Thank You, Somaxon Pharmaceuticals!

One year ago today, the pharmaceutical company Somaxon introduced Silenor, a new medication for the treatment of insomnia, and today I wish to say “thanks.”  Not because I think Silenor represented a bold new entry into the insomnia marketplace, but because Somaxon’s R&D and marketing departments have successfully re-introduced doctors to a cheap, old medication for a very common clinical complaint.

You see, Silenor is a branded version of a generic drug, doxepin, which has been around since the 1970s.  Doxepin is classified as a tricyclic antidepressant, even though it’s not used much for depression anymore because of its side effects, mainly sedation.  Of course, in psychiatry we sometimes exploit the side effects of certain drugs to treat entirely different conditions, so it’s not surprising that doxepin—which has been generic (i.e., cheap) for the last few decades—has been used occasionally for the treatment of insomnia.  However, this is an “off-label” use, and while that doesn’t prevent doctors from prescribing it, it may make us less likely to consider its use.

Somaxon spent several years, and millions of dollars, developing Silenor, a low-dose formulation of doxepin.  Stephen Stahl (paid by Somaxon) even publicized low-dose doxepin in his CNS Spectrums column.  Generic doxepin is currently available in comparatively high doses (10, 25, 50, 75, 100, and 150 mg), but Somaxon found that lower doses (6 and 3 mg, even 1 mg) can be used to treat insomnia.  Silenor is sold at 3 and 6 mg per tablet.

The obvious question here (to both expert and layman alike) is, what’s so special about the 3 or 6 mg dose?  Why can’t I just take a generic 10 mg pill and cut it in half (or thereabouts), for a homemade 5-mg dose?  Well, for one thing, the 10 mg dose is a capsule, so it can’t be split.  (There is a generic 10 mg/ml doxepin solution available, which would allow for very accurate dosing, but I’ll ignore that for now.)

Okay, so there’s the practical issue: pill vs. capsule.  But is 6 mg any better than 10 mg?  For any drug, there’s always variability in how people will respond.  The relative difference between 6 and 10 is large, but when you consider that people have been taking doses of up to 300 mg/day (the maximum approved dose for depression) for decades, it becomes relatively meaningless.  So what gives?

It’s natural to ask these questions.  Maybe Somaxon was hoping that doctors and patients simply assume that they’ve done all the necessary studies to prove that, no, doxepin is an entirely different drug at lower doses, and far more effective for sleep at 3 or 6 mg than at any other dose, even 10 mg.  Indeed, a few papers have been published (by authors affiliated with Somaxon) showing that 3 and 6 mg are both effective doses.  But they still don’t answer:  how are those different from higher doses?

I contacted the Medical Affairs department at Somaxon and asked this very question.  How is 3 or 6 mg different from 10 mg or higher?  The woman on the other end of the line, who (one would think) must have heard this question before, politely responded, “Doxepin’s not approved for insomnia at doses of 10 mg or higher, and the 3 and 6 mg doses are available in tablet form, not capsule.”

I knew that already; it’s on their web site.  I would like to think that no psychiatrist asking my question would settle for this answer.  So I asked if she had some additional information.  She sent me a six-page document entitled “Is the 10 mg Doxepin Capsule a Suitable Substitute for the Silenor® 6 mg tablet?”  (If you’re interested in reading it, please email me.)

After reading the document, my response to this question is, “well, yes, it probably is.”  The document explains that doxepin hasn’t been studied as an insomnia agent at higher doses (in other words, nobody has tried to get FDA approval for doxepin in insomnia), and the contents of the tablet are absorbed at a different rate than the capsule.

But what really caught my eye was the following figure, which traces plasma concentration of doxepin over a 12-hour period.  The lower curve is for 6 mg of Silenor.  The higher curve is for “estimated” 10 mg doxepin.

Huh?  “Estimated”?  Yes, that’s right, the upper curve was actually obtained by giving people 50 mg doxepin capsules and then “estimating” the plasma concentrations that would result if the person had actually been given 10 mg capsules.  (I know, I had to read it twice myself.)  I don’t know how they did the estimation.  Did they divide the plasma concentration by 5?  Use some other equation involving fancy things like logarithms or integrals?  I don’t know, and they don’t say.  Which only begs the question: why didn’t they just use 10 mg capsules for this study???

That seems a little fishy.  At any rate, their take-home message is the fact that with the lower dose, there’s less doxepin left over in the bloodstream after 8 hours, so there’s less of a “hangover” effect the next morning.  But this just raises even more questions for me.  If this is the case, then what about all those people who took 75-150 mg each day for depression?  Wouldn’t that result in a constant “hangover” effect?  I didn’t practice in the 1970s and 1980s, but I’m guessing that depressed people on doxepin weren’t in bed 24 hours a day, 7 days a week.  (I know, the serotonergic and noradrenergic effects “kick in” at higher doses, but the histamine and alpha-1 adrenergic receptors are already saturated.)  A related question is, what plasma concentration of doxepin is required to induce sleep anyway?  What plasma concentration accounts for a “hangover” effect?  0.5?  1.0?  2.0?  Does anyone know?

The Somaxon document states that “clinical trials demonstrated only a modest increase in mean sleep maintenance efficacy when the dose is increased from 3 mg to 6 mg.”  But according to the graph above, the 3 mg curve would be expected to look quite different, as it’s a 50% reduction in dose.  (And I can’t even begin to think what the 1 mg curve would look like, but that apparently works, too.)

We all know (or should know) that tables, charts, and graphs can be used to convey just about any message.  It’s important to look at which data are presented, but also which data are not presented, in order to draw any conclusions.  We must also ask what the data actually mean (i.e., the importance of a plasma concentration—what does it actually mean for a clinical effect?).  In the end, Somaxon’s “explanation” seems like a pretty flimsy explanation for using a very expensive name-brand drug.

That said, I do have to say “thank you” to Somaxon for reminding me of yet another medication that I can use to help treat insomnia.  Not Silenor, but low-dose generic doxepin (10 mg).  It’s a shame they had to spend the millions of dollars on R&D, clinical trials, and marketing, to convince me to prescribe the generic version of their drug, which costs only pennies a pill, but then again, you pays your money, you takes your chances.

(Postscript:  Speaking of money, Somaxon stock closed at $2.70/share today, down from a high of $10.01 on the day Silenor was approved, a loss of $258 million of market capitalization.  Imagine all the soft pillows, soothing music CDs, and OTC sleep aids that money could have bought…)

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26 Responses to Thank You, Somaxon Pharmaceuticals!

  1. David Allen says:

    I did practice psychiatry in the 70′s, and most people require about 25 mg of doxepin to get enough sedation to go to sleep, and tolerate it just fine.

  2. doctorz says:

    I’ve been prescribing low-dose Doxepin (10-20mg qhs) for years and find it particularly effective in terminal insomnia, which in my experience is more difficult to treat. And it appears Somaxon is promoting Silenor for this as well as early insomnia. You raise excellent points questioning the integrity of their studies, and it appears investors are equally skeptical. In the final analysis, I think it’s a safe bet that Silenor won’t be the blockbuster that Adderall was for Shire; ie, recycling an old diet pill, Obetrol, and using it for ADHD. Are there any other old psychotropics that we can dust off and dress up for new indications?? Years ago, I had an idea for a combination benzo and Antabuse for management of protracted anxiety for alcoholics in remission, but I never explored it further.

  3. Tiffany says:

    I have been having trouble sleeping for at least a year now. I don’t have difficulty falling asleep but I wake up between 4- 6 times every night. The lack of sleep has started to take a toll on my body and mind, My doctor prescribed me Doxepin 10mg about a week ago, and I took it for the first time on March 24th. I took it immediately before bedtime, around 10:00pm, when I awoke for work at 6:30am, I was dizzy and disoriented. I felt completely drunk and confused. I ended up having to take the day off work because there is no way I could drive my 45 minute commute to work. I called my doctor and told him what happened. While I did get a full night of sleep without waking at all, there is no way I could take this during the workweek and still be able to function for work. I had a migraine headache the entire day and felt hung over after taking the 10mg Doxepin. My doctor told me to stop by and pick up some samples of a lower dose medication with was essential the same drug. I picked up some samples of Silenor (3mg). I was hesitant, but I decided to take the 3mg Silenor the next night, March 25th. The first difference I noticed was that I didn’t have that sense of euphoria shortly after taking it, like I did experience with the Doxepin (Sorry I forgot to mention that earlier) After taking the Silenor, I woke the next morning and I had none of the bad side effects that I had with the Doxepin. I didn’t feel drunk, I wasn’t dizzy, and I wasn’t confused and stumbling on my words. I was functional! The downside is that I did wake up once during the night. I decided to take the Silenor for the second time last night and again woke up once in the middle of the night. While this is better than waking up 4-6 times each night, I wonder if the 6mg Silenor would be more effective? With that being said, I am nervous about increasing my dose, because of how bad I felt on the 10 mg Doxepin. I wasn’t even functional until a good 20 hours after taking it.

    • Javier Chaoone says:

      Hi, I suffer from insomnia for several years, I have been taking Wellbutrin XL, the other day my psychiatrist game me samples of the doxepin in the 3mg and the 6mg. I had taken the generic 25mg and the 50mg daily. I slept like a baby and didnt feel much of the side effects you experienced. Well, I figured I would give this ” new ” pill which happens to have a $ 75.00 off the medication, very nicely presented a try. Well, to me this is just garbage, it might work for someone who happens to have occasional insomnia but not for me, I had taken the 6mg twice and still did nothing, I think you should give the 10mg doxepin more time and you will be fine, remember you are taking a pill you havent taken before, so the body obviously responds differently.

  4. Chandrasekaran,N says:

    I strongly believe the study was worth the result they obtained. First of all if you prescribe doxipen 10mg(as a trusted MD) for insomnia knowing that it is not FDA approved is it ethical? You have to inform the patient that doxipen 10mg is approved for depression not insomnia. 3 or 6 mg is indicated and FDA approved for sleep maintenance insomnia and they clearly say it is not for sleep onset. why take the risk. The side effects described by Tiffany is true for many. What if she has an accident driving. Will the MD be willing to risk prescribing 10mg for sleep. The only problem is the cost. Generic 10 mg if you break the capsule what are the side effects. Can some one prove it.Until then I would be afraid of the 10mg doxipen for sleep.

  5. Ann Smith says:

    As one who had the withdrawal from h-ll with severe rebound insomnia, in spite of tapering very slowly from Doxepin, good luck to those folks who find the medication doesn’t work.

    I feel that Doxepin along with Wellbutrin XL caused tinnitus that may be permanent.

    And I don’t feel it was that great of a med for insomnia. Unfortunately, when I increased the dose from 10mg to 20mg, the tinnitus that ensued was intolerable. I was already taking Remeron for sleep as an FYI.

    • stevebMD says:

      Ann, I tried and tried to figure out what you meant by “h-ll.” (H2 antagonists??) Then I realized you meant “hell” and it all made sense. :) No need to worry about your language here, Ann… Feel free to swear away! (unless it’s directed at someone else)

      Thanks for your comment!

    • israel says:

      HELLO.. ANN…mi name is israel..i been suffering from tinnitus for over a month now …im almost sure doxepin has something to do with this…I WAS TAKEN DOXEPIN 10mg for insomnia and some depression…,i remembe when i first wake up at 4am with this terrible sound in my ears.!!…….DO U TINNITUS GOT ANYBETTER ..WITH TIME.?…please reply!!….and thanks!!

  6. Behrooz says:

    You have accepted the fact that Somoxon R&D did the work and showed and get the FDA approval for SILENOR as a treatment of insomnia. Before all of this research and clinical trials, you did not know that Doexpin is good for insomnia and no doctors prescribed it before. Now that the research and clinical trials has been done for several years you want take a cheat route and give no credit to them. I agree that they need to make it cheaper, but they did the work and even if you want to prescribe doxepin I think they need to be credited for that and maybe some sort of royalties. Use of previously approved compound for a new drug is common practice in pharma industry for making a new drug.

    • stevebMD says:

      Behrooz,

      The reason we “did not know that doxepin is good for insomnia and no doctors prescribed it before” (which is not entirely true, see some of the comments above) is that no one had any financial interest in showing that a decades-old generic drug could be used as a safe sleep aid.

      You’re right, Somaxon “did the work” to get FDA approval, but that doesn’t necessarily mean that I should show my appreciation by prescribing their drug when the generic alternative costs two orders of magnitude less.

      The process by which we approve drugs should be streamlined so that existing drugs can be used for new indications, without the excessive commitment of time and money that only a pharmaceutical company can bear. In the meantime, I have a responsibility to my patients and to society to prescribe what’s most effective and least costly, and unfortunately Silenor just doesn’t fit that bill.

      • Behrooz says:

        I appreciate your responsibility in seeking the most efficient and least costly medication to treat your patients. However, the costly process that FDA needs to approve a drug should not hold against Somaxon. They did something which was required to do. Also my understanding from your article is that you would not prescribe the 10 mg Doxepin to the patient for insomnia and tell them break it in half if it were not for Silenor. I agree that they should be pushed to make the Silenor cheaper, but I think they should have the right to their product and the patent. You mentioned in response to my previous comments that they showed “old generic drug could be used as a safe sleep aid”. My questions is: Now that doctors know doxepin is a “safe sleep aid” should they start prescribing 10 mg doxepin or Silenor? or in other words should Somaxon get anything their work and investment?
        This is true for many other patented products. There are many products which after their inventions are very straightforward and everybody can do it, but they hold the patent and licensing. E.g Starbucks coffee cup holder …

      • Jackie says:

        Behrooz, my opinion is that doctors should prescribe the generic 10 mg. doxepin and advise patients to cut it in half or, even better, tell patients to pick up some Benadryl at the drug store. The latter would be just as effective, as it works on the same mechanisms.

        Patients, society, doctors, insurance companies, etc. have no obligation to Somaxon. The real costs of developing this drug were done decades ago by some Big Pharma company that has since lost its patent — Somaxon has spent comparatively little in the big scheme of things.

        Now, it could be that some people are reassured by taking a brand-name drug (that’s what Somaxon is counting on) and that’s fine. Let them take Silenor and let them pay for it — Nobody is saying that the product and the patent should be taken away.

        But neither should doctors just prescribe this “old sauce in new bottle” at great cost to everybody, when the exact same thing is available for practically nothing in generic form.

    • Javier Chaoone says:

      Well, this is like Britney Spears performing a Madonna’s hit, I dont believe they spent millions of dollars in doing the research, they have spent it doing their Advertising Campaign which will be a waste of money. Just like Rozerem spent millions to try to sell the pill, people just didnt buy it, because it didnt help those in needed of such a medication. When I was first prescribed Doxepin 25mg the Doctor did tell me, this was an old drug that over the years they have found out it works well for insomnia and to give it a try. When I did, I slept better than ever before.

  7. I understand the objection to Silenor being so expensive compared to generic doxepin. I also understand the irritation at the attempts by Somaxon to use labeling information to promote their product over other low dose forms of doxepin. The logic would be even more tortured if pressed to attack 3 or 6 mg doses of doxepin solution.

    However, taking a step back, it is not clear to me whether or not Silenor will drive up the price of health care. In order to determine this one would need to consider other factors such as the price of the other hypnotics that Silenor would replace, e.g., zolpidem, and the costs of managing adverse events from the various hypnotics.

    One adverse event that occurs with some hypnotics is addiction. I am glad when prescribers have non-addictive alternatives available, both to avoid contributing to the development of addiction (although this is uncommon) and also to have medicines, such as doxepin in whatever form, that do not present a threat to recovery.

  8. I took Doxepin for a brief period in 1993 for depression and insomnia and it made my joints very stiff. I had a similar experience about 2 years ago with Remeron. I’m wondering if I should try Silenor? I don’t remember what dose of Doxepin I was on. With Remeron, I was mostly on 15 MG, although the psychiatrist tried to get me to increase to 30 MG, until I started cutting the 15 MG pills in half to try to avoid the stiffness before finally abandoning them.
    So, since I seemed to have had such an adverse reaction to the Doxepin, whatever dose it was – let’s say, for argument’s sake it was 10 MG night, although the psychiatrist I was seeing at the time prescribed huge dose of other antidepressants: 20 MG Zoloft for 3 days, then 40 MG of Zoloft for 3 days, then a panic attack that went on for months – so it’s possible I was on more than 10 MG of Doxepin/day – I’m wondering if I should avoid Silenor? What do you think? I really think I’m becoming addicted to Xanax and Ambien and need to do something else. Thanks.

  9. Renew says:

    Thank you Steve for this insightful info. And here I was worried that taking more than 6 mgs was “never to be done”. What a bogus way to try and make sure people stick to your brand. Read thru the fine print…it sucks anyway. No sleep for me and the rebound was so horrible, I had to up the ambien intake.

  10. Paul says:

    Of course they had no incentive to study if the 10mg was effective for insomnia since there was a generic at that dosage. Doxepin 10mg helped me stay asleep a better but not fall asleep. 20mg helped me fall asleep and stay asleep with mild residual drowsiness in the morning. I may ask my doctor for the doxepin solution so I can measure out 15mg myself.

    I’m much happier using something “off label” but obviously safe than I am using something addictive or expensive. Lunesta won’t be available in a generic until late 2013.

  11. Yvette says:

    Yvette says,
    as for using generic Doxepin off label for insomnia, yes I do and I simply informed the patient the obvious, the 10 mg may be a bit high or it may in fact be a bit low. Take it first on a weekend or when you know you don’t have to be up early and see how you do. In todays economy as many as 50-60% of my patients are uninsured and an expensive med for sleep is simply not possible so the beauty of practicing medicine is that sometimes you have to work with what is available in a safe manor. Hey weve been prescribing trazadone for sleep for a long time and people are on all kinds of different doses.

  12. anthony dagostino says:

    I suffer from major deppresssion, adult adhd, and chronic insomnia. I had been using ambien(generic) to limited sucsess. Being on focalin (10mg morning, 5 mg noon), we are uncertain of any lingering effects causing the ambiens to not work as well. So my doc stopped the ambiens and told me to try Pms or mutilated because it provides for less night waking. It worked and it didn’t. I didn’t help me fall asleep but it did help me wake up less. But even on a 25mg dose which is low, I still had that groggy hangover the next day. So we tried doxapen. Well on just 10mg at 10 pm, I did not fall aslepp until 2 am and 4:30 am. And I could not function at all the past 2 days. To the extreme that the focalins have lost any ability to keep me awake let alone focused. I am afraid to try night 3 because I will lose my job if I miss more days due to this. The hangover feels exactly like a benadry hangover and I’ve been researching to see what the difference is. And take away the technical Mumbo jumbo, it foes the same thing. Looks like ill be calling my doc for the generic ambiens again sense they at the very least don’t cause the hangover. All this info is greatly appreciated. I am interested to try the doxamin at a much lower dose 3.3 mg. I may try that on the weekend. But I can’t risk it during the work week.

  13. JMO says:

    OMG-Nobody on here really seems to know much about doxepin. I was diagnosed with a chronic disease in 2003. I didn’t deal with it well. Suffered from extreme insomnia.Long story short, tried almost everything, Remeron, Benedryl, Paxil, Lexapro, Ativan, Trazadone, Seroquel, etc. NOTHING worked. I slept an average of 3 hours a night and was very sick too. I ended up having a breakdown and a dr finally listened to me and gave me doxepin. I slept like a baby. I was on 150 mg. I recovered and tapered off. And yes, with ANY drug, there were side effects, I had to take a nap everyday the first week but it goes away. I ended up tapering off of it after a couple years. I am currently again on 25 mg due to end of marriage and loss of a loved one. Still sleeping like a baby. Works great at 10 mg too but I can’t imagine 3-6 though. Seems like too small of a dose to work well. When it first came out my thought was to buy stock in the company because it is non-addictive and I know it works. I have gone off of it more than once without any side effects. Never had rebound insomnia. Just my opinion. If I wouldn’t have broken the insomnia I think I wouldn’t be here today. That being said, I would use 10 mg doxepin since Silenor is expensive and it’s a ridiculously small dose especially if someone has hardcore insomnia.

  14. [...] is David Hale, who also founded—and is Chairman of—Somaxon Pharmaceuticals, a company I wrote about last year when it tried to bring low-dose doxepin to the market as a sleep aid, and then used its patent [...]

  15. don miller says:

    Seem like we have an old dr. Going with older meds for my wife sleep deprivation. Every month or so we go in tell him they’re not working or we don’t Like the effects of the last new trial med then we get yet another new rx old med use to be used for something entirely differant soon to be discarded old not working try. All she wants and needs is a good regular full nights sleep. And the big problem is sleeoing thru the night waking refreshed that’s all.

  16. Ugh, I’ve been taking Silenor for the past few months at the preposterous price of $200+. I finally had to have my doctor call my insurance company so they would cover it at a mere price of $95.00 per month. I’m on disability so I really cannot afford the $95.00 per month, let alone the $200+ per month. But what’s a person with chronic insomnia going to do? I only found out today that it’s been discontinued because I tried to get a refill, so I hopped on the WWW to see what’s up. People, like me, get sucked into these “scams” by pharmaceutical companies and we pay the price the bastards deem necessary. I’m having a “A HA” moment and wondering how a class action suit against them would make them feel. arrrrgggg. Color me disgusted, disillusioned and plain ole fed up with phamaceutical companies.

  17. Suze says:

    Doxepin liquid comes in a 120 ml bottle at strength of 10 mg/ml. Cost is about $50 for the bottle which should last you 6 mos- 1 yr. Ask the pharmacy to sell you a TB syringe (25 cents), which is a total of 1 ml, scored in the tenths of a ml. Easily to draw up 0.3 – 0.6 ml, which is equal to 3-6 mg liquid doxepin which is equal to 3-6 mg silenor. Squirt it in a few ounces of water.

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