Pfizer Inc. and BioNTech SE's COVID-19 vaccine brought in more than $36 billion in 2021, taking the mantle of best-selling pharmaceutical product from AbbVie Inc.'s arthritis blockbuster Humira.

Despite falling to second place, Humira's sales still passed the $20 billion mark for the first time in 2021, according to an S&P Global Market Intelligence analysis. Moderna Inc.'s own COVID-19 vaccine came third, bringing in $17.7 billion.

The success of both COVID-19 vaccines in a year dominated by the pandemic meant Merck & Co. Inc.'s blockbuster cancer treatment Keytruda dropped to fourth place with over $17.2 billion in sales.

Sales of Pfizer, AbbVie and Merck's top products far outstripped their second-biggest sellers — blood thinner Eliquis, blood cancer drug Imbruvica and human papillomavirus vaccine Gardasil, respectively — each of which took less than $6 billion during the year.

With Comirnaty's dependence on pandemic-related sales and loss of patent protection for Humira and Keytruda approaching in the next few years, the companies are expected to seek out M&A opportunities to bolster future revenue and reduce reliance on single blockbusters. The drugmakers most likely to deploy capital to acquire new products include Pfizer, Merck and Johnson & Johnson, JP Morgan analyst Christopher Schott said in a Feb. 14 note.

Bristol Myers Squibb Co. showcased a more balanced portfolio in 2021 with almost $13 billion in sales of cancer therapy Revlimid, and more than $10 billion and $7 billion from Eliquis and Opdivo, respectively. However, the New York-based drugmaker is also likely to see a drop-off in Revlimid sales as patents expire beginning in 2022.

In terms of the most profitable disease areas for the top pharmaceutical companies, oncology led the way with almost $64 billion in 2021 sales, headed up by Merck's Keytruda and Bristol Myers' Revlimid and Opdivo.

Immunology took the second spot with $47.5 billion, while the success of COVID-19 vaccines meant the disease overtook diabetes as the third biggest-selling therapy area with $40.7 billion.