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As one of the most studied synthetic drugs in modern history, quinacrine HCI was first used as an antimalarial and later to treat rheumatic skin diseases, including lupus. With May designated as Lupus Awareness month, learn more about quinacrine HCI and the twists and turns of its storied past. Quinacrine hydrochloride (HCI) (atabrine, mepacrine, chinacrin), developed in the late 1920s, was the first synthesized form of quinine — a natural alkaloid isolated from the South American cinchona bark tree that was used for centuries by indigenous people to treat fevers, chills and other malaria-type symptoms.1-3
During World War II (WWII), quinacrine replaced quinine for use in U.S. soldiers as an antimalarial prophylaxis and to treat soldiers infected with malaria — most notably those stationed in the South Pacific. According to a U.S. Surgeon General Office report, quinacrine was administered to more than three million soldiers. The soldiers were routinely monitored for safety and efficacy, which made quinacrine one of the most extensively studied synthetic drugs in the history of modern medicine.1,2 The monitoring also led to recognition of symptom relief in soldiers afflicted with differing types of lupus.
It's important to note that quinacrine was not the only drug synthesized from quinine pre- and post-WWII. Chloroquine phosphate was developed in 1934; however, due to an initial evaluation that determined toxicity levels were too high for human use, chloroquine was not used as an antimalarial until after the conclusion of WWII.3 Hydroxychloroquine sulfate, developed in the 1950s to reduce the toxicity of chloroquine, is another synthesized form.4
Collectively, antimalarials quinacrine, chloroquine and hydroxychloroquine were studied throughout the decades following WWII. Although the mode of action remains disputed, the antimalarials would ultimately gain recognition as effective treatments for systemic lupus erythematosus and cutaneous lupus erythematosus.1-4
Types of Lupus: Systemic & Cutaneous
An autoimmune disease, where a person’s immune system attacks healthy tissue, lupus often causes pain and inflammation in any part of an afflicted person’s body. In addition to affecting skin and joints, lupus can also affect internal organs. Lupus primarily affects women, with onset generally occurring between ages 15 – 45.
Systemic lupus erythematosus (SLE) is the most prevalent form of lupus. Although symptoms vary among individuals, typical symptoms include arthritis; fevers; fatigue; a malar or “butterfly” rash that appears across the nose and cheeks; hair loss; sensitivity to the sun; swollen glands; swelling in the legs or around the eyes; pain when breathing deeply or lying down; headaches, dizziness, depression, confusion or seizure; and abdominal pain. Inflammation caused by SLE can led to damage in internal organs, including kidney failure (lupus nephritis); seizures and memory problems; heart valve damage due to scarring, inflammation of the lining around the heart muscle (pericarditis) and inflammation of the heart muscle itself (myocarditis); inflammation of blood vessels (vasculitis); blood clots due to high levels of antiphospholipid antibodies; low blood cell counts; and inflammation of tissue that surrounds the lungs (pleurisy).6
Cutaneous lupus erythematosus (CLE) primarily affects the skin and is composed of three main types: acute cutaneous lupus (acute skin lupus), subacute cutaneous lupus (subacute lupus) and chronic cutaneous lupus (discoid lupus), the latter of which is the most common type.7 Discoid lupus appears on the scalp or in the bowl of the ear as a red to purple rash that causes discoloration, scarring and hair loss. Although CLE primarily affect the skin, providers are advised to closely monitor patients to ensure the disease does not affect internal organs.8
In October 1951, Francis Page reported in Lancet his observations on the treatment of 18 cases of lupus erythematosus with quinacrine HCI at daily doses ranging from 100 to 300 mg. Of the 18, 14 patients showed good or excellent improvement of skin lesions. Three patients showed slight improvement, while one patient had no visible change.9
The success of quinacrine HCI spurred others to conduct similar studies. In 1953, Bernard L. Rhodes, M.D., and Manuel F. Allende, M.D., reported before the California Medical Association that 25 patients with chronic discoid lupus erythematosus were administered 100 mg. of quinacrine HCI three times daily for two to three weeks, followed by 100 mg. daily until satisfactory results were obtained. Twenty-one of the 25 patients showed satisfactory improvement, seven of whom had complete clearing of lesions. The remaining four did not improve.10
Throughout the following decades, quinacrine HCI — often compounded with hydroxychloroquine or chloroquine — remained a standard treatment for SLE and CLE.1-6
Section 503A and 503B of the Drug Quality and Security Act (DQSA) establish criteria for bulk drug substances used in the respective compounding environments. FDA has also issued interim policies while they work to finalize lists of bulk substances for 503A and 503B; items that appear on Category 1 of the interim lists may be eligible for enforcement discretion until the FDA issues a final rule on those items. In 2016, PCCA nominated quinacrine HCI for inclusion on the 503A Bulks List. However, during the FDA evaluation process, several FDA Divisions and Committees, including the Pharmacy Compounding Advisory Committee (PCAC) and the Office of New Drugs (OND), raised safety concerns about quinacrine HCI. Remarkably, the OND advised that “although quinacrine might be safe at the 100 mg/day dose prescribed for rheumatic skin diseases, generalists might prescribe the drug at higher doses and for alternative indications that were not formally studied.” As a consequence, the PCAC voted against adding quinacrine to the 503A Bulks List. However, FDA ultimately placed quinacrine HCI on Category 1 with a restriction, “(except for intrauterine administration),” allowing for oral use in compounded preparations by 503A compounding pharmacies. FDA also placed quinacrine HCl on the 503B Category 1 interim bulks list with the restriction “for oral use only.”11,12
The FDA proposed a final rule for the inclusion of quinacrine HCI in March 2021 to the 503B Bulks List for oral dosage forms, stating “it meets a clinical need for patients with CLE…and has a long history of use in compounding, in addition to a significant body of literature demonstrating its potential effectiveness for the treatment of patients with CLE.”11 The FDA added quinacrine HCI — for oral use only — to the 503B Positive Bulks List on April 6, 2023.13 To date, the FDA has not issued a rule for quinacrine in 503A pharmacies; as such, quinacrine HCI remains part of the interim policy.
Listen as PCCA Vice President of Clinical Services, A.J. Day, PharmD, discusses the return of quinacrine HCI for patient care on the Mortar & Pestle podcast.
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.