CMAAO CORONA FACTS and MYTH BUSTER 60 OFF LABEL POLICY
Dr K K Aggarwal
President Confederation of Medical Associations of Asia and Oceania, HCFI and Past National President IMA
633 : Off label use of Hydroxychloroquine and Azithromycin in COVID 19
A plea seeking directions to the government to make necessary changes in the treatment guidelines for seriously ill COVID-19 patients, who are receiving a combination of anti-malarial drug hydroxychloroquine and antibiotic azithromycin, has been filed in the Supreme Court claiming that they have lethal side effects.
The PIL filed by People for Better Treatment (PBT) said the use of HCQ and AZM were recommended for the most serious COVID-19 patients by the Health Ministry based primarily on anecdotal evidence and not as a specific therapy.
The petition has also sought directions to take necessary steps for immediate implementation of all the specific preventive measures recommended in hospitals across India to protect the lives of COVID-19 patients who are being treated with an unproven and “off label” HCQ and AZM following guidelines dated 31st March 2020 passed by the Ministry of Health.
Indian Council of Medical Research (ICMR), Department of Health Research, Ministry of Health and Family Welfare, Government of India had issued Recommendation for empiric use of hydroxy-chloroquine for prophylaxis of SARS-CoV-2 infection dated 22.03.2020. The relevant part of recommendation is reproduced hereunder:
“Hydroxy-chloroquine is found to be effective against coronavirus in laboratory studies and in-vivo studies. Its use in prophylaxis is derived from available evidence of benefit as treatment and supported by pre-clinical data. The following recommendation for the use of hydroxy-chloroquine as a prophylactic agent against SARS-CoV-2 infection is based on these considerations, as well as risk benfit consideration, under exceptional circumstances that call for the protection of high risk individuals.
The National Task force for COVID-19 recommends the use of hydroxy-chloroquine for prophylaxis of SARS-CoV-2 infection for selected individuals.”
Government of India, Ministry of Health & Family Welfare through Directorate General of Health Services (EMR Division) had issued Revised Guidelines on Clinical Management of COVID – 19 on 31st March 2020 vide which the Government of India had accepted the recommendations of ICMR and stated about the specific therapy which is as follows:
“NO SPECIFIC ANTIVIRALS have been proven to be effective as per currently available data. However, based on the available information (uncontrolled clinical trials), the following drugs may be considered as an off – label indication in patients with severe disease and requiring ICU management:
• Hydroxychloroquine (Dose 400mg BD – for 1 day followed by 200mg 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 above medication is presently not recommended for children less than 12 years, pregnant and lactating women.”
Meaning of Off label use of a drug
Off-label use means that the particular drug is used for an indication that is not otherwise approved by the regulatory authority, which is the Drug Controller General of India (DCGI) in India, and is not included in the package insert or label carrying instructions about indications, contraindications and dosing and other instructions. Off-label use of drugs is common in clinical practice all over the world.
HCFI Expert Round Table Sutra
“In absence of any unethical considerations or a safety issue AND in presence of strong international or national scientific evidence; off-label use in other country; guideline or consensus statement; prevalent use in the clinical practice WITH no reported side effects under PvPI and the drug is not under RISK MAP category THEN the use of the available DCGI approved drug (including medical devices and disposables) is justified for off-label indications under implied consent. In all other situations, one needs to take an informed consent.”
Off Label use of Anti Malaria drug for the treatment of COVID
Thus, with no proven treatment and 15% mortality in 80 plus [people, 8% in 70 plus people and 3 % in 60 plus people it becomes necessary to use off label drugs in the treatment.
Both chloroquine and hydroxychloroquine have been reported to inhibit SARS-CoV-2 in vitro, although hydroxychloroquine appears to have more potent antiviral activity [1].
Chloroquine is included in treatment guidelines from China's National Health Commission and was reportedly associated with reduced progression of disease and decreased duration of symptoms [2,3]. However, primary data supporting these claims have not been published [4].
In an open-label study of 36 patients with COVID-19, use of hydroxychloroquine (200 mg three times per day for 10 days) was associated with a higher rate of undetectable SARS-CoV-2 RNA on nasopharyngeal specimens at day 6 compared with no specific treatment (70 versus 12.5 percent) [5].
It is reasonable to use one or both of these agents in hospitalized patients with severe or risk for severe infection, particularly if they are not eligible for other clinical trials.
The European Union Clinical Trials Register shows that the Marseille study was accepted on 5th March by the National Medicines Safety Agency (ANSM). It could include up to 25 COVID-19 positive patients, comprising five aged 12–17 years, 10 aged 18–64 years, and 10 more aged 65 years or over. Unblinded study showed a strong reduction in viral load with hydroxychloroquine.
After 6 days, the percentage of patients testing positive for COVID-19 who received hydroxychloroquine fell to 25% versus 90% for those who did not receive the treatment (a group of untreated COVID-19 patients from Nice and Avignon).
In addition, comparing untreated patients, those receiving hydroxychloroquine and those given hydroxychloroquine plus the antibiotic azithromycin, the results showed there was "a spectacular reduction in the number of positive cases" with the combination therapy. At 6 days, among patients given combination therapy, the percentage of cases still carrying SRAS-CoV-2 was no more than 5%. (6)
The case in question
1. It is one of the leg part of WHO solidarity trial
2. It is cleared by ICMR and DGHS
3. DCGS has cleared it as an off-label indication
4. In an emergency situation and National Interest, the MOH has powers to do so
5. Earlier the Indian government On January 21, 2016, the DCGI took the bold step of prohibiting the use of intraocular bevacizumab as off-label treatment for various retinal diseases. Unfortunately, this decision put a large percentage of the population at risk of inaccessibility to treatment for common blinding retinal diseases. But, after 2 months, the DCGI agreed to withdraw the alert notice, enabling retinal surgeons to again use bevacizumab. This decision is a landmark judgment for India and other countries around the world to look at evidence-based off-label use of drugs.
6. The plasma therapy now approved by ICMR for thr treatment of COVID 19 is also a off label use of plasma.
1. Yao X, Ye F, Zhang M, et al. In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Clin Infect Dis 2020.
2. Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends 2020; 14:72.
3. Colson P, Rolain JM, Lagier JC, et al. Chloroquine and hydroxychloroquine as available weapons to fight COVID-19. Int J Antimicrob Agents 2020; :105932.
4. Cortegiani A, Ingoglia G, Ippolito M, et al. A systematic review on the efficacy and safety of chloroquine for the treatment of COVID-19. J Crit Care 2020.
5. Gautret et al. (2020) Hydroxychloroquine and azithromycin as a treatment of COVID‐19: results of an open‐label non‐randomized clinical trial. International Journal of Antimicrobial Agents – In Press 17 March 2020 DOI:10.1016/j.ijantimicag.2020.105949.
6. The Marseille Study [International Journal of Antimicrobial Agents].
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