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Hydroxychloroquine

Our pharmacy has hydroxychloroquine capsules (also known as Plaquenil) in stock and available to fill prescriptions.  For more information, contact us via the form below or give us a call at 855-790-0100.

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Information For Health Care Providers

For which medical conditions was hydroxychloroquine sulfate usually prescribed before the coronavirus (SARS-CoV-2) pandemic?

Commercially manufactured hydroxychloroquine sulfate 200mg tablets are approved by the Food and Drug Administration (FDA) for the treatment of certain forms of malaria, certain forms of lupus erythematosus, and certain forms of rheumatoid arthritis. The drug was first approved in 1955. Hydroxychloroquine sulfate is also part of the current treatment guidelines for several immune system disorders (including dermatomyositis, sarcoidosis, Sjogren syndrome and lichen planopilaris), porphyria cutanea tarda, Q fever, and Whipple disease. In the treatment of these disorders, hydroxychloroquine is used alone or in combination with other medications. 

The FDA-approved package inserts for the various commercially available hydroxychloroquine sulfate tablets can be accessed at the following link.

https://dailymed.nlm.nih.gov/dailymed/search.cfm?labeltype=all&query=HYDROXYCHLOROQUINE+SULFATE)

What is the mechanism of action of hydroxychloroquine sulfate?

The mechanism through which hydroxychloroquine inhibits Plasmodium is not completely understood. Hydroxychloroquine is a weak base and it is hypothesized that after oral administration, hydroxychloroquine enters the parasite and is enriched within specific vesicles. There, the drug increases the pH, preventing the parasite from polymerizing heme, a toxic byproduct the parasite produces from digesting the hemoglobin. High levels of heme are toxic to the parasite. Hydroxychloroquine’s properties as a weak base are also assumed to facilitate its inhibitory effect on Coxiella bacteria in patients with Q fever. The bacteria’s growth is inhibited through an increased pH within intracellular structures responsible for bacterial replication.

Similarly, we have not yet fully characterized hydroxychloroquine’s complex anti-inflammatory and immune-modulatory effects in the treatment of patients with various inflammatory immune-mediated disorders. It appears that the medication’s weak basic character and its ability to increase the pH in certain acidic environments, such as inflamed tissues and lysosomes, plays a major role in its mechanism of action. By increasing the pH, hydroxychloroquine might inhibit the function of lysosomes. This may interfere with the processing and presentation of antigens that – sometimes erroneously – results in immune activation, thereby blunting the undesired immune response. Furthermore, hydroxychloroquine inhibits a number of signaling pathways that typically contribute to the activation of the immune system, including pathways involving toll-like receptor (TLR) 7 and 9. These two receptors are important in the immune system’s ability to recognize foreign genetic material derived from infectious organisms, but sometimes also contribute to an inappropriate recognition of the body’s own genetic material (autoimmune activity). By altering the pH in certain vesicles that typically release the functional forms of TLR 7 and 9, hydroxychloroquine reduces the amount of functional TLR 7 and 9 available to activate the immune system, decreasing erroneous immune activity in autoimmune disorders like lupus. Hydroxychloroquine’s ability to bind to nucleic acids can additionally prevent remaining functional TLR 7 and 9 from interacting with DNA, thus further suppressing TLR signaling. In addition, hydroxychloroquine interferes with cyclic GMP-AMP synthase activity typically involved in the interferon production. Finally, hydroxychloroquine inhibits various inflammatory cells’ ability to produce cytokines responsible for facilitating inflammation pathways (including interleukins, tumor necrosis factors and interferons). A very recent review article that discusses the various mechanisms of action of hydroxychloroquine can be found here. (Link: https://www-ncbi-nlm-nih-gov.eresources.mssm.edu/pubmed/32034323 )          

FDA emergency use authorization (EUA) for the use of hydroxychloroquine sulfate for the treatment of COVID-19

Via its EUA, the FDA permitted the emergency use of hydroxychloroquine sulfate from the Strategic National Stockpile to treat adults and adolescents who weigh 50kg or more, are hospitalized for COVID-19, and are not part of a clinical trial. 

FDA’s authority to release EUAs is described in the Federal Food, Drug, and Cosmetic Act. The Act states that the FDA Commissioner may allow (i) unapproved medical products, or (ii) unapproved uses of approved medical products (e.g. the use of hydroxychloroquine sulfate for the treatment of COVID-19) to be used in an emergency to diagnose, treat, or prevent serious or life-threatening diseases or conditions caused by CBRN (chemical, biological, radiological and nuclear) threat agents when there are no adequate, approved, and available alternatives. The complete EUA for hydroxychloroquine can be found here. (Link: https://www.fda.gov/media/136537/download )

Given the current lack of sufficient data from clinical trials, FDA states that optimal dosing and duration of treatment in patients with COVID-19 are unknown. However, FDA suggests a dosing schedule of 800mg by mouth on day 1, followed by 400mg by mouth daily for four to seven days of total treatment.  

What is the basis for FDA’s EUA for hydroxychloroquine sulfate?

Among other drugs, hydroxychloroquine sulfate might potentially help in the management of COVID-19, however informative data from clinical trials in patients with COVID-19 are not yet available.

Several laboratory studies have shown that infection of cells with the SARS-CoV-2 virus (which causes COVID-19 in humans) can generally be inhibited if hydroxychloroquine sulfate is present. One investigation showed that the virus could not infect monkey cells grown in vitro in the presence of hydroxychloroquine sulfate to the same extent as when the drug was not present. The study suggests that hydroxychloroquine interferes with the entry of the virus into host cells and with early processes necessary for the release of the viral genome in the host cell. A full report of this study can be found here (Link: https://www.ncbi.nlm.nih.gov/pubmed/32194981). Using the same type of monkey cells, another study also demonstrated that hydroxychloroquine sulfate inhibits the infection of the cells with SARS-CoV-2 (https://www.ncbi.nlm.nih.gov/pubmed/32150618). These observations are an important step to discover a treatment or prevention of COVID-19. 

In addition, a recent study provided a detailed description of the clinical manifestations of 41 patients infected with SARS-CoV-2. A link to this report is provided here. (Link: https://www.ncbi.nlm.nih.gov/pubmed/31986264). All COVID-19 patients had higher levels of several different cytokines in their plasma than healthy subjects. Patients with more severe disease had higher cytokine plasma levels than patients with less severe disease, sometimes leading to “cytokine storm” and its associated severe organ damage. Since hydroxychloroquine sulfate has been shown to reduce cytokine production in patients with immune disorders such as lupus, it is hypothesized that it may also be beneficial in the treatment of COVID-19 patients via its anti-inflammatory effects. 

Chloroquine or hydroxychloroquine?

EUA was also given for the use of chloroquine phosphate for COVID-19, and the FDA fact sheet can be found here. (Link: https://www.fda.gov/media/136536/download )

Both of the above-mentioned laboratory studies also investigated chloroquine and found that this drug also reduced the infection of monkey cells grown in vitro with the SARS-CoV-2 virus. While one study suggests that chloroquine is more effective than hydroxychloroquine in inhibiting the infection of these cells with SARS-CoV-2, the other study found that hydroxychloroquine is more effective. This discrepancy shows that results obtained from in vitro studies may vary sometimes, depending on the conditions of the experiment, and confirmation of the drug’s clinical efficacy in humans is needed from clinical trials to come to a sound conclusion.

Based on what is already known from the previous use of hydroxychloroquine and chloroquine to treat various diseases in humans, hydroxychloroquine is usually better tolerated by patients and is associated with fewer side effects and drug-drug interactions. Therefore, hydroxychloroquine is considered safer for the use in humans and may be favored for the treatment of COVID-19 if both drugs were to show similar efficacy in clinical trials.

What clinical data are currently available for the treatment of COVID-19 with hydroxychloroquine sulfate?

Given the urgent need for efficacious treatment options for COVID-19, several different drug candidates and combinations of different drugs are currently under investigation in clinical trials. Some of these trials focus on the clinical efficacy of hydroxychloroquine sulfate, collecting data on whether this drug is beneficial in the treatment of COVID-19 patients, and to investigate if hydroxychloroquine sulfate can prevent healthy volunteers from becoming infected with SARS-CoV-2 after exposure to the virus.

To date, very limited information is available on the efficacy of hydroxychloroquine sulfate in the treatment of COVID-19. Some clinical results that have been obtained are currently being discussed on various platforms and are not yet published in internationally renowned, peer-reviewed medical journals. Such results must be treated with great caution as these studies have not been evaluated by unbiased experts in the field, and thus it is unclear whether or not these studies meet the strict requirements of a clinical trial design that is likely to lead to conclusive, informative data. Often, such reports do not provide a dataset that is complete enough to draw valid conclusions.

One study that was published in a peer-reviewed medical journal (International Journal of Antimicrobial Agents) was carried out in France. The link to this study can be found here. (Link: https://www.ncbi.nlm.nih.gov/pubmed/32205204). This study compared 20 hospitalized patients with COVID-19 who received hydroxychloroquine sulfate (200mg three times a day for 10 days) with 16 hospitalized COVID-19 patients who did not receive drug treatment. Of note, six patients who received hydroxychloroquine sulfate also received azithromycin (500mg on day one, followed by 250mg daily for another four days) to prevent bacterial superinfection secondary to a weakened immune system. On study day six, the nasopharyngeal samples of 70% of patients who received hydroxychloroquine only tested negative for the virus, compared to 12.5% in the control group of patients who did not receive hydroxychloroquine. Interestingly, all six of the patients who received hydroxychloroquine and azithromycin together tested negative, suggesting that azithromycin may contribute to the positive effects of hydroxychloroquine. While these results seem encouraging, this study has also received a lot of criticism: (i) The study included only a small number of patients which makes it difficult to correctly interpret its results. A higher number of study participants is more likely to yield reliable data. (ii) The study was an open-label trial and not placebo-controlled and therefore it did not control for observations that might not be due to hydroxychloroquine itself, but maybe just to the fact that a treatment was administered. (iii) The study did not explain its inclusion criteria well and it is unclear at which disease state patients started treatment. Therefore, it is difficult to know if patients who received hydroxychloroquine were similar to control patients, and if the treated patients tested negative because of the drug or because their bodies were further along in clearing the virus.   

The same study group also published results from a second study – the link can be found here. (Link: https://www.ncbi.nlm.nih.gov/pubmed/32289548). In this trial, 80 patients with COVID-19 were hospitalized and treated with a combination of hydroxychloroquine sulfate (200mg by mouth three times daily, for 10 days) and azithromycin (500mg by mouth on day one, followed by 250mg once daily for four days). The authors provide a more extensive description of the enrolled patient population as in their first report. However, this study did not include a control group, and thus a comparison between drug treatment and no drug treatment, to establish the potential clinical efficacy of hydroxychloroquine and azithromycin, is not feasible. 

A third study that was carried out in France reported on 11 hospitalized COVID-19 patients who received a combination of hydroxychloroquine and azithromycin, following the same dosing regimen mentioned above. A link to this study is here. (Link: https://www.ncbi.nlm.nih.gov/pubmed/322407190). This study did not observe negative virus testing of nasopharyngeal samples on day six, which is in contrast to the findings of the first study discussed above. The authors state that no evidence for clinical benefit of drug treatment was observed, however this study did not include a control group of patients, making a meaningful comparison between drug treatment and no drug treatment impossible.

Large randomized placebo-controlled clinical trials are needed to establish if hydroxychloroquine is beneficial for patients with COVID-19 and/or infection prevention. Some of the ongoing studies that are evaluating the potential benefit of hydroxychloroquine for COVID-19, as monotherapy or in combination with other drugs, can be found here. (Link: https://clinicaltrials.gov/ct2/results?cond=COVID&term=hydroxychloroquine&cntry=&state=&city=&dist=) 

 

What are the current dispensing guidelines for hydroxychloroquine sulfate?

Due to the novel use of hydroxychloroquine sulfate for COVID-19, and the nationwide shortage of commercially manufactured hydroxychloroquine sulfate tablets, many states have released dispensing guidelines for the drug. As these dispensing guidelines are currently being amended and change frequently, we would be very happy to check for the most up-to-date guidelines if you have any questions – just let us know. In states that do have dispensing guidelines for hydroxychloroquine in effect, patients already taking the medication should have no interruption in their treatment. Certain dispensing limits may be in effect for the treatment of patients diagnosed with COVID-19. In addition, prescriptions for hydroxychloroquine require a valid diagnosis, to establish whether dispensing limits will apply.

Conclusion

Hydroxychloroquine sulfate is an FDA-approved drug with a long history of safety and efficacy in the treatment of certain bacterial and parasitic infections as well as several immune disorders.  While the mechanism of action of this medication is not fully understood, we know that it increases the cellular pH within microorganisms, inhibiting their ability to replicate, and it modulates the inflammatory cascade by interfering with antigen presentation and inhibiting cytokine production. Several small studies have shown that hydroxychloroquine may be helpful in the treatment or prevention of COVID-19, however reliable evidence from well-conducted trials is lacking.        

Information For Patients

 Information on hydroxychloroquine: Traditional use and use for Coronavirus Disease 2019 (COVID-19)

What disorders are usually treated with hydroxychloroquine?

Hydroxychloroquine has been used to treat many conditions since it was first approved in 1955. The medication has Food and Drug Administration (FDA) approval for the treatment of malaria (an infectious disease caused by a parasite that is spread by mosquitos), lupus erythematosus (a disease that happens when various organs are attacked by someone’s own immune system), and rheumatoid arthritis (a progressive disorder that occurs when patient’s own immune system attacks his or her joints). Doctors also have a lot of experience prescribing hydroxychloroquine for several other disorders of the immune system, such as dermatomyositis, sarcoidosis, Sjogren syndrome and lichen planopilaris.  The drug is also used to treat a blood disorder called porphyria cutanea tarda. Other infectious diseases for which hydroxychloroquine is useful include Q fever (an infection caused by Coxiella burnetii bacteria), and Whipple disease (a rare infection caused by Tropheryma whipplei bacteria). Sometimes hydroxychloroquine is used alone, and sometimes it is part of a regimen with other drugs. You can find the FDA-approved package inserts for hydroxychloroquine tablets here. 

(Link: https://dailymed.nlm.nih.gov/dailymed/search.cfm?labeltype=all&query=HYDROXYCHLOROQUINE+SULFATE)

How does hydroxychloroquine work?

For most diseases, the exact way that hydroxychloroquine works is not completely known.

For malaria, we think hydroxychloroquine exerts its effect by changing the pH within specific parts of the parasite.  Substances with a high pH are called “bases,” and an example of a well-known base is bleach. Substances with a low pH are called “acids.” Lemon juice and vinegar are common acids. Hydroxychloroquine is a base, and when someone with malaria takes this medication, it enters the parasite and is taken up by specific vesicles that the parasite needs to process toxins. Once inside the vesicles, hydroxychloroquine raises their pH, thereby inactivating them, toxins build up within the parasite, and the parasite is destroyed. Hydroxychloroquine’s properties as a base are also thought to be the reason it is useful in treating Q fever.  Hydroxychloroquine raises the usually low pH of certain structures within the bacteria that are needed for the bacteria to replicate. In doing so, the medication inhibits the bacteria’s growth.

As we mentioned, hydroxychloroquine is effective in treating many autoimmune diseases.  Autoimmune diseases are conditions in which a person’s immune system mistakenly identifies parts of the person’s own body as pathogenic invaders and, through the process of excessive inflammation,  attacks these body parts. Hydroxychloroquine exerts its anti-inflammatory effects in several ways. The first way, just like with malaria and Q fever, is through its property as a base. Inflamed tissues are acidic, and it is believed that increasing the pH in these tissues interferes with communication between immune cells. This inability of immune cells to communicate with one another blunts the inflammatory response. Hydroxychloroquine also inhibits the function of lysosomes that are found in immune cells.  Lysosomes are little packets of enzymes that certain immune cells use to process molecules and present the processed molecules to other immune cells. These cells then trigger the inflammatory response. By inhibiting the lysosomes, hydroxychloroquine interferes with the presentation of these molecules that – sometimes erroneously – activate the immune system. This slows down the undesired immune response. Furthermore, hydroxychloroquine inhibits several signaling pathways that are responsible for activating the immune system.  One way it does this is by binding to the genetic material (DNA). This blocks other molecules from binding to the DNA which would stimulate the inflammatory pathway. Another way hydroxychloroquine inhibits signaling pathways is by altering substances secreted by immune cells, called cytokines, that drive the inflammatory cascade forward. A very recent review article that discusses the various mechanisms of action of hydroxychloroquine can be found here. (Link: https://www-ncbi-nlm-nih-gov.eresources.mssm.edu/pubmed/32034323 ).

How can hydroxychloroquine work in patients with COVID-19?  Can it change the pH of cells in the body and make it more difficult for the virus to enter? Can it bind to the virus’s genetic material (RNA) and prevent it from being replicated? Can it change the way our bodies react to the virus by altering our immune response?  We do not know the answers to these questions yet, but there are many studies trying to figure this out.

 

FDA greenlights an emergency use authorization (EUA) to permit the use of hydroxychloroquine for the treatment of COVID-19

The FDA has permitted the emergency use of hydroxychloroquine to treat patients hospitalized for COVID-19.

The complete EUA for hydroxychloroquine can be found here.

(Link: https://www.fda.gov/media/136537/download )

What is the basis for FDA’s EUA for hydroxychloroquine sulfate?

Hydroxychloroquine sulfate might help in the management of COVID-19, however we do not have any high-quality studies to prove this. Although there are risks associated with taking hydroxychloroquine, granting the EUA indicates that the FDA has determined that the benefits might potentially outweigh these risks.

Studies have shown that in the presence of hydroxychloroquine, SARS-CoV-2 (the virus that causes COVID-19 in humans) was less infectious to cells grown in a laboratory. One investigation showed that, in the presence of hydroxychloroquine, the virus could not infect monkey cells grown in a dish in the lab to the same extent as when hydroxychloroquine was not present. The study suggests that hydroxychloroquine interferes with the entry of the virus into host cells, and therefore the virus cannot establish an infection. A full report of this study can be found here (Link: https://www.ncbi.nlm.nih.gov/pubmed/32194981).  Using the same type of monkey cells, a second study demonstrated similar results. (Link: https://www.ncbi.nlm.nih.gov/pubmed/32150618). 

In addition, a recent study that observed 41 patients with COVID-19 described the clinical features associated with a SARS-CoV-2 infection in great detail. A link to this report is provided here. (Link: https://www.ncbi.nlm.nih.gov/pubmed/31986264). All of the COVID-19 patients had higher levels of several different cytokines circulating in their blood compared to healthy subjects. Patients with more severe disease had higher cytokine levels compared to patients with less severe disease. As discussed above, cytokines are molecules that facilitate inflammation which can eventually lead to severe organ damage. Because hydroxychloroquine sulfate is known to reduce the cytokine levels, it is believed that it may be beneficial to COVID-19 patients.

Chloroquine or hydroxychloroquine?

The FDA has also permitted the emergency use of chloroquine to treat patients hospitalized for COVID-19. The FDA fact sheet can be found here. (Link: https://www.fda.gov/media/136536/download )

Both of the above-mentioned laboratory studies also investigated chloroquine. The studies found that chloroquine made the SARS-CoV-2 virus less infectious to monkey cells that were grown in a dish. One study suggests that chloroquine is more effective than hydroxychloroquine. The other study found that hydroxychloroquine is more effective. This discrepancy shows that results obtained from such studies can vary and may not translate to an effect in patients. Clinical studies are needed to confirm of the drug’s efficacy in humans. Based on what is already known from the use of hydroxychloroquine and chloroquine, hydroxychloroquine is usually safer and better tolerated by patients.

What have we learned from COVID-19 patients who were already treated with hydroxychloroquine?

To date, only very limited information is available regarding hydroxychloroquine’s effectiveness against COVID-19. Some of the results that are being discussed on various platforms have not been published in peer-reviewed medical journals. Such results need to be treated with great caution, as these studies have not been evaluated by unbiased experts in the field, and thus it is unclear whether these studies are valid or not. 

One study that was published in a peer-reviewed medical journal (International Journal of Antimicrobial Agents) was carried out in France. The link to this study can be found here. (Link: https://www.ncbi.nlm.nih.gov/pubmed/32205204). This study compared 20 hospitalized patients with COVID-19 who received hydroxychloroquine with 16 hospitalized COVID-19 patients who did not receive this drug. Of note, six patients who received hydroxychloroquine also received azithromycin to prevent bacterial superinfection (a condition that can happen in patients with a weakened immune system). On the sixth study day, nasal samples from 70% of patients who received hydroxychloroquine without azithromycin tested negative for the virus, compared to 12.5% in the control group of patients who did not receive hydroxychloroquine. Interestingly, all of the patients who received hydroxychloroquine and azithromycin together tested negative, suggesting that azithromycin may increase the beneficial effects of hydroxychloroquine. While these results seem encouraging, this study has also received a lot of criticism: (i) The study included only a very small number of patients, which makes it difficult to correctly interpret its results. A higher number of study participants is needed to yield reliable data. (ii) The study was an open-label trial and not placebo-controlled. Therefore, the findings might not be due to hydroxychloroquine itself, but may have occurred if any treatment were administered. (iii) The study did not establish sufficient criteria for enrollment, and it is unclear at which disease state patients started treatment with hydroxychloroquine. Because of this, we do not know to which types of patients this study relates.   

The same researchers published a second study – the link can be found here. (Link: https://www.ncbi.nlm.nih.gov/pubmed/32289548). A group of 80 patients with COVID-19 were hospitalized and treated with a combination of hydroxychloroquine and azithromycin. The researches stated that the enrolled patients were “relatively mildly infected”, and most patients “improved”.   Although the authors provided a more extensive description of the enrolled patient population, this study did not include a control group of patients who did not receive drug treatment. This means that there is no comparison between drug treatment and no drug treatment to establish the potential clinical efficacy of hydroxychloroquine and azithromycin. 

A third study that was carried out in France reported on 11 hospitalized COVID-19 patients who received a combination of hydroxychloroquine and azithromycin. A link to this study is here. (Link: https://www.ncbi.nlm.nih.gov/pubmed/322407190). This study did not observe negative virus testing of nasopharyngeal samples on day six, which contrasts with the findings of the first study discussed above. The authors state that no evidence for a benefit of drug treatment was observed, however this study did not include a control group of patients either, making a meaningful comparison between drug treatment and no drug treatment impossible.

In conclusion, large randomized placebo-controlled clinical trials are needed to establish if hydroxychloroquine is beneficial for the treatment or prevention of COVID-19. Some of the ongoing studies that are evaluating the potential benefit of hydroxychloroquine for COVID-19 can be found here. 

(Link: https://clinicaltrials.gov/ct2/results?cond=COVID&term=hydroxychloroquine&cntry=&state=&city=&dist=) 

What are the current dispensing guidelines for hydroxychloroquine sulfate?

Hydroxychloroquine is a prescription medication. It must be prescribed by a healthcare provider and dispensed by a pharmacy. Due to the novel use of hydroxychloroquine sulfate for COVID-19, and the nationwide shortage of commercially manufactured hydroxychloroquine sulfate tablets, many states have released dispensing guidelines for the drug which doctors and pharmacists have to keep in mind.

Conclusion

Hydroxychloroquine is a medication that has been used for 65 years to treat infectious diseases and autoimmune diseases.  It is currently being evaluated for its potential role in the prevention and/or treatment of COVID-19. Although conflicting data exist regarding the effectiveness of hydroxychloroquine in the treatment of COVID-19 patients, we are lacking results from randomized, placebo-controlled trials, which are the best types of studies to determine a medication’s safety and efficacy.  We are anxiously awaiting the results of such studies.

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