This document discusses off-label use of medications to treat COVID-19. It provides background on what constitutes off-label use and examples of drugs like hydroxychloroquine and azithromycin being used off-label to treat COVID-19 since they are approved to treat other conditions. It notes both potential benefits but also risks of off-label use, especially without evidence from controlled clinical trials, as side effects may be mistakenly attributed to the disease. It emphasizes the need for robust trials to evaluate potential treatments and verify their safety and efficacy.

1. OFF-LABEL USE OF
MEDICATIONS FOR COVID-19
TREATMENT
April 16, 2020
Off-label - Of, relating to, or being a drug used to treat a
condition for which it has not been officially approved.
Compiled by: Belachew Weldegebriel (Bpharm)
E-mail: bellachew@gmail.com
Jimma University, Jimma, Ethiopia

2. Off-label
• Prescribing off-label medications
• Off-label is a term that is becoming more and more
common
• Ackerman said….Off-label is when we have an FDA
approved medication like hydroxychloroquine, which we
are all hearing about, where the drug is an FDA approved
drug for malaria, it’s an FDA approved drug for lupus. It is
off-label for COVID-19. (Mayo Clinic)
• The use of licensed medicines for indications that have
not been approved by a national medicines regulatory
authority is considered “off-label” use. (WHO)
https://www.who.int/news-room/commentaries/detail/off-label-use-of-
medicines-for-covid-19

3. Saraha Derr when talking about hydroxychloroquine
• “It’s a very old drug. It’s been around for a very long time”
She said. “It’s not something new to us, but this use is a
new indication for the medication that we haven’t really
seen before. . . There is really no evidence that it is going
to be the cure-all for COVID-19.”
• FDA still needs more evidence it works.

4. Is it absolutely wrong to prescribe drugs off-label?
• Still Ackerman said doctors can prescribe off-label medications.
• The good news is this medication could potentially help
save somebody’s life. The tricky part is that the drugs can
be deadly, depending on whom doctors prescribe it to.
• “These medications hydroxychloroquine and azithromycin,
the medications we are hearing about, they have an
unwanted side effects of drug induced sudden cardiac
arrest,” Ackerman said.
• Ackerman said, doctors who prescribe hydroxychloroquine
for patients to treat the coronavirus are taking a big risk.
• The Mayo Clinic is putting out the urgent call to all providers
and patients to test for what is called their “QTC Value”.
Brandi Powell March 30 2020 Mayo Clinic urges Caution for health care providers
prescribing off-label meds for COVID-19. kstp.com 5 ETEWITNESS NEWS

5. Another report
• A Los Angeles doctor said he is seeing significant success
in prescribing the malaria drug hydroxychloroquine in
combination with zinc to treat patients with severe
symptoms of COVID-19.
• The drug has been used for treatment of malaria and
conditions such as lupus and arthritis but is not technically
approved by the FDA for COVID-19.
• The agency, however, is encouraging trials and has
provided limited emergency authorization for its use to
treat COVID-19 patients.

6. Witness from a doctor
• Every patient I’ve prescribed it to has been very, very ill and
within 8 to 12 hours, they were basically symptom- free.”
Cardillo told Eyewitness News. “so clinically I am seeing a
resolution.”
• He said he has found it only works if combined with zinc. The
drug, he said, opens a channel for the zinc to enter the cell
and block virus replication.
• The doctor emphasized that
• “It should be reserved for people who are really sick, in the
hospitals or at home very sick, who need that medication.
Otherwise we’re going to blow through our supply for patients
that take it regularly for other disease processes.”

7. • The drug should net be prescribed for
• those who are presenting only mild symptoms
• patients who have COVID who are well
• Chloroquine or hydroxychloroquine, has been approved to
treat and prevent malaria since 1944. Because the drug is
on the market, doctors can use it for off-label purpose.
• President Trump has touted it as a possible cure but the
government’s top coronavirus expert, Dr. Anthony Fauci,
has been much more cautious, saying there is only
“anecdotal evidence” demonstrating its effectiveness.
• Experts are also concerned about potential misuse.

8. • The FDA advises against taking any form of chloroquine
unless prescribed by a doctor and obtained from a
legitimate source.
• Another drug that has shown some potential for treating
COVID-19 is remdesivir, a drug that was initially
developed as a potential treatment for Ebola. A Palo Alto
woman was accepted into a clinical trail for remdesivir
and said it was effective in improving her condition.
LA doctor seeing success with hydroxychloroquine to treat COVID-19 Health &
Fitness abc7.com

9. Unlicensed Products
• Under the Medicines Act 1968 a company may only market, i.e.
advertise and sell, their products in the United Kingdom if they
hold a marketing authorisation for that product. Furthermore, the
therapeutic or diagnostic purposes for which the product can
be marketed are limited by the terms of the authorisation.
• Thus a product licensed only for the treatment of gastric ulcers
may not be marketed for the treatment of indigestion.
• However, this legislation does not affect the clinical freedom of
doctors to prescribe what they believe is best for their patient.
They may use or recommend medicines which do not have a
licence (unlicensed), or use medicines in ways different to
those specified in the marketing authorisation (off-label).

10. Unlicensed products
• Doctors may prescribe several categories of unlicensed products.
Some substances, e.g. raw chemicals may on occasions be
prescribed as medicines, although they are not normally thought of as
medicines, and are not marketed as such.
• Reasons for using unlicensed products
• They may be used because:
• The medicine is prepared by the original manufacturer, but is not for
sale in United Kingdom.
• It is the prescriber’s own formula for a specific patient.
• It is an unusual form, e.g. liquid preparation of a medicine normally
available only as capsules.
• It is an unusual strength.
• It is an unusual combination of active ingredients.
• It is an unusual formulation, e.g. no preservative eye drops, lactose
free tablets.

11. Off-label use
• “Off-label” medicine describes the use of licensed
medicines in a dose, age group or by a route not in the
product licence specification. The product cannot be
marketed for any use outside the licence conditions,
but doctors are free to prescribe outside those conditions.
Such use is now generally referred to by the US term “off-
label use”.
• Many medicines used for children are prescribed and
used off-label. Clinical trials are rarely carried out on
children, especially very young children, so the licensed
use is restricted to those groups of patients where clinical
trials have been carried out. (pp 138)
Janathan Merrills and Jonathan Fisher Pharmacy Law and Practice (4th ed)
Elsevier B.V (2006) (PP 138)

12. Liability issues
• Special consideration should be given to issues of liability
when unlicensed products are used, or when products
are used off-licence.
• The summary of product characteristics gives some
information about the use of any particular medicine, and
prescribing within its limitations is unlikely to give rise to
claims of negligence on the part of either doctor or
pharmacist. Other information may be obtainable from
specialist units.

13. Legal Matters
• The prescriber assumes legal liability when he
prescribes unlicensed or off-label products. If a patient is
harmed by the prescribing of an unlicensed or off-label
product, then it may be alleged that the prescriber and/or
the pharmacist has been negligent. The test of whether a
doctor or pharmacist is negligent is referred to as the
“Bolam test”. This broadly states that a professional
person will not be negligent if what he does would be
approved of by a responsible body of opinion in his
profession.
• The liability of the manufacturer for any harm caused by
off-label use remains untested in court, although
theoretically there could be liability under the Consumer
Safety Act 1987.

14. • Similarly there may be a possibility that the pharmacist
might be liable in circumstances where he was aware of
the use, where he knew about the possibility of harm, and
where he could have taken action.
• Advice given to doctors
• The Medical Defence Union has advised doctors in using
off-label products for child patients that they must explain
to those with parental responsibility that the drug is not
appropriately licensed for paediatric use.
• Several studies recently have indicated that many doctors
are unaware of the limitations for use set out in the data
sheets for a product, and they may be grateful for a
reminder.

15. The Code of Ethics
• The Code of Ethics covers the use of unlicensed
products, or use off-licence, in Part 3, Section 4(d)
• Where a product is ordered on a prescription a
pharmacist must supply a product with a marketing
authorisation, where such a product exists and is
available, in preference to an unlicensed medicine or food
supplement.
• In addition a Factsheet, entitled “The use of unlicensed
medicines in pharmacy” is available from the RPSGB
Fitness to Practise and Legal Affairs Directorate.(pp 138)

16. COVID-19 battle: Govt Suggests “off-label” use
of Combo drugs
• Ministry of Health of India
• Hydroxychloroquine and Azithromycin for patients with
severe infection of SARS-coV2 and those requiring ICU
management.
• Hydroxychloroquine dose of 400mg twice a day (BID)
for one day, followed by 200mg two times a day for 4 days
in combination with Azithromycin 500mg once a day for
five days under close monitoring
• This is a shift from the government’s earlier
recommendation that had restricted the use of this drug
only for high risk people, i.e. healthcare workers or
caregivers of Covid-19 patients.

17. • These drugs are not recommended for children less than
12 years, pregnant and lactating women, the health
ministry said.
• Indian government’s recommendation comes two days
after the USFDA approved these drugs as a treatment
protocol for covid-19 patients.
Diviya Rajagopal April 1, 2020 07.56 AM IST COVID-19 battle: Govt Suggests
“off-label” use of Combo drugs

18. Current Off-label use
• The world is now facing a pandemic of SARS-CoV-2
(severe acute respiratory syndrome coronavirus 2, the
cause of COVID-19), for which no proven specific
therapies are available, other than supportive care.
• In China, and now Italy, France, and Spain, a large
number of patients have received off-label and
compassionate use therapies such as chloroquine,
hydroxychloroquine, azithromycin, lopinavir-ritonavir,
favipiravir, remdesivir, ribavirin, interferon, convalescent
plasma, steroids, and anti–IL-6 inhibitors, based on either
their in vitro antiviral or anti-inflammatory properties.

19. Coronavirus, Chloroquine, and “off-label” use
• Prior to 1962, drug makers were required to convince the FDA
their product was safe to consume and met the FDA’s criteria
for providing drug information, use, and dosage on their
labels. But the 1962 Kefauver-Harris Amendments to the Food
Drug and Cosmetics act of 1938 added the additional burden
of proving the drugs efficacy in treating the condition for which
it was developed.
• Efficacy requirements add years to the approval process.
Ironically, once a drug is thus approved for the treatment of the
condition for which it was initially intended, the FDA has no
restrictions on using the drug in any other setting. Using it to
treat a condition for which it was not initially approved is called
“off-label,” because the label is only allowed to state the
condition for which its use was FDA- approved.
Jeffrey A. Singer March 23, 2020 1:27PM Coronavirus, Chloroquine, and “off-
label” use www.cato.org/blog/coronavirus-chloroquine-label-use

20. Coronavirus, Chloroquine, and “off-label”use
• Clinicians use drugs “off-label” very frequently. In act
according to the Agency for Healthcare Research and
Quality, “one in five prescriptions written today are for off-
label use”.
• An example of off-label use in my specialty of general
surgery that immediately comes to mind is the antibiotic
erythromycin to treat paralyzed intrinsic muscles of the
stomach, a condition called gastric atony.
• Many years often pass before clinical trials convince the
FDA to update its approved use of a drug to include what
has been an off-label use. Aspirin had been used off-label
to prevent recurrent stroke or heart attack or many years
before the FDA approved it for that use.
Jeffrey A. Singer March 23, 2020 1:27PM Coronavirus, Chloroquine, and “off-
label” use www.cato.org/blog/coronavirus-chloroquine-label-use

21. • The prescription of medicines for off-label use by doctors
may be subject to national laws and regulations. All
health care workers should be aware of and comply with
the laws and regulations governing their practice.
Further, such prescribing should be done on a case-by-
case basis.

22. • The world is now facing a pandemic of SARS-CoV-2
(severe acute respiratory syndrome coronavirus 2, the
cause of COVID-19), for which no proven specific
therapies are available, other than supportive care.
• In China, and now Italy, France, and Spain, a large number
of patients have received off-label and compassionate use
therapies such as chloroquine, hydroxychloroquine,
azithromycin, lopinavir-ritonavir, favipiravir, remdesivir,
ribavirin, interferon, convalescent plasma, steroids, and
anti–IL-6 inhibitors, based on either their in vitro antiviral or
anti-inflammatory properties.
• These therapies have been mostly given without controls,
except for a few randomized trials started in China, and
more recently in the US.3

23. • A common interpretation of off-label use and
compassionate use of drugs is that is that if the patient
died, they died from the disease, but if the patient
survived, they survived because of the given drug. This is
not true.
• As a practical example, chloroquine/hydroxychloroquine,
azithromycin, and lopinavir-ritonavir have a variety of
adverse effects, including QT prolongation, torsades de
pointes, hepatitis, acute pancreatitis, neutropenia, and
anaphylaxis.

24. Dangers of off-label use of drugs
• Considering that most patients who have died from
COVID-19 were elderly and had cardiovascular
comorbidities and that affected patients frequently have
cardiac arrhythmias,4,5 chloroquine/hydroxychloroquine,
azithromycin, and lopinavir-ritonavir could potentially
increase the risk of cardiac death.
• Additionally, hepatitis and neutropenia are clinical
manifestations of COVID-19, and both hepatic and bone
marrow dysfunction could be made worse by the off-
label use of these drugs; thus, it would be impossible to
differentiate the drug-related adverse effects from the
disease manifestations in the absence of a control group.

25. • Compassionate use of drugs that have not been previously
approved for clinical use (eg, remdesivir) could cause serious
adverse effects that were not previously detected because of
the very small number of exposed patients.
• With respect to anti-inflammatory therapy, the use of
intravenous steroids has been associated with delayed
coronavirus clearance in both blood and lungs with MERS-
CoV6 and SARS-CoV,7 and steroids were associated with
significantly increased risk of mortality and secondary
infections in patients with influenza.8
• Furthermore, even low-dose steroids have shown harm in
patients with sepsis, and IL-6 inhibitors may cause even more
profound immunosuppression than steroids, increasing the risk
of sepsis, bacterial pneumonia, gastrointestinal perforation, and
hepatotoxicity.9,10

26. • Yet, despite substantial evidence of potential harm,
steroids and IL-6 inhibitors are now being given to
patients with COVID-19 in several countries.
• Accordingly, even for treatments previously utilized in
other diseases, it is critical to evaluate these drugs in
studies that have a concurrent control group.
• In contrast, compared with RCTs, the administration of old
or new drugs (eg, off-label use, compassionate use,
single-group cohorts, case-historical controls, clinical trials
without controls) may be less safe, and moreover, will not
lead to the discovery of any new therapy.

27. • Yet without robust clinical trials to verify its potential, the
treatment could do more harm than the disease itself.
• Repurposing drugs cleared for one purpose to use for
another also has a tragic history of severe harm to
patients.
• On the other hand, a treatment like hydroxychloroquine
could do more damage than good if prescribed to
patients without proper testing to see which
circumstances make the most sense to use the drug.
• The drug can also have harmful interactions with
medicines used to treat diabetes, epilepsy, and heart
problems.(Umair, 2020)

28. • The FDA has granted emergency use authorization of
hydroxychloroquine and chloroquine to fight Covid-19. But
expanding the use of these drugs to sick but not critical
patients still warrants further testing due to the potential
side effects.
• High blood pressure and diabetes, for example, already
make the infected more likely to suffer severely from
Covid-19.
• So a treatment like hydroxychloroquine could worsen
those underlying conditions, or could result in a
dangerous interaction with the medicines used to treat
those conditions.

29. • Meanwhile, a dispatch posted this week to MedPage
Today, a blog and medical news service widely read by
doctors, warned that chloroquine can cause hemolytic
anemia if administered to people with a common genetic
condition called G6PD deficiency. Hemolytic anemia can
lead to shortness of breath, rapid heartbeat, and in severe
cases, kidney failure and death.
• “Chloroquine is not a harmless panacea for COVID-19,”
wrote Dr. Dan J. Vick, a pathologist who teaches
healthcare administration at Central Michigan University.
Its use is specifically discouraged in patients with G6PD
deficiency.

30. Dangers
• Fatal Side effects
• People who use these medications could face serious
health consequences.
• Both chloroquine and hydroxychloroquine can have
serious side effects, such as irregular heartbeat, mood
changes, or convulsions.
• Azithromycin can also have serious side effects, including
the risk of potentially fatal heart rhythms.
• Adrew Thorburn, DPhil, professor and chairman of the
University of Colorado School of Medicine Department of
Pharmacology warns that these side effects could be
more dangerous even though he admits that all drugs
have side effects.

31. Dangers
• Self-treatment Tendency by Patients
• People who have access to one of these drugs may be
tempted to self-treat if they think they have COVID-19.
• U. S. News reports that a man from Arizona died after taking
chloroquine phosphate, an additive used to clean fish tanks. His
wife, who also took the substance, is in critical condition.
• There are already concerns that if people start hoarding
hydroxychloroquine, those who already use it to treat their
lupus or rheumatoid arthritis won’t be able to get the drug.
• A similar high demand has occurred for the antiviral
remdesivir, which is also being investigated for its use against
COVID-19. So much so that manufacturer Gilead had to
suspend emergency access to the drug.
Arizona Death Prompts Warning Against Self-Medication. U.S News
https://www.usnews.com/news/best-states/arizona/articles/2020-03-23/banner-
health-opens-drive-thru-sites-in-phoenix-tucscon

32. • Around 80 percent of people recover from COVID-19
without needing special treatment, taking unprescribed
medications could be riskier than waiting it out.

33. References
 Experts Warning: Don’t Use Off-Label Medications for COVID-19 Treatment
https://www.healthline.com/health-news/dont-use-unproven-medications-to-treat-covid-
19#Serious-health-consequences
• Doctors and experts warn of the risks of using malaria drugs to treat COVID-19
https://www.latimes.com/science/story/2020-03-28/risks-of-using-malaria-drugs-off-label-
to-treat-covid-19 By Melissa Healy Staff Writer March 28, 2020 1:07 PM
• The evidence for using hydroxychloroquine to treat Covid-19 is flimsy Why experts
say we need clinical trials before using the drug to treat the coronavirus. By Umair Irfan
Apr 7, 2020, 12:00pm EDT https://www.vox.com/2020/4/7/21209539/coronavirus-
hydroxychloroquine-covid-19-clinical-trial
• Treating COVID-19—Off-Label Drug Use, Compassionate Use, and Randomized
Clinical Trials During Pandemics Andre C. Kalil, MD, MPH1 Author Affiliations Article
Information JAMA. Published online March 24, 2020. doi:10.1001/jama.2020.4742
March 24, 2020
• Jeffrey A. Singer March 23, 2020 1:27PM Coronavirus, Chloroquine, and “off-label”use
www.cato.org/blog/coronavirus-chloroquine-label-use
• Diviya Rajagopal April 1, 2020 07.56AM IST COVID-19 battle: Govt Suggests “off-label”
use of Combo drugs

34. References
• Janathan Merrills and Jonathan Fisher Pharmacy Law and Practice (4th
ed) Elsevier B.V (2006) (PP 138)
• LA doctor seeing success with hydroxychloroquine to treat COVID-19
Health & Fitness abc7.com
• Brandi Powell March 30 2020 Mayo Clinic urges caution for health care
providers prescribing off-label meds for COVID-19. kstp.com 5
ETEWITNESS NEWS. https://kstp.com/coronavirus/mayo-clinic-urges-
caution-for-health-care-providers-prescribing-off-label-meds-for-covid-
19/5686148/
• Off-label use of medicines for COVID-19. Scientific brief. World Health
Organization. 31 March 2020. https://www.who.int/news-
room/commentaries/detail/off-label-use-of-medicines-for-covid-19
• Arizona Death Prompts Warning Against Self-Medication. U.S News.
https://www.usnews.com/news/best-states/arizona/articles/2020-03-23/banner-
health-opens-drive-thru-sites-in-phoenix-tucscon
My Stay at Home Contribution.