Off-label use of Avastin in Pakistan: Lessons from the 2023 Punjab outbreak

Abstract

Off-label drug use, which involves prescribing medications beyond approved indications or dosages, is common in countries like Pakistan where regulatory oversight is limited. Avastin (Bevacizumab), originally approved for cancer treatment, is widely used off-label in ophthalmology to treat conditions such as diabetic retinopathy due to its anti-VEGF effects and lower cost compared to approved alternatives like Ranibizumab. However, its intravitreal use requires strict sterility and compounding standards. In 2023, an outbreak of vision loss occurred in Punjab, Pakistan, affecting 66 patients following intravitreal Avastin injections. Investigations linked the incident to contamination caused by improper repackaging and handling outside sterile conditions, revealing significant gaps in regulatory enforcement and clinical safety protocols. This outbreak highlights the urgent need for clear national guidelines, strict compounding practices, and informed consent to ensure patient safety. Although Avastin remains valuable for ophthalmic use, its safe administration depends on rigorous quality control. Lessons from this incident should guide efforts to improve drug safety and prevent future adverse events.

Main manuscript

Background

Off-label drug use is the prescription of pharmaceutical agents for indications, populations, dosages, or routes not approved by regulatory authorities. It is a widespread and often necessary aspect of modern clinical practice. ¹ While this approach may be supported by scientific rationale or therapeutic urgency, it also introduces significant risks, especially when practiced in the absence of robust regulatory oversight. Historical examples such as thalidomide, fenfluramine, and Wellbutrin illustrate the severe consequences that can arise from poorly controlled off-label use. ²

In developing countries like Pakistan, off-label drug use is common, yet largely unregulated. Physicians frequently prescribe medications without clear legal frameworks, evidence-based guidelines, or mechanisms for adverse event monitoring. ³ Aamir et al. ⁴ reported that in neonatal care, off-label drugs were prescribed more frequently (52.14%) than approved ones (33.5%), underscoring systemic regulatory gaps. Informed consents are legally required when prescribing drugs outside of approved uses and are often overlooked, and risk-benefit evaluations are inconsistently applied. ⁴

Avastin, a monoclonal antibody originally approved for the treatment of various cancers, is widely used off-label in ophthalmology due to its anti-VEGF activity and significantly lower cost compared to approved alternatives like ranibizumab (Lucentis). While cost-effectiveness is a motivating factor, the repackaging and intravitreal administration of Avastin for ocular diseases demand strict adherence to sterility and compounding standards—conditions that are often not met in low-resource settings. ⁵

This issue became particularly prominent in 2023, when an outbreak of vision loss was reported in Punjab, Pakistan. Sixty-six patients reportedly developed blindness after receiving intravitreal injections of Avastin for diabetic retinopathy. ⁶ Investigations suggested that improper handling, non-sterile compounding, and inadequate quality control may have contributed to this adverse event. The incident prompted the Drug Regulatory Authority of Pakistan (DRAP) to suspend the drug’s use temporarily, while the manufacturer, Roche, maintained that the drug was used outside its approved indications. ⁷

Avastin: An off-label drug use in various eye diseases

Avastin, also known as Bevacizumab, is an immunoglobulin that targets vascular endothelial growth factor (VEGF), commonly used to counteract pro-angiogenic factors in various carcinomas of the colon, lung, breast, and kidney. ⁸ When administered intravenously, a single vial of Avastin contains a clear, colorless solution. Its application in ophthalmology stems from its anti-VEGF properties. In conditions like diabetic retinopathy and age-related macular degeneration (AMD), where VEGF overexpression promotes angiogenesis, Avastin's inhibition of VEGF becomes particularly relevant. Inhibiting VEGF has been shown to delay the progression of these diseases, consequently making Avastin an important prognostic value. ⁹ It is used as an intravitreal injection at a dose of 1.25 mg in diabetic retinopathy and age-related macular degeneration (AMD) off-label. ¹⁰ Compared to the approved drug “Lucentis” (Ranibizumab), derived from the same parent molecule, Avastin is much cheaper and more accessible to physicians. However, it might pose greater side effects than “Lucentis” (Ranibizumab). Considering different indications, Lucentis is packed to meet standards of United States Pharmacopeia (USP) Standards for ophthalmic solutions (USP789); hence, it meets rigorous sterility and particulate matter standards. ¹¹ However, Avastin does not follow the same standards, with more particulate matter in its vial. This poses a threat of endophthalmitis in the eyes during intravitreal administration. Avastin is also prepared as a vial that, in practice for AMD, needs to be compounded into smaller doses in sterile syringes, which can introduce particulate matter into the syringe.^10,11

Commonly reported side effects of Avastin include headache, epistaxis, rhinitis, proteinuria, rectal hemorrhage, skin rash, and hypertension. ¹² Yet there are also reports of patients developing serious and potentially life-threatening complications involving multiple organs.

An increase in mean intraocular pressure in non-glaucomatous patients and endophthalmitis after intravitreal Avastin have also been reported. ¹³ Other serious ocular complications include retinal tear, which is found to have an incidence rate as high as 17% after intravitreal Avastin. ¹⁴ In addition to acneiform and acne-like eruptions, a case with subacute cutaneous lupus erythematosus has been reported.^15,16

Avastin incident in Punjab

In September 2023, an outbreak of vision loss in multiple districts of Punjab, Pakistan, was linked to the off-label intravitreal use of Avastin for treating diabetic retinopathy. ⁶ The Punjab government reported that approximately 66 individuals were affected, with cases spanning multiple districts, including Multan, Khanewal, Rahim Yar Khan, and Bahawalpur. While Avastin is approved for systemic cancer therapy, it is commonly repurposed for ocular diseases due to its anti-VEGF activity. However, in this case, the drug had been extracted from large oncology vials and repackaged into smaller syringes without following appropriate ophthalmic compounding and sterility standards. ¹⁷ This improper handling likely led to microbial contamination and subsequent endophthalmitis. The exact mechanism of harm remains inconclusive, as the investigation faced difficulties in determining whether the product degradation occurred during storage, repackaging, or administration. The incident underscores the significant risk associated with using Avastin intravitreally when not prepared under sterile, controlled conditions specifically required for ophthalmic use. ¹⁸

Lessons learned from the incident

The incident involving off-label intravitreal use of Avastin highlights significant gaps in clinical oversight and regulatory enforcement. Healthcare practitioners must prescribe such drugs based on scientific evidence and a clear benefit-risk assessment, such as the BRAvO framework. ¹⁹

Regular follow-ups and informed consent are crucial to minimize complications. The lack of globally standardized guidelines and poor manufacturer regulation underscore the need for strict evaluation of drug handling, storage, and administration practices. ²⁰ Awareness of red flags like new uses, high-risk drugs, and improper dosage routes must guide prescriber decisions to prevent harm.^21,22

Conclusion: Call for action

Off-label use of Avastin has shown efficacy in ophthalmology but carries serious risks when safety protocols are not followed. The Punjab outbreak illustrates how repackaging and administration outside of sterile conditions can result in severe harm, including vision loss. To prevent similar incidents, off-label use must be regulated with clear national guidelines, compounding standards, and informed consent. Physicians should retain clinical autonomy but within a framework that protects patient safety. Global examples of regulatory practices must inform Pakistan’s efforts to ensure responsible use of off-label therapies like Avastin.