Subject: Antidepressants, SSRIs/SNRIs/other

Status	Drug	PR-B/D	PR	PR-QL	PR-AL	ST	M EX‡	TOC§
Selective Serotonin Reuptake Inhibitors (SSRIs)
C	citalopram			X
C	fluoxetine			X
C	fluvoxamine			X
C	paroxetine			X
C	Zoloft®  (sertraline)			X		X	X	X
NC	Celexa®  (citalopram)			X		X	X
NC	Lexapro®  (escitalopram)			X		X	X	X
NC	Paxil®  (paroxetine)			X		X	X
NC	Paxil CR®  (paroxetine SR)			X		X	X
NC	Pexeva®  (paroxetine)			X		X	X
NC	Prozac®  (fluoxetine)			X		X	X
NC	Prozac® Weekly  (fluoxetine)			X		X	X
NC	Rapiflux®  (fluoxetine)			X		X	X
NC	Sarafem®  (fluoxetine)			X			X
Selective Norepinephrine-Reuptake Inhibitors (SNRIs)
C	Cymbalta®  (duloxetine)			X		X	X	X
C	Effexor®  (venlafaxine)			X		X	X	X
NC	Effexor XR®  (venlafaxine SR)			X		X	X	X
Tetracyclic Antidepressants
C	maprotiline			X
C	mirtazapine			X
NC	Remeron®  (mirtazapine)			X		X	X
Miscellaneous Antidepressants
C	budeprion			X
C	bupropion, bupropion SR			X
C	nefazodone					X	X
C	trazodone
C	Wellbutrin XL®  (bupropion SR)			X		X	X
NC	Desyrel®  (trazodone)					X	X
NC	Wellbutrin®  (bupropion)			X		X	X
NC	Wellbutrin SR®  (bupropion SR)			X		X	X

Policy:

1. Precertification Criteria

Under some plans, including plans that use an open or closed formulary, budeprion, bupropion, bupropion SR, citalopram, fluoxetine, fluvoxamine, maprotiline, mirtazapine, paroxetine, Celexa, Cymbalta, Effexor, Effexor XR, Lexapro, Paxil, Paxil CR, Pexeva, Prozac, Prozac Weekly, Rapiflux, Remeron, Sarafem, Wellbutrin, Wellbutrin SR, Wellbutrin XL and Zoloft are subject to precertification.   If precertification requirements apply, Aetna considers these drugs to be medically necessary for those members who meet the following precertification criteria:

A. Quantity Limits  

According to the manufacturers, these antidepressants can be dosed up to a maximum daily dose at the interval(s) as indicated in the table below.  A quantity of each drug will be considered medically necessary as indicated in the table below:


Drug	Maximum Daily Dose/ Dosing Interval	Dosage Strength	Quantity Limits
bupropion Wellbutrin	450 mg/ Three times daily	75 mg, 100 mg	Up to 180 tablets in 30 days
bupropion SR Wellbutrin SR budeprion	400 mg/ Once or twice daily	100, 150, 200 mg	Up to 60 tablets in 30 days
Wellbutrin XL	300 mg/ Once daily	150, 300 mg	Up to 30 tablets in 30 days
citalopram Celexa	40 mg/ Once daily	10, 20, 40 mg	Up to 30 tablets in 30 days
Cymbalta	60 mg/ Once or twice daily	20 mg, 30 mg	Up to 60 capsules in 30 days
Cymbalta	60 mg/ Once or twice daily	60 mg	Up to 30 capsules in 30 days
Effexor	375 mg/ Two or three times daily	25 mg, 100 mg	Up to 90 tablets in 30 days
Effexor	375 mg/ two or three times daily	37.5 mg	Up to 120 tablets in 30 days
Effexor	375 mg/Two or three times daily	50 mg	Up to 180 tablets in 30 days
Effexor	375 mg/ Two or three times daily	75 mg	Up to 150 tablets in 30 days
Effexor XR	225 mg/ Once daily	37.5 mg, 75 mg, 150 mg	Up to 60 capsules in 30 days
fluoxetine Prozac	80 mg/ Once or twice daily	10, 40 mg	Up to 30 tablets or capsules in 30 days
fluoxetine Prozac	80 mg/ Once or twice daily	20 mg capsules	None
fluoxetine Rapiflux	80 mg/ Once or twice daily	20 mg tablets	Up to 30 tablets in 30 days
fluoxetine Prozac	80 mg/ Once or twice daily	Liquid 20 mg/5 ml	Up to 300 ml in 30 days (10ml/day)
Prozac Weekly	90 mg/Once weekly	90 mg	Up to 4 capsules in 28 days
fluvoxamine	300 mg/ Once or twice daily	25 mg, 50 mg	Up to 30 tablets in 30 days
fluvoxamine	300 mg/ Once or twice daily	100 mg	Up to 90 tablets in 30 days
Lexapro	20 mg/ Once daily	5, 10, 20 mg	Up to 30 tablets in 30 days
Lexapro	20 mg/ Once daily	Solution 5 mg/5 ml	Up to 600 ml in 30 days
maprotiline	225 mg/ Once or in divided doses	25 mg	Up to 30 tablets in 30 days
maprotiline	225 mg/ Once or in divided doses	50 mg	Up to 60 tablets in 30 days
maprotiline	225 mg/Once or in divided doses	75 mg	Up o 90 tablets in 30 days
mirtazapine Remeron	45 mg/ Once daily	15 mg, 30 mg, 45 mg	Up to 30 tablets or dissolving tablets in 30 days
paroxetine Paxil, Pexeva	60 mg/ Once daily	10 mg, 20 mg	Up to 30 tablets in 30 days
paroxetine Paxil, Pexeva	60 mg/ Once daily	30 mg, 40 mg	Up to 60 tablets in 30 days
paroxetine Paxil, Pexeva	60 mg/ Once daily	Suspension 10 mg/5 ml	Up to 900 ml in 30 days
Paxil CR	75 mg/ Once daily	12.5 mg, 25 mg, 37.5 mg	Up to 60 tablets in 30 days
Sarafem	80 mg/ Once daily	10 mg	Up to 30 capsules in 30 days
Sarafem	80 mg/ Once daily	20 mg	Up to 60 capsules in 30 days
Zoloft	200 mg/ once daily	25 mg, 50 mg	Up to 30 tablets in 30 days
Zoloft	200 mg/ once daily	100 mg	Up to 60 tablets in 30 days
Zoloft	200 mg/ once daily	Liquid 20 mg/ml	Up to 300 ml in 30 days





For coverage of additional quantities, a member's treating physician must request prior authorization through the Aetna Pharmacy Management Precertification Unit.  A prior authorization will be granted for coverage of additional quantities of these antidepressants for those members who meet ANY of the following criteria:

• Member requires a dose including half tablets OR
• Member's dose is being titrated by physician (3-month limit) OR
• Member has had intolerance to drug administered as a single daily dose OR
• Member's physician provides documentation (controlled clinical trial) from the peer-reviewed medical literature for use of a higher dose.
  



2. Step Therapy Criteria

Under some plans, including plans that use an open or closed formulary, Celexa, Cymbalta, Desyrel, Effexor, Effexor XR, Lexapro, nefazodone, Paxil, Paxil CR, Pexeva, Prozac, Prozac Weekly, Rapiflux, Remeron, Wellbutrin, Wellbutrin SR, Wellbutrin XL and Zoloft are subject to step-therapy.  Aetna considers these drugs to be medically necessary for those members who are new starts on these medications not those who are currently stabilized on the medication and who meet the following step-therapy criteria:

For Celexa, Cymbalta, Desyrel, Lexapro, nefazodone, Paxil, Paxil CR, Pexeva, Prozac, Prozac Weekly, Rapiflux, Remeron, Wellbutrin, Wellbutrin SR, Wellbutrin XL and Zoloft

A documented trial of one month of one of budeprion, bupropion, bupropion SR, citalopram, fluoxetine, fluvoxamine, paroxetine, mirtazapine, or trazodone - alternatives on the Aetna Medicare Preferred Drug List.

For Effexor and Effexor XR

A documented trial of one month of one of budeprion, bupropion, bupropion SR, citalopram, fluoxetine, fluvoxamine, paroxetine, mirtazapine, or trazodone AND one month of the SNRI Cymbalta - alternatives on the Aetna Medicare Preferred Drug List.

If it is medically necessary for a member to be treated initially with a medication subject to step-therapy, or if the member meets transition of coverage (TOC) criteria for a medication subject to TOC, the member's treating physician may contact the Aetna Pharmacy Management Precertification Unit to request coverage as a medical exception at 1-800-414-2386. (See criteria under section III below.)


3. Medical Exception Criteria

Cymbalta, Effexor, Wellbutrin XL, nefazodone and Zoloft are currently listed on the Aetna Step-Therapy List.* If it is medically necessary for a member to be treated initially with one of these medications subject to step-therapy, Aetna considers these drugs to be medically necessary for those members who are new starts on these medications and who meet the criteria specified below.  

Celexa, Desyrel, Effexor XR, Lexapro, Paxil, Paxil CR, Pexeva, Prozac, Prozac Weekly, Rapiflux, Remeron, Wellbutrin and Wellbutrin SR are currently Not Covered Part D drugs under the Aetna Medicare Prescription Drug Plan* and are on the Aetna Step-Therapy List.*  Therefore, they are excluded from coverage for members enrolled in prescription drug benefit plans that use a closed formulary or that require step-therapy criteria, unless a medical exception is granted.  Aetna considers these drugs to be medically necessary for those members who are new starts on these medications and who meet the criteria specified below:


For Celexa, Desyrel, nefazodone, Paxil, Paxil CR, Pexeva, Prozac, Prozac Weekly, Rapiflux, Remeron, Wellbutrin, Wellbutrin SR and Wellbutrin XL

A.   A documented:

• Intolerance to one generic preferred alternative agent - budeprion, bupropion, bupropion SR, citalopram, fluoxetine, fluvoxamine, paroxetine, mirtazapine, or trazodone OR
• Contraindication to one generic preferred alternative agent - budeprion, bupropion, bupropion SR, citalopram, fluoxetine, fluvoxamine, paroxetine, mirtazapine, or trazodone OR
• Allergy to one generic preferred alternative agent - budeprion, bupropion, bupropion SR, citalopram, fluoxetine, fluvoxamine, paroxetine, mirtazapine, or trazodone OR
• Failure of an adequate trial of one month of one generic preferred alternative agent - budeprion, bupropion, bupropion SR, citalopram, fluoxetine, fluvoxamine, paroxetine, mirtazapine, or trazodone.
  

OR

B.    Member is documented to be currently stabilized on one of these antidepressants - Paxil CR, Paxil suspension and Wellbutrin XL ONLY

OR

C.   Transition of Coverage:

• Member is within 90 days of his or her effective date of enrollment
• Member is stable on Paxil CR, Paxil suspension and Wellbutrin XL  for 30 days or longer

If applicable, quantity limits, age or gender edits will apply.  Approval is valid one year from the date of request.
If the member has been a Medicare member for 91 days or longer and is not residing in a LTC facility then standard precertification, step-therapy, or medical exception criteria will apply.


For Cymbalta, Lexapro and Zoloft - (A OR B OR C)

A.   A documented:

• Intolerance to one generic preferred alternative agent - budeprion, bupropion, bupropion SR, citalopram, fluoxetine, fluvoxamine, paroxetine, mirtazapine, or trazodone OR
• Contraindication to one generic preferred alternative agent - budeprion, bupropion, bupropion SR, citalopram, fluoxetine, fluvoxamine, paroxetine, mirtazapine, or trazodone OR
• Allergy to one generic preferred alternative agent - budeprion, bupropion, bupropion SR, citalopram, fluoxetine, fluvoxamine, paroxetine, mirtazapine, or trazodone OR
• Failure of an adequate trial of one month of one generic preferred alternative agent - budeprion, bupropion, bupropion SR, citalopram, fluoxetine, fluvoxamine, paroxetine, mirtazapine, or trazodone OR
• Diagnosis of DPNP (Diabetic Peripheral Neuropathic Pain) (Cymbalta only)

OR

B.   Member is documented to be currently stabilized on one of these antidepressants - Cymbalta, Lexapro, or Zoloft

OR

C.   Transition of Coverage:

• Member is within 90 days of his or her effective date of enrollment
• Member is stable on Cymbalta, Lexapro, or Zoloft for 30 days or longer

If applicable, quantity limits, age or gender edits will apply.  Approval is valid one year from the date of request.
If the member has been a Medicare member for 91 days or longer and is not residing in a LTC facility then standard precertification, step-therapy, or medical exception criteria will apply.


For Effexor and Effexor XR - (A OR B OR C)

A.   A documented:

• Intolerance to one generic preferred alternative agent - budeprion, bupropion, bupropion SR, citalopram, fluoxetine, fluvoxamine, paroxetine, mirtazapine, or trazodone - AND the SNRI Cymbalta OR
• Contraindication to one generic preferred alternative agent - budeprion, bupropion, bupropion SR, citalopram, fluoxetine, fluvoxamine, paroxetine, mirtazapine, or trazodone - AND the SNRI Cymbalta OR
• Allergy to one generic preferred alternative agent - budeprion, bupropion, bupropion SR, citalopram, fluoxetine, fluvoxamine, paroxetine, mirtazapine, or trazodone - AND the SNRI Cymbalta OR
• Failure of an adequate trial of one month of one generic preferred alternative agent - budeprion, bupropion, bupropion SR, citalopram, fluoxetine, fluvoxamine, paroxetine, mirtazapine, or trazodone - AND one month of the SNRI Cymbalta
  

OR

B.   Member is documented to be currently stabilized on one of these antidepressants - Effexor or Effexor XR

OR

C.   Transition of Coverage:

• Member is within 90 days of his or her effective date of enrollment
• Member is stable on Effexor or Effexor XR for 30 days or longer

If applicable, quantity limits, age or gender edits will apply.  Approval is valid one year from the date of request.
If the member has been a Medicare member for 91 days or longer and is not residing in a LTC facility then standard precertification, step-therapy, or medical exception criteria will apply.


Sarafem is currently a Not Covered Part D drug under the Aetna Medicare Prescription Drug Plan.* Therefore, Sarafem is excluded from coverage for members enrolled in prescription drug benefit plans that use a closed formulary, unless a medical exception is granted.   Aetna considers Sarafem to be medically necessary for those members who are new starts and who meet the criteria specified below:
            

A.  A documented: 

• Contraindication to a preferred alternative: fluoxetine, paroxetine, citalopram, fluvoxamine OR
• Intolerance to a preferred alternative: fluoxetine, paroxetine, citalopram, fluvoxamine OR
• Allergy to a preferred alternative: fluoxetine, paroxetine, citalopram, fluvoxamine OR
• Failure of an adequate trial of one month of a preferred alternative: fluoxetine, paroxetine, citalopram, fluvoxamine
  

Special Notes:

SSRI Use in Children
In the past decade, SSRIs have been increasingly used as first line treatment in children with depression.  Recently, questions have been raised concerning the safety and efficacy of these agents in this population.  Currently, fluoxetine is the only SSRI approved for treatment of major depressive disorder in children as young as 8 years of age.  Fluoxetine and fluvoxamine are indicated for obsessive-compulsive disorder in children 8 years and older, and sertraline in children 6 years and older.

There are few robust studies suggesting the use of one SSRI over another considering the population to be studied.  Fluoxetine is the oldest agent in this class and therefore, has the most experience associated with its use.  It has demonstrated a favorable risk-benefit profile in studies with children down to age 7. 52, 53  There is some evidence to suggest that paroxetine does not improve depressive symptoms and has an increased risk of suicidal ideation and/or suicide attempt.54  In 2003, the FDA recommended that paroxetine not be used in children or adolescents for treatment of depression.55  Sertraline and citalopram marginally improve depressive symptoms and may be associated with a slightly increased risk of suicide ideation and/or attempts.56, 57

With the exception of paroxetine, the other SSRIs mentioned above may be effective options for treating children with depression.  Again, the literature currently available does not validate the use of one SSRI over another in the pediatric population.  Additional, well-designed studies are warranted.

SSRI Use in Pregnancy and Lactation
SSRIs are effective in treating both antenatal and postpartum depression.  However, benefit-risk assessments should be done before prescribing these agents.  At this time, all SSRIs have a pregnancy risk factor C; evidence suggests that there may be a fetal risk for developmental toxicity in the 3rd trimester, or close to delivery.58  However, in September 2005, the manufacturer of Paxil/Paxil CR and the FDA notified healthcare professionals of results of a retrospective epidemiologic study of major congenital malformations in infants born to women taking antidepressants during the first trimester of pregnancy. This study suggested an increase in the risk of overall major congenital malformations for paroxetine as compared to other antidepressants.59  Fluoxetine is the most studied agent in pregnant women.  There also does not appear to be an increased risk of major congenital malformations with the other SSRIs at this time; however, information on sertraline, fluvoxamine, escitalopram, and citalopram is limited.60

The risk of the different SSRIs in neonatal toxicity or withdrawal is not currently established.  The FDA altered the warning labeling for all agents stating that newborns exposed to SSRIs in utero may experience symptoms that prolong hospitalization and require respiratory and nutritional support.  Generally, these symptoms have been transient.  Paroxetine may be associated with more SSRI-induced neonatal convulsions due to the fact that paroxetine metabolizes the fastest, with increased clearance from the body, resulting in a withdrawal effect.61

In lactation, sertraline and paroxetine has very little concentrations present in breast milk and nursing infants.  Fluoxetine and citalopram have higher concentrations detected in nursing infants but do not appear to cause adverse effects.58   Women can continue fluoxetine or citalopram if they were effective during pregnancy.62   

* Coverage is provided through a Medicare Prescription Drug Plan Sponsor with a Medicare contract and benefits, limitations, service areas and premiums are subject to change on January 1 of each year.

Place of Service:

Outpatient

The above policy is based on the following references:

1. Hirschfeld R. Long-term side effects of SSRIs: Sexual dysfunction and weight gain. J Clin Psychiatry 2003;64 (suppl 18):20-4.
2. Alvarez Jr W and Pickworth KK. Safety of antidepressant drugs in the patient with cardiac disease: A review of the literature. Pharmacotherapy. 2003;23(6):754-71.
3. Golden RN, Nemeroff CB, McSorley P, et al. Efficacy and tolerability of controlled-release and immediate-release paroxetine in the treatment of depression. J Clin Psychiatry 2002;63:57-84.
4. US Food and Drug Administration. Antidepressant use in children, adolescents, and adults. Issued March 23, 2004. Available at: http://www.fda.gov/cder/drug/antidepressants/default.htm. Accessed 4/7/2004.
5. Clayton AH, Pradko JF, Croft HA, et al. Prevalence of sexual dysfunction among newer antidepressants. J Clin Psychiatry. 2002;63:357-66.
6. Gregorian Jr RS, Golden KA, Bahce A, et al. Antidepressant-induced sexual dysfunction. Ann Pharmacother. 2002;36:1577-89.
7. Lam RW, Wan DDC, Cohen NL, and Kennedy SH. Combining antidepressants for treatment-resistant depression: A review. J Clin Psychiatry. 2002;63:685-93.
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9. Glassman AH, O'Connor CM, Califf RM, et al. Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA. 2002;288:701-9.
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53. Emslie GJ, Heiligenstein JH, Wagner KD, et al.  Fluoxetine for acute treatment of depression in children and adolescents: a placebo-controlled, randomized clinical trial.  J Am Acad Child Adolesc Psychiatry. 2002;41:1205-15.
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56. Wagner KD, Ambrosinin P, Rynn M, et al.  Efficacy of sertraline in the treatment of children and adolescents with major depressive disorder: two randomized controlled trials.  JAMA. 2003;290:1033-41.
57. Whittington CJ, Kendall T, Fonagy P, et al.  Selective serotonin reuptake inhibitors in childhood depression: systematic review of published versus unpublished data.  Lancet. 2004;363:1341-1345.
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Property of Aetna Inc. All rights reserved. Pharmacy Clinical Policy Bulletins are developed by Aetna to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. This Clinical Policy Bulletin contains only a partial, general description of plan or program benefits and does not constitute a contract. Aetna does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Aetna or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. This Clinical Policy Bulletin may be updated and therefore is subject to change.

July 24, 2006