Exubera Label Review
Let’s have a look at newly approved Exubera’s (inhaled rDNA insulin, Pfizer) label. As soon as it’s available publicly, I’ll also review the approved post-marketing safety surveillance and risk management plan, which Pfizer is touting as the new industry standard. To my knowledge, Exubera is the first approved protein therapeutic that is intentionally delivered systemically via the lungs. It replaces/supplements a popular subctaneous-injectable medicine in so doing. For these reasons, it is an important precedent molecule that the biotech community should observe carefully.
The key label provisions of general industry interest are shown below.
Smoking: Exubera is contraindicated in smokers and recent ex-smokers, not because of a risk of lung damage but because of enhanced insulin effects:
“In smokers, the systemic insulin exposure for EXUBERA is expected to be 2 to 5 fold higher than in non-smokers. EXUBERA is contraindicated in patients who smoke or who have discontinued smoking less than 6 months prior to starting EXUBERA therapy. If a patient starts or resumes smoking, EXUBERA must be discontinued immediately due to the increased risk of hypoglycemia, and an alternative treatment must be utilized (see CONTRAINDICATIONS).”
Patients with Underlying Lung Diseases: Unlike the smoking contraindication, lung diseases present a risk to the patient that has not been quantified. Unstable lung disease is a contraindication due to altered absorption of insulin. The average clinician will be confused between a stable and an unstable lung disease, as am I. The risk management program will need to address this source of confusion. Look for this imprecise labeling as a potential area for product liability issues to arise.
“The use of EXUBERA in patients with underlying lung disease, such as asthma or COPD, is not recommended because the safety and efficacy of EXUBERA in this population have not been established (see WARNINGS). The use of EXUBERA is contraindicated in patients with unstable or poorly controlled lung disease, because of wide variations in lung function that could affect the absorption of EXUBERA and increase the risk of hypoglycemia or hyperglycemia (see CONTRAINDICATIONS).”
Effect on Pulmonary Function: All patients require baseline PFTs before starting therapy. I have to wonder how HMOs will view this from a reimbursement perspective. It will depend on whether they view the total cost of Exubera treatment, including screening and follow-up pulmonary testing, as cost-effective. That will depend, in part, on the perceived quality/credibility of Pfizer’s existing cost-effectiveness studies and models.
“Because of the effect of EXUBERA on pulmonary function, all patients should have pulmonary function assessed prior to initiating therapy with EXUBERA (see PRECAUTIONS: Pulmonary Function).”
“In clinical trials up to two years duration, patients treated with EXUBERA demonstrated a greater decline in pulmonary function, specifically the forced expiratory volume in one second FEV1) and the carbon monoxide diffusing capacity (DLCO), than comparator-treated patients. The mean treatment group difference in pulmonary function favoring the comparator group, was noted within the first several weeks of treatment with EXUBERA, and did not change over the two year treatment period (See ADVERSE REACTIONS: Pulmonary Function). During the controlled clinical trials, individual patients experienced notable declines in pulmonary function in both treatment groups. A decline from baseline FEV1 of = 20% at last observation occurred in 1.5% of EXUBERA-treated and 1.3% of comparator-treated patients. A decline from baseline DLCO of = 20% at last observation occurred in 5.1% of EXUBERA-treated and 3.6% of comparator treated patients.
Because of the effect of EXUBERA on pulmonary function, all patients should have spirometry FEV1) assessed prior to initiating therapy with EXUBERA. Assessment of DLCO should be considered. The efficacy and safety of EXUBERA in patients with baseline FEV1 or DLCO Carcinogenicity: A lack of carcinogenicity studies will deter some physicians from using the drug, their concern being the local effects of chronic growth factor administration on tumor promotion in the lung. It will be interesting to see if this issue is addressed specifically in the post-marketing surveillance plans.
“Two-year carcinogenicity studies in animals have not been performed.”
Pediatric Use: Children were not specifically studied, but Exubera use in children is not contraindicated. Children make up a significant proportion of new insulin users.
“Long-term safety and effectiveness of EXUBERA in pediatric patients have not been established.”
Safety Database: Note the safety database size. It’s reasonable to assume that a similar size would be required of other systemically delivered inhaled proteins intended for a large population.
“Approximately 2000 patients were exposed to EXUBERA for greater than 6 months and more than 800 patients were exposed for more than 2 years (see CLINICAL PHARMACOLOGY, Special Populations).”
Adverse Effects: Transient, immediate cough was the most common adverse effect associated specifically with Exubera.
Medication Guide: The package includes a thorough medication guide for patients, including detailed color images showing how to use the product.
