Nathalie Dagenais, BSc, PharmD1
Franky Liu, RPh, BScPhm, MSc2
Maria Zhang, RPh, BScPhm, PharmD, MSc 2,3
1Hamilton Health Sciences, Hamilton, Ontario
2Leslie Dan Faculty of Pharmacy, University of Toronto
3Centre for Addiction and Mental Health, Toronto, Ontario
Depression is the leading cause of disability worldwide, affecting over 298 million people globally1, 2. While its treatment is multimodal, with medications frequently a cornerstone, current pharmacotherapies are limited by delayed onset of clinically significant antidepressant effects and significant relapse rates3. In fact, approximately one-third of individuals with major depressive disorder will experience treatment-resistant depression (TRD), defined as a suboptimal response to two or more appropriate trials of antidepressant therapy4. To address these gaps in treatment, there has been growing interest in the use of ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, as well as its newly marketed stereoisomer, esketamine. With the increased use of these agents in hospital and community settings, pharmacists play an invaluable role in optimizing treatment selection, and monitoring medication effectiveness and safety.
KETAMINE AND ESKETAMINE IN TREATMENT RESISTANT DEPRESSION
The 2016 Canadian Network for Mood and Anxiety Treatments (CANMAT) guideline lists intravenous ketamine infusions as an ‘experimental treatment’ reserved for the acute management of TRD in academic depression treatment centres5. Most of the evidence for this recommendation stems from single doses6, 7, though newer evidence suggests that repeated ketamine infusions may prolong the duration of antidepressant response3, 4, 8, 9. Currently, the optimal dose, frequency, and safety of repeated infusions beyond four weeks remain unclear4, 10. Despite its inclusion in the CANMAT guidelines, intravenous ketamine remains largely inaccessible for those with TRD. Understandably, there is much interest in non-parenteral forms of ketamine, including intranasal delivery. There are a variety of important clinical, pharmaceutical, operational, and legal considerations that a pharmacist should evaluate when considering compounded intranasal ketamine. These considerations should be taken in context of the recently available, patented-delivery intranasal esketamine.
In May 2020, Health Canada approved intranasal esketamine (SPRAVATO®) for the treatment of major depressive disorder in adults who have not responded adequately to at least two separate courses of treatment with different antidepressants, each of adequate dose and duration, in the current moderate to severe depressive episode. The medication is to be used in combination with a selective serotonin or norepinephrine reuptake inhibitor11. While the product continues to be reviewed for its cost-effectiveness in Canada and in the United Kingdom, draft recommendations from the UK are negative as there are doubts regarding esketamine’s true efficacy12, 13. Notably, studies compared esketamine simultaneously with an oral antidepressant started de novo, with a matching placebo and an oral antidepressant. This comparator is not reflective of how treatment-resistant depression is typically managed (i.e., an antidepressant augmented with lithium or an antipsychotic, electroconvulsive therapy, and/or psychotherapy)13. Additionally, given the mandatory monitoring period of two hours post medication administration, significant operational issues exist in its implementation.
Table 1: Comparison of intranasal ketamine and esketamine
|Compounded intranasal ketamine||Parenteral ketamine for intranasal administration||Intranasal esketamine (Spravato®)|
|Commercially available product?||No||No. Active pharmaceutical ingredient itself is commercially available but not formulated specifically for intranasal administration||Yes, inclusive of drug and delivery device|
|Indicated for treatment resistant depression?||No||No||Yes|
|Prescribing restrictions?||No||No||Yes, only prescribers and pharmacists who have enrolled in the manufacturer’s program are permitted to prescribe and dispense the medication.|
|Restrictions in medication distribution||No restrictions beyond what is typically expected of narcotic drugs.|
|Patient access||Following a prescription, patient can pick up the medication from a pharmacy of their choice and then self-administer the medication unsupervised||Following a prescription, clinic staff must pick up the medication from an authorized retailer. Patient self-administers the medication under the mandatory supervision of a health care provider.|
|Approximate drug cost (decreases with time as frequency of administration wanes)||Variable, ranges to approximately $100 for 30-day supply; does not include cost of atomizer||Variable, approximately $100 to $120 for 30-day supply; does not include cost of atomizer||Approximately $5000 for first month|
|Monitoring||No mandatory clinical monitoring by a health care provider||Mandatory monitoring for 2 hours post-dose by a health care provider|
|Should be tracked as a general non-methadone controlled compounded substance via the Ontario Narcotic Monitoring System (manual process), using Pseudo-DIN 09857417||Is tracked as ketamine via the Ontario Narcotic Monitoring System using DIN assigned to parenteral ketamine product||Is tracked as esketamine via the Ontario Narcotic Monitoring System|
|Effectiveness: measures of antidepressant effect (e.g., Patient Health Questionnaire-9, Quick Inventory of Depressive Symptoms)
Safety: Dissociation, blood pressure, heart rate, nausea/vomiting, changes in mental status, vertigo, sedation, suicidal ideation, substance use disorder, ulcerative or interstitial cystitis, cognitive impairment
Pharmaceutically, intranasal absorption is complicated by high inter- and intra-individual variability, differing with drug formulation, delivery device, insufflation technique and individual patient factors. Intranasal absorption is further limited by administered fluid volume: doses should be divided into 0.1 mL sprays with a maximum volume of 0.3-0.5 mL per nostril to avoid being swallowed and subject to first-pass metabolism1416.
With a commercially available racemic isolate available, pharmacy professionals should exercise careful professional judgment before proceeding with product formulation: these factors could include consideration for continuity of care; market availability or shortage of products and/or excipients; or compelling socioeconomic factors.
If compounding intranasal ketamine is deemed necessary, it must be compounded from powder or parenteral solution and manually assembled into a syringe fitted with an atomizer, which introduces further variability. Studies examining intranasal ketamine have exclusively used commercially available parenteral ketamine solution17, 18.
If intranasal ketamine is to be inhaled from a solution compounded from powder, rather than the commercially available parenteral formulation, pharmacy professionals should consider the following when deciding to compound a ketamine preparation:
- Ketamine as an active pharmaceutical ingredient refers to a racemic mixture of two stereoisomers of (R)-(-)-ketamine and (S)-(+)-ketamine that exist in approximately equal proportion, with distinct medicinal chemical, pharmacodynamic and pharmacokinetic profiles that may complicate replicability in dosage form preparation and therapeutic effect19.
- Ketamine is listed as a drug in the Narcotic Control Regulations under the Controlled Drugs and Substances Act and should be adjudicated through the province-wide Narcotic Monitoring System (NMS)20. If it is compounded from a powder without a DIN, it must be submitted using the general non-methadone compounded controlled substance pseudo-DIN (09857417)21.
- Special attention to isotonicity and pH are required to ensure patient acceptability and pharmaceutical elegance. For instance, ketamine is a weak organic base that is soluble in low pH. Excipients selected, particularly preservatives, should be chemically compatible to prevent inadvertent precipitation, dose variability and irritation to nasal mucosa2224. In this regard, preservative addition is generally expected due to its aqueous formulation.
- Compounders should observe the requirements outlined in both the USP 795 chapter on Nonsterile Preparations (which lists nasal preparations for local applications)25 and NAPRA guidance document
swhen setting beyond-use dates and assigning lot numbers26.
- Compounders should maintain a robust quality assurance program as part of NAPRA’s Model Standards for Pharmacy Compounding of Non-sterile Preparations; compounders may also consult the USP <795> for nonsterile preparations chapter on quality assurance for guidance on factors to observe25. Documentation should include rationale for excipient choice and/or omission, references to published formulae (if applicable), and quality control parameters which may include pH, mass analyses and/or organoleptic analyses25, 26. These records should be easily retrievable should any clinical issues arise, which could include adverse reaction management and reporting, therapeutic efficacy assessment or assessing batch variance.
Compounding is typically reserved for situations where “there is a therapeutic need or lack of product availability” and should not duplicate “an approved drug product”27. Arguably, with esketamine’s Canadian market entrance, the use of intranasal ketamine, particularly to address treatment-resistant depression, will diminish.
Given the significant burden of illness and caveats in the effectiveness of current antidepressants, there is much interest in non-traditional pharmacotherapies for depression. With their novel mechanism of action and potential efficacy in TRD, ketamine and esketamine have emerged as medications of high interest. However, the quantity and quality of evidence supporting the use of these products vary depending on the formulation, route of administration, and/or dosage form. Pharmacists in all direct patient care settings will need to use their clinical judgment, knowledge of pharmaceutics, and patient care skills to ensure the safe and rational use of these emergent therapies.
- Collins PY, Patel V, Joestl SS, March D, Insel TR, Daar AS. Grand challenges in global mental health. Nature. 2011 Jul 6;475(7354):2730.
- Steensma C, Loukine L, Orpana H, McRae L, Vachon J, Mo F, et al. Describing the population health burden of depression: health-adjusted life expectancy by depression status in Canada. Health Promot Chronic Dis Prev Can. 2016 Oct;36(10):20513.
- Coyle CM, Laws KR. The use of ketamine as an antidepressant: a systematic review and meta-analysis. Hum Psychopharmacol. 2015 May;30(3):15263.
- Singh JB, Fedgchin M, Daly EJ, De Boer P, Cooper K, Lim P, et al. A Double-Blind, Randomized, Placebo-Controlled, Dose-Frequency Study of Intravenous Ketamine in Patients With Treatment-Resistant Depression. Am J Psychiatry. 2016;173(8):81626.
- Kennedy SH, Lam RW, McIntyre RS, Tourjman SV, Bhat V, Blier P, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder. Can J Psychiatry. 2016 Sep;61(9):54060.
- Wilkinson ST, Ballard ED, Bloch MH, Mathew SJ, Murrough JW, Feder A, et al. The Effect of a Single Dose of Intravenous Ketamine on Suicidal Ideation: A Systematic Review and Individual Participant Data Meta-Analysis. Am J Psychiatry. 2018 01;175(2):1508.
- McGirr A, Berlim MT, Bond DJ, Fleck MP, Yatham LN, Lam RW. A systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials of ketamine in the rapid treatment of major depressive episodes. Psychological Medicine. 2015 Mar;45(4):693704.
- Vande Voort JL, Morgan RJ, Kung S, Rasmussen KG, Rico J, Palmer BA, et al. Continuation phase intravenous ketamine in adults with treatment-resistant depression. J Affect Disord. 2016;206(h3v, 7906073):3004.
- Aan het Rot M, Collins KA, Murrough JW, Perez AM, Reich DL, Charney DS, et al. Safety and Efficacy of Repeated-Dose Intravenous Ketamine for Treatment-Resistant Depression. Biological Psychiatry. 2010 Jan 15;67(2):13945.
- Short B, Fong J, Galvez V, Shelker W, Loo CK. Side-effects associated with ketamine use in depression: a systematic review. Lancet Psychiatry. 2018;5(1):6578.
- Janssen Inc. SPRAVATO® Esketamine Nasal Spray Product Monograph [Internet]. 2020. Available from: https://pdf.hres.ca/dpd_pm/00055812.pdf
- Canadian Agency for Drugs and Technologies in Health (CADTH). Esketamine Hydrochloride Common Drug Review [Internet]. CADTH.ca. 2020. Available from: https://www.cadth.ca/esketamine-hydrochloride
- National Institute for Health and Care Excellence (NICE). Esketamine for treating treatment-resistant depression [Internet]. 2020. Available from: https://www.nice.org.uk/guidance/GID-TA10371/documents/129-2
- Stapleton S, Valdez A, Killian M, Bradford J, Cooper M, Horigan A, et al. Clinical Practice Guideline: Intranasal Medication Administration. Journal of Emergency Nursing. 2018 Jan 1;44(1):5.e1-5.e43.
- Streeter L, Male L, Brown S, McLennan J, Paul S. Intranasal Medication Administration [Internet]. Winnipeg Regional Health Authority (WRHA) Evidence Informed Practice Tools. 2017 [cited 2019 Aug 26]. Available from: http://www.wrha.mb.ca/extranet/eipt/files/EIPT-055.pdf
- Bitter C, Suter-Zimmermann K, Surber C. Nasal drug delivery in humans. Curr Probl Dermatol. 2011;40:2035.
- Lapidus KAB, Levitch CF, Perez AM, Brallier JW, Parides MK, Soleimani L, et al. A randomized controlled trial of intranasal ketamine in major depressive disorder. Biol Psychiatry. 2014;76(12):9706.
- G?lvez V, Li A, Huggins C, Glue P, Martin D, Somogyi AA, et al. Repeated intranasal ketamine for treatment-resistant depression – the way to go? Results from a pilot randomised controlled trial. J Psychopharmacol (Oxford). 2018 Apr;32(4):397407.
- Yang C, Yang J, Luo A, Hashimoto K. Molecular and cellular mechanisms underlying the antidepressant effects of ketamine enantiomers and its metabolites. Translational Psychiatry. 2019 Nov 7;9(1):111.
- Ontario College of Pharmacists. Prescription Regulation Summary Chart [Internet]. 2020. Available from: https://www.ocpinfo.com/wp-content/uploads/2019/05/Prescription-Regulation-Summary-Chart-Summary-of-Laws.pdf
- Ontario Public Drug Programs Division. Important Notice from the Executive Officer: Proper Submissions to the Narcotics Monitoring System (NMS) [Internet]. 2012. Available from: http://www.health.gov.on.ca/en/pro/programs/drugs/opdp_eo/notices/exec_office_odb_20120924.pdf
- Newton DW. Drug incompatibility chemistry. Am J Health Syst Pharm. 2009 Feb 15;66(4):34857.
- Loyd A Jr. Ketamine 25-mg/mL Nasal Spray. International Journal of Pharmaceutical Compounding [Internet]. 2004 Dec [cited 2020 Sep 20];8(6). Available from: https://ijpc.com/Abstracts/Abstract.cfm?ABS=2090
- Gebhardt U, Knoch A, Rauchfuss R, Schneider, M. Stable ketamine solutions. WO Patent 1994023711A1. 1993.
- The United States Pharmacopeial Convention. Pharmaceutical CompoundingNonsterile Preparations Revision Bulletin [Internet]. 2019. Available from: https://www.uspnf.com/sites/default/files/usp_pdf/EN/USPNF/revisions/gc-795-postponement-rb-notice-20191122.pdf
- National Association of Pharmacy Regulatory Agencies. Model Standards for Pharmacy Compounding of Non-Sterile Preparations [Internet]. 2018. Available from: https://napra.ca/sites/default/files/documents/Mdl_Stnds_Pharmacy_Compounding_Nonsterile_Preparations_March2018_FINAL.pdf
- Health Canada. Policy on Manufacturing and Compounding Drug Products in Canada (POL-0051) [Internet]. aem. 2009 [cited 2021 Jan 2]. Available from: https://www.canada.ca/en/health-canada/services/drugs-health-products/compliance-enforcement/good-manufacturing-practices/guidance-documents/policy-manufacturing-compounding-drug-products.html