Regulatory Approvals

U.S. – Food and Drug Administration (FDA)

https://www.fda.gov/media/136534/download

Emergency Use Authorization For Use of Chloroquine Phosphate or Hydroxychloroquine Sulfate Supplied From the Strategic National Stockpile for Treatment of 2019 Coronavirus Disease

Special situation: “Public Health Emergency”

• Grant of Emergency Usage Authorisation (EUA) by USFDA for Hydroxychloroquine and Chloroquine to treat patients of Covid-19 (March 28, 2020)
• “SARS-CoV-2 can cause serious or life threatening disease or condition, including severe respiratory illness, to humans infected by this virus”

Rationale for Issuance

• “Based on the totality of scientific evidence available to FDA….. the known and potential benefits of chloroquine phosphate and hydroxychloroquine sulfate when used to treat Covid-19 outweigh the known and potential risks of such products; and”
• “There is no adequate, approved and available alternative to the emergency use of chloroquine phosphate and hydroxychloroquine sulfate for the treatment of COVID-19”

Scope of Authorization

• Administered by a healthcare provider pursuant to a valid prescription of a licensed practitioner
• Adult and adolescent patients >50kg weight – for whom a clinical trial is not available or feasible

Conditions

Use within scope:

• Maintaining detailed records (lot numbers, quantities, receiving site, receipt date)
• Adverse event monitoring mechanism
• Patient information records

France – High Council of Public Health

https://www.legifrance.gouv.fr/affichTexte.do?cidTexte=JORFTEXT000041755775&categorieLien=id

Authorisation for Usage (March 23, 2020)

• “..Hydroxychloroquine and lopinavir / ritonavir can be prescribed, dispensed and administered under the responsibility of a doctor to patients affected by COVID-19, in the healthcare establishments that support them, as well as, for the continuation of their treatment if their condition permits and with the authorization of the initial prescriber, at home.”
• National Security Agency of Drug and Health products is responsible, for these drugs, to develop a protocol of use therapy for healthcare professionals and to establish the modalities of information adapted to the attention of patients
• Pharmacovigilance data reporting
• Export prohibition

India – National Task Force, Indian Council of Medical Research (ICMR)

https://www.mohfw.gov.in/pdf/AdvisoryontheuseofHydroxychloroquinasprophylaxisforSARSCoV2infection.pdf

Advisory issued by The National Task Force for Covid-19 constituted by the Indian Council of Medical Research (adopted by Ministry of Health 22 March, 2020) recommends the use of Hydroxychloroquine for prophylaxis of SARS-CoV-2 infection for selected individuals:

• Asymptomatic healthcare workers involved in the care of suspected or confirmed cases of COVID-19
• Asymptomatic household contacts of laboratory confirmed cases

Dose

• Asymptomatic healthcare workers: 400mg twice a day on Day 1, followed by 400mg once weekly for next 7 weeks to be taken with meals
• Asymptomatic household contacts: 400mg twice a day on Day 1, followed by 400mg once weekly for next 3 weeks to be taken with meals

Exclusion / Contraindications

• < 15 years
• Known case of retinopathy; hypersensitivity to Hydroxychloroquine, 4-aminoquinoline compounds

Rationale

• Its use as treatment is based on In-vitro effectiveness of Hydroxychloroquine against Coronavirus and in-vivo studies
• Its use as prophylaxis is derived from available evidence of benefit as treatment and supported by pre-clinical data
• Risk-benefit consideration
• Exceptional circumstances

Conditions

• Prescription of a registered medical practitioner
• Physician assessment of potential drug interaction before use
• Pharmacovigilance reporting
• Asymptomatic contacts should remain under home quarantine during prophylactic therapy
• All protective measures should remain in place
• Further studies should be taken up expeditiously to guide further changes

China – Expert consensus on chloroquine phosphate for the treatment of novel coronavirus pneumonia

https://www.ncbi.nlm.nih.gov/pubmed/32164085

A multicenter collaboration group of Department of Science and Technology of Guangdong Province and Health Commission of Guangdong Province for chloroquine in the treatment of novel coronavirus pneumonia developed this expert consensus

Rationale

• Previous studies have shown that chloroquine phosphate (chloroquine) had a wide range of antiviral effects, including anti-coronavirus
• Treating the patients diagnosed as novel coronavirus pneumonia with chloroquine might improve the success rate of treatment, shorten hospital stay and improve patient outcome

Dose

• Chloroquine phosphate tablet, 500mg twice per day for 10 days for patients diagnosed as mild, moderate and severe cases of novel coronavirus pneumonia and without contraindications to chloroquine

Medical Society Guidelines for Use

Cardiovascular risks of hydroxychloroquine in treatment and prophylaxis of COVID-19 patients: A scientific statement from the Indian Heart Rhythm Society

https://doi.org/10.1016/j.ipej.2020.04.003

Background

• This statement from Indian Heart Rhythm Society (IHRS) addresses the use of hydroxychloroquine in COVID-19
• It includes a brief review of its cardiovascular effects, its propensity to cause QT elongation and potentially lethal cardiac arrhythmia in certain patients

Findings

• Hydroxychloroquine has been observed to inhibit ACE2 receptor-mediated entry of the SARS-CoV-2 virus through various actions
• It also has anti-inflammatory and immunomodulator actions which could be relevant in the crisis generated by cytokine storm
• Hydroxychloroquine can lead to QT interval prolongation and torsades de pointes (TdP) in susceptible individuals
• Not all patients with drug-induced QTc prolongation will develop TdP and its side effect is rare, but co-prescription of other drugs such as azithromycin could amplify this risk

Guidance

• It is recommended to have a baseline ECG to estimate the QTc interval in individuals receiving hydroxychloroquine treatment
• The normal upper limit for QTc interval is 460 ms for women and 450 ms for men
• Although ECG is a simple tool, it still poses challenges of the risk of contamination to equipment by a positive COVID-19 patient and the need of PPEs for the operators
• Alternatives to the conventional 12-lead ECG system can be:
  • Standard telemetry systems equipped with real time QTc monitoring
  • Using a smartphone-enabled mobile QTc app or the FDA approved mobile ECG devicesuch as AliveCor
• Patients should be categorized into A) Low risk group (normal QT-interval), B) Moderate risk group (QTc ≤ 500 ms) and, C) High risk group (QTc ≥ 500 ms)
• Treat group A without further risk stratification; group B with caution and attempt to resolve correctable risk factors; group C with reassessment of COVID-19 risk (low risk – avoid therapy; high risk – continue with caution)
• In patients with QTc ≥ 500 ms at baseline, perform ECG 2-4 hrs after first dose (followed by checkups at 48 and 96 hrs)
• In patients with QTc prolongation more than 60 ms, reassess risk-benefit of continuing hydroxychloroquine therapy
• The Government of India, Ministry of Health and Family Welfare Guidelines recommends the following dosing for patients with severe disease and requiring ICU management:
  • Hydroxychloroquine: 400 mg BD for one day followed by 200 mg BD for 4 days, in combination with
  • Azithromycin: 500 mg OD for 5 days
• These drugs should be administered under close medical supervision, with monitoring for side effects including QTc interval
• The National Task Force for COVID-19 constituted by Indian Council of Medical Research (ICMR) has also recommended hydroxychloroquine for prophylactic use as follows:
  • Asymptomatic healthcare workers: 400 mg BD on day 1 followed by 400 mg once weekly for 7 weeks
  • Asymptomatic household members of COVID-19 patients: 400 mg BD on day 1 followed by 400 mg once weekly for 3 weeks (with meals)
• When hydroxychloroquine is used for prophylaxis, although it is preferable to have a baseline ECG to measure the QTc interval
• Efforts should be made to identify all potentially high-risk individuals and their ECG exams be conducted

Inferences

• The guidelines are likely to change as more data from randomized clinical trials is available
• The decision to use hydroxychloroquine for COVID-19 should take into account the occasional possibility of cardiac arrhythmia
• The Indian Heart Rhythm Society strongly discourages its use for the general public without medical supervision and prescription
• The measures of restrained advocacy for potentially beneficial effects of hydroxychloroquine and advice against self-medication can help prevent adverse events related to this drug

Ventricular Arrhythmia Risk Due to Hydroxychloroquine-Azithromycin Treatment For COVID-19

https://www.acc.org/latest-in-cardiology/articles/2020/03/27/14/00/ventricular-arrhythmia-risk-due-to-hydroxychloroquine-azithromycin-treatment-for-covid-19

American College of Cardiology, March 29, 2020

Suggested Monitoring for In-Patient Clinical Use

Baseline (Before commencing treatment, do the following):

• Discontinue and avoid all other non-critical QT prolonging agents
• Assess a baseline ECG, renal function, hepatic function, serum potassium and serum magnesium
• Have an experienced cardiologist/electrophysiologist measure QTc, and seek advice in case acute renal or hepatic failure is diagnosed

Relative contraindications (subject to modification based on potential benefits of therapy):

• History of long QT syndrome, or
• Baseline QTc >500 msec (or >530-550 msec in patients with QRS greater than >120 msec)

Ongoing monitoring, dose adjustment and drug discontinuation:

• Place on telemetry prior to start of therapy
• Monitor and optimize serum potassium daily
• Acquire an ECG 2-3 hours after the second dose of hydroxychloroquine, and daily thereafter
• If QTc increases by >60 msec or absolute QTc >500msec (or >530-550 msec if QRS >120 msec), discontinue azithromycin (if used) and/or reduce dose of hydroxychloroquine and repeat ECG daily
• If QTc remains increased >60 msec and/or absolute QTc >500 msec (or >530-550 msec if QRS >120 msec), reevaluate the risk/benefit of ongoing therapy, consider consultation with an electrophysiologist, and consider discontinuation of Hydroxychloroquine

Suggested Monitoring for In-Patient Clinical Use

Baseline (Before commencing treatment, do the following):

• Discontinue and avoid all other non-critical QT prolonging agents
• Assess a baseline ECG, renal function, hepatic function, serum potassium and serum magnesium
• When possible, have an experienced cardiologist/electrophysiologist measure QTc
• Avoid outpatient initiation in case acute renal or hepatic failure is diagnosed

Relative contraindications (subject to modification based on potential benefits of therapy):

• History of long QT syndrome, or
• Baseline QTc >480 msec (or >510-530 msec if QRS >120 msec), or
• Tisdale risk score ≥11

Ongoing monitoring, dose adjustment and drug discontinuation:

• If quarantine or resource constraints are prohibitive, consider no further ECG / telemetry assessment, if Tisdale risk score ≤6. Also consider use of alternative mechanisms of QT and arrhythmia assessment outlined below
• Otherwise, repeat ECG 2-3 hours after dosing on day 3 of therapy. If QTc increases by >30-60 msec or absolute QTc >500msec (or >530-550 msec if QRS >120 msec), consider discontinuing therapy

Annexure: Tisdale Chart – Risk Score for Drug Associated QTc Prolongation

A Tisdale score of ≤ 6 predicts low risk, 7-10 medium risk, and ≥ 11 high risk of drug-associated QT prolongation.