In Replay Of Avandia Ban, Saudi Arabia First Regulator To Withdraw Long-acting Beta Agonists As Sole Therapy

The Saudi Arabia Food and Drug Authority appears to be the first regulatory agency to announce a withdrawal of long acting beta agonists that are not combined with corticosteroids, citing evidence of a linkage to an increased risk of death from asthma-related complications.

For the second time, the Saudi regulator was a step ahead of other global regulators in withdrawing a drug from the market. In March, the Saudi FDA banned manufacturing and distribution of GlaxoSmithKline's Avandia (rosiglitazone), while U.S. FDA was still evaluating the primary data and South Koreans sent out advisory letters to physicians cautioning about prescribing the drug (Also see "Saudi Regulators Suspend Use Of Avandia; GSK Says Action Not Based On Recent Data" - Scrip, 25 Mar, 2010.).

Other countries soon followed the Saudi lead, including the European Union, and its use is now severely limited in the U.S. by distribution restrictions ('FDA, EMA Decisions On Avandia Reflect The Power Of REMS,' The Pink Sheet, Sept. 27, 2010).

Will the withdrawal of LABA monotherapies cause others to follow suit? Analysts say it's unlikely, except, perhaps, in neighboring countries.

First, the data cited by SFDA is not news to regulators around the world. Adopted from U.S. FDA's study released last year, the report pointed to dangers of using LABA therapy alone and advised patients not to take them without combining therapy with an inhaled corticosteroid.

"The SFDA's decision to remove LABA monotherapies is not a big shift in policy," wrote Data Monitor International analyst Dan Rosen, "but makes it easier for doctors to ensure that LABAs are not actively exacerbating patients' conditions." Unlike Avandia, he said, other regulators have long known the adverse effects of using LABAs alone, but chose not to act upon that information, instead trusting doctors and patients to follow the label for combined therapy with ICS.

However, Dubai-based Pricewaterhouse Coopers partner Sally Jeffery thinks that other Gulf countries may be swayed by the Saudi decision. "There is certainly a risk others will follow in the Gulf Council countries, although not without examining their own local evidence and seeking the opinion of the various regulatory bodies," Jeffery told PharmAsia News.

Meanwhile, U.S. FDA has heightened safety requirements for LABA drug makers. The agency announced in February safety controls aimed at limiting use of all LABA-containing drugs for asthma. The agency is also requiring manufacturers of LABA/ICS combination products to conduct post-marketing studies to identify the safety risks associated with these drugs (' (Also see "FDA Calls For Class-Wide REMS For LABA Asthma Drugs" - Pink Sheet, 18 Feb, 2010.)).

Gearing Toward Combo Therapies

Analysts estimated that the impact to the industry will be less significant as well. Four LABA monotherapies that are withdrawal targets include GlaxoSmithKline's Severent (salmeterol) Inhaler and Accuhaler, Novartis's Foradil (formoterol) and AstraZenica's Oxis (formoterol).

The 2009 worldwide sales for Severent were $381 million and $357 million for Foradil. Oxis sold $63 million.

The respiratory treatment industry is decisively leaning toward combination therapies, which are dominating the asthma and chronic obstructive pulmonary disease markets. Leading products include GSK's Advair (fluticasone/salmeterol) and AstraZenica's Symbicort (budesonide/formoterol). Novartis also is developing QMF149, a LABA/corticosteroid combination, aiming for a launch in 2015.

"The unavailability of products containing LABAs alone does not affect management of COPD symptoms, as LABAs are still available in combination with ICS. Furthermore, alternative long acting bronchodilators are also available in the Saudi market," said the SFDA in a statement.

According to BMI's Rosen, the only product that might lose slight market share is AstraZenica's Pulmicort (budesonide) corticosteroid inhaler. However, the loss will be small as "Pulmicort is used by a wide spectrum of patients with respiratory dysfunction, and patients also taking monotherapy LABAs are like to account for only a proportion of that market." Pulmicort 2009 sales amounted to $1.3 billion. Worldwide, the market is estimated to be worth $54 billion in 2009.

Taking Too Tough A Stand?

"The SFDA is taking a tough stand, most likely to show that they are on top of the issue," Dubai-based consulting firm Swiss Arab Managing Director Stephan Stauffer earlier told PharmAsia News. Stauffer said the agency wanted to take the action to be seen as a "doer" instead of a follower.

"The SFDA is very safety conscious," said PwC's Jeffery. "The adverse drug reaction [ADR] mechanisms in Saudi are not very consistent or rigorously enforced and hence they tend to be overly cautious, especially with drugs that don't have at least five years history. "

In February, SFDA followed a move in the EU to revoke the registration license and withdrew Abbott's obesity drug Reductil (sibutramine).

In comparison, Korea FDA banned new prescriptions for sibutramine last month while it recommended "voluntary withdrawal" of the product following similar actions in the U.S. and Europe, drawing criticism that KFDA is too reliant on foreign agencies for monitoring drug safety (Also see "Korea FDA Withdraws Abbott's Meridia; Criticism Increases On Agency's Dependence On U.S. FDA For Safety" - Scrip, 14 Oct, 2010.).

The Saudi agency has good reason to show its seriousness towards pharmacovigilance. As the largest oil-rich gulf nation, Saudi Arabia has seen an increasing presence of pharmaceutical companies and new product launches in the country.

In October, Saudi Arabia was among six nations mentioned in a U.S. probe of major drug companies suspected of paying bribes to officials in other countries to garner favorable treatment ('China, Five Other Nations Eyed In U.S. Drug Maker Bribery Probe,' PharmAsia News, Oct. 5, 2010).

In September, Taiwan-based Orient Europharma announced an agreement to transfer production technology to Cooper Pharma of Morocco to market drugs in Saudi Arabia, Morocco and French-speaking areas in West Africa ('Taiwan's Orient Europharma Negotiates Opening In Middle East, Africa Markets,' PharmAsia News, Sept. 27, 2010).

- Brian Yang ([email protected])