New Pharmacy Compounding Opportunities with Azelastine

By Nat Jones

We’re excited that patients and physicians now have access to Azelastine Hydrochloride USP as an ingredient option in compounded medications. There are some commercial products available, including a combination product, but when those items don’t fit the specific needs of patients, we need to put on our thinking caps and start looking for other options for them. We’re sure that you compounders out there can come up with a few of your own as well. To help you get started, here’s a little physiology and pharmacology review.

Histamine and Its Receptors

The human body has an elaborate defense system, and one of its missions is to protect us from foreign substances that are potentially harmful. When we come in contact with anything that is perceived as a threat, our immune system can get stimulated both at an innate and an acquired level. Either way, one of the substances involved in the fight is histamine. Released by mast cells and basophils in response to injury and in allergic and inflammatory reactions, histamine causes contraction of smooth muscle and dilation of capillaries.

In order for histamine to have effect, however, it must stimulate its receptors. There are four types of histamine receptors: H1–H4. For this discussion we will focus on the H1 receptor. Located in various tissues and systems in the body, such as the skin, H1 receptors can stimulate inflammation and itch and even pain stimulus in nociceptors. It is important to note that other substances can cause itching and inflammation, too, such as substance P, cytokines, proteases, etc. H1 receptors are also found in the upper respiratory tract where they can stimulate swelling and congestion in the nasal passages and pharyngeal area.

Azelastine Overview

Azelastine is an H1 receptor antagonist, or blocker. It is one of the “second-generation” antihistamines generally considered to be low- or non-sedating and has negligible anticholinergic activity, as opposed to “first-generation” drugs, such as diphenhydramine, that usually cause a lot of drowsiness because of sedative and muscarinic properties. H1 antihistamines are used in the treatment of allergic rhinitis, allergic conjunctivitis, contact dermatitis, rhinorrhea, urticaria, angioedema and pruritus, and as an adjunct in the treatment of anaphylactic or anaphylactoid reactions.

In addition to its antihistaminic activity, azelastine is a mast-cell stabilizer, inhibiting histamine release from mast cells at a level that is 5,000 times more potent than cromolyn sodium, astemizole or theophylline. It also inhibits other mediators of allergic reactions, such as leukotrienes and platelet-activating factor (PAF).¹

The bioavailability of intranasal azelastine solutions is about 40%, and the oral biological half-life is approximately 22 hours. However, the nasal product may need to be administered twice daily depending on response and potency. There have been no reported over-dosages with azelastine nasal spray.² There are a few adverse events reported for the nasal products (Table 1), so keep these in mind when counseling and evaluating your patients and their responses to therapy.

Azelastine in Combination Formulas

At present, there are two azelastine nasal solutions on the market, a 0.1% and a 0.15% indicated for allergic and vasomotor rhinitis. There is a 0.05% ophthalmic solution that is FDA-approved for allergic conjunctivitis and ocular pruritus. There is also a nasal spray product, Dymista®, which is a combination of azelastine with fluticasone indicated for seasonal allergic rhinitis. The patent issued for it in 2012 is set to expire in 2023, so there is no generic version at this time. These products leave plenty of room for compounding pharmacists to create personalized combination medications for patients.

One combination we’ve looked at includes montelukast, a leukotriene antagonist. In addition to its other benefits, azelastine intranasal spray reduces substance P release into nasal lavage fluid, which may be an important aspect of the clinical efficacy of topical azelastine in perennial non-allergic rhinitis patients.³ But azelastine also shows anti-inflammatory properties in therapeutically relevant concentrations by reducing TNF alpha release and inhibiting leukotriene C4 production in allergically stimulated human nasal polyp cells.⁴ This is some of the evidence that led us to create nasal combination formulations with montelukast.

It seems of late that no discussion is complete without mentioning naltrexone as a potential API in compounding, so nasal and topical uses are no exception. The toll-like receptor 4 (TLR4) signal pathway plays an important role in initiating the innate immune response, and its activation by bacterial endotoxin is responsible for chronic and acute inflammatory disorders.  Low-dose naltrexone has anti-inflammatory activity by affecting TLR4, and topical naltrexone has shown efficacy in treating pruritus.^5,6 This led us to including naltrexone in some of our combination formulas, too.

Azelastine also seems to have an inhibitory effect on eosinophil and neutrophil activation in patients with nasal polyps.⁷ Nasal corticosteroids are successful in treating sinonasal polyposis, so combining them with azelastine was also a logical step in both creation of nasal spray and irrigation formulas.

Though the manufacturer has a patent on a combination with fluticasone, compounders can formulate combinations with mometasone or budesonide when clinically relevant. In addition to working with these, we also formulated a triple combination of azelastine and fluticasone with montelukast.

The potential benefits of a MucoLox™ nasal formulation—because of it mucoadhesive properties—can help keep the APIs in contact with the mucosa longer, creating a greater chance for better clinical outcomes for your patients. Increased contact time may also lead to less frequent dosing, potentially just once a day. As the references indicate, the nasal spray formulas we have developed may potentially be options for patients with non-allergic and seasonal allergic rhinitis, chronic rhinitis/rhinosinusitis, vasomotor rhinitis, and nasal polyps. 

PCCA members can access some examples of nasal-spray formulas with azelastine here.

We have also created several unique formulas for sinonasal irrigation with LoxaSperse® and/or XyliFos®. As the references indicate, these may be potential options for patients with non-allergic and seasonal allergic rhinitis, chronic rhinitis/rhinosinusitis, vasomotor rhinitis, and sinonasal polyps as well. At present there are no manufactured azelastine irrigation products on the market.

 PCCA members can access some examples of sinonasal-irrigation formulas with azelastine here.

Although oral azelastine has never been marketed, it has been studied in doses ranging from 2–16 mg, and one area in which it was tested is dermatology. There is evidence for use in contact dermatitis, chronic idiopathic urticaria, pruritus and radiation dermatitis.^8,9,10,11 Discontinuation of the nasal spray product is even recommended 48 hours prior to intradermal allergy testing due to its ability to decrease wheal response by 40% from baseline. These activities give compounding pharmacists another unique opportunity not yet marketed: PCCA Formula #12946, a combination topical cream in VersaBase®. (PCCA members can access it here.) This formulation takes advantage of the properties of two other APIs with known dermatologic benefits.

Azelastine can provide many possibilities to help you address your patients’ needs. The example formulas I’ve referred to are just the start.

If PCCA members have questions about compounding with Azelastine Hydrochloride USP, they can contact our Pharmacy Consulting Department at 800.331.2498.

Nat Jones, RPh, FIACP, is a Clinical Compounding Pharmacist at PCCA.

A version of this article was originally published the Summer 2018 issue of the Apothagram, PCCA’s quarterly, members-only magazine.

References
1.    Castillo, M., Scott, N. W., Mustafa, M. Z., Mustafa, M. S., & Azuara-Blanco, A. (2015). Topical antihistamines and mast cell stabilisers for treating seasonal and perennial allergic conjunctivitis. Cochrane Database of Systematic Reviews, (6). https://doi.org/10.1002/14651858.CD009566.pub2  
2.    Azelastine. (2012). In Toxnet Toxicology Data Network. Retrieved from https://toxnet.nlm.nih.gov/cgi-bin/sis/search2/r?dbs+hsdb:@term+@rn+@rel+58581-89-8 
3.    Gawlik, R., Jawor, B., Rogala, B., Parzynski, S., & DuBuske, L. (2013). Effect of intranasal azelastine on substance P release in perennial nonallergic rhinitis patients. American Journal of Rhinology & Allergy, 27(6), 514-516. https://doi.org/10.2500/ajra.2013.27.3955 
4.    Küsters, S., Schuligoi, R., Hüttenbrink, K. B., Rudert, J., Wachs, A., Szelenyi, I., & Peskar, B. A. (2002). Effects of antihistamines on leukotriene and cytokine release from dispersed nasal polyp cells. Arzneimittelforschung [Drug Research], 52(2), 97-102. https://doi.org/10.1055/s-0031-1299863 
5.    Younger, J., Parkitny, L., & McLain, D. (2014). The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain. Clinical Rheumatology, 33(4), 451-459. https://dx.doi.org/10.1007%2Fs10067-014-2517-2 
6.    Frech, T., Novak, K., Revelo, M. P., Murtaugh, M., Markewitz, B., Hatton, N., … Sawitzke, A. D. (2011). Low-dose naltrexone for pruritus in systemic sclerosis. International Journal of Rheumatology, 2011, 1-5. https://dx.doi.org/10.1155%2F2011%2F804296 
7.    Mösges, R., & Klimek, L. (1998). Azelastine reduces mediators of inflammation in patients with nasal polyps. Allergy & Asthma Proceedings, 19(6), 379-383. 
8.    De Weck, A. L., Derer, T., & Bähre, M. (2000). Investigation of the anti-allergic activity of azelastine on the immediate and late-phase reactions to allergens and histamine using telethermography. Clinical & Experimental Allergy, 30(2), 283-287. https://doi.org/10.1046/j.1365-2222.2000.00724.x
9.    Camarasa, J. M., Aliaga, A., Fernández-Vozmediano, J. M., Fonseca, E., Iglesias, L., & Tagarro, I. (2001). Azelastine tablets in the treatment of chronic idiopathic urticaria: Phase III, randomised, double-blind, placebo and active controlled multicentric clinical trial. Skin Pharmacology and Applied Skin Physiology, 14(2), 77-86. https://doi.org/10.1159/000056337
10.    Henz, B. M., Metzenauer, P., O'Keefe, E., & Zuberbier, T. (1998). Differential effects of new-generation H1-receptor antagonists in pruritic dermatoses. Allergy, 53(2), 180-183. https://doi.org/10.1111/j.1398-9995.1998.tb03867.x
11.    Murakami, R., Baba, Y., Nishimura, R., Furusawa, M., Yokoyama, T., Yamashita, Y., … Ono, T. (1997). The effect of azelastine on acute radiation dermatitis in mice models. International Journal of Radiation Oncology • Biology • Physics, 37(4), 907-911. https://doi.org/10.1016/S0360-3016(96)00621-9

These statements are provided for educational purposes only. They have not been evaluated by the Food and Drug Administration, and are not to be interpreted as a promise, guarantee or claim of therapeutic efficacy or safety. The information contained herein is not intended to replace or substitute for conventional medical care, or encourage its abandonment.