Subject: Compounded Drug Products

Policy:

In the absence of a published Aetna Clinical Policy Bulletin to the contrary, compounded drug products are considered medically necessary if ALL of the following criteria are met:

1. The product contains at least one prescription ingredient AND
2. The prescription ingredient is FDA-approved for medical use in the United States AND
3. The compounded product is not a copy of commercially available FDA-approved drug product AND
4. The safety and effectiveness of use for the prescribed indication is supported by FDA-approval or adequate medical and scientific evidence in the medical literature.
   
   Note: Medical and scientific evidence is defined as any one of the following:
   
   a. Peer-reviewed scientific studies published in or accepted for publication by medical journals that meet nationally recognized requirements for scientific manuscripts and that submit most of their published articles for review by experts who are not part of the editorial staff.
   b. Peer-reviewed literature, biomedical compendia, and other medical literature that meet the criteria of the National Institute of Health's National Library of Medicine for indexing in index Medicus, Excerpta Medicus (EMBASE), Medline, or MEDLARS database Health Services Technology Assessment Research (STAR).
   c. Medical journals recognized by the Secretary of Health and Human Services, under Section 1861(t)(2) of the Social Security Act (42 U.S.C. 1395x).
   d. The following standard reference compendia:

e. Findings, studies, or research conducted by or under the auspices of federal government agencies and nationally recognized federal research institutes including the:

f. Peer-reviewed abstracts accepted for presentation at major medical association meetings.
The following compounded preparations are examples of preparations that Aetna considers to be experimental and investigational, because there is inadequate evidence in the peer-reviewed published medical literature of their effectiveness:

Background/Notes

Pharmacist compounding of medication is the combination of the art and science of pharmacy. The pharmacist begins with the unique needs of the individual patient for a medication not commercially available in the strength, flavor, or dosage form required. Pharmacist compounding may be required:

• For preparation of a medication that has been withdrawn form the marketplace due to economic concerns, NOT safety; 
• For those patients that cannot or have trouble swallowing and require a concentrated liquid or a rectal suppository; 
• For those patients who have sensitivity to dyes, preservatives, or fillers in commercial products and require allergy-free medications; 
• For children who require liquid medications

According to the FDA Compliance Policy Guide on Pharmacy Compounding, there is a list of factors that the FDA will consider in exercising its enforcement discretion regarding pharmacy compounding. The FDA recognizes that pharmacists traditionally have extemporaneously compounded and manipulated reasonable quantities of human drugs upon receipt of a valid prescription for an individually identified patient from a licensed practitioner. However, when the scope and nature of a pharmacy's activities raise the kinds of concerns normally associated with a drug manufacturer and result in significant violations of the Federal Food, Drug and Cosmetic Act, the FDA has determined that is should seriously consider enforcement action. In determining whether to initiate such an action, the Agency has stated that it will consider whether the pharmacy engages in any of the following acts:

1. Compounding of drugs in anticipation of receiving prescriptions, except in very limited    quantities in relation to the amounts of drugs compounded after receiving valid prescriptions.
2. Compounding drugs that were withdrawn or removed from the market for safety reasons. Appendix A provides a list of such drugs that will be updated in the future, as appropriate.
3. Compounding finished drugs from bulk active ingredients that are not components of FDA approved drugs without an FDA sanctioned investigational new drug application (IND) in accordance with 21 U.S.C. § 355(i) and 21 CFR 312.
4. Receiving, storing, or using drug substances without first obtaining written assurance from the supplier that each lot of the drug substance has been made in an FDA-registered facility.
5. Receiving, storing, or using drug components not guaranteed or otherwise determined to meet official compendia requirements.
6. Using commercial scale manufacturing or testing equipment for compounding drug products.
7. Compounding drugs for third parties who resell to individual patients or offering compounded drug products at wholesale to other state licensed persons or commercial entities for resale.
8. Compounding drug products that are commercially available in the marketplace or that are essentially copies of commercially available FDA-approved drug products. In certain circumstances, it may be appropriate for a pharmacist to compound a small quantity of a drug that is only slightly different than an FDA-approved drug that is commercially available. In these circumstances, FDA will consider whether there is documentation of the medical need for the particular variation of the compound for the particular patient.
9. Failing to operate in conformance with applicable state law regulating the practice of pharmacy.
   

Place of Service:

Outpatient

The above policy is based on the following references:

General Compounding

1.http://www.fda.gov/cder/pharmcomp/default.htm

Bioidentical Drugs

1. Aetna Medical CPB #0388: Complementary and Alternative Medicine revised April 18, 2006; http://www.aetna.com/cpb/data/CPBA0388.html.
2. Boothby LA, Doering PL, Kipersztok S. Bioidentical hormone therapy: A review. Menopause. 2004;11(3):356-367.
3. ACOG Committee on Gynecologic Practice. ACOG Committee Opinion #322: Compounded bioidentical hormones. Obstet Gynecol. 2005;106(5 Pt 1):1139-1140.
4. Boothby LA, Doering PL, Kipersztok S. Bioidentical hormone therapy: a review. Menopause. 2004 May-Jun;11(3):356-67.

Implantable estradiol pellets

1. Aetna Medical CPB #0345: Implantable Hormone Pellets revised June 23, 2006; http://www.aetna.com/cpb/data/CPBA0345.html.
2. FDA Center for Drug Evaluation and Research meeting of Pharmacy Compound Advisory Committee, October 14, 1998. page 51.

NSAIDs in PLO (pluronic lecithin organogel)

1. Moore RA, Tramer MR, Carroll D, et al. Quantitive systematic review of topically applied non-steroidal anti-inflammatory drugs. BMJ. 1998;316:333-8.
2. Sheu MT, Chen LC, Ho HO. Simultaneous optimization of percutaneous delivery and adhesion for ketoprofen poultice. In J Pharm. 2002;233:257-62.
3. Ceschel GC, Maffei P, Lombardi Borgia S. Correlation between the transdermal permeation of ketoprofen and its solubility in mixtures of a pH 6.5 phosphate buffer and various solvents. Drug Deliv. 2002;9:39-45.
4. Ozaki M, Minami K, Sata T, Shigematsu A. Transdermal ketoprofen mitigates the severity of postoperative sore throat. Can J Anaesth. 2001;48:1080-3.
5. El-Kattan Af, Asbill CS, Kim N, Michniak BB. Effect of formulation variables on the percutaneous permeation of ketoprofen from gel formulations. Drug Deliv. 2000.7:147-53.
6. Hong JY, Lee IH. Suprascapular nerve block or a piroxicam patch for shoulder tip pain after day case laparoscopic surgery. Eur J Anaesthesiol. 2003;20:234-8.
7. Cheong HA, Choi HK. Enhanced percutaneous absorption of piroxicam via salt formation with ethanolamines. Pharm Res. 2002;19:1375-80.
8. Curdy C, Kalia YN, Naik a, Guy RH. Piroxicam delivery into human stratum corneum in vivo: iontophoresis versus passive diffusion. J control Release. 2001;76:739.
9. Beetge E, duPlessis J, Muller DG, et al. The influence of the physicochemical characteristics and pharmacokinetic properties of selected NSAID's on their transdermal absorption. Int J Pharm. 2000;193:261-4.
10. Cordero JA, Alarcon L, Escribano E, Obach R, Domenech J. A comparative study of the transdermal penetration of a series of nonsteroidal anti-inflammatory drugs. J Pharm Sci. 1997;86:503-8.
11. Ritchie LD. A clinical evaluation of flurbiprofen LAT and piroxicam gel: a multicentre study in general practice. Clin Rheumatol. 1996;15:243-7.
12. Russell AL. Piroxicam 0.5% topical gel compared to placebo in the treatment of acute soft tissue injuries: a double-blind study comparing efficacy and safety. Clin Invest Med. 1991;14:35-43.
13. Whitefield M, O'Kane CJ, Anderson S. Comparative efficacy of a proprietary topical ibuprofen gel and oral ibuprofen in acute soft tissue injuries: a randomized, double-blind study. J Clin Pharm Ther. 2002;27:409-17.
14. Machen J, Whitefield M. Efficacy of a proprietary ibuprofen gel in soft tissue injuries: a randomized, double-blind, placebo-controlled study. In J Clin Pract. 2002;56:102-6.
15. Padilla M, Clark GT, Merrill RL. Topical medications for orofacial neuropathic pain: a review. J Am Dent Assoc. 2002;131:184-95.
16. Berti JJ, Lipskys JJ. Transcutaneous drug delivery: a practical review. Mayo clin Proc. 1995;70:581-6.

Hydroxyprogesterone injection

1. American College of Obstetricians and Gynecologists. ACOG Committee Opinion. Use of progesterone to reduce preterm birth. Obstet Gynecol. 2003 Nov; 102(5 Pt 1): 1115-6.
2. Brancazio LR, Murtha AP, Heine RP. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med. 2003 Sep 11; 349(11): 1087-8; author reply 1087-8.
3. Greene MF. Progesterone and preterm delivery-déjà vu all over again. N Engl J Med. 2003 Jun 12; 348(24): 2453-5.
4. Meis PJ, Klebanoff M, Thom E, et al; National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med. 2003 Jun 12; 348(24): 2379-85.
5. Spong CY. Recent developments in preventing recurrent preterm birth. Obstet Gynecol. 2003 Jun; 101(6): 1153-4.

Verapamil in Peyronie's disease

1. Levine LA. Review of current nonsurgical management of Peyronie's disease. Int J Impot Res. 2003 Oct;15 Suppl 5:S113-20.
2. Di Stasi SM, Giannantoni A, Capelli G, Jannini EA, Virgili G, Storti L, Vespasiani G. Transdermal electromotive administration of verapamil and dexamethasone for Peyronie's disease. BJU Int. 2003 Jun;91(9):825-9.
3. Levine LA, Estrada CR, Shou W, Cole A. Tunica albuginea tissue analysis after electromotive drug administration. J Urol. 2003 May;169(5):1775-8.
4. Levine LA, Estrada CR. Intralesional verapamil for the treatment of Peyronie's disease: a review. Int J Impot Res. 2002 Oct;14(5):324-8.
5. Martin DJ, Badwan K, Parker M, Mulhall JP. Transdermal application of verapamil gel to the penile shaft fails to infiltrate the tunica albuginea. J Urol. 2002 Dec;168(6):2483-5.
6. Levine LA, Goldman KE, Greenfield JM. Experience with intraplaque injection of verapamil for Peyronie's disease. J Urol. 2002 Aug;168(2):621-5; discussion 625-6.
7. Cavallini G, Biagiotti G, Koverech A, Vitali G. Oral propionyl-l-carnitine and intraplaque verapamil in the therapy of advanced and resistant Peyronie's disease. BJU Int. 2002 Jun;89(9):895-900.
8. Hellstrom WJ, Bivalacqua TJ. Peyronie's disease: etiology, medical, and surgical therapy. J Androl. 2000 May-Jun;21(3):347-54.
9. Riedl CR, Plas E, Engelhardt P, Daha K, Pfluger H. Iontophoresis for treatment of Peyronie's disease. J Urol. 2000 Jan;163(1):95-9.
10. Mirone V, Imbimbo C, Palmieri A, Fusco F. Our experience on the association of a new physical and medical therapy in patients suffering from induratio penis plastica. Eur Urol. 1999 Oct;36(4):327-30.
11. Lasser A, Vandenberg TL, Vincent MJ, Hellstrom WJ. Intraplaque verapamil injection for treatment of Peyronie's disease. J La State Med Soc. 1998 Sep;150(9):431-4.
12. Rehman J, Benet A, Melman A. Use of intralesional verapamil to dissolve Peyronie's disease plaque: a long-term single-blind study. Urology. 1998 Apr;51(4):620-6.
13. Levine LA. Treatment of Peyronie's disease with intralesional verapamil injection. J Urol. 1997 Oct;158(4):1395-9.
14. Levine LA, Merrick PF, Lee RC. Intralesional verapamil injection for the treatment of Peyronie's disease. J Urol. 1994 Jun;151(6):1522-4.
15. Aetna Medical CPB #7: Erectile Dysfunction, revised February 13, 2004; http://www.aetna.com/cpb/data/CPBA0007.html

Nebulized anti-infectives, nasal administration

1. Aetna Medical CPB #593: Aerosolized Anti-infective Treatment for Sinusitis, revised November 3, 2006; http://www.aetna.com/cpb/data/CPBA0593.html.
2. American Academy of Pediatrics. Subcommittee on Management of Sinusitis and Committee on Quality Improvement. Clinical Practice Guideline: Management of sinusitis. Pediatrics. 2001;108(3):798-808.
3. Snow V, Mottur-Pilson C, Hickner JM; American Academy of Family Physicians; American College of Physicians-American Society of Internal Medicine; Centers for Disease Control; Infectious Diseases Society of America. Principles of appropriate antibiotic use for acute sinusitis in adults. Ann Intern Med. 2001;134(6):495-497.
4. Spector SL, Bernstein IL, Li JT, et al. Parameters for the diagnosis and management of sinusitis. Ann Allergy Asthma Immunol. 1998;102(6 Pt 2):S107-S144.
5. University of Michigan Health System. Acute rhinosinusitis in adults. Ann Arbor, MI: University of Michigan Health System; December 1999.
6. Institute for Clinical Systems Improvement. Acute sinusitis in adults. ICSI health care guidelines; no. GRD02. Bloomington, MN: Institute for Clinical Systems Improvement (ICSI); December 1999.
7. Institute for Clinical Systems Improvement. Rhinitis. Bloomington, MN: Institute for Clinical Systems Improvement (ICSI); June 2000.
8. Agency for Healthcare Research and Quality (AHRQ). Diagnosis and treatment of acute bacterial rhinosinusitis. Evidence Report/Technology Assessment Number 9. AHCPR Publication No. 99-E016. Rockville, MD: AHRQ, 1999.
9. Brooks I, Gooch WM 3rd, Jenkins SG, et al. Medical management of acute bacterial sinusitis. Recommendations of a clinical advisory committee on pediatric and adult sinusitis. Ann Otol Rhinol Laryngol Suppl. 2000;182:2-20.
10. Ressel G. Principles of appropriate antibiotic use: Part III. Acute rhinosinusitis. Centers for Disease Control and Prevention. Am Fam Physician. 2001;64(4):685-686.
11. No authors listed. Antimicrobial treatment guidelines for acute bacterial rhinosinusitis. Sinus and Allergy Health Partnership. Otolaryngol Head Neck Surg. 2000;123(1 Pt 2):5-31.
12. Scheinberg PA, Otsuhi A. Nebulized antibiotics for the treatment of acute exacerbations of chronic rhinosinusitis. Ear Nose Throat J. 2002;81(9):648-652.
13. Desrosiers MY, Salas-Prato M. Treatment of chronic rhinosinusitis refractory to other treatments with topical antibiotic therapy delivered by means of a large-particle nebulizer: Results of a controlled trial. Otolaryngol Head Neck Surg. 2001;125(3):265-269.
14. Vaughan WC. Nebulization of antibiotics in management of sinusitis. Curr Infect Dis Rep. 2004;6(3):187-190.
15. Wahl KJ, Otsuji A. New medical management techniques for acute exacerbations of chronic rhinosinusitis. Curr Opin Otolaryngol Head Neck Surg. 2003;11(1):27-32.
16. Vaughan WC, Carvalho G. Use of nebulized antibiotics for acute infections in chronic sinusitis. Otolaryngol Head Neck Surg. 2002;127(6):558-568.
17. Klepser ME. Role of nebulized antibiotics for the treatment of respiratory infections. Curr Opin Infect Dis. 2004;17(2):109-112.
18. Slavin RG, Spector SL, Bernstein IL, et al. The diagnosis and management of sinusitis: A practice parameter update. J Allergy Clin Immunol. 2005;116(6 Suppl):S13-S47.
19. Hagerman JK, Hancock KE, Klepser ME. Aerosolised antibiotics: A critical appraisal of their use. Expert Opin Drug Deliv. 2006;3(1):71-86.

Ketamine gel

1. Kronenberg RH. Ketamine as an analgesic: parenteral, oral, rectal, subcutaneous, transdermal and intranasal administration. J Pain Palliat Care Pharmacother. 2002; 16(3): 27-35.
2. Lynch ME, Clark AJ, Sawynok J. A pilot study examining topical amitriptyline, ketamine, and a combination of both in the treatment of neuropathic pain. Clin J Pain. 2003 Sep-Oct;19: 323-8.
3. Oatway M, Reid A, Sawynok J. Peripheral antihyperalgesic and analgesic actions of ketamine and amitriptyline in a model of mild thermal injury in the rat. Anesth Analg. 2003 Jul; 97: 168-73.
4. Quan D, Wellish M, Gilden DH. Topical ketamine treatment of postherpetic neuralgia. Neurology. 2003 Apr 22; 60(8): 1391-2.
5. Ushida T, Tani T, Kanbara T, Zinchuk VS, Kawasaki M, Yamamoto H. Analgesic effects of ketamine ointment in patients with complex regional pain syndrome type 1. Reg Anesth Pain Med. 2002 Sep-Oct; 27(5): 524-8.
6. Ohata H, Iida H, Nagase K, Dohi S. . The effects of topical and intravenous ketamine on cerebral arterioles in dogs
7. receiving pentobarbital or isoflurane anesthesia. Anesth Analg. 2001 Sep; 93: 697-702.
8. Azevedo VM, Lauretti GR, Pereira NL, Reis MP. Transdermal ketamine as an adjuvant for postoperative analgesia after abdominal gynecological surgery using lidocaine epidural blockade. Anesth Analg. 2000 Dec; 91(6): 1479-82.
9. Kolesnikov YA, Pasternak GW. Peripheral blockade of topical morphine tolerance by ketamine. Eur J Pharmacol. 1999 Jun 18; 374(2): R1-2.
10. Pedersen JL, Galle TS, Kehlet H . Peripheral analgesic effects of ketamine in acute inflammatory pain. Anesthesiology. 1998 Jul; 89(1): 58-66.
11. Hirota K, Zsigmond EK, Matsuki A, Rabito SF. Topical ketamine inhibits albumin extravasation in chemical peritonitis in rats. Acta Anaesthesiol Scand. 1995 Feb; 39(2): 174-8.
 

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.

Appendix A:

LIST OF COMPOUNDING DRUGS THAT WERE WITHDRAWN OR REMOVED FROM THE MARKET FOR SAFETY REASONS

Adenosine phosphate: All drug products containing adenosine phosphate.
Adrenal cortex: All drug products containing adrenal cortex.
Aminopyrine: All drug products containing aminopyrine.
Astemizole: All drug products containing astemizole.
Azaribine: All drug products containing azaribine.
Benoxaprofen: All drug products containing benoxaprofen.
Bithionol: All drug products containing bithionol.
Bromfenac sodium: All drug products containing bromfenac sodium.
Butamben: All parenteral drug products containing butamben.
Camphorated oil: All drug products containing camphorated oil.
Carbetapentane citrate: All oral gel drug products containing carbetapentane citrate.
Casein, iodinated: All drug products containing iodinated casein.
Chlorhexidine gluconate: All tinctures of chlorhexidine gluconate formulated for use as a patient preoperative skin preparation.
Chlormadinone acetate: All drug products containing chlormadinone acetate.
Chloroform: All drug products containing chloroform.
Cisapride: All drug products containing cisapride.
Cobalt: All drug products containing cobalt salts (except radioactive forms cobalt and its salts and cobalamin and its derivatives).
Dexfenfluramine hydrochloride: All drug products containing dexfenfluramine hydrochloride.
Diamthazole dihydrochloride: All drug products containing diamthazole dihydrochloride.
Dibromsalan: All drug products containing dibromsalan.
Diethylstilbestrol: All oral and parenteral drug products containing 25 milligrams or more of diethylstilbestrol per unit dose.
Dihydrostreptomycin sulfate: All drug products containing dihydrostreptomycin sulfate.
Dipyrone: All drug products containing dipyrone.
Encainide hydrochloride: All drug products containing encainide hydrochloride.
Fenfluramine hydrochloride: All drug products containing fenfluramine hydrochloride.
Flosequinan: All drug products containing flosequinan.
Gelatin: All intravenous drug products containing gelatin.
Glycerol, iodinated: All drug products containing iodinated glycerol.
Gonadotropin, chorionic: All drug products containing chorionic gonadotropins of animal origin.
Grepafloxacin: All drug products containing grepafloxacin.
Mepazine: All drug products containing mepazine hydrochloride or mepazine acetate.
Metabromsalan: All drug products containing metabromsalan.
Methamphetamine hydrochloride: All parenteral drug products containing methamphetamine hydrochloride.
Methapyrilene: All drug products containing methapyrilene.
Methopholine: All drug products containing methopholine.
Mibefradil dihydrochloride: All drug products containing mibefradil dihydrochloride.
Nitrofurazone: All drug products containing nitrofurazone (except topical drug products formulated for dermatalogic application).
Nomifensine maleate: All drug products containing nomifensine maleate.
Oxyphenisatin: All drug products containing oxyphenisatin.
Oxyphenisatin acetate: All drug products containing oxyphenisatin acetate.
Phenacetin: All drug products containing phenacetin.
Phenformin hydrochloride: All drug products containing phenformin hydrochloride.
Pipamazine: All drug products containing pipamazine.
Potassium arsenite: All drug products containing potassium arsenite.
Potassium chloride: All solid oral dosage form drug products containing potassium chloride that supply 100 milligrams or more of potassium per dosage unit (except for controlled-release dosage forms and those products formulated for preparation of solution prior to ingestion).
Povidone: All intravenous drug products containing povidone.
Reserpine: All oral dosage form drug products containing more than 1 milligram of reserpine.
Sparteine sulfate: All drug products containing sparteine sulfate.
Sulfadimethoxine: All drug products containing sulfadimethoxine.
Sulfathiazole: All drug products containing sulfathiazole (except those formulated for vaginal use).
Suprofen: All drug products containing suprofen (except ophthalmic solutions).
Sweet spirits of nitre: All drug products containing sweet spirits of nitre.
Temafloxacin hydrochloride: All drug products containing temafloxacin.
Terfenadine: All drug products containing terfenadine.3,3',4',5-tetrachlorosalicylanilide: All drug products containing 3,3',4',5-tetrachlorosalicylanilide.
Tetracycline: All liquid oral drug products formulated for pediatric use containing tetracycline in a concentration greater than 25 milligrams/milliliter.
Ticrynafen: All drug products containing ticrynafen.
Tribromsalan: All drug products containing tribromsalan.
Trichloroethane: All aerosol drug products intended for inhalation containing trichloroethane.
Troglitazone: All drug products containing troglitazone.
Urethane: All drug products containing urethane.
Vinyl chloride: All aerosol drug products containing vinyl chloride.
Zirconium: All aerosol drug products containing zirconium.
Zomepirac sodium: All drug products containing zomepirac sodium.

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.

January 01, 2007