After last week's unveiling of the new NNRTI rilpivirine, now we have a different kind of drug approval from the FDA:
FDA granted approval for a generic formulation fixed dose combination of lamivudine and zidovudine tablets, 150 mg/300 mg, two nucleoside analogue reverse transcriptase inhibitors, indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection ... FDA has determined that the generic formulation is bioequivalent and, therefore, therapeutically equivalent to the reference listed drug, Combivir Tablets...
Now that's a surprise -- most HIV providers thought that the next generic antiviral would be lamivudine (3TC) on its own. Some were even expecting it last year. After all, 3TC is incredibly safe and effective, has been used in literally millions of patients both here and abroad since its approval in 1995, and already is available as a generic all over the world.
Adding the zidovudine (AZT) part to 3TC definitely makes this generic much less appealing. Zidovudine hasn't been a "preferred" or "recommended" part of first-line regimens for several years due to its association with GI side effects, anemia, lipoatrophy, and the requirement for twice-daily dosing.
So why generic "Combivir" (it won't be called that anymore) and not 3TC alone? Some thoughts:
Coformulation magic. All of us have had patients who didn't tolerate individual drugs -- efavirenz, for example -- who later went on to be quite happy taking that same drug as part of a combination pill (e.g., Atripla, which has efavirenz in it). The same thing happened when branded Combivir was approved. Suddenly, AZT was fine. Go figure.
There are a lot of pregnant women with HIV out there. Yes, most of the pregnant women with HIV are treated with Combivir. But if the rest of the country is practicing the way we do, they are switched to something safer and better tolerated when the pregnancy ends. So I doubt this is it.
Studies suggest that everyone already on TDF/FTC, TDF/FTC/EFV, and ABC/3TC will stay on them. Our patients love these coformulated drugs (see #1 above). Perhaps a survey of patients, providers, payors, and other interested parties found little appetite for breaking these combinations up, which is what would be required to get generic 3TC prescribed.
Some "business plan" we don't understand. My next door neighbor is a smart guy who went to business school. He's not a doctor. And he says that everyone he works with knows that doctors are lousy with money issues, negotiate poorly, and are easily duped into paying top dollar for things that aren't worth very much (electronic medical records and billing systems are his favorite examples). So maybe we just don't understand the finances of selling combination AZT/3TC vs 3TC alone. Right.
A deal involving companies and lawyers and back room deals. It goes something like this: The makers of branded HIV drugs have made an elaborate deal with the generic companies involving the transfer of huge sums of cash (preferably to an off-shore bank account) in exchange for not making generic 3TC. The exploitation of an obscure legal loophole would undoubtedly have been required. If it can happen with potassium ... Something for the conspiracy theorists to mull over.
In sum, the real reason there's no generic 3TC remains a mystery.
Of course the FDA could announce its availability next week, in which case this whole post is irrelevant.
Paul Sax is Clinical Director of Infectious Diseases at Brigham and Women's Hospital. His blog HIV and ID Observations is part of Journal Watch, where he is Editor-in-Chief of Journal Watch AIDS Clinical Care.