some Available
Formulations

Initial Adult
Dosage1

Usual Adult
Dosage1

2, 5, 10, 15, 20, 30 mg tabs
2, 5, 10, 15, 20, 30 mg tabs13
10, 15 mg ODT

15 mg once/d

15-30 mg once/d

Asenapine3,8 – Saphris (Allergan)

2.5, 5, 10 mg sublingual tabs

10 mg bid

5-10 mg bid

1006.10

Cariprazine3,8 – Vraylar (Allergan)

1.5, 3, 4.5, 6 mg caps

1.5 mg once/d

3-6 mg once/d

1006.10

Drug

Cost2

Second-Generation Antipsychotics
Aripiprazole3,8 – generic
Abilify (BMS/Otsuka)
orally disintegrating – generic

$770.70
892.00
919.10

Lurasidone14 – Latuda (Sunovion)

20, 40, 60, 80, 120 mg tabs

20 mg once/d

20-120 mg once/d

921.90

Olanzapine3,4,8 – generic
Zyprexa (Lilly)
orally disintegrating – generic
Zyprexa Zydis

2.5, 5, 7.5, 10, 15, 20 mg tabs13

10-15 mg once/d

5-20 mg once/d

7.00
367.10
53.60
396.50

50-100 mg once/d
or divided bid
50-300 mg once/d

300-800 mg
divided bid
300-800 mg once/d

56.40
782.40
638.40

5, 10, 15, 20 mg ODT

Quetiapine – generic3,4,14
Seroquel (AstraZeneca)3,4,14
extended release – Seroquel XR3,4,8,14

25, 50, 100, 200, 300, 400 mg tabs

Risperidone3,8 – generic
Risperdal (Janssen)
orally disintegrating – generic

Risperdal M-Tab

0.25, 0.5, 1, 2, 3, 4 mg tabs;
1 mg/mL soln15
0.25, 0.5, 1, 2, 3, 4 mg ODT
0.5, 1, 2, 3, 4 mg ODT

2-3 mg once/d

4-6 mg once/d

11.20
714.30
373.20
857.10

Ziprasidone3,4,8 – generic
Geodon (Pfizer)

20, 40, 60, 80 mg caps

40 mg bid

40-80 mg bid

116.00
880.40

6/25 mg once/d in
the evening

6/25-12/50 mg once/d
in the evening

347.60
402.30

50, 150, 200, 300, 400 mg tabs

Second-Generation Antipsychotic/SSRI Combination
Olanzapine/fluoxetine14 – generic
Symbyax (Lilly)
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.

3/25, 6/25, 6/50, 12/25,
12/50 mg caps

Not FDA-approved for treatment of bipolar disorder.
Patients taking conventional tablets can be switched to the suspension on a mg-per-mg basis, but in smaller, more frequent doses.
FDA-approved for treatment of mixed episodes.
Chewable tablets should be administered whole. If necessary, the dose should be rounded down to the nearest whole tablet.

For monotherapy, titrate to a goal of 200 mg/day as follows: 25 mg/day for 2 weeks, then 50 mg/day for 2 weeks, then 100 mg/day for 1 week, then 200 mg/day.
Available as valproate sodium.
When switching from Depakote to Depakote ER, an 8-20% increase in the dosage may be required to maintain serum concentrations.
Also available for rapid intramuscular injection for agitation associated with bipolar mania.
FDA-approved for treatment of depressive episodes in bipolar disorder.
Also available as a long-acting injectable for maintenance treatment of bipolar disorder.

DRESS syndrome (drug reaction with eosinophilia and
systemic symptoms) has been reported with use of
carbamazepine.13
Lamotrigine – Adverse effects of lamotrigine include
nausea, dizziness, and somnolence. About 10% of
patients develop a mild rash. Severe, life-threatening
rash, including Stevens-Johnson syndrome and toxic
epidermal necrolysis, has occurred in <1% of patients;
gradual up-titration of the dose may minimize the risk
of serious rash.14
Second-Generation Antipsychotics – Antipsychotics
can cause somnolence, weight gain, diabetes,
extrapyramidal symptoms, QT interval prolongation,
and hyperprolactinemia. Bipolar patients are
particularly susceptible to extrapyramidal effects;
quetiapine appears to have the lowest risk. Lurasidone
appears to have minimal metabolic effects, but more
studies are needed.15,16 DRESS syndrome has been
reported rarely with olanzapine and ziprasidone.17,18

PREGNANCY — Lithium use during pregnancy has
been associated with congenital cardiac abnormalities; the absolute risk is low. High neonatal lithium
concentrations are a risk factor for lower Apgar scores,

longer hospital stays, and reversible neurologic toxicity;
the risk can be minimized or avoided by withholding
lithium for 24 hours before delivery.
Valproate can cause neonatal toxicity, cleft palate,
neural tube defects, cardiac and other major teratogenic effects, and impairment of neurocognitive
development with reductions in IQ.19 Unless there
is no alternative, it should not be used during
pregnancy and should probably be avoided in women of childbearing age.
Carbamazepine is not recommended for use during
pregnancy because of an increased risk of major
malformations, including neural tube defects, low birth
weight, and fetal and neonatal vitamin K deficiency,
which can lead to neonatal hemorrhage.
105


The Medical Letter

®

Vol. 58 (1501)

August 15, 2016

Table 2. Some Drug Interactions1
Drug

Comments

Carbamazepine

Carbamazepine is an inducer of P-glycoprotein and a strong inducer of multiple hepatic enzymes, including
CYP3A4; increases in dosage of 3A4 substrates may be required. It is also a 3A4 substrate; dosage of
carbamazepine may need to be adjusted when used concurrently with strong 3A4 inducers or inhibitors.

Lamotrigine

Lamotrigine does not induce or inhibit CYP enzymes. Enzyme-inducing drugs such as carbamazepine reduce
lamotrigine concentrations. Valproate increases lamotrigine concentrations more than 2-fold and increases the
risk of Stevens-Johnson syndrome; dosage of lamotrigine should be reduced with concurrent use.

Lithium

Thiazide diuretics, ACE inhibitors, and NSAIDs (except aspirin) reduce renal clearance of lithium; reduction
of lithium dosage may be required with concurrent use. Carbamazepine increases the risk of neurotoxicity; a
reduction in dosage of lithium may be required with concurrent use. Other drugs, including theophylline and
caffeine, can decrease lithium concentrations.2

Valproate

Valproate is a moderate inhibitor of CYP2C9; reductions in dosage of 2C9 substrates may be required.
Phenytoin, carbamazepine, phenobarbital, and rifampin increase renal clearance of valproate; an increase
in the dosage of valproate is recommended. Valproate increases lamotrigine concentrations more than
2-fold and increases the risk of Stevens-Johnson syndrome; dosage of lamotrigine should be reduced with
concurrent use.

1. Inhibitors and inducers of CYP enzymes and P-glycoprotein. Med Lett Drugs Ther 2016; 58:e46.
2. PR Finley. Drug interactions with lithium: an update. Clin Pharmacokinet 2016; 55:925.

Data on use of lamotrigine during pregnancy are

inconsistent; it has a lower risk of adverse fetal outcomes than valproate or carbamazepine, but midline
clefts have been reported.20
Data on use of second-generation antipsychotics
during pregnancy are limited; increased birth weight
has been reported.21
ELECTROCONVULSIVE THERAPY (ECT) — Brief ECT
is a safe and effective treatment for both acute
mania and acute depression and may be particularly
useful for pregnant women and patients with drugresistant mania. ■
1. GM Goodwin et al. Evidence-based guidelines for treating bipolar disorder: revised third edition recommendations from the
British Association for Psychopharmacology. J Psychopharmacol 2016; 30:495.
2. LN Yatham et al. Canadian Network for Mood and Anxiety
Treatments (CANMAT) and International Society for Bipolar
Disorders (ISBD) collaborative update of CANMAT guidelines
for the management of patients with bipolar disorder: update
2013. Bipolar Disord 2013; 15:1.
3. C Datto et al. Bipolar II compared with bipolar I disorder: baseline characteristics and treatment response to quietapine in
a pooled analysis of five placebo-controlled clinical trials of
acute bipolar depression. Ann Gen Psychiatry 2016. March 11
(epub).
4. A Loebel et al. Lurasidone monotherapy in the treatment of bipolar I depression: a randomized, double-blind, placebo-controlled study. Am J Psychiatry 2014; 171:160.
5. A Loebel et al. Lurasidone as adjunctive therapy with lithium or
valproate for the treatment of bipolar I depression: a randomized, double-blind, placebo controlled study. Am J Psychiatry
2014; 171:169.
6. MT Silva et al. Olanzapine plus fluoxetine for bipolar disorder:
a systematic review and meta-analysis. J Affect Disord 2013;
146:310.
7. I Pacchiarotti et al. The International Society for Bipolar Disor-

106

ders (ISBD) task force report on antidepressant use in bipolar
disorders. Am J Psychiatry 2013; 170:1249.
8. L Tondo and RJ Baldessarini. Long-term lithium treatment in
the prevention of suicidal behavior in bipolar disorder patients.
Epidemiol Psichiatr Soc 2009; 18:179.
9. JR Geddes et al. Lamotrigine for treatment of bipolar depression:
independent meta-analysis and meta-regression of individual
patient data from five randomised trials. Br J Psychiatry 2009;
194:4.
10. JR Geddes and DJ Miklowitz. Treatment of bipolar disorder.
Lancet 2013; 381:1672.
11. E Severus et al. Lithium for prevention of mood episodes in
bipolar disorders: systematic review and meta-analysis. Int J
Bipolar Disord 2014; 2:15.
12. YW Shi et al. Association between HLA and Stevens-Johnson
syndrome induced by carbamazepine in Southern Han Chinese:
genetic markers besides B*1502? Basic Clin Pharmacol Toxicol
2012; 111:58.
13. P Cacoub et al. The DRESS syndrome: a literature review. Am J
Med 2011; 124:588.
14. SH Joe et al. Feasibility of a slower lamotrigine titration
schedule for bipolar depression: a naturalistic study. Int Clin
Psychopharmacol 2009; 24:105.
15. RH Belmaker. Lurasidone and bipolar disorder. Am J Psychiatry
2014; 171:131.
16. Lurasidone (Latuda) for schizophrenia. Med Lett Drugs Ther
2011; 53:13.
17. TJ Bommersbach et al. Management of psychotropic druginduced DRESS syndrome: a systematic review. Mayo Clin Proc
2016; 91:787.

18. FDA Drug Safety Communication: FDA warns about rare but
serious skin reactions with mental health drug olanzapine
(Zyprexa, Zyprexa Zydis, Zyprexa Relprevv, and Symbyax).
Available at: www.fda.gov/Drugs/DrugSafety/ucm499441.htm.
Accessed August 2, 2016.
19. FDA Drug Safety Communication: valproate anti-seizure products contraindicated for migraine prevention in pregnant women due to decreased IQ scores in exposed children. Available at:
www.fda.gov/Drugs/DrugSafety/ucm350684.htm. Accessed
August 2, 2016.
20. JL Moore and P Aggarwal. Lamotrigine use in pregnancy. Expert Opin Pharmacother 2012; 13:1213.
21. S Gentile. Antipsychotic therapy during early and late
pregnancy. A systematic review. Schizophr Bull 2010; 36:518.


The Medical Letter

▶

Vol. 58 (1501)

®

Sofosbuvir/Velpatasvir (Epclusa)
for Hepatitis C

The FDA has approved Epclusa (Gilead), a fixed-dose
combination of sofosbuvir (Sovaldi) and velpatasvir,
a new direct-acting antiviral agent, for oral treatment
of chronic hepatitis C virus (HCV) infection. Epclusa
is the first oral combination to be approved for
treatment of all six major HCV genotypes.

Pronunciation Key
Sofosbuvir: soe fos' bue veer
Epclusa: ep kloo' suh
Velpatasvir: vel pat' as veer

HCV GENOTYPES — The prevalence of HCV genotypes
in the US is about 75% for genotype 1, 20-25% for
genotypes 2 and 3, and <2% for genotypes 4, 5, and
6 combined. Genotype testing is recommended to
determine the optimal treatment regimen.1
MECHANISM OF ACTION — Sofosbuvir inhibits HCV
NS5B RNA-dependent RNA polymerase, which is
essential for viral replication. Velpatasvir inhibits viral
replication by binding to the NS5A protein. In vitro,
both sofosbuvir and velpatasvir have potent activity
against all major HCV genotypes (1-6), including
strains resistant to protease inhibitors.2-4
Table 1. Sofosbuvir/Velpatasvir Clinical Trials
Study Design

Duration

SVR12 Rate

Treatment-Naive and -Experienced Patients with or without
Compensated Cirrhosis
ASTRAL-1: genotypes 1, 2, 4, 5, 61; double-blind2
Sofosbuvir/velpatasvir (n=624)
12 weeks
99%3

Placebo (n=116)
12 weeks
0%
ASTRAL-2: genotype 2; open-label4
Sofosbuvir/velpatasvir (n=134)
12 weeks
99%5
Sofosbuvir + ribavirin (n=132)
12 weeks
94%
ASTRAL-3: genotype 3; open-label4
Sofosbuvir/velpatasvir (n=277)
12 weeks
95%5
Sofosbuvir + ribavirin (n=275)
24 weeks
80%
Treatment-Naive and -Experienced Patients with Decompensated
(Child-Pugh B) Cirrhosis
ASTRAL-4: genotypes 1, 2, 3, 4, 5, 66; open-label7
Sofosbuvir/velpatasvir (n=90)
12 weeks
Sofosbuvir/velpatasvir
12 weeks
+ ribavirin (n=87)
Sofosbuvir/velpatasvir (n=90)
24 weeks

83%
94%

86%

SVR12 = sustained virologic response (HCV RNA <15 IU/mL) at 12 weeks after
the end of treatment
1. Because of the small number of patients with HCV genotype 5 (n=35), all
received the active treatment.
2. JJ Feld et al. N Engl J Med 2015; 373:2599.
3. SVR12 rates by genotype: 1a - 98%, 1b - 99%, 2 - 100%, 4 - 100%, 5 - 97%,
and 6 - 100%.
4. GR Foster et al. N Engl J Med 2015; 373:2608.
5. Statistically significant difference versus sofosbuvir + ribavirin for
ASTRAL-2 (p = 0.02) and ASTRAL-3 (p<0.001).
6. No subjects with genotype 5 and only 1 with genotype 6 were enrolled.
7. MP Curry et al. N Engl J Med 2015; 373:2618.

August 15, 2016

CLINICAL STUDIES — Approval of sofosbuvir/
velpatasvir was based on the results of four randomized trials in treatment-naive and -experienced
patients with HCV infection. ASTRAL-1, -2, and -3
enrolled patients with or without cirrhosis, but excluded those with decompensated cirrhosis.5,6 ASTRAL-4
enrolled only patients with moderate (Child-Pugh B)
decompensated cirrhosis.7 The results for the rate of
sustained virologic response at 12 weeks after the
end of treatment (SVR12), the primary endpoint, are
summarized in Table 1.
In an open-label trial (ASTRAL-5), available only as
an abstract, 106 treatment-naive and -experienced
patients coinfected with HCV (genotypes 1-4) and HIV
were treated with sofosbuvir/velpatasvir for 12 weeks.

The overall SVR12 rate was 95%.8
ADVERSE EFFECTS — Sofosbuvir/velpatasvir was
generally well tolerated in clinical trials. The most
common adverse effects, occurring in ≥10% of
patients, were headache and fatigue.
PREGNANCY — No adequate studies of sofosbuvir/
velpatasvir in pregnant women are available. In animal
studies, no adverse effects on fetal development occurred
at exposures greater than those achieved in humans
at the recommended dose. Ribavirin is teratogenic and
embryotoxic; it is contraindicated for use in pregnant
women and in men whose partners are pregnant.
DRUG INTERACTIONS — Sofosbuvir/velpatasvir
and amiodarone should not be taken concurrently;
serious symptomatic bradycardia has been reported
in patients taking sofosbuvir with amiodarone.9
Both sofosbuvir and velpatasvir are substrates of
P-glycoprotein (P-gp) and breast cancer resistance
protein (BCRP). Velpatasvir is minimally metabolized
by CYP2B6, 2C8, and 3A4. Inducers of these pathways,
such as efavirenz and carbamazepine, may decrease
serum concentrations of either or both components of
the combination; concurrent use is not recommended.10
Velpatasvir is an inhibitor of P-gp, BCRP, and organic
anion transporting polypeptide (OATP) 1B1, 1B3,
and 2B1, and may increase intestinal absorption
of drugs that are substrates of these transporters.
Sofosbuvir/velpatasvir has been shown to increase
serum concentrations of digoxin, rosuvastatin, and
tenofovir and is expected to increase concentrations

of atorvastatin.
Absorption of velpatasvir decreases as gastric pH
increases. Coadministration of Epclusa and a proton
107


The Medical Letter

August 15, 2016

Vol. 58 (1501)

®

Table 2. Some Oral Regimens for HCV Infection
Approved
Genotypes

Brand Name

Formulation

Usual Dosage

Epclusa (Gilead)

400/100 mg sofosbuvir/
velpatasvir tabs

1 tab once/d x 12 wks

Harvoni (Gilead)

90/400 mg ledipasvir/
sofosbuvir tabs

Sovaldi (Gilead)
+ Daklinza (BMS)

Number of
Tabs/Day

Cost1

1-6

4

1

$74,760

1 tab once/d x 12 wks3,5

1, 4, 5, 6

14

94,500

400 mg sofosbuvir tabs
+ 60 mg daclatasvir tabs

1 sofosbuvir3 tab and 1 daclatasvir
tab once/d x 12 wks6

1, 3

24

147,000

Sovaldi (Gilead)
+ Olysio (Janssen)

400 mg sofosbuvir tabs
+ 150 mg simeprevir caps

1 sofosbuvir3 tab and 1 simeprevir7
cap once/d x 12 wks8

1

2

150,360

Technivie (Abbvie)

12.5/75/50 mg ombitasvir/

paritaprevir/ritonavir tabs

2 tabs qAM x 12 wks9,10

4

24

76,653

Viekira Pak (Abbvie)

12.5/75/50 mg ombitasvir/
paritaprevir/ritonavir tabs
+ 250 mg dasabuvir tabs

2 ombitasvir/paritaprevir/ritonavir
tabs qAM and 1 dasabuvir
tab bid x 12 wks10,11

1

44

83,319

Viekira XR (Abbvie)

200/8.33/50/33.33 mg dasabuvir/ 3 tabs once/d x 12 wks10,11
ombitasvir/paritaprevir/ritonavir

extended-release tabs

1

34

83,31912

Zepatier (Merck)

50/100 mg elbasvir/
grazoprevir tabs

1, 4

14

54,600

2,3

1 tab once/d x 12 wks10,13

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. July 5, 2016. Reprinted with permission by First
Databank, Inc. All rights reserved. ©2016. www.fdbhealth.com/policies/drug-pricing-policy.
2. Patients with decompensated cirrhosis should also take ribavirin 1000 mg/day (<75 kg) or 1200 mg/day (≥75 kg).
3. Not recommended for use in patients with severe renal impairment (eGFR <30 mL/min/1.73 m2) or end-stage renal disease.
4. Patients requiring ribavirin would also take 4-7 tablets or capsules of ribavirin 200 mg/day in two divided doses with food. A 12-week supply of ribavirin for a 70-kg
patient costs about $600.

5. 8 weeks may be considered for treatment-naive genotype 1 patients without cirrhosis with baseline HCV RNA <6 million IU/mL. 24 weeks for treatment-experienced genotype 1 patients with compensated cirrhosis. Genotype 1 patients with decompensated cirrhosis and genotype 1 or 4 post-liver-transplant patients
without cirrhosis or with compensated cirrhosis should also take ribavirin 1000 mg/day (<75 kg) or 1200 mg/day (≥75 kg).
6. Genotype 1 or 3 patients with decompensated cirrhosis or post-liver-transplant should also take ribavirin 1000 mg/day. Genotype 3 patients with compensated cirrhosis should also take ribavirin 1000 mg/day (<75 kg) or 1200 mg/day (≥75 kg).
7. Not recommended for use in patients with moderate or severe hepatic impairment.
8. 24 weeks for patients with compensated cirrhosis.
9. Technivie is used in combination with ribavirin 1000 mg/day (<75 kg) or 1200 mg/day (≥75 kg). Technivie alone may be considered in treatment-naive patients
who cannot tolerate ribavirin.
10. Contraindicated for use in patients with moderate or severe hepatic impairment.
11. 24 weeks for patients with HCV genotype 1a and compensated cirrhosis (12 weeks may be considered in this population based on prior treatment history). All
patients with HCV genotype 1a should also take ribavirin 1000 mg/day (<75 kg) or 1200 mg/day (≥75 kg).
12. WAC according to the manufacturer.
13. Patients with HCV genotype 1a with baseline NS5A resistance-associated polymorphisms at amino acid positions 28, 30, 31, or 93 should also take ribavirin
for 16 weeks. Genotype 1a or 1b patients previously treated with peginterferon, ribavirin, and an HCV NS3/4A protease inhibitor should also take ribavirin for
12 weeks. Genotype 4 patients previously treated with peginterferon and ribavirin should also take ribavirin for 16 weeks. The recommended dosage of ribavirin for those with CrCl >50 mL/min is: <66 kg = 800 mg/day, 66-80 kg = 1000 mg/day, 81-105 kg = 1200 mg/day, >105 kg = 1400 mg/day.

pump inhibitor is not recommended. Antacids should
be taken 4 hours before or after Epclusa; H2-receptor
antagonists and Epclusa can be taken at the same
time or 12 hours apart.
DOSAGE — The recommended dosage of Epclusa
is one tablet once daily for 12 weeks. Patients with
decompensated cirrhosis (Child-Pugh B or C) should
also take ribavirin.
CONCLUSION — Sofosbuvir/velpatasvir (Epclusa),
taken as one tablet daily for 12 weeks, is effective for
treatment of chronic hepatitis C virus (HCV) infection
caused by any of the six major HCV genotypes.
Addition of ribavirin is recommended in patients with
decompensated cirrhosis. ■
1. American Association for the Study of Liver Diseases and the

Infectious Diseases Society of America. HCV Guidance: Recommendations for testing, managing, and treating hepatitis
C. Available at . Accessed August 2,
2016.

108

2. Sofosbuvir (Sovaldi) for chronic hepatitis C. Med Lett Drugs
Ther 2014; 56:5.
3. G Cheng et al. GS-5816, a second generation HCV NS5A inhibitor with potent antiviral activity, broad genotypic coverage and
a high resistance barrier. J Hepatol 2013; 58 suppl 1:S484. Absctract 1191. Available at: www2.kenes.com/liver-congress/
scientific/pages/ScientificProgramme1.aspx. Accessed August 2, 2016.
4. EJ Lawitz et al. Clinical resistance to velpatasvir (GS-5816), a
novel pan-genotypic inhibitor of the hepatitis C virus NS5A protein. Antimicrob Agents Chemother 2016 Jun 27 (epub).
5. JJ Feld et al. Sofosbuvir and velpatasvir for HCV genotype 1, 2,
4, 5, and 6 infection. N Engl J Med 2015; 373:2599.
6. GR Foster et al. Sofosbuvir and velpatasvir for HCV genotype 2
and 3 infection. N Engl J Med 2015; 373:2608.
7. MP Curry et al. Sofosbuvir and velpatasvir for HCV in patients
with decompensated cirrhosis. N Engl J Med 2015; 373:2618.
8. D Wyles et al. Sofosbuvir/velpatasvir in HIV-HCV co-infected
patients. Available at: />sofosbuvirvelpatasvir_epclusa__master.pdf. Accessed August
2, 2016.
9. In brief: Severe bradycardia with sofosbuvir and amiodarone.
Med Lett Drugs Ther 2015; 57:58.
10. Inhibitors and inducers of CYP enzymes and P-glycoprotein.
Med Lett Drugs Ther 2016; 58:e46.


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Determine the most appropriate therapy given the clinical presentation of an individual patient with bipolar disorder.
Review the efficacy and safety of sofosbuvir/velpatasvir (Epclusa) for treatment of hepatitis C virus (HCV) infection caused by any of the six major HCV genotypes.

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Issue 1501 Questions
(Correspond to questions #31-40 in Comprehensive Exam #75, available January 2017)
Drugs for Bipolar Disorder
1. Patients treated with lithium or valproate for an acute manic
episode generally require:
a. rapid up-titration of dosage
b. careful monitoring for rash

c. adjunctive treatment with an antipsychotic drug
d. all of the above
2. Which of the following drugs has been shown to have protective
effects against suicide when used for treatment of depression
in patients with bipolar disorder?
a. lithium
b. quetiapine
c. olanzapine
d. all of the above
3. The drug of choice for maintenance treatment of bipolar
disorder is:
a. lithium
b. valproate
c. carbamazepine
d. lamotrigine

6. Use of valproate with lamotrigine increases the risk of:
a. thrombocytopenia
b. fatal hepatotoxicity
c. Stevens-Johnson syndrome
d. switching from depression to mania
7. A 36-year-old woman taking lithium for maintenance treatment
of bipolar disorder has a manic episode during her third
month of pregnancy that does not respond to treatment with
a second-generation antipsychotic. A reasonable treatment
option for this patient would be:
a. brief ECT
b. valproate
c. carbamazepine
d. all of the above

Sofosbuvir/Velpatasvir (Epclusa) for Hepatitis C
8. The most prevalent HCV genotype in the US is:
a. 1
b. 4
c. 5
d. 6

4. Adverse effects of lithium include:
a. renal toxicity
b. hypothyroidism
c. tremor
d. all of the above
5. Concurrent administration of lithium and a thiazide diuretic, an
ACE inhibitor, or an NSAID can:
a. increase the risk of gastrointestinal bleeding
b. decrease the renal clearance of lithium
c. cause hypotension
d. cause hypokalemia

9. Unlike sofosbuvir/ledipasvir (Harvoni), sofosbuvir/velpatasvir
(Epclusa):
a. is FDA-approved for treatment of HCV genotypes 2 and 3
b. is taken twice daily
c. can be taken with amiodarone
d. all of the above
10. A 65-year-old man with HCV genotype 1 infection,
decompensated cirrhosis (Child-Pugh C), hyperlipidemia,
and gastroesophageal reflux disease is beginning treatment
with sofosbuvir/velpatasvir (Epclusa). His other medications
include omeprazole and rosuvastatin. Which of the following

statements about the use of sofosbuvir/velpatasvir in this
patient is true?
a. addition of ribavirin is recommended
b. concurrent use of omeprazole is not recommended
c. it can increase serum concentrations of rosuvastatin
d. all of the above

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PRESIDENT: Mark Abramowicz, M.D.; VICE PRESIDENT AND EXECUTIVE EDITOR: Gianna Zuccotti, M.D., M.P.H., F.A.C.P., Harvard Medical School; EDITOR IN CHIEF: Jean-Marie Pflomm,
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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;
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