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


Reference:

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.

Dangerous Medication - Part 3 - A Risk-Averse Approach To Prescribing Bupropion

Bupropion is a widely prescribed antidepressant.  It is a safe and effective medication according to the FDA.  It can be safely prescribed with a high level of success.  It is probably more widely prescribed with the advent of guidelines suggesting that it is an augmenting agent for situations where antidepressant monotherapy is ineffective.  It may also end up being used with another antidepressant if a patient is interested in using it for smoking cessation and in an off label manner for attention deficit hyperactivity disorder and to treat sexual dysfunction associated with SSRI type antidepressants.  Bupropion does have a unique position in antidepressant pharmacotherapy.  With the increased focus on electrocardiogram abnormalities, it is probably the antidepressant that  is least likely to affect the QTc interval.

Bupropion is generally well tolerated, but there are some people who develop increased anxiety, agitation and insomnia.  This people generally need to stop taking the medication or reduce the dose.  A small number of people will develop mild to moderate hypertension and depending on the situation, the medication should be discontinued or the hypertension treated.  The largest problem I see with this medication is deciding when to stop and start it based on its contraindications.  The FDA package insert (from the FDA website using the brand name) on the matter is clear:

CONTRAINDICATIONS
WELLBUTRIN is contraindicated in patients with a seizure disorder. 
 WELLBUTRIN is contraindicated in patients treated with ZYBAN® 13 (bupropion hydrochloride) Sustained-Release Tablets, or any other medications that contain bupropion because the incidence of seizure is dose dependent. 
WELLBUTRIN is also contraindicated in patients with a current or prior diagnosis of bulimia or anorexia nervosa because of a higher incidence of seizures noted in such patients treated with WELLBUTRIN. 
WELLBUTRIN is contraindicated in patients undergoing abrupt discontinuation of alcohol or sedatives (including benzodiazepines). 
The concurrent administration of WELLBUTRIN and a monoamine oxidase (MAO) inhibitor is contraindicated. At least 14 days should elapse between discontinuation of an MAO inhibitor and initiation of treatment with WELLBUTRIN. 
WELLBUTRIN is contraindicated in patients who have shown an allergic response to 
bupropion or the other ingredients that make up WELLBUTRIN Tablets

The package insert goes into some of the evidence for these contraindications, but the details seem fairly clear to me.  So why is it that the following happens?

1.  Patients who are not aware of the fact that bupropion can cause seizures.
2.  Patients who are prescribed this medication in spite of the contraindications.
3.  Patients with a past history or an active eating disorder taking this medication.
4.  Patients who are regularly drinking alcohol +/- sedative hypnotics taking this medication.
5.  Patients who have had generalized tonic clonic seizures taking this medication and the medicine is still prescribed.

I could go into much greater detail about some of the most extreme situations where this occurs, but I think it would be more instructive if I just cut to a few basic recommendations for the safe use of this medication:

1.  Do not prescribe it in the presence of contraindications.
2.  Do not prescribe it to anyone who has a known problem with alcohol or sedative abuse problems.  In fact, obtain a new history for those disorders at the time you are obtaining informed consent for the prescription and revisit the contraindications every time you increase the dose since the seizure risk increases with dose increases.
3.  Discontinue bupropion immediately if you are treating the patient for alcohol or sedative hypnotic withdrawal.  Have a serious conversation with that person about seizure risk an the FDA contraindications before restarting it.  People provided with that information quickly reassess the need for the medication and whether or not it has been helpful.
4. Discuss the warnings with the patient if they have medical comorbidity that is flagged in the package insert such as:

Hepatic Impairment: WELLBUTRIN should be used with extreme caution in patients with severe hepatic cirrhosis. In these patients a reduced dose and/or frequency is required, as peak bupropion, as well as AUC, levels are substantially increased and accumulation is likely to occur in such patients to a greater extent than usual. The dose should not exceed 75 mg once a day in these patients.

and:

The risk of seizure is also related to patient factors, clinical situations, and concomitant 
medications, which must be considered in selection of patients for therapy with WELLBUTRIN. 
Patient factors: Predisposing factors that may increase the risk of seizure with bupropion use include history of head trauma or prior seizure, CNS tumor, the presence of severe hepatic cirrhosis, and concomitant medications that lower seizure threshold. 
Clinical situations: Circumstances associated with an increased seizure risk include, among others, excessive use of alcohol or sedatives (including benzodiazepines); addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; and diabetes treated with oral hypoglycemics or insulin. 
Concomitant medications: Many medications (e.g., antipsychotics, antidepressants, theophylline, systemic steroids) are known to lower seizure threshold. 

5.  Seriously weigh the seizure risk of adding any medication that might lower the seizure threshold to any person who is stable on bupropion and keep that person involved of the possible seizure risk.  Do a detailed and individualized risk assessment for prescribing medications to any patients.
6.  Document the vital signs of any patient on bupropion and the trend.
7.  Do not prescribe bupropion again to anyone who has had a seizure while taking it.

I have seen bupropion prescribed in the context of all of the contraindications and warnings without seizures or other complications.  Risking a low frequency but serious complication is not the optimal way to prescribe it.  The other consideration is that the risk assessment needs to be done on an individualized basis.  A general number quoted as an average side effects from clinical trials obviously would not apply to a patient with multiple risk factors or a patient who reliably gets side effects every time he or she takes the drug.  Population based care sounds good when it is promoted by managed care companies or government agencies, but this is a good example of where that concept fails.  As I think about all of the high risk ways I have seen bupropion prescribed, I go back to the recent post on overprescriber biases and how that influences the process.  No physician trained in psychopharmacology would have these deficits on a purely cognitive level, but in the case of treatment resistant depression and a contraindication the situation may become higher risk.

That is an ideal time for consultation or referral rather than taking a chance.

If you are reading this from the patient perspective, I encourage reading the Medline Plus handout on any medication that you are taking. The FDA approved package insert is usually available on the Internet, even in the case of most generics.  I would exercise caution if you decide to study it.  In a previous post, I point out that a lot of people really don't want to know about detailed side effects in advance because they fear developing them by mere suggestion or they might avoid taking a useful medication entirely.  Some package inserts have specific "Information to the patient" that is usually designed to communicate important information.

George Dawson, MD, DFAPA