Subject: Benzodiazepines (excluding insomnia) Limit Policy 675-H 03-2022

Drug

ANTI-ANXIETY AGENTS

ALPRAZOLAM INTENSOL  (alprazolam oral solution concentrate)

alprazolam orally disintegrating tablet

ATIVAN  (lorazepam)

chlordiazepoxide

clonazepam orally disintegrating tablet

DIAZEPAM INTENSOL  (diazepam oral solution concentrate)

diazepam oral solution

KLONOPIN  (clonazepam)

lorazepam oral concentrate solution

LOREEV XR  (lorazepam extended-release)

oxazepam

TRANXENE  (clorazepate)

VALIUM  (diazepam)

XANAX  (alprazolam)

XANAX XR  (alprazolam extended-release)

Policy:

FDA-approved Indications
Alprazolam Intensol Oral Solution
Anxiety Disorders
Alprazolam Intensol Oral Solution is indicated for the management of anxiety disorder (a condition corresponding most closely to the APA Diagnostic and Statistical Manual [DSM-III-R] diagnosis of generalized anxiety disorder) or the short-term relief of symptoms of anxiety. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic.
Generalized anxiety disorder is characterized by unrealistic or excessive anxiety and worry (apprehensive expectation) about two or more life circumstances, for a period of 6 months or longer, during which the person has been bothered more days than not by these concerns. At least 6 of the following 18 symptoms are often present in these patients: Motor Tension (trembling, twitching, or feeling shaky; muscle tension, aches, or soreness; restlessness; easy fatigability); Autonomic Hyperactivity (shortness of breath or smothering sensations; palpitations or accelerated heart rate; sweating, or cold clammy hands; dry mouth; dizziness or light-headedness; nausea, diarrhea, or other abdominal distress; flushes or chills; frequent urination; trouble swallowing or ‘lump in throat’); Vigilance and Scanning (feeling keyed up or on edge; exaggerated startle response; difficulty concentrating or ‘mind going blank’ because of anxiety; trouble falling or staying asleep; irritability). These symptoms must not be secondary to another psychiatric disorder or caused by some organic factor.
Anxiety associated with depression is responsive to Alprazolam Intensol Oral Solution.
Panic Disorder
Alprazolam Intensol Oral Solution is also indicated for the treatment of panic disorder, with or without agoraphobia.
Studies supporting this claim were conducted in patients whose diagnoses corresponded closely to the DSM-III-R/IV criteria for panic disorder.
Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, i.e., a discrete period of intense fear or discomfort in which four (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, or accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or abdominal distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization (feelings of unreality) or depersonalization (being detached from oneself); (10) fear of losing control; (11) fear of dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes.
Demonstrations of the effectiveness of Alprazolam Intensol Oral Solution by systematic clinical study are limited to 4 months duration for anxiety disorder and 4 to 10 weeks duration for panic disorder; however, patients with panic disorder have been treated on an open basis for up to 8 months without apparent loss of benefit. The physician should periodically reassess the usefulness of the drug for the individual patient. 

Alprazolam Orally Disintegrating Tablet
Generalized Anxiety Disorder
Alprazolam orally disintegrating tablets are indicated for the treatment of generalized anxiety disorder.
The efficacy of alprazolam in the treatment of generalized anxiety disorder was demonstrated in 5 short-term, placebo-controlled trials.
Panic Disorder
Alprazolam orally disintegrating tablets are also indicated for the treatment of panic disorder, with or without agoraphobia.
The efficacy of alprazolam in the treatment of panic disorder was established in 2 short-term, placebo-controlled trials.
Demonstrations of the effectiveness of alprazolam by systematic clinical study are limited to 4 months in duration for generalized anxiety disorder and 4 to 10 weeks duration for panic disorder; however, patients with panic disorder have been treated on an open basis for up to 8 months without apparent loss of benefit. The physician should periodically reassess the usefulness of the drug for the individual patient. 

Ativan and Lorazepam Oral Concentrate
Ativan (lorazepam) and lorazepam oral concentrate are indicated for the management of anxiety disorders or for the short-term relief of the symptoms of anxiety or anxiety associated with depressive symptoms. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic.
The effectiveness of Ativan (lorazepam) and lorazepam oral concentrate in long-term use, that is, more than 4 months, has not been assessed by systematic clinical studies. The physician should periodically reassess the usefulness of the drug for the individual patient. 

Chlordiazepoxide
Chlordiazepoxide hydrochloride capsules are indicated for the management of anxiety disorders or for the short-term relief of symptoms of anxiety, withdrawal symptoms of acute alcoholism, and preoperative apprehension and anxiety. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic.
The effectiveness of chlordiazepoxide hydrochloride capsules in long term use, that is, more than 4 months, has not been assessed by systematic clinical studies. The physician should periodically reassess the usefulness of the drug for the individual patient. 

Klonopin, Clonazepam Orally Disintegrating Tablet
Seizure Disorders
Klonopin and clonazepam orally disintegrating tablets are useful alone or as an adjunct in the treatment of the Lennox-Gastaut syndrome (petit mal variant), akinetic and myoclonic seizures. In patients with absence seizures (petit mal) who have failed to respond to succinimides, Klonopin and clonazepam orally disintegrating tablets may be useful. In some studies, up to 30% of patients have shown a loss of anticonvulsant activity, often within 3 months of administration. In some cases, dosage adjustment may reestablish efficacy.
Panic Disorder
Klonopin and clonazepam orally disintegrating tablets are indicated for the treatment of panic disorder, with or without agoraphobia, as defined in DSM-V. Panic disorder is characterized by the occurrence of unexpected panic attacks and associated concern about having additional attacks, worry about the implications or consequences of the attacks, and/or a significant change in behavior related to the attacks. The efficacy of Klonopin and clonazepam orally disintegrating tablets was established in two 6- to 9-week trials in panic disorder patients whose diagnoses corresponded to the DSM-IIIR category of panic disorder.
Panic disorder (DSM-V) is characterized by recurrent unexpected panic attacks, i.e., a discrete period of intense fear or discomfort in which four (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart or accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or abdominal distress; (8) feeling dizzy, unsteady, lightheaded or faint; (9) derealization (feelings of unreality) or depersonalization (being detached from oneself); (10) fear of losing control; (11) fear of dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes.
The effectiveness of Klonopin and clonazepam orally disintegrating tablets in long-term use, that is, for more than 9 weeks, has not been systematically studied in controlled clinical trials. The physician who elects to use Klonopin and clonazepam orally disintegrating tablets for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.

Loreev XR
Loreev XR is indicated for the treatment of anxiety disorders in adults who are receiving stable, evenly divided, three times daily dosing with lorazepam tablets. 

Oxazepam
Oxazepam is indicated for the management of anxiety disorders or for the short-term relief of the symptoms of anxiety. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic.
Anxiety associated with depression is also responsive to oxazepam therapy.
This product has been found particularly useful in the management of anxiety, tension, agitation, and irritability in older patients.
Alcoholics with acute tremulousness, inebriation, or with anxiety associated with alcohol withdrawal are responsive to therapy.
The effectiveness of oxazepam in long-term use, that is, more than 4 months, has not been assessed by systematic clinical studies. The physician should periodically reassess the usefulness of the drug for the individual patient. 

Tranxene
Tranxene is indicated for the management of anxiety disorders or for the short-term relief of the symptoms of anxiety. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic.

Tranxene tablets are indicated as adjunctive therapy in the management of partial seizures.

The effectiveness of Tranxene tablets in long-term management of anxiety, that is, more than 4 months, has not been assessed by systematic clinical studies. Long-term studies in epileptic patients, however, have shown continued therapeutic activity. The physician should reassess periodically the usefulness of the drug for the individual patient.
Tranxene tablets are indicated for the symptomatic relief of acute alcohol withdrawal.

Valium, Diazepam Intensol, Diazepam Oral Solution
Valium, Diazepam Intensol, and diazepam oral solution are indicated for the management of anxiety disorders or for the short-term relief of the symptoms of anxiety. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic.
In acute alcohol withdrawal, Valium, Diazepam Intensol, and diazepam oral solution may be useful in the symptomatic relief of acute agitation, tremor, impending or acute delirium tremens and hallucinosis.
Valium, Diazepam Intensol, and diazepam oral solution are a useful adjunct for the relief of skeletal muscle spasm due to reflex spasm to local pathology (such as inflammation of the muscles or joints, or secondary to trauma); spasticity caused by upper motor neuron disorders (such as cerebral palsy and paraplegia); athetosis; and stiff-man syndrome.
Oral Valium, Diazepam Intensol, and diazepam oral solution may be used adjunctively in convulsive disorders, although it has not proved useful as the sole therapy.
The effectiveness of Valium, Diazepam Intensol, and diazepam oral solution in long-term use, that is, more than 4 months, has not been assessed by systematic clinical studies. The physician should periodically reassess the usefulness of the drug for the individual patient. 

Xanax
Xanax is indicated for the acute treatment of generalized anxiety disorder in adults and for the treatment of panic disorder with or without agoraphobia in adults.

Xanax XR
Xanax XR is indicated for the treatment of panic disorder with or without agoraphobia, in adults. 

1. Precertification Criteria

LIMIT CRITERIA  Limits should accumulate across all drugs and strengths up to the highest quantity listed depending on the order the claims are processed.
	1 Month Limit*	3 Month Limit*
Alprazolam Intensol solution (1 mg/mL)	300 mL / 25 days	900 mL / 75 days
Alprazolam ODT (0.25, 0.5, 1, 2 mg)	150 tablets / 25 days	450 tablets / 75 days
Ativan (0.5, 1, 2 mg)	150 tablets / 25 days	450 tablets / 75 days
Chlordiazepoxide (5, 10, 25 mg)	360 capsules / 25 days	1080 capsules / 75 days
Clonazepam ODT (0.125, 0.25, 0.5, 1, 2 mg)	300 tablets / 25 days	900 tablets / 75 days
Diazepam solution (5 mg/5 mL)	1200 mL / 25 days	3600 mL / 75 days
Diazepam Intensol solution (5 mg/mL)	240 mL / 25 days	720 mL / 75 days
Klonopin (0.5, 1, 2 mg)	300 tablets / 25 days	900 tablets / 75 days
Lorazepam Intensol solution (2 mg/mL)	150 mL / 25 days	450 mL / 75 days
Loreev XR (1, 1.5, 2 mg)	150 capsules / 25 days	450 capsules / 75 days
Loreev XR (3 mg)	90 capsules / 25 days	270 capsules / 75 days
Oxazepam (10, 15, 30 mg)	120 capsules / 25 days	360 capsules / 75 days
Tranxene (3.75, 7.5, 15 mg)	180 tablets / 25 days	540 tablets / 75 days
Valium (2, 5, 10 mg)	120 tablets / 25 days	360 tablets / 75 days
Xanax (0.25, 0.5, 1, 2 mg)	150 tablets / 25 days	450 tablets / 75 days
Xanax XR (0.5, 1, 2 mg)	150 tablets / 25 days	450 tablets / 75 days
Xanax XR (3 mg)	90 tablets / 25 days	270 tablets / 75 days
*The duration of 25 days is used for a 30-day fill period and 75 days is used for a 90-day fill period to allow time for refill processing.

 

 

 

 

Place of Service:

Outpatient

The above policy is based on the following references:

1. Alprazolam Intensol oral solution (concentrate) [package insert]. Eatontown, NJ: West-Ward Pharmaceuticals Corp.; March 2017.
2. Alprazolam Orally Disintegrating Tablet [package insert]. Parsippany, NJ: Teva Pharmaceuticals; September 2021.
3. Ativan [package insert]. Bridgewater, NJ: Bausch Health US, LLC; February 2021.
4. Chlordiazepoxide [package insert]. Laurelton, NY: Epic Pharma, LLC; July 2021.
5. Clonazepam Orally Disintegrating Tablet [package insert]. Bedminster, NJ: Alembic Pharmaceuticals, Inc.; September 2021.
6. Diazepam oral solution, Diazepam Intensol oral solution (concentrate) [package insert]. Eatontown, NJ: West-Ward Pharmaceuticals Corp.; February 2021.
7. Klonopin [package insert]. South San Francisco, CA: Genentech USA, Inc.; February 2021.
8. Lorazepam Oral Concentrate [package insert]. Greenville, SC: Pharmaceutical Associates, Inc.; February 2021.
9. Loreev XR [package insert]. Morristown, NJ: Almatica Pharma LLC; December 2021.
10. Oxazepam [package insert]. Parsippany, NJ: Teva Pharmaceuticals, Inc.; September 2021.
11. Tranxene [package insert]. Lebanon, NJ: Recordati Rare Diseases, Inc.; May 2018.
12. Valium [package insert]. Little Falls, NJ: Roche Laboratories Inc.; February 2021.
13. Xanax [package insert]. New York, NY: Pharmacia and Upjohn Company LLC; March 2021.
14. Xanax XR [package insert]. New York, NY: Pharmacia and Upjohn Company LLC; March 2021.
15. Lexicomp Online, AHFS DI (Adult and Pediatric) Online, Hudson, Ohio: UpToDate, Inc.; 2022; Accessed January 27, 2022.
16. Micromedex (electronic version). IBM Watson Health, Greenwood Village, Colorado, USA. Available at: https://www.micromedexsolutions.com. Accessed January 27, 2022.

Copyright 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.

April 30, 2022