Children’s and Women’s Health Centre of BC, Department of Pharmacy Summer 2015 4. Pre-printed Orders Updates from C&W Pharmacy, Therapeutics and Nutrition The C&W PT&N has been busy approving pre-printed orders as part of the Clinical Systems Transformation in addition (PT&N) Committee to our C&W-specific pre-printed orders. The following C&W Jennifer Kendrick, BScPharm, PharmD pre-printed orders have been approved since January: The C&W PT&N Committee serves as the Pediatric Acute T Cell Mediated Kidney Rejection subcommittee to the Provincial Pharmacy and Bruising or bleeding and suspected child Therapeutics Committee. We continue to have maltreatment - initial screening panel – CPSU representation from other Health Authorities, in addition to our membership from C&W. Eating Disorders Unstable Patient Medical Admission 1. Policies & Procedures: Immune Globulin (IVIG) Infusion The following policies & procedures have been approved Intranasal Midazolam for Procedural Sedation and are being posted on the C&W intranet: WH Antepartum – Admission Intranasal Midazolam is now approved for procedural WH Severe Nausea & Vomiting of Pregnancy sedation on inpatient units. There is an accompanying (hyperemesis) Antepartum Admission pre-printed order and updated Procedural Sedation Guidelines and Standards. WH Evolving Chorioamnionitis WH Isolated Fever in Labour with Epidural Inhaled Nitrous Oxide was approved for use in the Dentistry Clinic. Nitrous oxide is also used for procedural WH Mobile Labour Epidural / CSE Analgesia pain and anxiety in the Emergency Department and WH Magnesium Sulfate (MgSO ) Administration for Orthopedic Clinic. 4 Seizure Prevention Fosphenytoin monographs have been updated in our WH Magnesium Sulfate (MgSO4) Administration for BCCH Drug Dosing Handbook and Parenteral Drug Manual. Fetal Neuroprotection Fosphenytoin dosing is now expressed as “phenytoin equivalents” (PE), which is in line with the product monograph and other WH Magnesium Sulfate (MgSO4) Administration for dosing references. The injectable formulation is available in POSTPARTUM vials as 50 mg/mL of PE (equivalent to 75 mg/mL of fosphenytoin). Note that many of the C&W pre-printed orders are available Fosphenytoin is available as a second-line alternative to as print-on-demand and can be found on the Intranet. phenytoin for status epilepticus when IV access is not available (as it can be administered IM), or when IV access is tenuous and extravasation poses a serious risk to the patient. Fosphenytoin is similarly effective to phenytoin. Note that phenytoin drug levels following a fosphenytoin loading dose should be drawn 2 hours following an IV dose or 4 hours following an IM dose. BCCH Empiric Antibiotic Guidelines were updated for 2015. 2. Formulary Changes: Levofloxacin was approved for addition to formulary for the treatment of fever and neutropenia in select low-risk patients. The updated Fever and Neutropenia Guidelines will be released in the coming months. Zoledronic acid restriction to osteogenesis imperfecta was removed. There is evidence to support its use in other In This Issue: populations of children with osteoporosis, as an alternative to pamidronate. PT&N Committee Update…1 3. Medication Backorders: Empiric Antimicrobial Guidelines 2015 Update…2 Health Canada Advisory: High Dose Ibuprofen…3 We continue to face medication shortages and the Pharmacy Health Canada Advisory: ADHD medications…4 Department continues to monitor supplies and usage. We appreciate the assistance in reviewing options to mitigate Latex Containing Medication…4 shortages (using oral/rectal routes, changing to alternative Errors with Transdermal Drug Delivery…5 medications, changing to other brands and strengths, etc). Poly-Vi-Sol/Tri-Vi-Sol Product Change…7 Pancuronium Discontinued by Manufacturer…7 Gentamicin injectable and cefixime suspension remain on extended backorder. The anticipated return of gentamicin is Congratulations to Dr. Mary Ensom…7 in the first quarter of 2016. Cefixime tablets are available Research, Education & Awards…7 now, with anticipated return of the suspension in September 2015. Pharmacy Informer Editorial Board…7
1 Empiric Antimicrobial Guidelines · Cefotaxime vs. ceftriaxone: a comment has been added that cefotaxime may be interchanged with 2015 Update ceftriaxone for children over 30 days-old and not on Karen Ng, BScPharm, PharmD, BCPS calcium-containing parenteral products (e.g. TPN). Reviewed by Dr. Ashley Roberts, Infectious The spectrum of antibacterial coverage is very Diseases and Antimicrobial Stewardship similar between cefotaxime and ceftriaxone, but ceftriaxone has a longer half-life of 5-9 hours After an annual review of available evidence and guidelines, (dosed Q12H to Q24H) and is 85-95% protein the Antimicrobial Stewardship Program has updated the BC bound, versus cefotaxime which has a shorter half-life Children’s Hospital Empiric Antimicrobial Guidelines, now of 1-1.5 hours (usually dosed Q6H to Q8H) and is posted onto Medworxx. Therapeutic updates in this version 31-50% protein bound.[5] Ceftriaxone is now include: slightly less costly than cefotaxime, provides more convenient dosing, is a formulary agent in BC Children’s · Sepsis and meningitis: age cutoffs have been changed and Women’s Hospital, and can be used interchangeably from 6 weeks to 4 weeks, in accordance to CPS[1] and with cefotaxime. IDSA[2] guidelines. Beware that ceftriaxone can precipitate with calcium- · Sepsis <4 weeks: the addition of acyclovir to empiric containing parenteral products and cause end-organ therapy has been changed to an optional “±”, to curb damage, and thus should not be co-administered to any overuse of acyclovir in infants with low suspicion of patient, whether mixed or administered simultaneously meningitis and HSV infection. or via Y-site.[6,7] Ceftriaxone also competes with bilirubin for binding to serum albumin and can increase · Meningitis <4 weeks: the option of using gentamicin the risk of bilirubin encephalopathy by significantly instead of cefotaxime, in combination with ampicillin decreasing the reserve albumin concentration in newborn and acyclovir, has been deleted. Cefotaxime is more serum and increasing free bilirubin, and is contraindicated active against Escherichia coli based on in vitro data in neonates.[8] as measured by MICs and MBCs, and is therefore In addition to therapeutic updates, a hyperlink has been preferred over gentamicin for the treatment of neonatal added to the BC Children’s and Women’s antibiogram, meningitis. and hyperlinks have been updated for new BC Children’s Hospital treatment guidelines, IDSA guidelines for skin · Mastoiditis, orbital cellulitis, community-acquired and soft tissue infections, and to the new editions of pneumonia, parapneumonic pneumonia and Feigin and Cherry, Mandell, and the Red Book. hospital-acquired pneumonia: the addition of cloxacillin to cefotaxime for methicillin-sensitive New lanyard cards with the 2015 updates are available. Staphylococcus aureus (MSSA) has been deleted for If you have not yet received yours, please contact empiric treatment, as cefotaxime provides satisfactory Karen Ng ([email protected]) or Ashley Roberts MSSA coverage for empiric use. For these infections, ([email protected]) for your copy. cefotaxime monotherapy is sufficient, unless if MRSA is suspected, in which case the addition of vancomycin should be considered. If MSSA is isolated, antibiotic therapy should then be tailored to optimize coverage. No evidence exists that empiric double coverage of MSSA is necessary, and double coverage is not routine in most other acute-care sites in our province. Although local susceptibility of MSSA to third-generation cephalosporins is unconfirmed because it is not tested, the European Committee on Antimicrobial Susceptibility Testing (EUCAST) states that susceptibility is assumed in MSSA.
· Community-acquired pneumonia>3 months, moderate and severe: the addition of empiric oseltamivir has been given an optional “±”, to align with the BCCH influenza treatment algorithm. During influenza season, empiric oseltamivir should be considered in patients hospitalized with influenza- References 1. Le Saux N; Canadian Paediatric Society, Infectious Diseases and like-illness with risk factors for complications and in Immunization Committee. Guidelines for the management of suspected those presenting with severe symptoms. and confirmed bacterial meningitis in Canadian children older than one month of age. Paediatr Child Health 2014; 19: 141-52. Full Text 2. Tunkel AR, Hartman BJ, Kaplan SL et al. Practice guidelines for the management · Pelvic inflammatory disease: in accordance with of bacterial meningitis. Clin Infect Dis 2004; 39: 1267-84. Full Text updated guidelines from BCCDC, azithromycin has been 3. BC Centre for Disease Control [Internet]. Vancouver (BC): BCCDC replaced by doxycycline as first-line therapy due to its Clinical Prevention Services; c2015. Pelvic inflammatory disease; 2015 March. Accessed July 3, 2015. Link to BCCDC PID Decision Support Tool increased effectiveness for the co-treatment of 4. Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the Chlamydia.[3] diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America. Clin Infect Dis 2014, 59: 147-59. Full Text · Cellulitis: cloxacillin has been replaced by cefazolin 5. Lexicomp Online, Pediatric & Neonatal Lexi-Drugs, Hudson, Ohio: Lexi- for the additional streptococcal coverage.[4] Comp, Inc.; July 3, 2015. 6. Steadman E, Raisch DW, Bennett CL, et al. Evaluation of a potential clinical interaction between ceftriaxone and calcium. Antimicrob Agents · Necrotizing fasciitis: this category has been divided Chemother 2010; 54: 1534-40. Full Text into necrotizing fasciitis of unknown etiology 7. Bradley JS, Wassel TT, Lee L, Nambiar S. Intravenous ceftriaxone and requiring empiric broad coverage with piperacillin- calcium in the neonate: assessing the risk for cardiopulmonary adverse effects. Pediatrics 2009; 123: 609-13. Abstract tazobactam + vancomycin + clindamycin, and documented 8. Gulian JM, Gonard V, Dalmasso C, Palix C. Bilirubin displacement by ceftriaxone group A streptococcal necrotizing fasciitis requiring in neonates: evaluation by determination of ‘free’ bilirubin and erythrocyte- targeted penicillin and clindamycin.[4] bound bilirubin. J Antimicrob Chemother 1987;19: 823-9. Abstract
2 Health Canada Advisory: Risk of Heart Attack and Stroke with High Dose Ibuprofen Vanessa Paquette BScPharm, PharmD; reviewed by: Rumi McGloin BScPharm, PharmD
Cyclooxygenase-2 (COX-2) selective non-steroidal anti-inflammatory drugs (NSAIDs)and non-selective NSAIDs are unequivocally associated with an increased risk of atherothrombotic events in patients with and without cardiovascular (CV) disease as demonstrated in observational studies, randomized controlled trials, systematic reviews, and meta analyses, however, uncertainty remains about the safety of specific NSAID regimens.[1-3] On April 23, 2015, Health Canada released new safety information for prescription strength ibuprofen regarding the risk of serious CV side effects when used at doses of 2400 mg or greater per day.[4]
A safety review was initiated by Health Canada following the 2013 publication of a meta-analysis conducted by the Coxib and traditional NSAID Trialists’ (CNT) Collaboration that assessed vascular and gastrointestinal side effects of NSAIDs.[5] The researchers undertook the above meta-analysis to address limitations of the 2006 trial-level meta-analysis assessing the risk of atherothrombosis with COX-2 selective NSAIDs or nonselective NSAIDs which demonstrated an increase in cardiovascular events, particularly myocardial infarction (MI), with use of COX-2 selective NSAIDs and of higher dosages of diclofenac and ibuprofen, though not naproxen.[1] The 2013 CNT meta-analysis included data from 280 placebo- controlled and 474 active-controlled NSAID trials, using individual patient level data when available. Included patients were predominantly female (68%) and Caucasian (79%) with a mean age of 61 years being treated for arthritis (83%). Only 9% of patients had pre-existing atherosclerotic disease and diabetes and 20% used aspirin. The mean body mass index (BMI) was 29 kg/m2, blood pressure was 132/79 mm Hg, total cholesterol was 5.3 mmol/L and 13% were current smokers.[5]
The primary outcome of major vascular events (non-fatal MI, non-fatal stroke, death from a vascular cause) was significantly increased in participants receiving any COX-2 selective NSAID compared to placebo. There was no significant difference in major vascular events between COX-2 selective NSAID and high dose (2400 mg per day) ibuprofen. Through an indirect comparison, high dose ibuprofen did not significantly increase major vascular events versus placebo, however, did significantly increase the subsidiary vascular outcome of major coronary events (non-fatal MI, death from coronary disease). High dose ibuprofen significantly increased the outcome of hospitalization due to heart failure but not of stroke or all-cause mortality. The study data allowed estimates of the excess absolute risk of major vascular events with varying baseline CV risk. For patients with low baseline CV risk (0.5% per annum risk of a major vascular event), high dose ibuprofen use would result in an excess of two events per 1000 persons per year. For patients with high CV risk (2% per annum risk of a major vascular event), high dose ibuprofen use would result in an excess of nine events per 1000 persons per year including three fatal events.[5] Overall, the authors concluded that ibuprofen possibly has vascular risks similar to the COX-2 selective NSAIDs.[5]
Limitations of the CNT meta-analysis to be considered and unanswered questions that still remain include the following[6]: Some trials included in the meta-analysis were missing individual patient data so trial level meta-analysis methods were necessary. Most of the data from the COX-2 selective NSAID trials were available at the patient level, whereas only half of the data from the non-selective NSAID trials (including ibuprofen) were available at the patient level. Secondly, comparisons of ibuprofen to placebo were derived indirectly from non-selective NSAIDs to COX-2 selective NSAIDs comparisons and COX-2 selective NSAIDs to placebo comparisons. Also, events were too sparse to determine to what extent the risk varies with duration of treatment and data only pertained to one dose level for ibuprofen. No associations between ibuprofen and stroke were reported in this meta-analysis, however, the number of events was relatively small.[5] Lastly, it is still definitively unclear whether the risk for CV thrombotic events is similar for all NSAIDs.[6]
At the time of Health Canada’s review, they had received 26 Canadian case reports of serious heart attack and stroke related adverse events suspected of being associated with ibuprofen use. Of the 15 case reports further evaluated for causality, ibuprofen was found to be a possible cause of these adverse events in 11 of them.[4]
Health Canada concluded that there is evidence of an association between oral ibuprofen at a daily dose of 2400 mg or more and an increased risk of CV thrombotic adverse events that is comparable to the risk associated with the COX-2 selective NSAIDs.[4] This risk likely increases with dose and duration of use. The maximum recommended daily dose for prescription ibuprofen is 2400 mg, however, this dose should be avoided in patients with ischemic heart disease, cerebrovascular disease, congestive heart failure or in patients with risk factors for cardiovascular disease.[4] So far, there is no evidence that ibuprofen presents an increased cardiovascular risk at daily doses of 1200 mg or less when used for short durations.[4] Health Canada will continue to monitor any vascular risk associated with daily doses between 1800 and 2400 mg. Health Canada states that the overall benefits of ibuprofen use continue to outweigh its risks if used as recommended.[4]
Recently, on July 9, 2015, the US Food and Drug Administration (FDA) also released a safety communication and consum- er report strengthening its warning that non-aspirin NSAIDs are associated with serious vascular events and are requiring updates to the drug labels of all prescription and over the counter NSAIDs including ibuprofen.[7,8] The recommendations and conclusions made by the FDA are similar to those made by Health Canada.
The bottom line is that ibuprofen is an effective treatment for pain, inflammation and fever and should continue to be offered to patients accordingly at the lowest effective dose for the shortest duration possible. The increased risk of CV thrombotic events conferred by its use should be communicated to patients especially with use at higher doses and/or known CV disease or risk factors for CV disease. Changes have been made to reflect this recommendation in the BCCH pediatric drug dosage handbook.
3 References (ibuprofen) In 2014 a large Swedish national health register-based 1. Kearney PM, Baigent C, Godwin J, et al. Do selective cyclooxygenase 2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase study in the British Medical Journal found no evidence for a the risk atherothrombosis? Meta-analysis of randomized trials. BMJ 2006; positive association between the use of ADHD drug 332: 1302-8. Full Text treatments and the risk of concomitant suicidal behaviours 2. McGettigan P, Henry D. Cardiovascular risk with non-steroidal anti- inflammatory drugs: systematic review of population based controlled among ADHD patients[5]. Among stimulant users, a observational studies. PLoS Med 2011; 8: e1001098. Full Text reduced within-patient rate of suicide related adverse 3. Trelle S, Reichenbach S, Wandel S, et al. Cardiovascular safety of non- events was observed during treatment periods[5]. steroidal anti-inflammatory drugs: network meta-analysis. BMJ 2011; 342: c7086. Full Text 4. Health Canada, Health Protection Branch. New safety information for Warnings regarding the increased risk of suicidal behaviour prescription-strength ibuprofen: Risk of heart attack and stroke at high have been incorporated into our patient medication doses. Accessed online March 30, 2015 Link to Safety Information 5. Bhala N, Emberson J, Merhi A, et al. Coxib and Traditional NSAID Trialists’ information handouts for relevant products, which are Collaboration group: Vascular and upper gastrointestinal effects on non- available from the KeltyMentalHealth.ca website. steroidal anti-inflammatory drugs: metal analysis of individual participant data from randomized trials. Lancet 2013; 382: 769-79. Full Text References 6. FDA Briefing Document Joint Meeting of the Arthritis Advisory Committee 1. Health Canada, Health Protection Branch. ADHD drugs may increase risk of and the Drug Safety and Risk Management Advisory Committee. Non- suicidal thoughts and behaviours in some people; benefits still outweigh steroidal anti-inflammatory drugs and cardiovascular thrombotic risk. risks. RA-52759. Ottawa, ON: March 30, 2015. Accessed online March 30, February 10-11, 2014. Accessed July 14, 2015 Link to Briefing Document 2015 Link to Safety Information 7. FDA Drug Safety Communication. FDA strengthens warning that non 2. Health Canada. Summary Safety Review - Amphetamines - Suicidal aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) can cause heart Thoughts and Behaviours (Suicidality). Ottawa, ON: March 30, 2015. attacks or strokes. July 9, 2015. Accessed July 20, 2015. Link to Warning Accessed online March 30, 2015 Link to Summary Safety Review 8. FDA Consumer Health Information. FDA Strengthens Warning of Heart 3. Health Canada. Summary Safety Review - Methylphenidate - Suicidal Attack and Stroke Risk for Non-Steroidal Anti-inflammatory Drugs. July Thoughts and Behaviours (Suicidality). Ottawa, ON: March 30, 2015. 9, 2015. Accessed July 20, 2015. Link to Warning Accessed online March 30, 2015 Link to Summary Safety Review 4. Canadian ADHD Resource Alliance (CADDRA). Response to March 30th, 2015: Health Canada Announcement: “ADHD drugs may increase risk of Health Canada Advisory: ADHD Drugs suicidal thoughts and behaviours in some people; benefits still outweigh and Suicidal Thoughts & Behaviours risks”. Markham, ON: April 2, 2015. Accessed online April 2, 2015 Link to Response Letter Dean Elbe, PharmD, BCPP 5. Chen Q, Sjolander A, Runseon B et al. Drug treatment for attention- deficit/hyperactivity disorder and suicidal behaviour: register based study. reviewed by Dr. Russet Jones, Br Med J 2014; 348: g3769. doi: 10.1136/bmj.g3769. Full Text Provincial ADHD Clinic In March 2015, Health Canada issued an advisory[1] regarding the class of ADHD medications (including the Latex Containing Medication psychostimulant drugs, such as amphetamine and Jennifer Kendrick (BScPharm, PharmD) methylphenidate derivatives, as well as non-stimulants such as atomoxetine and guanfacine extended-release (XR) and Marianne Tofan (DiplPharm) and risk of suicidal thoughts and behaviours that will be incorporated into the official labelling for these products. Most products used in the hospital environment are latex- free. However, some medication vial stoppers contain The advisory states that there have been reports of suicide- natural rubber latex or have unknown latex composition. related events in patients treated with ADHD drugs. The Manufacturers are not required to list the latex content of reports involved thoughts of suicide, suicide attempts, and medications on the packaging. Some of the medications in a very small number of cases, completed suicide. The that are known to contain latex at this time include insulin advisory also states: “There is little evidence to establish that (Humulin R® brand), alteplase, alprostadil, and magnesium these drugs cause suicidal thoughts and behaviours, but it is sulfate (PPC brand). Vaccines known to contain latex are possible that they may contribute to the risk... It is Health listed on the BC Centre for Disease Control website. Canada's view that the benefits of these drugs in the effective management of ADHD continue to outweigh their risks.” Medications should not be assumed to be latex-free unless The reports cited by Health Canada stem from their internal it is explicitly stated on the packaging or the manufacturer Summary and Safety reviews on the risk of suicidal has confirmed the absence of latex for that product. thoughts and behaviours and ADHD drugs containing amphetamines[2] and methylphenidate[3]. These reviews Potential contamination of medication with latex from the were based on reports received by the Vigilance Canada vial stopper may occur with prolonged contact (e.g. during Adverse Reaction Reporting Database. Despite a warning shipping or storage) or at the time of needle puncture being issued, there was no summary review provided for through the stopper.[1] The risk of adverse reactions in atomoxetine or guanfacine XR). Atomoxetine already carried latex-allergic patients is not clear from the literature. While a suicidality warning from 2005, due to its structural there are a handful of case reports of rash and positive and pharmacological similarity to the SSRI antidepressant skin prick test and one case of anaphylaxis from medication fluoxetine. Despite a warning being issued for the recently vials known or suspected to contain latex, causality is unclear marketed non-stimulant ADHD treatment guanfacine and the true frequency of reactions is unknown.[1] extended-release, the Vigilance Canada adverse reaction reporting database does not include any reports of suicide In the past, hospital pharmacies and clinicians would remove related behaviours with this medication. the vial stopper prior to administering the medication to a latex-allergic patient in order to minimize any latex contamination The Canadian ADHD Resource Alliance (CADDRA) issued a from the needle puncture.[1,2] However, a study comparing statement following the Health Canada warning[4], which this method to a single puncture of the vial stopper found stated in part: “…while patients and family members should no difference in latex allergen content.[3] In recent years, be made aware of the risk of suicidal thoughts and guidelines advocate the single puncture method.[2,4] Most behaviours among people with ADHD…[they]…should also hospital pharmacies, including the pharmacy at Children’s be told the new warning is not a cause for panic. ADHD and Women’s Hospital (C&W), use this method. medication should not be changed or stopped without medical advice.” The pharmacy at C&W recommends applying latex precautions Literature shows there is a positive relationship between when administering medication to a patient with latex allergy ADHD, impulsive behaviours and risk to self, and the effect as the best way to minimize the risk of allergic reaction. of co-morbidities like substance use and delinquency are difficult to separate in this relationship. (…Continued)
4 If a medication vial is not listed as “latex free”, assume Transdermal drug delivery occurs via diffusion: a high drug that it contains latex and use the following precautions: concentration in the transdermal device creates a gradient when applied to the skin, resulting in drug absorption into · Use a new medication vial for each dose. the bloodstream. Transdermal patches are available in · Puncture vial only once using the smallest gauge limited, set dosage strengths, which deliver doses that are needle possible. often too large for children. Cutting the patch into quarters · If reconstituting powder with diluent, do not remove or halves to achieve tailored dosing is often seen as an needle from stopper. Dissolve powder in vial and appealing strategy. For some types of patches, the amount withdraw appropriate dose. of drug delivered into the skin is directly proportional to the · Change the needle if adding the medication to an IV surface area of the patch and cutting the patch to reduce the solution or administering directly to the patient. dose may be an option.[5] For other types of patches, however, cutting the patch does not reduce the dose All injectable medications provided by C&W Pharmacy in ready- delivered to the patient, and can pose serious harm to patients. to-administer forms (e.g. syringes, IV bags) are prepared by using latex precautions and are therefore safe to be Not all patches are created equal administered to latex-allergic patients. There are two types of transdermal delivery systems References currently available on the market: reservoir or ‘membrane- 1. Heitz JW, Bader SO. An evidence-based approach to medication controlled’ patches and matrix or ‘drug-in-adhesive-layer’ preparation for the surgical patient at risk for latex allergy: is it time to patches.[6] stop being stopper poppers? J Clin Anesth 2010; 22: 477-83. Abstract 2. Hamilton RG, Brown RH, Veltri MA et al. Administering pharmaceuticals to latex-allergic patients from vials containing natural rubber latex In reservoir or membrane-controlled patches, the drug is closures. Am J Health-Syst Pharm 2005; 62: 1822-7. Abstract contained in a reservoir system, and its release into the skin 3. Canadian Society of Hospital Pharmacists. Natural rubber latex sensitive/allergic patients: guidelines for preparing medications. Ottawa is limited by a rate-controlling microporous membrane.[7] (ON): Canadian Society of Hospital Pharmacists; 2001. If the rate-controlling membrane is damaged in any way, 4. Thomsen DJ, Burke TG. Lack of latex allergen contamination of solutions the reservoir dose contents can be released immediately, withdrawn from vials with natural rubber stoppers. Am J Health-Syst Pharm 2000; 57: 44-7. Abstract posing risk of unintentional overdose. Some patches use ‘micro-reservoir’ systems to mitigate this risk, where the drug is contained in multiple, smaller drug reservoirs, versus Patch Pitfalls: Administration Errors one large depot.[7] If the membrane is compromised in with Transdermal Drug Delivery these patches, some reservoirs may remain intact, reducing the risk of sudden “dose-dumping.” A micro-reservoir system, Katie Haubrich, BScPharm, PharmD however, does not guarantee that cutting a patch in half will reviewed by result in a 50% dosage reduction. Because it is unpredictable Charmaine Ngo, BScPharm, ACPR how many microreservoirs will be damaged by cutting the device, dosing may not be consistent between each manipulated patch. Case Matrix or drug-in-adhesive-layer patches, on the other hand, A 5 year-old boy presents to the emergency department have drug evenly distributed in a polymer-based adhesive. with sudden onset of incoherent speech, bizarre In these patches, the amount of drug released is dependent behaviour, hyperactivity and confusion. On physical on diffusion and is directly proportional to the surface area exam, the patient has slightly dilated pupils and mild of the patch.[7] As such, cutting these patches poses less tachycardia. All other vital signs are normal. Discussion risk of unintentional overdose, and is sometimes a viable with family members reveals no history of head option for dose adaptation. Most commercially available trauma, ingestions or medication use, except for patches are matrix patches (Table 1). a half-patch of transdermal scopolamine (1.5 mg) applied behind the child’s ear. As reported by the parents, To cut, or not to cut? the patch was applied 18 hours prior to presentation to prevent motion sickness on a long-distance flight. Reservoir Patches Due to the risk of sudden “dose- dumping,” reservoir, micro-reservoir or membrane- Transdermal Drug Delivery controlled patches should never be cut or altered.[10] If the required dose of a reservoir patch is not commercially Drug delivery through transdermal patches provides a available, the desired dose may be achieved by placing an number of advantages over other routes of administration. impermeable material (such as Tegaderm® adhesive or Transdermal patches, for example, maintain more constant Bioclusive®) on the skin underneath the patch. The surface drug levels in the plasma than intermittently administered area of the patch which is blocked should be proportionate oral or parenteral dosage forms, and are convenient to to the desired dose reduction. It is recommended that the use.[1] As patches provide steady drug release over a long patch and impermeable material are then covered by placing period of time, transdermal drug delivery may reduce dose- another adhesive overtop. This technique may only be used related adverse effects, increase tolerability, and improve in scenarios when exact dosing is not critical, for example adherence.[2] Patches also deliver drug directly to the with use of hormone replacement therapy patches (e.g. systemic circulation, bypassing the ‘first-pass effect’ and Estraderm®).[11] For medications with a narrow therapeutic presenting a desirable option for patients unable to take window (e.g. fentanyl or clonidine), this technique is not medications orally. As a result of these advantages, recommended. While this technique is commonly used, transdermal patches have become a common route of drug there is very little information in the literature to support delivery for medications such as narcotic analgesics, nicotine, this practice. hormones and contraceptives. Matrix Patches Though the amount of drug released is Administration of transdermal patches can be challenging, proportional to surface area in a matrix-system patch, most however, and medication errors involving patches have manufacturers advise against cutting the patches due to a been frequently reported.[3,4] Accidental overdoses lack of safety and efficacy data.[2,8] The available data and deaths have resulted from inappropriate administration, regarding alteration of patches shows that the rate and as well as improper storage, removal and disposal of patch extent of drug absorption may be less predictable in matrix devices. patches that have been cut.[9] (…Continued)
5 Cutting the patch may also result in sharp edges, which can Healthcare providers should also be aware that dose impair adhesion to the skin.[2] The use of a cut matrix patch adjustment by cutting patches can result in toxicity and should take into consideration manufacturer specific adverse events, and should be reserved only for certain recommendations, the need for exact dosing, the therapeutic matrix patches after considering medication and patient index of the drug and the patient’s ability to accurately alter specific factors. the patch surface area. In patients using partial doses of Case Discussion matrix patches, careful monitoring for potential adverse Transdermal scopolamine is commercially available over- effects and lack of efficacy should occur. the-counter as a reservoir-system patch (Transderm-V®). High risk for error and harm If these reservoir or membrane-controlled patches are cut, the full dose contained in the device may be suddenly Gaps in healthcare provider knowledge and awareness of released when the partial patch is applied to the skin. transdermal patch systems, and inappropriate patient Given scopolamine’s anticholinergic effects, symptoms information subsequently being provided, has been such as tachycardia, hyperthermia, mydriasis, hallucinations, identified as a major cause for transdermal patch psychoses, seizures and coma may result from overdose. administration errors.[1] The patch systems themselves, In a reported case of toxicity resulting from inappropriate which vary in frequency and site of administration, shape, scopolamine patch use in a child, symptoms resolved with size, colour, and dosage units, can cause confusion with patch removal and supportive care.[14] patients and healthcare professionals alike, resulting in potential for error. Additionally, the patch system may differ If a partial dose of transdermal scopolamine is required, between interchangeable brands of the same medication. an impermeable material (such as Tegaderm®) should be Serious harm to patients has been reported in numerous placed on the skin underneath the patch, covering the cases involving inappropriate administration of transdermal proportionate surface area to desired dose reduction, patches. In a study of medication errors with use of as discussed above. transdermal fentanyl and buprenorphine, 78% of errors References were identified as occurring in the administration stage of 1. Lampert A, Seiberth J, Haefeli WE, Seidling HM. A systematic review of the medication process.[3] Supratherapeutic doses and medication administration errors with transdermal patches. Expert Opin toxicity have resulted from patients applying multiple Drug Saf 2014; 13: 1101-14. Abstract 2. Durand C, Alhammad A, Willett KC. Practical considerations for optimal patches, failing to remove old patches, applying patches to transdermal drug delivery. Am J Health-Syst Pharm 2012; 69: 116-24. incorrect body sites, applying heat to patch sites and cutting Abstract patches prior to application.[1] Failure to remove patch 3. Lövborg H, Holmlund M, Hägg S. Medication errors related to transdermal opioid patches: lessons from a regional incident reporting liners or protective foil prior to application and patch system. BMC Pharmacol Toxicol 2014; 15: 31. Full Text displacement due to improper application have resulted 4. Lövborg H, Jönsson AK, Hägg S. A fatal outcome after unintentional in inadequate drug absorption and poor efficacy. Appropriate overdosing of rivastigmine patches. Curr Drug Saf 2012; 7:30–2. Abstract 5. Izumoto T, Aioi A, Uenoyma S et al. Relationship between the education of patients and caregivers prescribed transdermal transference of a drug from a transdermal patch and the physicochemical drug devices is essential in preventing such errors. properties. Chem Pharm Bull ( Tokyo) 1991; 40: 456-8. Abstract 6. Lee HA, Anderson PO. Giving partial doses of transdermal patches. Am J Infants and young children may be at higher risk for harm Health-Syst Pharm 1997; 54: 1759-60. Abstract when transdermal drug delivery systems are used, due to 7. Cohen MR, Smetzer JL. ISMP Medication Error Report Analysis. Risk of cutting certain medication patches. Hosp Pharm 2009; 44: 18-21. Full Text the increased danger for patch ingestion. Ingestion of 8. Individual Product Monographs. e-CPS [Internet]. Ottawa (ON): fentanyl and clonidine patches have been linked to several Canadian Pharmacists Association; c2015. Accessed online July 20, 2015 pediatric deaths.[12,13] Patches should be stored and from www.e-cps.ca. 9. Zuppa AF, Tejani SM, Cullen EJ Jr, Nadkarni VM. Plasma concentrations disposed of safely in order to avoid inadvertent ingestion. following application of whole versus cut transdermal clonidine patches In young children or patients with reduced mental capacity, to critically ill children. J Pediatr Pharmacol Ther 2004; 9: 43-8. Full Text patches should be placed on body surfaces difficult to reach 10. Ball AM, Smith KM. Optimizing transdermal drug therapy. Am J Health- Syst Pharm 2008; 65: 1337-46. Abstract (e.g. upper back), to prevent removal and ingestion. 11. Cupp M. Characteristics of Transdermal Patches. Pharmacist’s Letter/ Prescriber’s Letter August 2012. Full Text Conclusion 12. Horowitz R, Mazor SS, Aks SE, Leikin JB. Accidental clonidine patch ingestion in a child. Am J Ther 2005; 12: 272–4. Abstract Transdermal patches are prone to administration errors, 13. Teske J, Weller JP, Larsch K, et al. Fatal outcome in a child after ingestion and represent an important safety concern for patients, of a transdermal fentanyl patch. Int J Legal Med 2007; 121: 147–51. Abstract particularly as their popularity as a method of drug delivery 14. Lin YG, Chen PH, Chang FY, Wu LT, Liao KY, Wu TC. Delirium due to scopolamine patch in a 4-year-old boy. J Formos Med Assoc 2011; 110: increases. To minimize the risk of patient harm, healthcare 208-11. Abstract providers should provide appropriate patient counselling.
Matrix System Patches Reservoir System Patches Brand Name (Manufacturer) Generic Brand Name (Manufacturer) Generic Apo-Fentanyl Matrix® Fentanyl Androderm® Testosterone Co-Fentanyl® Fentanyl Catapres-TTS® Clonidine Bu-Trans® Buprenorphine (special access only) Climara® Estradiol Nicoderm® Nicotine Climara Pro® Estradiol and Levonorgestrel Transderm-Nitro® Nitroglycerin Duragesic MAT® Fentanyl Transderm-V® Scopolamine Estalis® Estradiol and Norethindrone Estradot® Estradiol Evra® Ethinyl Estradiol and Norelgestromin Exelon® Rivastigmine Habitrol® Nicotine Minitran® Nitroglycerin Nitro-Dur® Nitroglycerin Neupro® Rotigotine Oesclim® Estradiol Teva-Fentanyl® Fentanyl Trinipatch® Nitroglycerin Sdz-Estradiol Derm® Estradiol
6 Research, Education & Awards Karen Ng, BScPharm, PharmD, BCPS
Research Burgess S, Mabasa VH, Chow I, Ensom MHH. Evaluating Outcomes of Alternative Dosing Strategies for Cefipime: A Qualitative Systematic Review. Ann Pharmacother 2015;49:311-22. doi: 10.1177/1060028014564179 Abstract Wang EHZ, Bolt JL, Decarie D, Semchuck W, Ensom MHH. A Study of Dabigatran Stability in 3 Clinically-Relevant Environments: Manufacturer’s Blister Pack, Unit-Dose Packaging, and Community Pharmacy Blister Pack. Can J Hosp Pharm 2015;68:16-21. Full Text Egan G, Ensom MHH. Measuring Anti-Factor Xa Activity to Monitor Low Molecular Weight Heparin in Obesity: A Critical Review. Can J Hosp Pharm 2015;68:33-47. Full Text Kanji S, Hayes M, Ling A, Shamseer L, Chant C, Edwards DJ, Edwards S, Ensom MHH, Foster DR, Hardy B, Kiser T, La Porte C, Roberts J, Shulman R, Walker S, Zelenitsky S, Moher D. Reporting Inside the Pharmacy Dispensary, New Orleans Pharmacy Museum, Guidelines for Clinical Pharmacokinetic Studies. The ClinPK New Orleans, LA. Photo: Dean Elbe Statement. Clin Pharmacokinet 2015; 54: 783-95. doi:10.1007/s40262-015-0236-8 Abstract Pawluk SA, Roels CA, Wilby KJ, Ensom MHH. A Review of Poly-Vi-Sol and Pharmacokinetic Drug-Drug Interactions with the Anthelmintic Tri-Vi-Sol Product Change Medications Albendazole and Mebendazole. Clin Pharmacokinet 2015; 54: 371-83. doi: 10.1007/s40262-015-0243-9. Abstract The vitamin A content in Poly-Vi-Sol and Tri-Vi-Sol has been Reardon J, Lau TTY, Ensom MHH. Vancomycin Loading Doses: A reduced from 1500 international units (IU) per mL to 750 IU Systematic Review. Ann Pharmacother 2015; 49: 557-65 per mL. This change was made to reduce the risk of infants doi: 10.1177/1060028015571163 Abstract exceeding the tolerable upper limit (TUL) of vitamin A Rainkie D, Ensom MHH, Carr RR. Pediatric Assessment of from all sources. The Institute of Medicine recommends Vancomycin Empiric Dosing (PAVED): a Retrospective Review. a TUL for vitamin A of 600 micrograms (2000 IU) per day. Pediatric Drugs 2015; 17: 245-53. doi: 10.1007/s40272-015-0122-8 Link to Table of Dietary Reference Intakes (DRI) Abstract Kiang TKL, Wilby KJ, Ensom MHH. A Critical Review on the Clinical Pancuronium Discontinued Pharmacokinetics, Pharmacodynamics, and Clinical Trials of Ceftaroline. Clin Pharmacokinet 2015 May 5. [Epub ahead of print] by Manufacturer Abstract Marra F, Ng K. Controversies around epidemiology, diagnosis and After more than 2 years on backorder, pancuronium has treatment of Clostridium difficile infection. Drugs 2015; 75: 1095- now been discontinued by the manufacturer. Other 118. doi:10.1007/s40265-015-0422-x Abstract neuromuscular blockers available at Children’s and Bridging The Gap: An Oak Tree Clinic Interdisciplinary Outreach Women’s Health Centre include rocuronium, atracurium, Approach to HIV Care at Alouette Correctional Centre for Women in cisatracurium, and succinylcholine. Programs who have BC. Pick N, Friesen K, Quaia C, Paquette T, Slater A, Kestler M, Krell been using alternate neuromuscular blockers during the S, Moody C, Mervyn L, Feder D, Murray M. Poster presentation at 4th pancuronium shortage are advised to continue to do so. International Workshop on HIV & Women, January 13-14, 2014. Awards Congratulations to Dr. Mary Ensom Mary Ensom was one of only 4 individuals to be inducted into the Inaugural Class of the Hall of Distinguished Alumni, University on the Publication of Her 500th Paper of Kentucky College of Pharmacy (March 2015) Link to Story
Dr. Mary Ensom, Professor of the Faculty of Pharmaceutical Editor’s Corner Sciences and Distinguished University Scholar at UBC, a Senior Associate Clinician Scientist at CFRI, and a Clinical Pharmacy There have been significant changes in some of our Specialist at the Children’s and Women’s Health Centre of BC, distribution channels since we resumed publishing, and we has achieved the remarkable milestone of the publication continue to work to make sure everyone has access to our th of her 500 paper. She has contributed immensely to research content. If you did not automatically receive a copy (or in clinical pharmacokinetics and pharmacodynamics, notification of where you can download a copy) of this pharmacogenetics and pharmaceutical outcomes evaluations, among other areas, and has been recognized with newsletter, please contact one of the editors at the email numerous prestigious national and international awards. addresses listed below. For those of you who may have missed our Winter 2015 issue, the newsletter has been That she has published over posted on the UBC Department of Pediatrics website. 500 papers is a testament to her dedication, perseverance, Pharmacy Informer Editorial Board passion, and willingness to collaborate and Dean Elbe, BScPharm, PharmD, BCPP (Editor) encourage others to [email protected] contribute to clinical improvements via research. Karen Ng, BScPharm, PharmD, BCPS (Editor) [email protected] With heartfelt congratulations, we applaud Mary’s exceptional Sharon Ho, BScPharm, ACPR accomplishments and her continued inspiration and Jennifer Kendrick, BScPharm, PharmD (PT&N Liaison) mentorship to both her colleagues and students! Roxane Carr, BScPharm, PharmD, BCPS, FCSHP (Clinical Coordinator)
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