According to the National Institutes of Health’s Center National Center for Advancing Translational Sciences, many drugs approved for other uses already have been tested in humans, so detailed information is available on their pharmacology, formulation, and potential toxicity. 

Therefore, trying a Food and Drug Administration (FDA)-approved drug for one disease as a new therapy for an unrelated disease could allow the treatment to be ready for clinical trials more quickly thus speeding the FDA’s review and, if approved, its integration into health care.1 This is more commonly referred to as “drug re-purposing” or “off-label use.”

FDA approval on a repurposed drug can take approximately three to four years as compared to an investigational new drug (IND), which may take greater than 10 years. The approval rate for a repurposed drug in approximately 30 percent1 whereas an IND is less than 12 percent.

ADDENDUM 1 is a summary of the different phases required by the FDA prior to drug approval.3

In an effort to combat the coronavirus (COVID-19), front-line physicians have already repurposed two drugs: hydroxychloroquine (brand name Plaquenil®—commonly used for malaria and rheumatoid arthritis) and azithromycin (multiple brand names including Zithromax® Zithromax Tri-Pak®, Azythromycin Dose Pack®, Zithromax Z-Pak® and Zmax®)—a macrolide antibiotic used to treat common infections of the respiratory system, the ear and the eye.

Both drugs are known to be low-risk ototoxic agents; however, there is no published research about the synergistic ototoxic effects of these drugs in treating COVID-19. At the present time, it is not known if hearing loss and/or tinnitus will be a late onset of this COVID-19 drug intervention. Therefore, case history questions will need to be added to accommodate this new population of patients.

A detailed summary of this repurposing and the potential impact it could have on audiology patient management can be found in a previously published article.

The Emergency Use Authorization (EUA) authority allows the FDA to facilitate the availability and use of medical counter measures (MCM) needed during public health emergencies such as COVID-19. Under section 564 of the Federal Food, Drug, and Cosmetic Act, unapproved medical products or unapproved uses of approved medical products can be used in an emergency when there are no adequate, approved, or available alternatives.4 

The National Institutes of Health (NIH) National Library of Medicine has a website that lists all clinical trials taking place throughout the world on a myriad of health issues. The access is easy and fast: www.clinicaltrials.gov.

There is a topic/keyword(s) filter to narrow down a search. For this report, the following filters were applied on 5/13/20.

  • Recruitment: Recruiting
  • Eligibility Criteria: All ages
  • Sex: All
  • Study Type: Interventional (Clinical Trials)
  • Study Results: All
  • Study Phase: Early Phase 1, Phase 1, Phase 2 and Phase 3
  • Funder: All funders
  • Study Documents: blank

TABLE 1 identifies the FDA-approved drugs currently being repurposed for COVID-19 intervention research based on the above filters selection. Biologics are not included.

TABLE 1. 
BRAND NAME GENERIC USES ALREADY APPROVED BY THE FDA AUDITORY SIDE EFFECTS

Actemra®

tocilizumab

rheumatoid arthritis

None (multiple sources)

Calan®

verapamil

Ventricular tachycardia or venticular fibrillation NOTE: This drug is being used in a compartive study with amiodarone  (see  Pacerone©)

 

Tinnitus (www.rxlist.com)

Colcrys®

colchicines

gout

None (multiple sources)

Cozaar®

losartin

hypertension

tinnitus; vertigo <1% each (www.pdr.net)

 

Desferal®

deferoxamine

treatment of acute iron intoxi cation and of chronic iron overload due to transfusion-dependent anemias

HF SNHL and/or tinnitus (www.rxlist.com)

Etopophos®

toposide

lung/testicular cancers

None (multiple sources)

Kaletra®

lopinavir/ritonavir

HIV-1 infection

tinnitus, vertigo <1% each (www.pdr.net)

Ketalar®

ketamine

anesthetic agent

None (multiple sources)

Kevzara®

sarilumab

moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs(DMARDs).

None (multiple sources)

Luvox®

fluvoxamine

Obsessive Compulsive Disorder (OCD)

None (multiple sources)

Pacerone®

amiodarone

ventricular tachycardia or ventricular fibrillation. NOTE: This drug is being used in a comparative study with verapamil (see Calan©)

None (multiple sources)

Paquenil®

hydroxychloroquine/ chloroquine

rheumatoid arthritis, malaria, lupus

SN HL (temp. or perm.) (multiple sources)

Pepcid®
(also avail. OTC)

famotidine

intestinal ulcers

Tinnitus (www.rxlist.com)

Rapamune®

sirolimus

immunosuppressant; renal transplant rejection

None (www.drugs.com) (www.pfizer.com)

Vitamin B9

folic acid

folate deficiency; megaloblastic anemia

None (multiple sources)

Vitamin C

L-ascorbic acid

multiple health uses (see www.webMD.com)

None (multiple sources)

Vivitrol®

naltrexone

opiod antagonist; pain relief

Tinnitus (<1%) (www.pdr.net)

Xpovio®

selinexor

multiple myeloma

Ear congestion (www.drugs.com)

Zithromax® 

Zithromax Tri-Pak®

Azythromycin Dose Pack®

Zithromax Z-Pak®

Zmax®

azithromycin

respiratory and other infections

SN HL (temp./perm.) 
(multiple sources)

Conclusion

Currently, 19 FDA-approved drugs are being repurposed as part of clinical research to identify the efficacy and safety for regular use in the treatment of COVID-19. Several vaccine biologics are also be evaluated using the above filters but they are not include in TABLE 1.

The following side effects information is already known to the principal investigator(s) from the drug manufacturer’s findings during their own pre-FDA approval clinical trials and not from any preliminary reports of the drug’s use with COVID-19 patients. Sources are cited in TABLE 1.

  • Ten (52.6 percent) have no auditory/vestibular side effects.
  • Six (31.5 percent) have tinnitus as a side effect.
  • Three (15.8 percent) have sensorineural hearing loss as a side effect (including one specifically reporting a “high frequency” loss).
  • Two (10.5 percent) have temporary or permanent hearing loss as a side effect.
  • Two (10.5 percent) have vertigo as a side effect.
  • One (5.3 percent) has ear congestion (negative middle ear pressure) as a side effect.

Finally, for the audiologist, additional questions will need to be added to the case history section under Past Medical History: Were you diagnosed with COVID-19? What medications were you given? Were you part of a clinical trial? Patients should know if they were involved in a clinical trial because an “Informed Consent” form will be signed prior to the start of the trial. 

If it is determined that the hearing loss, tinnitus, or vertigo can be traced to the experimental use of this drug for COVID-19 treatment (time line data needed), the audiologist must notify the clinical investigator (if known) or report this finding online to the FDA’s MedWatch Program (NOTE: Professionals use FDA Form 3500, Consumers/Patients use FDA Form 3500B] or by calling 1-800-FDA-1088 (1-800-332-1088).

ADDENDUM 1.

FDA CLINICAL TRIAL PHASES

PHASE I STUDIES

Assess the safety of a drug or device. can take several months to complete, usually includes a small number of healthy volunteers (20 to 100); designed to determine the effects of the drug or device on humans including how it is absorbed, metabolized, and excreted; investigates the side effects that occur as dosage levels are increased. About 70 percent of experimental drugs pass this phase of testing.

PHASE II STUDIES

Test the efficacy of a drug or device; can last from several months to two years, and involves up to several hundred patients; are randomized trials where one group of patients receives the experimental drug, while a second "control" group receives a standard treatment or placebo; are "blinded" which means that neither the patients nor the researchers know who has received the experimental drug (allows investigators to provide the pharmaceutical company and the FDA with comparative information about the relative safety and effectiveness of the new drug). About one-third of experimental drugs successfully complete both Phase I and Phase II studies.

PHASE III STUDIES

Involve randomized and blind testing in several hundred to several thousand patients; can last several years, provides the pharmaceutical company and the FDA with a more thorough understanding of the effectiveness of the drug or device, the benefits and the range of possible adverse reactions. Seventy percent to 90 percent of drugs that enter Phase III studies successfully complete this phase of testing. Once Phase III is complete, a pharmaceutical company can request FDA approval for marketing the drug.

PHASE IV STUDIES

Often called Post Marketing Surveillance Trials; conducted after a drug or device has been approved for consumer sale. Pharmaceutical companies have several objectives at this stage: (1) to compare a drug with other drugs already in the market; (2) to monitor a drug's long-term effectiveness and impact on a patient's quality of life; and (3) to determine the cost-effectiveness of a drug therapy relative to other traditional and new therapies. Phase IV studies can result in a drug or device being taken off the market or restrictions of use could be placed on the product depending on the findings in the study. Time frame ~10 years