Saturday, June 30, 2018

Package Insert For Epidiolex - Does It Suggest A Problem With Medical Cannabis?

Cannabidiol (C21H30O2)

Epidiolex was approved by the FDA two weeks ago for Lennox-Gastaut syndrome or Dravet syndrome in patients 2 years of age and older.  Epidiolex is cannabidiol (abbreviated CBD) one of several compounds in the plant Cannabis sativa.   I had a previous post on this compound but that was before the package insert came out.  I like to study package inserts of all of the pharmaceuticals I encounter to prevent unexpected side effects, anticipate drug interactions, look at the current prescribing recommendations, and study all of the safety considerations.  Every drug has a section in that package insert about the pharmacokinetics, pharmacodynamics, and considerations in the case of hepatic or renal impairment.  In some cases there are very specific recommendations for dosing with metabolic impairment or potential drug-drug interactions.  The other interesting aspect in this case is that Epidiolex is considered the first botanical extract to be FDA approved and the first cannabis derived compound.  A significant part of the population considers cannabis to be a benign natural product with none of the usual pharmaceutical concern about organ toxicity and drug interactions.

Reading the actual package insert a few things jump out at me today.  The original indications are the same, but the logical question is whether this medication will be used for off labeling prescribing for other indications.  After hearing one of the top epileptologists  in state talk about the use of cannabinoids for epilepsy, there is also the question of whether the diagnosis is correct.  In that lecture he pointed out that a case example in the news media probably did not have the diagnosis and that the expert in the state who could make that diagnosis was not consulted.

The dosing of the drug is fairly robust going from 5 mg/kg/day up to 20 mg/kg/day.  For a 70 kg man that comes out to a max dose of 1400 mg/day putting it in the range of several other anticonvulsants from different classes.

There are warnings about hepatotoxicity.  Early in the document, it states that some patients will experience elevated liver function tests and in some cases with develop overt side effects leading to drug discontinuation.  Baseline screening is recommended with AST, ALT, and total bilirubin.  Patients with elevated baseline transaminases were more likely to experience further elevation of these tests than those subjects with no baseline elevation.  The Child Pugh classification of severity of liver disease is used as a metric with dose adjustments suggested for mild, moderate, and severe disease.

Thirteen percent of patients had ALT elevations that were three times the upper limit of normal (ULN).  Less than 1% had transaminases that were 20 times the ULN and some patients were hospitalized.  In a third of the cases the transaminase elevation resolved without treatment.  In the other two thirds it resolved with discontinuation of the Epidiolex or the associated anticonvulsant (valproate).

Risk factors (associated drugs - clobazam, valproate), dose, and baseline transaminases) were discussed as well as monitoring.  Given the prevalence of the problem screening transaminases at 1 month, 3 months, and 6 months and as indicated after that.  More importantly - screening for the physical illness from drug induced liver disease ("explained nausea, vomiting, right upper quadrant abdominal pain, fatigue, anorexia, or jaundice and/or dark urine") can lead to further evaluation.  Three scenarios for discontinuing the Epidiolex are recommended:

1.  Transaminase levels greater than 3 times the ULN.

2.  Bilirubin levels greater than 2 times the ULN.

3.  Transaminase levels greater than 5 times the ULN. 

My read of the difference between 1 and 3 is that 1 can be a temporary measure but 3 should be permanent.  In my experience with valproate, I would definitely discontinue with these levels.  That is based on the well validated concern that valproate can cause significant hepatotoxicity. It is still possible that additional trials and post marketing surveillance will show that there is not long term concern with CBD.  In the trials transaminase elevation was the most frequent reason that the drug was discontinued (24% versus 3% on placebo).

Drug interactions noted that could be clinically significant. Epidiolex is metabolized by  CYP3A4 and CYP2C19 so that inhibitors of these enzymes can potentially increase the plasma levels.  Strong inhibitors of CYP3A4 include HIV antivirals, antifungals, and buprenorphine.  There are no strong CYP2C19 inhibitors.

Inducers of the same enzymes can lower Epidiolex levels and the standard inducers of those enzymes are carbamazepine, oxcarbazapine, phenytoin, HIV antivirals, prednisone and glucocorticoids, and St. John's Wort. 

Additional warnings about the use of the drug include somnolence and sedation (32%), suicidal ideation and behavior, hypersensitivity reactions, and the risk of withdrawing an anticonvulsant and need to do it gradually.   Regarding the suicidal ideation and behavior the only data presented was from a large (N=199) pooled analysis of clinical trials.  It is a standard warning on all anticonvulsant drugs and there was nothing specific to Epidiolex or CBD.

Clearly Epidiolex or CBD extracted and used at pharmaceutical doses may have some of the power of pharmaceuticals but also has the same significant side effects.  The side effect profile and drug interaction concerns are very similar to other pharmaceuticals that are used to treat epilepsy. This raises some interesting issues in states like Minnesota where high potency extracts of cannabis are being sold as medical cannabis and there is minimal medical supervision - primarily because there is scant evidence that cannabis extracts are medical treatments.  As I previously observed from the most recent report of the Minnesota medical cannabis program, extracts are being sold in this state that result in the ingestion of 12.2 - 1,439.2 mg/day of CBD.  The middle to high end of that range is clearly in the dose range for Epidiolex and the extracts are not prescribed or monitored by physicians - at least there is no requirement for that to happen.  Looking at all of the available data it is clear that the person taking 1,439.2 mg/day is an outlier and the next cluster of patients is at the 100-200 mg/day range. 

In Minnesota, a medical provider certifies a patient as having a condition that qualifies them for medical cannabis. In the case of this report it is chronic pain.  That patient goes to a medical cannabis dispensary and discusses what they want with a pharmacist.  In the case of high CBD products, as far as I know there is no recommended screening, monitoring, or patient education.  Just based on what I read in the current Epidiolex package insert, if the CBD content of the medical cannabis is in a similar dose range that is the equivalent of taking a new pharmaceutical and making it an over the counter drug.  The neurologists prescribing Epidiolex have good guidance on what needs to be monitored and are undoubtedly very familiar with the compound.  Other physicians including psychiatrists need an awareness of the pharmacology of CBD - especially if the dose is in the range suggested by this package insert.

If it was needed, this seems like further evidence that the miracle of medical cannabis has affected the judgment of many who seem to consider it a benign natural product. It turns out in this case, it can have a therapeutic effect on specific seizures at a significant dose for conditions that did not have many good options.  That treatment comes with clear risks.  The risk is reduced since all of the patients treated for the indicated seizure disorders are being followed by neurologists who specialize in the polypharmacy necessary to treat complex seizure disorders.  That includes monitoring potential drug interactions and toxic effects.  Can we say the same thing for people obtaining it through the medical cannabis program or being prescribed the drug off label?

Medical cannabis needs to be taken as seriously for the side effects as it does for the purported benefits.

George Dawson, MD, DFAPA


Full Prescribing Information for Epidiolex. FDA approved package insert.

Supplementary 1:

Any FDA package insert is available online by Googling:  "[Drug name] FDA Package Insert"   The PDF of that drug insert will pop up and you will have access to same the full prescribing information that any physician has.

Supplementary 2:

In Minnesota, there are two companies that are the exclusive providers of non-smokable medical cannabis products Leafline Labs and Minnesota Medical Solutions.  Actual THC and CBD content is available on the web sites of both companies.

Leafline Labs has a vaporization product, a sublingual spray, an oral suspension, and a topical preparation.  The highest concentration of CBD in the oral solution is 20 mg/ml.  Epidiolex is 100 mg/ml.

Minnesota Medical Solutions has similar delivery forms and their oral products are capsules and solutions in both 47.5 mg CBD or 100 mg per milliliter CBD.  The latter is the same as prescription strength Epidiolex.


  1. From a business article I read:

    "Elemer Piros at Roth Capital Partners expects Epidiolex to be priced around $36,000 per year in the U.S. However, some analysts project an annual price as high as $60,000 per year."

    And the tone of the article was that they were trying to price the drug more "reasonably" that other new drugs.

    Until the costs of these new drugs are addressed, it's difficult to get excited about any new developments.

    Emsam was dead on arrival for me once I figured out the cost to patients.

    1. Agree with you about Emsam.

      Interesting that the equivalent amount of CBD though the Minnesota program would cost $35,866/year.

      When I wrote the original post on Epidiolex, I wondered what their patent would cover and if similar preparations would be in violation of that patent.

      The Minnesota Medical Solutions supplier produces Violet Oral Solution that is 2500 mg/25 ml bottle for $249.

      Doing the arithmetic for a 1,000 mg/day dose of CBD or 30,000 mg/month that would require 12 bottles for a total of $249 x 12 = $2988 or $35,856/year.

      I wonder if that is where the analyst came up with the $36,000/yr estimate.

      I can't imagine it costs that much to extract CBD (both companies allude to a carbon dioxide process) and if it did - how much harder can it be to synthesize?

    2. They'll tell you that the cost is not in the manufacture but in the R&D and regulatory burden. Which runs in the billions. They're right of course, and there has to be a better system. Maybe eliminating phase III. The current system of drug development is not sustainable nor viable economically.

    3. Although it is interesting that Minnesota came up with a comparable product completely on their own with no development costs and no regulatory burden. I think the shocker for most cannabis advocates is that growing your own and smoking it with not produce the desired pharmaceutical effect of this product. The shocker for the minority of medical cannabis advocates is that the final product is more expensive that practically all synthesized pharmaceuticals and there is far less science in it.

  2. Sorry, the shocker is how many people have been duped into this faux medical marijuana sales pitch how it is going to benefit so many people, when it really only benefits a minority population of probably less than a third of those allegedly using it for documentable medical purposes.

    imagine if a heroin user somehow had a serendipitous reduction of a medical problem while using. Could you imagine this person being the poster child that heroin can cure some illness, when it likely had been an adjunct reaction to something else, or just truly that random chance moment of illicit substance having a benefit.

    Yeah, my skepticism and cynicism is beyond redemption, but, addiction is going to really be the malignancy that is the destruction of psychiatry. So many people rationalize their illicit substance abuse, their pursuit of Controlled Substances for likely illicit use, or just a relentless pursuit of a quick fix that likely is related to past addiction use at the very least.

    It's what I see it's what I hear and it's what I know for the last 10 or more years at least...

    1. I share your concern. Musto was the theorist in the 20th century who illustrated how drug epidemics in America were cyclical and roughly superimposed on societal permissiveness versus restrictiveness.

      Never has the culture been so steeped in so many drugs at once. Never have there been so many ideas about street drugs being therapeutic in some way.

      High dose CBD is one of the exceptions and even then, an epilieptologist recommended its use long before it became the poster for medical cannabis.

      The only bright spot is a relatively constant and low rate of addiction - but there are probably a lot of additional costs associated with some of these attitudes.

  3. One of the more pernicious side effects of marijuana is the munchies.

    That's not an issue for the occasional user, but the daily user tends to put on the pounds with carbs and this increases cytokines and chronic inflammation.

    Which of course makes all those diseases that MJ is a wonderful cure for a hell of a lot worse.