The clozapine case study demonstrates that special requirements for approved use and other atypical restrictions can pose significant market barriers. Clozapine has a potentially fatal side-effect, agranulocytosis, that warrants strict patient monitoring. This contributed to clozapine's being approved as a second- or third-line therapy, i.e., for patients who are resistant to other treatments. The strict weekly monitoring of patients on clozapine increases the cost of treatment. Sandoz originally linked sales of the drug to its Clozaril Patient Monitoring System at a cost of almost $9,000 per patient per year, severely impeding the ability and willingness of payers to purchase this treatment and dampening sales.