Dear Colleagues! This is Asrar Qureshi’s Blog Post #859 for Pharma Veterans. Pharma Veteransaims to share knowledge and wisdom from Veterans for the benefit of Community at large. Pharma Veterans Blog is published by Asrar Qureshi on WordPress, the top blog site. Please email to firstname.lastname@example.org for publishing your contributions here.
Off-Label Drug Use
“Off-label drug use involves prescribing medications for an indication, or using a dosage or dosage form, that has not been approved by the FDA. Since the FDA does not regulate the practice of medicine, OLDU has become common”, says National Institute of Health, USA.
Off-label drug use is based on practice and experience and may even be supported by some clinical studies. However, large scale clinical trials and their review by a regulatory authority is missing. The off-label use spreads through word of mouth.
Avastin (bevacizumab) belongs to mAbs class of drugs and is approved for the treatment of colorectal cancer primarily. It is used in several other types of cancers also.
Avastin Use in Ophthalmology
Avastin was first used in certain eye conditions in 2005 and is not the only such drug to be used in eye. Lucentis (ranibizumab), Eylea (aflibercept), and Beovu (brolucizumab) are other drugs like Avastin which can be used in the same conditions. Avastin and Lucentis have been studied in comparison also; so, has been comparison between Avastin alone and Avastin + 5-fluorouracil. It appears that the use of Avastin in certain eye conditions is fairly old and quite widespread.
I am not mentioning the names of diseases because it would be an unnecessary technical detail. The important thing to know is that Avastin and other drugs of this class have been shown to be effective in slowing vision loss. Their use in diabetic patients is more common because diabetics develop certain typical eye conditions due to their metabolic disorder.
Avastin is available in packs containing 400mg bevacizumab in 16ml or 100mg in 4ml for use as anticancer. For ophthalmic use, the dose commonly given is 1.25mg in 0.05ml. It means that one vial of Avastin 100mg/4ml is divided into 80 (320 for 400mg inj.) ready to use injections, probably by packing in insulin syringes. It is a very fine job which must be done meticulously under sterile conditions. Any deviation in strength or quantity may not yield desired results. Any issue with sterility can play havoc with the patients.
Avastin is temperature sensitive and cold chain of 2 – 8C must be maintained throughout, even during repacking into micro doses, which must be supplied under cold chain.
Roche does not provide 1.25mg/0.05ml dosage form because it is not registered anywhere in the world. This job is done by third parties who must ensure that they deliver right quantity and quality with guaranteed sterility under cold chain.
Avastin Incidence in Pakistan – September 2023
Several cases were reported almost in the third week of September at once, reporting that 50-70 patients had lost vision after they were administered micro doses of Avastin for diabetic eye complications. It was reported that the patients developed severe eye infections after injection which led to loss of vision. Since the incidence was very serious and the numbers big enough, all stakeholders were suitably alarmed.
Drug Regulatory Authority Pakistan issued a rapid alert on September 24, 2023, to ophthalmologists, endocrinologists, health professionals, regulatory field force and general public. It is about the incidents of loss of vision in diabetic patients following treatment with Altered/Dispensed/Diluted Avastin injection. This product (Avastin) is approved by DRAP to treat colorectal and other metastatic carcinomas. The use of this drug in diabetic retinopathy or other ophthalmic conditions is one of the off-label uses and is not approved by DRAP.
DRAP said, “the incident is linked with the alteration/dispensing/dilution and sale of Avastin 100mg/4ml injection under unhygienic/ non-sterile conditions illegally and without any Drug Sale/Dispensing License (DSL) from Provincial Health Authority by M/s Genius Advanced Pharmaceutical Services Lahore”.
Following the incident, DRAP instructed Roche to recall the suspected batches of Avastin 100mg injections, which it said had been created illegally. Roche stated on its website, “The sale/distribution of registered Avastin injection has been put on halt till verification of its quality through sampling and laboratory testing to safeguard public health. In Pakistan, the vision loss from Avastin has been identified by the authorities as a case of contamination by a third-party supplier. Roche strongly condemns this criminal act of counterfeiting and is doing everything in its power to cooperate with the authorities to protect patients from counterfeits”.
I would like to add that it is impossible that Roche did not know that Avastin was being used in ophthalmology, or that who was supplying the micro doses. They would also know if M/s Genius was authorized to do it or not. Drugs like Avastin are not sold over the counter, these are supplied against prescription at selected places, most commonly by the distributor directly. How could the distributor supply to M/s Genius on regular basis if they did not have license?
Pakistan Today reported on September 26, 2023.[Quote] The interim Punjab government has thus far been unable to provide sufficient information regarding the production, quantity, and distribution of the injections linked to patients losing their eyesight. In the meanwhile, the number of vision loss cases in Punjab has surged to over 70.
According to the caretaker Health Minister of Punjab, Dr. Javed Akram, people were not affected by the side effects of this injection, but rather due to the use of counterfeit injections. The primary issue lies in the misuse of these injections.
Dr. Akram explained that the genuine problem with these sixteen-milliliter injections is their limited shelf life after being taken out of their protective seal. Addressing recent events in Punjab, Dr. Javed revealed that a private hospital in Lahore administered Avastin injections to several eye disease patients using separate syringes at different times, resulting in many patients losing their eyesight.
He also mentioned that the injection solution was tampered with to increase its volume, contributing to the adverse effects. These adulterated injections were produced by an unregistered fake company, a criminal offense according to the Drug Regulatory Authority of Pakistan (DRAP).
Dr. Javed Akram disclosed that these fake injections were being manufactured illegally within a private hospital in Lahore, specifically located at Thokar Niaz Baig area. Certain rooms in the private hospital were converted by a dispenser or doctor to illicitly produce this injection that is not safe for use.
Additionally, three individuals have been apprehended in connection with this illicit operation, and legal proceedings have been initiated against them. However, on one hand, Dr. Akram is discussing the punishment for the three accused individuals, while on the other hand, the Department of Health Care has only named two people, Naveed and Bilal, in the FIR.
Moreover, Dr. Akram explained that a comprehensive investigation is underway to determine the scope of the distribution network for these counterfeit injections. Simultaneously, stringent measures have been taken to immediately cease the sale of Avastin in the market, prioritizing public safety. [Unquote]
While there is no reason to doubt the professional competence and integrity of the doctors using the drug, the question certainly arises as to why they did not investigate the supplier, its authenticity, and its facilities. This is a serious omission. Curiously, no authority is questioning the doctors, and they are also in silent mode.
The whole incidence is a combination of negligence at all levels, DRAP, Provincial Health Authority, Field Regulators, and most of all the ophthalmologists. The incident shall stay in news for couple of days and then fade out. The patients who became blind shall probably be blind for the rest of their lives. Life moves on.
Disclaimer: Most pictures in these blogs are taken from Google Images and Pexels. Credit is given where known; some do not show copyright ownership. However, if a claim is lodged at any stage, we shall either mention the ownership clearly, or remove the picture with suitable regrets.