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For Information Only, For Those on Frisium/clobazam. Re: SHORTAGE SITUATION. Letter posted online June 4, 2016

Canadian League Against Epilepsy I Ligue canadienne contre l’épilepsie

Clobazam Shortage?Suggestions for Management of Pediatric & Adult Patients with Epilepsy

June 4, 2016

There are shortages of clobazam, generic and brand name (Frisium). The situation has worsened during the past month reaching a crisis level.

Health Canada arranged a teleconference on June 3, 2016 to discuss the clobazam supply situation. Canadian League Against Epilepsy members participated in this meeting to convey the serious implications of a widespread clobazam shortage for patients with epilepsy.

Improvements in the clobazam supply are expected by late June to early July. Apotex Inc., the major supplier of clobazam in Canada, will be returning to regular supply levels. Several batches of Apo-Clobazam are expected to be released to wholesalers during the last two weeks of June.

Also, there should be additional Frisium (brand name clobazam) in the coming weeks from Lundbeck LLC.

There may continue to be some serious supply problems during the next three to four weeks. It is hoped that efforts will be made to identify sources of clobazam in the drug supply chain in order to protect patients.

Clobazam is a Level 1 Critical Drug for patients with epilepsy, according to the Canadian Pharmacists Association classification.

Prescribers asked to switch a patient from clobazam to an alternate drug, due to the shortage, should first request that the patient’s pharmacist double check all supply avenues to obtain either the same formulation or an interchangeable form (generic or brand) of clobazam. In addition to regular wholesalers, pharmacists can explore if supply is available from other wholesalers, other pharmacies or directly from one of the manufacturers.

All supply avenues should be exhausted before a patient who has been stabilized on clobazam is switched to an alternate drug. A decision must be made more quickly if the patient has minimal supply remaining to prevent interruption in therapy.

Clobazam is a 1,5-benzodiazepine with a long duration of action and has been marketed as an antiseizure drug in Canada for nearly 20 years. This medication is commonly used to treat epilepsy.

Interruption or sudden discontinuation of antiseizure drug therapy can cause a loss of seizure control, or worsening of a patient’s condition, with significant short- and long-term implications for patient safety, independence and quality of life. Breakthrough seizures can have potentially fatal consequences.ii

There are additional concerns related to this particular drug shortage. Sudden discontinuation of clobazam can cause benzodiazepine withdrawal syndrome.iii Abrupt discontinuation of clobazam may exacerbate seizures and cause other benzodiazepine withdrawal symptoms.iv Abrupt withdrawal of clobazam can also put patients at risk of life-threatening status epilepticus.v

Suggestions for Patient Management During the Clobazam Shortage

Patients who require de novo treatment?In patients who require de novo treatment with an antiseizure medication during the clobazam shortage, physicians should consider whether an alternative medication could be used at least initially.

Patients currently taking clobazam?If all supply avenues have been exhausted and there is no clobazam available, an alternate medication should be substituted until clobazam can be resupplied to the patient.

The following rationale for the selection of clonazepam as an alternative medication to clobazam during a drug shortage is from a document written by J.C. Martin del Campo, MD, FRCP and Jorge G. Burneo, MD, MSPH in 2013vi:

From the benzodiazepine group, only two other drugs have been found useful for the chronic management of seizure disorders: nitrazepam and clonazepam.

While there is no published evidence of efficacy under the circumstances, the most reasonable substitute for clobazam is clonazepam.

It is not known if this will be efficacious in all patients or if the recommended equivalent will result in a decompensation of the seizure disorder, but it is reasonable to surmise that it may prevent the development of a withdrawal state resulting in status epilepticus. Any given dosage will need to be carefully monitored by the prescribing physician and adjustments made where necessary.

While making these recommendations, it is hoped that the health authorities and pharmaceutical companies will protect the public by urgently implementing a strategic plan that will prevent such shortages from occurring. It is imperative to be reminded of the potentially fatal consequences of breakthrough seizures.vii

Reproduced with permission from del Campo and Burneo.

Recommendations for Therapeutic Substitution of Clonazepam for Clobazam

Clonazepam (brand name Rivotril) is a 1,4-benzodiazepine. This medication is available as an oral tablet in 0.25 mg, 0.5 mg, 1 mg and 2 mg formulations.

ClonazePAM and cloBAZam have similar lipophilicity and protein binding therefore likely very similar CNS penetration.

Clonazepam is more potent than clobazam. It is at least 10X more potent than clobazam if not ?20X, therefore, 1 mg of clonazePAM may be similar in potency to 10 mg of cloBAZam but could be as potent as 20 mg of cloBAZam.viii

Following conversion to clonazepam, some dose titration may be required to achieve the desired therapeutic effect. Clinical judgement is necessary to determine the optimum dose for each patient.

Patients should be carefully monitored for changes in seizure frequency, as well as the emergence of any adverse effects (excessive sedation, ataxia, increased difficulty handling secretions, worsening liver function) following the switch. ClonazePAM causes more sedation than equipotent doses of cloBAZam and tolerance may be more likely to develop to its antiseizure activity.

The excipients and non-medicinal ingredients between formulations may be different so caution should be exercised in patients with known hypersensitivity to excipient. These, along with any differences in adverse event profiles, can be verified in the appropriate Product Monographs and labels. The Product Monographs are available from the Health Canada Drug Product Database.ix

ADULTS? Initiate at 0.5 mg clonazePAM for every 10 mg clobazam (1:20)x; in 3-5 days, in the absence of adverse effects, increase to 1 mg clonazePAM for every 10 mg clobazam if required, to a maximum of 3 mg clonazepam/day.

Consider initiating clonazepam with a simultaneous gradual tapering of cloBAZam by 5-10 mg/week if supply allows.

PEDIATRICS?Initiate at 0.5 mg clonazePAM for every 10 mg clobazam (1:20); direct substitution can be made, tapering of clobazam is not mandatory. Dose titration, up or down, should be based on patient response.

Dose increases in pediatric patients, if required, are typically 0.25-0.5 mg/day every 5-7 days to a maximum of 0.1 mg/kg/day (or 0.2mg/kg/day for patients on enzyme-inducing drugs)xi

SENIORS, PATIENTS WITH LIVER DISEASE OR PATIENTS ON MEDICATIONS THAT INHIBIT P450-3A4 Initiate clonazepam at lower dosages in the elderly, in patients with liver disease, or in patients who are currently on medications which inhibit cytochrome P450-3A4.

Drug Metabolism and Pharmacokinetics

CloBAZam and clonazePAM are primarily metabolized by CYP 3A4. CloBAZam’s active metabolite, N- desmethylclobazam, is primarily metabolized by CYP 2C19. When substituting clonazePAM for cloBAZam, a thorough drug interaction assessment should be done taking these metabolic paths into consideration.

Information and Support for Practitioners and Patients

Should practitioners have reservations or concerns about the clinical management of their patients with epilepsy during this shortage, they should consult their nearest neurologist with epilepsy expertise or comprehensive epilepsy centre.

Patients and caregivers can contact their local Canadian Epilepsy Alliance agency for information and support by calling 1-866-EPILEPSY (1-866-374-5377).

i “Level 1 Critical Drug: Drug therapy for disease is essential and cannot be interrupted for even one dose or one day.” From: Canadian Pharmacists Association (2010), Drug Shortages: A Guide for Assessment and Patient Management www.pharmacists.ca/cpha-ca/assets/File/cpha-on-the-issues/DrugShortagesGuide.pdf?ii Steinhoff, B.J., et al. (2009) Substitution of anticonvulsant drugs. Ther Clin Risk Manag., 5, 449–457. www.ncbi.nlm.nih.gov/pmc/articles/PMC2701486/pdf/tcrm-5-449.pdf

iii Frisium Product Monograph (2015) iv ibid

vii Steinhoff, B.J., et al. (2009) Substitution of anticonvulsant drugs. Ther Clin Risk Manag., 5, 449–457.?viii Sankar, R. et al. (2014) Clinical considerations in transitioning patients with epilepsy from clonazepam to clobazam: a case series. J. Med. Case Rep., 8: 429. www.ncbi.nlm.nih.gov/pmc/articles/PMC4302143/pdf/13256_2014_Article_3028.pdf?ix Product monographs are available for download from the Health Canada Drug Product Database: www.hc-sc.gc.ca/dhp-mps/prodpharma/databasdon/index-eng.php?x Benzodiazepine equivalence table http://www.benzo.org.uk/bzequiv.htm (accessed May 16, 2016)?xi Farrell, K. and Michoulas, A. (2008) Benzodiazepines. In J.M. Pellock et al. (Ed), Pediatric Epilepsy: Diagnosis and therapy, 3rd Edition. Demos Medical Publishing, New York, page 559.?xii Brodie, M.J., et al. (2016) Clobazam and clonazepam use in epilepsy: Results from a UK database incident user cohort study. Epilepsy Research 123, 68-74.?xiii ibid?xiv Comparison of benzodiazepines http://www.vhpharmsci.com/vhformulary/tools/benzodiazepines- comparison.htm (accessed May 18, 2016)

v Engel, J. (2013). Seizures and Epilepsy, 2nd Edition. Oxford University Press, New York, page 557.?vi Del Campo, M. and Burneo, J. (2013). Therapeutic alternative to clobazam: Medical recommendation for adults with epilepsy. Retrieved from Epilepsy Ontario website: epilepsyontario.org/wp- content/uploads/2014/01/Clobazam_Therapeutic-alternative-for-adults_Jan2013.pdf

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When I am asked to “prove” something by showing a study, it reminds me of how backwards we can be when it comes to stacking studies against each other to make a point. We come up with rebuttals like, “the patient size was too small”, “the study is too old” and “the study wasn’t double blinded”. In fact, virtually every study that has ever been done can be debated for some reason or other. As well, it is safe to say that not much has ever been proven of any value or consequence by just one study alone.

Let’s say that a colleague and myself have a disagreement on whether or not chromium has the ability to prevent hypoglycemia. This can start out with a quick exchange of some handpicked positive and negative outcome studies that may be well designed or not or maybe had the power to determine the outcome or not. Maybe a study hid some of the data or the statistical analysis was done improperly. Maybe my colleague had 10 times as many studies compared to mine. Is that what decides the outcome of all of these scientific studies? That one person can scrounge up more studies than someone else? How does that person explain a well-designed study that doesn’t back up his or her argument? Do they quietly pass off the study as a fluke or placebo effect or do they start to see what scientific study is for us – many studies that create a whole picture much like individual pieces of a puzzle make a picture.

Let’s say we have a puzzle. It is a puzzle of a field of green grass on a sunny day with blue sky and some white clouds. It turns out that this picture is a picture of a rabbit sitting in the field, only a very small part of the picture, less than one percent is taken up with the rabbit. This translates into just 2 pieces of the 500 piece puzzle. Let’s say my colleague and I divide the puzzle in two and each take half of the puzzle home with us. We separately lay out the pieces and get a vague idea about what the picture shows. It turns out I have both pieces that make up the rabbit, statistically not what we would expect but it happened. I call my colleague and tell him about the picture we are looking at and how it appears to be one with a rabbit in the field. He says, “that’s crazy, there’s no rabbit in this picture”. He said he’s looked at all of his pieces and no evidence of any rabbit.

So who is correct? Well based on what is in front of each of us, we are both correct. When we both meet to put the puzzle together on one table, the entire picture becomes clear. The puzzle changes from a field on a sunny day to a rabbit on a sunny day. Each piece of the puzzle is a scientific study.

This exercise shows us what the power of a study means, or an analysis of many studies can show. For an infrequent result, the amount of pieces that are required to find the rabbit are large. My colleague arrived at what would be called a negative result and mine was a positive result. In a book called Statistics Done Wrong, (Alex Reinhart) it is described that in a review of studies between 1975 and 1990 in prestigious medical journals, almost a third of these studies yielded negative results. A full 64% of these studies didn’t have the power to determine a 50% difference in the primary outcome they were looking for between treatment groups. When a 25% difference was present, a full 84% of studies didn’t have the power to find this.

As always, I believe that scientific studies are the best thing we have to unlock what we do not know. One study however, can be deceiving when taken as a single data point on a graph. Scientific studies are a group effort.

Guest post from Roni Davis