Covid-19: Be careful with chloroquine and hydroxychloroquine

March 25, 2020 – The Covid-19 pandemic keeps the word abreast. Drastic measures have been and are being taken worldwide by governments, hospitals, healthcare  care providers, and retiring homes in attempts to halt the spreading of Covid-19. Recently, there have been publications by Chinese clinical researchers in the Journal Cell Research and the International Journal of Antimicrob Agents indicating that both, the anti-malarial drug chloroquine and the broadband antiviral drug antiviral remdesivir could be effective in the treatment of Covid-19 infections.

Hydroxychloroquine, as “Plaquénil” on the market in France.

In the light of the absence of any anti-Covid 19 vaccine for the time being, these notions around chloroquine and remdesivir have stirred hype and hope at the same time. Physicians hope to be able to treat at least some Covid-19 strikes patients successfully; in the general public, many individuals have been taken by a hype that the two compounds, taken prophylactically, may spare them from becoming infected. As a consequence, uncontrolled intake of the compounds, particularly chloroquine, has become rampant with significant adverse events, fatalities included for quiet many individuals. Based on these experiences, the Australien Therapeutic Goods Administration (TGA) has now issued a warning and restrictions on the uses of hydroxychloroquine and of chloroquine. The latter is not marketed in Australia, while the former is on the market and used for treatment of certain autoimmune diseases and of cases of malaria. Apart from causing unwanted adverse effects, the reports of uncontrolled increase in off-label prescribing of medicines containing hydroxychloroquine have raised concerns that this will create a potential shortage of this product not only in Australia but also elsewhere.

Clinical trials are underway around the world examining the potential of hydroxychloroquine and chloroquine to treat COVID-19. However, these medicines pose wellknown serious risks to patients including cardiac toxicity (potentially leading to sudden heart attacks), irreversible eye damage, severe depletion of blood sugar (potentially leading to coma), severe skin reaction, GI-disturbances, and in the case of chloroquine also to worsening psoriasis and rare psychotic episodes, anxiety, personality change, seizures, and blood dyscrasias.

Given the still limited evidence for effect against COVID-19 at this time, as well as the risk of significant adverse effects, the TGA strongly discourages the use of hydroxychloroquine and/or chloroquine outside of the current indications other than in a clinical trial setting or in a controlled environment in the treatment of severely ill patients in hospital. TGA strongly discourages the public to obtain and use these medications prophylactically to combat Covid-19 ahead of a possible infection. Thus, in the case of hydroxychloroquine and in order to limit its use to currently approved indications, for Australia, there have been new restrictions placed on who can initiate therapy using it. Only certain types of specialists will be able to prescribe hydroxychloroquine to new patients. General practitioners and other medical practitioners (e.g., hospital Resident Medical Officers (RMOS) and doctors in training) can continue to prescribe repeats for hydroxychloroquine to patients in line with the registered indications for patients in whom the medication was prescribed prior to 24 March 2020. From 24 March 2020, general practitioners and doctors in training can only prescribe these medicines for continued treatment of patients where initial treatment has been authorised by one of the specialists. In any case, for the time being, information for health professionals has it that there are no medicines that have been approved by the TGA for treatment of COVID-19, therefore prescribing of any medicine for the treatment of COVID-19 is considered off-label use. There is currently no clear data to inform about clinical guidance on the use, dosing, or duration for COVID-19 treatment.

Consumers on the other hand, if concerned that they may have symptoms of COVID-19, should seek advice from a health professional to determine whether they need testing and how to manage their symptoms. If you as a patient are currently taking hydroxychloroquine for a chronic condition and are worried about being able to access this medicine, please speak to your health professional.

Overall, these advices/restrictions from Australia surrounding hydroxychloroquine and chloroquine, their role in treatment of Covid-19, and their associated serious adverse effects, some of them even fatal, might well apply to other parts of the world, where Covid-19 ravages and where physicians and patients alike are looking for treatment options. A balanced glocalized approach to the handling of hydroxychloroquine and chloroquine in face of Covid-19 would be highly recommended. Confusing hype and controversy do not help anyone.

Back on the level of an individual patient, it may be noteworthy to understand that a wide variability in the extent of adverse events and/or beneficial effects in treatment of Covid-19 disease of chloroquine has to be expected. This may come from the observation that chloroquine is metabolised in humans predominantly  by cytochrome P450C8 (CYP450C8) and to a lesser extent by CYP3A4/5 and CYP2D6 to its major metabolite N-desethylchloroquine (DCQ). CYP450C8 exists in the population in at least 11 allelic variant. Come of these variant exhibit normal metabolic capacity for Chloroquine, other exhibit decreased capacity and some have no catalytic activity at all. Consequently, receiving a so called “normal” dose of Chloroquine, some patients, over time, exposure to higher than intended doses or frank overdoses based on their genetic outfit. Without being genetically tested, patients cannot know in which category of “metabolisers” they would fall, and therefore are exposed to unknown risks for serious adverse events when taking Chloroquine.

Despite these uncertainties about Hydroxychloroquine and Chloroquine, and in the light of the accelerating Covid-19 crisis in the USA, the American Food and Drug Administration (FDA) on March 28 issued an Emergency Use Authorization (EUA) to allow hydroxychloroquine sulfate and chloroquine phosphate products to be distributed and used under strict controls for certain hospitalized patients with COVID-19. These drugs will be distributed for doctors to prescribe to adolescent and adult patients hospitalized with COVID-19, as appropriate, when a clinical trial is not available or feasible. The EUA requires that fact sheets that provide important information about using chloroquine phosphate and hydroxychloroquine sulfate in treating COVID-19 be made available to health care providers and patients, including the known risks and drug interactions. This is made possible through the anecdotally shown efficacy of the drugs to fight Covid-19 disease as shown in the above cited studies and the lack of an vaccine at the present time.

See here a short sequence on the (even political) controversy about the premature use of chloroquine in Covid-19:

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About the Author
Joseph Gut - thasso Ph.D.; Professor in Pharmacology and Toxicology. Senior expert in theragenomic and personalized medicine and individualized drug safety. Senior expert in pharmaco- and toxicogenetics. Senior expert in human safety of drugs, chemicals, environmental pollutants, and dietary ingredients.

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