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In the first week of April this year, over 20 eye patients, who were being treated at Guru Teg Bahadur (GTB) hospital in Delhi, reported breathlessness, blurred vision, redness, etc after they were injected with a drug called ‘Avastin’. This was not the first time such incident had happened. On January 13, 2016, 15 patients at CH Nagri Eye Hospital in Ahmedabad complained “loss of vision” after Avastin was injected in their eyes. In both the cases, the doctors stated that the incidents happened due to “contamination” of Avastin.
This contamination has been happening across the country for three reasons. First, Avastin is a cancer drug that does not contain any preservatives and it needs to be compounded — which means it has to be divided into small doses as per each patient’s need —through a “proper aseptic technique” before any ophthalmic usage. Second, it is impossible to divide this drug manually into small doses, which usually come to the value of 0.05 ml and therefore, precision instruments need to be used. Third, there are no guidelines of the Drug Controller General of India (DCGI) or of the health ministry for the safe and effective use of Avastin on eye diseases. The DCGI heads the Central Drugs Standard Control Organisation (CDSCO).
Avastin is a cancer drug of the multinational pharmaceutical company Roche. The molecule name of this drug is Bevacizumab. Opthalmologists across the world have been using Avastin to treat eyes diseases such as age-related macular degeneration (AMD) because it has been extremely cheap compared to other eye medicines in the market, especially Lucentis. The US Food and Drug Administration (FDA) approved the Lucentis – which is a brand of another multinational company Novartis — in 2006 for the treatment of AMD. Roche India told The Indian Express: “The product formulation of Avastin is only approved for single use in specific cancer indications. It is not a multi-dose preparation because it does not contain preservatives and is not designed to be injected in the eye. When a physician makes a choice to use it off-label in the eye, the original product is typically partitioned in a hospital or pharmacy, potentially for use in multiple patients. This process bears the risk of bacterial contamination and has already led to serious bacterial infections of the eye in other countries around the world.”
In July 2011, 16 eye patients in two states of America — Florida and Tennesse — reported severe eye infections and blindness after being injected with Avastin. In March 2016, 13 eye patients reported various eye problems at Cairo in Egypt after being injected with this drug. The company said that the information regarding these adverse events has been published and the risks are also included in its prescribing information, which is inserted in each pack. “We strongly recommend that Avastin should be used in line with the approved prescribing information and not for any eye indication,” it said.
When contacted, the DCGI did not respond to the query from The Indian Express.
According to industry executives, pharmacies and chemists in Europe and the US have the class 100 aseptic areas to do the compounding safely and precisely. “In India, the division of a drug like Avastin is done in a operation theater of a hospital in a belief that it is completely free of bacterial contamination. That is simply not true. In India, pharmacies do not have class 100 aseptic areas. Only few hospitals in the country has such areas. A class 100 aspetic area has extremely strict specifications of its own,” said a Delhi-based opthalmologist. A typical aseptic area comprises of a room that is maintained under positive pressure of air that is continuously filtered through 0.2 micron high efficiency particulate air (HEPA) filters. Entry to the room is protected by a series of three rooms (air-locks), each of them continuously supplied by HEPA filtered air. The main aseptic area has the highest positive pressure. The pressure of the three air-locks is adjusted in a sequentially decreasing value. This design ensures that whenever any door is opened, the air is always flowing out from the aseptic area in the direction towards the airlocks. Hence the aseptic area is always bacteria free.
Additionally, when a sterile product like Avastin is handled, it is conducted under a laminar flow equipment that essentially provides a blanket of HEPA filtered air in the zone. Lastly, the operator entering the sterile area has to remove the street clothes in the first air lock, scrub himself in the second airlock, wear sterile clothes in the third airlock and enter the sterile area. The operator has to be thoroughly trained so that he is proficient in aseptic area techniques. There are several other precautions which need to be taken by the operator to ensure that the activity of subdivision ensures equal dosing without compromising sterility.
GTB hospital of Delhi did not respond to the queries of The Indian Express. Avastin is available in the market in two pack presentations: vial containing 4 ml of injection solution (25 mg/ml), which means a total 100 mg dose, and in a vial containing 16 ml of injection solution (25 mg/ml), which means a total 400 mg dose. “Ophthalmologists in the Western countries, who have who have experimented with its ‘Off-Label’ use of Avastin to treat AMD, have arrived at a dose of 1.25 mg for treatment. Accordingly, to use Avastin for AMD, a 4 ml vial containing 100 mg Bevacizumab, would have to be subdivided into 80 doses of 0.05 ml each containing 1.25 mg of the drug. It is next to impossible to accurately dispense 0.05 ml solution manually. Accurate dispensing of such very small volumes is only possible with highly sophisticated machines which have precision pumps. Therefore, apart from the high risk of contamination, manual subdivision into 1.25 mg doses / 0.05 ml volume, will provide the patients varying amounts of the drug,” said a senior pharmaceutical industry executive based out of Ahmedabad.
On January 21, 2016, after media reports came out regarding 15 patients, who reported eye problems after being injected with Avastin, at C H Nagri Eye Hospital in Ahmedabad, the DCGI issued an alert notice. Through this, the DCGI restricted the use of Avastin for ophthalmology as a “precautionary measure”. This matter was then investigated by the health ministry’s experts panel. In March 2016, this committee suggested the DCGI to recall the medical alert and its restriction. It also asked the DCGI to let All India Ophthalmological Society (AIOS) and Vitreo Retinal Society of India (VRSI) form the guidelines for safe and effective use of Avastin for ophthalmic purpose. The committee’s recommendations were accepted by the DCGI. The AIOS and VRSI did not respond to the specific query of The Indian Express when asked if they have formed any guidelines related to the use of Avastin.