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SPECIAL SUPPLEMENT Mandatory Generic Substitution For Immunosuppressant Transplant Drugs Is it the safest and healthiest policy for patients? The potential for uncontrolled generic switching of immunosuppressant transplant
drugs, such as tacrolimus or cyclosporine, due to mandatory generic substitution plans, can negatively impact patient (plan member) safety and health outcomes, resulting in higher costs. Does your drug benefit plan have proper safeguards to avoid this scenario? Are mandatory generic substitution plans the best
switching from brand to generic drug, or between solution for all drugs?
different generic formulations, may result in less Mandatory generic substitution plans assume all brand optimal treatment. Plan sponsors must balance the drugs and their corresponding generics are equivalent need for cost containment while having plan mem- and will have similar clinical outcomes and adverse bers receive appropriate treatment by ensuring effects for patients. Generic equivalencies are based processes are in place for plan design exceptions. on Health Canada bioequivalence standards as wel as provincial legislation, regulations, and/or policies. In a mandatory generic substitution plan, plan sponsors will reimburse pharmacies and plan mem- bers only the price of the lowest generic equiva- lent of the brand drug. Pharmacists can substitute interchangeable generics at the pharmacy without consultation or approval by the physician. Pharmacy purchasing practices can also influence which drug a patient receives, as generic suppliers can change based on cost and availability. This is important as Health Brand vs. Generic Canada requires a generic manufacturer to prove that its drug is bioequivalent to the brand or reference drug, but does not have to show bio-equivalence to other generic versions. Generic substitution plans, in general, achieve their goal of providing similar clinical outcomes at a lower cost to the plan sponsor and member. These prac- tices have been a mainstay for both public and private Key Pharmacokinetic Parameters
drug benefit plans over the last few decades. How- � Area under the curve (AUC)→ marker of drug exposure ever, in a number of circumstances, the uncontrolled � Peak drug concentration achieved following dosing (Cmax)

What exceptions should be considered?
Desired Outcomes for Immunosuppressant
There are a number of immunosuppressant transplant Therapy in Transplantation
drugs that should be considered as exceptions in manda- tory generic substitution plans. These drugs have been des- ignated as ‘Critical Dose Drugs' (CDDs) by Health Canada. In 2012, Health Canada published an update to its ‘Guidance Document – Comparative Bioavailability Standards: For- mulations Used for Systemic Effects,' which defines bio- Minimize hypertension,
Prevent rejection, prolong
equivalence standards and exceptions. One important kidney damage, GI effects, life of graft & patient exception involves CDDs, which are defined as ‘drugs diabetes, infection, cancer.
where small differences in dose and blood levels may lead to serious therapeutic failures and/or serious adverse reac- tions which may be life-threatening, or result in hospi- talization, persistent disability or incapacity, or death.' A CDD has a narrow therapeutic range where blood levels, clinical response and toxicity are closely linked. Health Canada has designated several drugs within this category, includ- Between Efficacy and Toxicity ing the immunosuppressant transplant drugs: cyclosporine (Neoral®), sirolimus (Rapamune®), and tacrolimus (Prograf®). In the ‘Guidance Document,' Health Canada has not established guidelines or standards for generic substitution What are the unique patient considerations for
of CDDs. However, a number of European regulatory bod- ies have created exceptions for tacrolimus. For example, in With the advent of newer drug therapies, one-year kidney Spain and the United Kingdom, oral generic formulations graft survival rates have improved, from 65% in 1975 to of tacrolimus are branded by name. Prescribing and dis- over 97% in 2009 (Canadian Organ Replacement Register, pensing should be done by brand name only to minimize 2011, CIHI). Success in transplantation relies on manag- the risk of inadvertent switching between products, which ing the body's immune response to optimize graft survival. has been associated with reports of toxicity.1-4 In Denmark, The usual approach is ‘triple therapy' for long-term main- generic substitution of oral tacrolimus is not allowed.5 tenance, including one of the following CDDs: Prograf® Norway now recommends that tacrolimus should not be (tacrolimus immediate release capsules), Advagraf® (tacro- substitutable at pharmacies. The Italian Medicines Agency limus extended release capsules) or Neoral® (cyclosporine issued a statement ‘that oral tacrolimus may not be inter- capsules and solution). The goal for optimizing therapy in changed without careful therapeutic monitoring under these patients is to find the appropriate balance between the strict supervision of a transplant specialist, and the drug efficacy and toxicity while preventing graft rejection. chemist should always dispense the commercial name as "The appropriate management of immunosuppressive prescribed by the physician'.6 drug therapy is critical to success in transplantation. The level There are also a number of Canadian examples for excep- of the drug in blood is used as a surrogate marker to gauge tion approval processes of critical dose immunosuppressant an individual patient's level of immunosuppression. Drugs transplant drugs, two of which are in Ontario and Quebec.
like Prograf® (tacrolimus) require close blood level monitor- In Ontario, the Special Drugs Program (SDP) covers the ing to ensure that the level of drug in the blood remains in full cost of certain outpatient drugs used to treat a number the desired target range. As the therapeutic range is narrow, of serious conditions. Included in the program is Neoral® changes in exposure may compromise patient outcomes," (cyclosporine) for treatment in solid organ or bone marrow says Jennifer Harrison, Pharmacy Clinical Site Leader with transplant if prescribed by a physician on the medical staff the University Health Network in Toronto.  of a Group O hospital, under the Public Hospitals Act.7 Acute kidney graft rejection may be a consequence of inap- In Quebec, Liste de médicaments published by the Régie propriate dosing, which may result in hospitalization, more de l'assurance maladie du Québec (RAMQ) includes cyclo- intensive intravenous immunosuppressive therapy, infec- sporine as a narrow therapeutic index drug (Schedule VII). tion, possible shortening of graft life or actual loss of graft Cyclosporine is therefore exempt from the province's low- function. The patient may also experience other complica- est cost available policy and Neoral® is reimbursed when tions or adverse effects from intensified therapy. Unintended prescribed by a physician.8 consequences for a plan sponsor may include an increase in Canada's provincial drug plan and private drug benefit disability costs and absenteeism for its plan member.
managers can utilize these experiences for other critical dose immunosuppressant transplant drugs when generics What are the recommendations of healthcare
become available. The importance is paramount because professionals for the prescribing and dispensing of
as of this writing it is expected Health Canada will approve critical dose drugs?
generic oral tacrolimus in the near future without such In light of the potential problems with generic substitution exceptions in place.
of CDDs, in particular in relation to unsupervised switches in immunosuppressive transplant therapy, healthcare pro- fessionals through advisory meetings, consensus confer- In a number of circumstances, the ences and surveys in the U.S., Europe, and Canada, have uncontrolled switching from brand to made the following recommendations:9-11 generic drug, or between different generic 1. Generic immunosuppressant use should be approached
formulations, may result in less optimal with caution.
treatment. Plan sponsors must balance the
2. If a generic is used, it should be prescribed from the day
of transplantation rather than switching when there is need for cost containment while having plan
high risk of graft rejection. members receive appropriate treatment
3. Formulation switches should be initiated only by phy-
by ensuring processes are in place for plan sicians; repetitive switches (between generic drugs or design exceptions.
between generics and the brand drug) should be avoided. 4. Patient education is essential. Patients should be infor-
med when switches occur.
clinical monitoring is required with any dose or product 5. Following any formulation switch, blood level monitoring
change, whether a switch from a brand to a generic drug, or should occur until stable immunosuppression is established.
from one generic drug product to another. In the setting of 6. More extensive data should be made available regarding
mandatory generic substitution, where drug product selec- the efficacy and safety of generic immunosuppressive tion is defined by the insurer and dispensed at the retail therapy for proper use and monitoring.
pharmacy, the prescriber may not be informed of drug product switches. Without timely prescriber notification, Harrison further states that, "There is widespread con- the requisite monitoring cannot be performed, which poses sensus in the transplant community that blood level and a significant patient safety concern." The Case: Substituting Critical Dose Immunosuppressant Transplant Drug Generic A for Brand
On leaving hospital, patient receives a After two months, patient's pharmacist two-month supply of branded medications
dispenses Generic A in place of his
does not mean
ation 100%
Blood level profile of patient's Generic A is bioequivalent to patient's branded medication branded medication The Case: Substituting Critical Dose Immunosuppressant Transplant Drug Generic A and Generic B
(Generics may not be bioequivalent with each other) After six months, patient's pharmacist Patient may be switching between drugs
dispenses Generic B in place of Generic A
that are not bioequivalent with each other May have variability
in blood levels between
ation 100%
ation 100%
= generics. Variability
with critical dose immu-
plant drugs is associated
with poor outcomes
Generics A and B are both Generic B may not necessarily be bioequivalent to patient's branded medication bioequivalent to Generic A "There is widespread consensus in the transplant community that blood level and
clinical monitoring is required with any dose or product change, whether a switch from a brand to a generic drug, or from one generic drug product to another. In the setting of mandatory generic substitution where drug product selection is defined by the insurer and dispensed at the retail pharmacy, the prescriber may not be informed of drug product switches…"—Jennifer Harrison, University Health Network been approved as safe for use by Health Canada, uncon- trolled substitution for these drugs may be unsafe. Below are some suggestions for managing CDD immu- nosuppressant transplant therapy for plan sponsors, plan members, and healthcare professionals: 1. Drug substitution exception policies should be imple-
mented for these drugs in certain circumstances, such as switching after a patient is stabilized.
a. Establish standardized proactive exception pro-
cesses at the drug plan design level for these drugs (prior to prescribing by a physician).
2. Formulation switches should be initiated only by physi-
cians experienced in transplantation; repetitive switches (between generic brands) should be avoided.
a. Following any formulation switch, blood level
What are the new management challenges and
monitoring MUST occur until stable immuno- action plans for integrating generic transplant drugs
suppression is established.
into Canadian drug benefit plans?
3. Pharmacists must inform patients and physicians if
With the anticipated Health Canada approval of generic oral switches occur.
tacrolimus, and with the knowledge that additional critical 4. Create proactive mechanisms to ensure that blood levels
dose drugs used in immunosuppressive transplant therapy will likely have generic versions available in future years, it is imperative that guidelines, standards and policies are Due to the complexity and immediacy of the current sit- established (public and private) for these drugs to balance uation with possible uncontrolled mandatory substitution cost, clinical response, and positive patient outcomes. of generic critical dose drugs in transplant therapy, plan The challenges appear to be complex and do not fit into the sponsors should proceed with proactive plan design excep- standard practice of mandatory generic substitution plans, tion and monitoring changes to ensure appropriate ther- where exception processes for using critical dose drugs apy and safety for their plan members. are primarily reactive (i.e., at the pharmacy), thus poten- Steven Semelman, B.Sc.Pharm., Pharm.D., is currently tially delaying therapy. There needs to be an understand- Executive Director at Mapol Inc. Dr. Semelman has over 25 ing from all stakeholders that while generic formulations of years' experience in the public and private healthcare sectors critical dose immunosuppressant transplant drugs have holding both clinical and executive positions. REFERENCES1 Nota Informativa. Ministerio de Sanidad y politica Social. Tacrolimus. Apr 4, 2009.
2 British National Formulary. Immunosuppressant therapy. http://www.bnf.org.uk. Sep 15, 2008.
3 Commission on Human Medicines Press Release. Recommendations for prescribing and dispensing of all tacrolimus products. May 24, 2012.
4 Commission on Human Medicines Letter to Health Professionals on oral tacrolimus. May 23, 2012.
5 Danish Health and Medical Authority. Licensing of medicines notification on termination of generic substitution for oral medicines containing cyclosporine and tacrolimus. 6 Italian Medicines Agency (AIFA). Memorandum on measures designed to reduce the risk of therapeutic errors during treatment with oral formulations of tacrolimus. 7 Ontario Health Insurance Act. R.R.O. 1990, Regulation 552. Consolidated Jul 2013. Section 8(2). http://www.e-laws.gov.on.ca/html/regs/english/elaws_regs_900552_e.htm#BK5 8 Liste de medicaments-La Régie de l'assurance maladie du Québec (RAMQ). Schedule VII. Ed 43. Jun 2013. 9 Uber et al., Generic Drug Immunosuppression in Thoracic Transplantation: An ISHLT Educational Advisory. Consensus Statement. J Heart Lung Transplant. 2009;28:655-60.
10 European Society for Organ Transplantation (ESOT) Advisory Committee on Generic Substitution of Immunosuppressive Drugs. Mar 15, 2011.
11 Harrison et al. Generic Immunosuppression in Solid Organ Transplantation: A Canadian Perspective. Transplantation. 2012; 93(7):657-665.
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Source: http://mapol.ca/index.php/latest-news/item/download/176_24af8f077f21c4e016bc40eb12778589