Every year, the pharma market gets rattled by patent expirations that threaten the sales of blockbuster medications.

Falling off the patent cliff can translate into an enormous sales hit for major manufacturers. According to estimates by EvaluatePharma, a whopping $215 billion in sales for medications could be lost from patent expirations between 2015-2020 and $31 billion are at risk in 2018 alone. 

In theory, patent expirations leave the door open for generic products to enter the market. In practice, however, just because a patent expires, doesn’t mean that a generic version will be immediately ready to take its place in the market. Patent litigation, “pay for delay” agreements and various other highly debated tactics can prevent generics from entering the market. Drug companies can also extend patent protection by obtaining additional patents covering new formulations or new routes of administration or by winning pediatric exclusivity, which can delay competition by six months or more.

Also, the rise of biologic drugs has prompted many manufacturers to focus on developing biosimilars — meaning that they are highly similar to an existing approved innovative biological product— which can have a lengthier and more complicated approvals process.

According to data compiled using the National Pharmaceuticals Services (NPS) calendar, the FDA and the Therapeutic Research Center, here are 10 of the top drugs at risk this year.

1. Lyrica

   Last year, Pfizer’s blockbuster medication for nerve and muscle pain netted the company $3.46 billion in sales. Patent protection is scheduled to expire in December, but Pfizer is reportedly working on getting an extension for pediatric exclusivity.

2. Rituxan

   Roche’s top-selling treatment for blood cancers and rheumatoid arthritis raked in $7.9 billion in global sales last year. Competition from biosimilars in Europe has already begun chipping away at sales for the drug, and its patent in the U.S. is expected to end later this year.

3. Cialis

   Second only to Viagra in the market for erectile dysfunction medications, Cialis has been a major seller for Eli Lilly since it was approved in 2003. A settlement with generic drugmakers last year extended its patent life, but that is now set to expire in September.

4. Xolair
   

   Under a profit-sharing agreement, Roche and Novartis have both raked in hefty sales from this treatment for allergic asthma and chronic idiopathic urticarial. Although its patent is set to expire this year, there are no clear front-runners in the race to develop a biosimilar to challenge its place on the market.

5. Restasis
   

   Last year, Allergan made the much-criticized decision to license its patents for Restasis, a popular dry eye treatment, to the Saint Regis Mohawk Tribe, in the hopes that they would be protected under tribal sovereignty laws. The move did not pay off. After a string of courts ruled against Allergan, Restasis, which garnered $1.41 billion in sales last year, will begin facing competition from generics this year.

6. Advair

   Although the top-selling treatment for asthma and chronic pulmonary disease officially lost patent protection in 2010, no company has been able to get a generic version approved by regulators. What’s the holdup? GlaxoSmithKline’s specialized inhaler for the product. Several companies, including Teva, have attempted to produce a copycat, but all have failed. But analysts believe that Mylan could find success in the coming year.

7. Neulasta
   

   This white cell booster brought in $3.93 billion in sales for Amgen last year. Although its patent ended in 2015, a biosimilar developed by Mylan is only just now getting close to entering the market.

8. Zytiga
   

   Johnson & Johnson lost its last remaining patent on its profitable prostate cancer therapy this year, opening the door for generics competition. Although J&J maintains that there are no copycats ready for the market, some analysts believe threats from other companies are imminent.

9. Sensipar
   

   In March, the FDA approved the first generic versions of Amgen’s treatment for secondary hyperparathyroidism in patients on dialysis. Sales for Sensipar hit $1.58 billion in 2017 and the company is still in several patent disputes that could delay these generics making it to the market this year. But the company recently said that its outlook for Sensipar going forward remains uncertain.

10. Ampyra

    The upcoming loss of Acorda Therapuetics’ patent on Amprya, a drug that helps improve muscle strength in patients with multiple sclerosis, has already hit the company hard: Last year Acorda announced that it will have to lay off 20 percent of its workforce. The smaller biotech company is now hoping that other medications in its pipeline, including a Parkinson’s drug called Inbrija, will help make up for lost Amprya sales.