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Pierre Blier, MD, Ph.DEndowed Chair and DirectorMood Disorders ResearchInstitute of Mental Health ResearchUniversity of Ottawa, OntarioCanada Research Chair, Psychopharmacology
The Use of Generic Medicines:A focus on Mental Health
Disclosures
Interest Name of organisation
Grants / research support
Astra Zeneca, Bristol Myers Squibb, Canadian Institute of Health Research (CIHR), Forest, Janssen, Lundbeck, Merck, National Institute of Mental Health (NIMH-USA), Roche
Advisory board / consultantAstra Zeneca, Bristol Myers Squibb, Eli Lilly, Euthymics, Lundbeck, Otsuka, Pfizer, Servier, Shire, Sunovion, Takeda
Total Presciptions in Canada:Brand vs Generic-2009 data
Blier, Can J Diagnosis, September 2012
Approval process for Generic drugs*
A test drug must:
1.Contain the same active ingredients as the reference drug, although inactive ingredients may vary
2.Be identical to the reference drug in strength, dosage form and route of administration
3.Have the same use indications
4.Be bioequivalent to the reference drug
5.Meet the same batch requirements for identity, strength, purity, and quality
6.Be manufactured under the same strict FDA standards of Current Manufacturing Practice Regulations required for reference products
* US FDA standards (similar to Health Canada standards)
Approval process for Generic drugs
The therapeutic effectiveness is based on the bioequivalence study*
•Rationale: If identical plasma concentration-time profiles in human, there is no need to demonstrate that the 2 identical dosage forms will exhibit a difference in safety and efficacy
•No proof needed for therapeutic equivalence No clinical trial required
* Only one positive study is required
Subjects in bioequivalence studies
•Number of subjects: FDA 24-36; Canada 12
•Normal-non-patient
• In good health
•Non-smoking
•Young, generally 18-40 year old
•Males
•Goal is to minimize variations
CROSS-OVER DESIGN
•Each subject is his own control
•To diminish inter-patient variability
•Plasma levels of drug measured over time
Generic Generic
Reference Reference
SEQUENCE 1 SEQUENCE 2
Pharmacokinetic profile
• C max: Maximum plasma concentration• AUC: Area under the curve• Tmax: Time to achieve Cmax
Bioequivalence
In most countries (US + Europe)Two products are bioequivalent if:
1. The 90% Confidence Interval (CI) of the relative mean AUC of the test to reference product should be within the 80-125%
2. The 90% Confidence Interval (CI) of the relative mean of Cmax of the test to reference product should be within the 80-125%
* In Canada, no 2 is changed for• The relative mean of Cmax is within the 80-125% range
No standard related to 90% CI for Cmax unless a drug has a narrow therapeutic window or
could cause death (i.e. not for antidepressants or lithium)
• Manufacturers of innovator drug must not show a greater than 5 % variation.
• The 80-125% Tmax should be present as well, but not required
COMPARISON FOR REGISTRATION :GENERICS VS NEW DRUGS
Table 1. Comparison of bioequivalence testing and clinical testing
RequirementsBioequivalence
Testing
Clinical Research Standards for New
Drugs
Pharmacokinetic Measures
Steady-state conditions No Yes, normally
Longitudinal changes No Yes
Variability analysis No Yes
Patient characteristics
Transplant recipients No Yes
Patients with comorbidities No Yes
Pediatric patients No Yes
Differences between sexes Sometimes Yes
Differences between races No Yes, normally
Specialized tests
Fasting/ fed Pharmacokinetic testing
No Yes
Efficacy and safety tests No Yes
Unsuitability of healthy volunteers for psychoactive drugs: tolerance in patients vs
healthy volunteers
Cutler et al, J Clin Psychiat 62 (suppl 5): 10-13, 2001
•Every batch must meet specific requirements
•Content of active ingredient, purity, hardness, and dissolution
•A Carvedilol spot check of 35 products of 20 manufacturers from 19 countries :
17/35 failed the specifications 3 were outside the 95-105% brand content 1 had excess impurities (>0.3%) 11 had incorrect tablet hardness (outside 30-70 N) 9 had inadequate dissolution 7 failed two tests
• The three strengths of the brand met all requirements
GENERICS AND BRANDS:PHYSICOCHEMICAL REQUIREMENTS
Smith et al, Curr Med Res Opin 22: 709-720, 2006
• In November 2012, the FDA recalled quetiapine 25 mg tablets produced by Dr Reddy’s Laboratories (DRL)
•This happened after the FDA enforcement group carried out a 3-month stability test
•There was an out of specification (OOS) observation: it failed a dissolution test requirement
•Comment from a company representative:
“It was a very small batch and has no significance what so ever on Dr Reddy’s sales of Quetiapine Fumarate tablets in the US market” (!)
•Recall of RIVA, COBALT, SANIS-quetiapine because of trace amount of clindamycine (May 17, 2013)
GENERICS AND BRANDS:PHYSICOCHEMICAL REQUIREMENTS
Plasma levels of Budeprion XL
Jefferson, Psychiatric Times 26(5): 1-8, 2012
Cmax: equivalentAUC: equivalentTmax: different
THE FDA REMOVED BUDEPRION XL 300 MG FROM THE US MARKET
•There were 85 cases of adverse events, including 78 relapses most regained their benefit upon returning to the brand
•The FDA requested TEVA to repeat their bioequivalence study and to include patients
•After TEVA failed to comply, the FDA did their own study in 24 healthy volunteers and it was found to be bioinequivalent (data not available)
• In September 2012, Budeprion XL 300 mg was removed from the market
•All other generic companies producing bupropion were asked to provide new bioequivalence studies
Bioinequivalence of Budeprion 300 mg
Woodcock et al, New Eng J Med, Dec 24, 2012
THE INTRODUCTION OF TEVA-QUETIAPINE XR IN CANADA
• In the product monograph:
The plasma-concentration curves are those of Seroquel XR, not those of the TEVA generic (p. 45/80)
There is no data provided for the 300 mg tablets, which has been most often used in the studies in unipolar and bipolar depression (p. 54/80, 200 mg data; p. 55/80, 400 mg data)
For the 400 mg tablet, the Cmin not the Cmax is provided and the t1/2 is provided in all tables except for the 400 mg tablet
Cmax 90 Confidence Intervals (CI) are required in the USA & Europe, not Canada, but here are some variations:
The lower Cmax CI during fasting the 50 mg tablet is at 77% The higher Cmax CI during fasting for the 200 mg tab is at 134% The higher Cmax CI in the fed cond. for the 200 mg tab is at 128%
•Production of a medication is a complex procedure involving several steps (some intermediates may even be explosive!)
•Possibility of not eliminating impurities at certain steps
The tryptophan catastrophe in the USA in the 1990s A contaminant was left behind from a Japanese company A purification step was omitted to increase production yield 36 deaths, one only in Canada
Numerous cases of permanent neurological sequelae due to the eosinophilia-myalgia syndrome
GENERICS AND BRANDS:SYNTHESIS PROBLEMS
Smith et al, Curr Med Res Opin 22: 709-720, 2006
•Omission and substitution of ingredients have been reported:
Report markedly different in vitro dissolution rates of different preparations of carbamazepine constant-release (CR)
Two batches of drastically rapid dissolving rates of one of two TEVA generics (5 and 14% vs 65%)
The ingredient providing the slow-release property, methyl cellulose, was absent in the two delinquent batches
GENERICS AND BRANDS:PRODUCTION PROBLEMS
Gervasoni, Clin Ther 26 : 801-802, 2004
WHICH ONE(S) ARE YOU TAKING FROM MONTH TO MONTH?WHICH ONE(S) ARE YOU TAKING FROM MONTH TO MONTH?
(Health Canada,2006)
• PHL-citalopram, • DOM-citalopram,• Citalopram-40, • Citalopram-20, • Gen-Citalopram, • Ratio-Citalopram,• Sandoz Citalopram, • Novo-Citalopram, • CO Citalopram, • PMS-Citalopram,• APO-citalopram, • RIVA-citalopram
• PHL-citalopram, • DOM-citalopram,• Citalopram-40, • Citalopram-20, • Gen-Citalopram, • Ratio-Citalopram,• Sandoz Citalopram, • Novo-Citalopram, • CO Citalopram, • PMS-Citalopram,• APO-citalopram, • RIVA-citalopram
More generics: a 2012 update
Blier, Can J Diagnosis, September 2012
CONFIDENCE ABOUT TAKING THE SAME MEDICATION FROM MONTH TO MONTH CONFIDENCE ABOUT TAKING THE SAME MEDICATION FROM MONTH TO MONTH
Kesselhelm et al. Ann Int Med 161: 96-103, 2015: Post MI, non-persistence of medsdue to pill color change 34% and pill shape 69% in 3286 patients vs controls.
COMPARATIVE EFFECTIVENESS AND COSTS OF GENERIC AND BRAND-NAME
GABAPENTIN IN NEUROPATHIC PAIN
•1,369 EMR (400 brand, 969 generics)
•Persitence: 7.3 vs 6.3 months
•Adherence: 87% vs 81%
•Adjusted costs: 1,057€ vs 1,267€ (medical visits + purchase costs)
•Higher reduction of pain: by 8%
Sicras-Mainar et al. ClinicoEconomics and Outcomes Research 7:299-312, 2015
Epilepsy(Mood Stabilizers)
Antiepileptic drugs may have a narrow therapeutic index
•Especially with hard to control patients
• If change for generic With 80% dose Subtherapeutic Seizures (injury,
driver’s licence, death)
With 125% dose Toxic level Adverse events
Epilepsy
American Academy for Neurology Recommendations on generic substitution
•Physician should have complete autonomy in prescribing AEDs in epilepsy (ie pharmacy should have consent from patient + physician prior to generic substitution)
British Association for Epilepsy
•Epilepsy patients should receive the same version of AEDs when they get a repeat prescription unless their clinician prescribes otherwise
Transplantation
Cyclosporine is a major anti-rejection drug
Important disparity between different formulations of cyclosporine
Generic cyclosporine yielded to an 11% lower kidney graft survival over one year in 397 patients when compared to the control group on the original medication
Taber et al, Transplantation 80: 1633-1635, 2005Qazi et al, Clin Transplant 20:313-317, 2006www.ctstransplant.org (2001)
Oral Contraceptives: need we say more?
The recent inadvertent inclusion of a week of placebo in the Alesse generic (Apotex) could have been a problem…
ONGOING ISSUE WITH APOTEX IN CANADA AND THE USA
Canadian health minister has banned the import of all drugs and ingredients made in two Apotex plants in Bangaglore, India after two unanswered requests
Apotex facilities also failed numerous inspections, revealed through FDA inspection reports published online, but the Canadian findings remained confidential
In the fall of 2014, 65442 bottles of candesartan were recalled in the USA under FDA orders because of impurities
BMJ 2014;349:G7380
THE EXAMPLE OF LITHIUMTHE EXAMPLE OF LITHIUM
• Stabilization of a patient at 1.0 mEq/L using a preparation that is at 125% of the standard
• A switch to a preparation that provides a plasma level 80% of the standard would lead to a 0.5 mEq/l and possibly a destabilization
• Stabilization of a patient at 1.0 mEq/L using a preparation that is at 80% of the standard
• A switch to preparation that provides a plasma level of 125% of the standard would lead to a 1.5 mEq/l and a possible renal/thyroid toxicity
• Stabilization of a patient at 1.0 mEq/L using a preparation that is at 125% of the standard
• A switch to a preparation that provides a plasma level 80% of the standard would lead to a 0.5 mEq/l and possibly a destabilization
• Stabilization of a patient at 1.0 mEq/L using a preparation that is at 80% of the standard
• A switch to preparation that provides a plasma level of 125% of the standard would lead to a 1.5 mEq/l and a possible renal/thyroid toxicity
Example of an intrapatient variabilityin a single patient
Kluznick et al, J Clin Psychiat 62(suppl 5): 14-17, 2001
CLOZAPINE AND SCHIZOPHRENIACLOZAPINE AND SCHIZOPHRENIA
• Report of cases of relapses in patients with schizophrenia following a substitution to a generic
• Additional costs with relapse: hospitalisation, lodging, social services
• Worsening of symptoms without a relapse in patients switched to a generic without a full relapse
• Report of cases of relapses in patients with schizophrenia following a substitution to a generic
• Additional costs with relapse: hospitalisation, lodging, social services
• Worsening of symptoms without a relapse in patients switched to a generic without a full relapse
Divergent results of two double-blind switch studies with Clozaril
Oluboka et al, J Clin Pharmacol 50: 531-535, 2010
•40 patients; 6-month duration, Gen-clozapine
•No difference in plasma levels
•No major clinical differences
Divergent results of two double-blind switch studies with Clozaril
Kluznik et al, J Clin Psychiat 62 (Suppl5):14-17, 2001
•45 patients, 5-week baseline, 2 X 8 weeks, cross-over, ZGP-clozapine
•5/24 relapsed while on generic and 0/21 on Clozaril
•3 had not regained their pre-relapse functional level
•Overall, 16 patients deteriorated, 14/16 while on generic
•Significant but minor changes in doses (610 mg vs 630 mg) and plasma levels (238 vs 216 ng/ml) for brand vs generic (respectively)
• Suspicion and hostility towards an unfamiliar pill
- Nuss, CNS Drugs 18: 769-75, 2004
• Canadian perspective:
Switching a patient to a generic- Annual economy of 1241$ if the patient does
not relapse
- Cost of 9823$ if the patient relapses
• Suspicion and hostility towards an unfamiliar pill
- Nuss, CNS Drugs 18: 769-75, 2004
• Canadian perspective:
Switching a patient to a generic- Annual economy of 1241$ if the patient does
not relapse
- Cost of 9823$ if the patient relapses
CLOZAPINE AND SCHIZOPHRENIACLOZAPINE AND SCHIZOPHRENIA
Layton et al, Current Medical Research & Opinion 20: 453-459, 2004
Celexa vs generic citalopram
Case series from McMaster University 20 patients
• Switched from Celexa to generic citalopram (same dose) Gen-citalopram (n=18), Apo-citalopram (n=1), CO-citalopram
(n=1)
• Unknowingly switched
• Re-emergence of anxiety symptoms Mean time 3.4 weeks for re-emergence
– OCD (n=11), PDAG (n=5), Social Phobia (n=3), PTSD (n=1)
– 10 patients were taking other medications ( Ø Δ )
• All 20 patients responded to a switch back to Celexa Mean time 3.8 weeks to re-established previous treatment
response with a change back to Celexa (n=18 back at same dose)
Van Ameringen et al, J Psychopharmacol, 2007
Study Designs
Chenu et al, J Clin Psychiat 70: 958-966, 2009
Day 1
- Blood sample (t0)- 1st medication - Blood samples (t 2,3,4,5 and 6)
Last medication
1 Blood sample
Wash-out Period (8 days)
Day 4
Day 5
Day 1
Day 4
Day 5
- Blood sample (t0)- 1st medication - Blood samples (t 2,3,4,5 and 6)
Last medication
1 Blood sample
B- Venlafaxine
Day 1
- Blood sample (t0)- 1st medication - Blood samples (t 2,3,4,5 and 6)
Wash-out Period (14 days)
Day 7
Day 1
Day 7
- Blood sample (t0)- 1st medication - Blood samples (t 2,3,4,5 and 6)
A- Citalopram
- Blood sample (t0)- 1st medication - Blood samples (t 2,3,4,5 and 6)
- Blood sample (t0)- 1st medication - Blood samples (t 2,3,4,5 and 6)
Levels of citalopram with a single dose
0 60 90 120 150 180
0
5
10
15
20
25
30
Pla
sma
Con
cent
ratio
n, n
g/m
L
Time, min
Generic: Gen-citalopram
Brand
Chenu et al, J Clin Psychiat 70: 958-966, 2009
Levels of citalopram at steady-state and after an additional dose
Pla
sma
Con
cent
ratio
n, n
g/m
L
0 60 90 120 150 180
0
10
20
30
40
50
60
70
80
80
Time, min
Gen-citalopramBrand
Chenu et al, J Clin Psychiat 70: 958-966, 2009
Levels of venlafaxine
0 120 180 240 300 360 Day 5
0
10
20
30
40
50
60
70
Pla
sma
Con
cent
ratio
n, n
g/m
L
Time, min
******
***Generic: novo
Brand
+51%
Chenu et al, J Clin Psychiat 70: 958-966, 2009
Levels of O-desmethyl-venlafaxine
Pla
sma
Con
cent
ratio
n, n
g/m
L***
0 120 180 240 300 360 Day 5
0
10
20
30
40
50
60
70
80
Time, min
***
***
*
Generic: novo-ven
Brand
Chenu et al, J Clin Psychiat 70: 958-966, 2009
Effexor vs novo-venlafaxine
• 3 X more side effects reported with novo-venlafaxine• Implications for long-term compliance
Chenu et al, J Clin Psychiat 70: 958-966, 2009
Different sizes of granules
Effexor XR 75
Novo-venlafaxine XR 75
COMPARATIVE EFFECTIVENESS AND COSTS OF GENERIC AND BRAND-NAME
VENLAFAXINE IN ANXIETY
•841 EMR (370 brand, 471 generics)
•Persitence: 8.8 vs 8.1 months
•Adherence: 82% vs 79%
•Adjusted costs: 928€ vs 1,110€ (medical visits + purchase costs)
•Higher reduction of pain: by 13%
Sicras-Mainar et al. ClinicoEconomics and Outcomes Research 7:299-312, 2015
Costs Evaluation
Balance between
•Saving costs with generic drugs
•Costs of health care resources if a deterioration or a relapse occurs*
Consultation
Hospitalization
Adverse events
* For lamotrigine, the costs was 1,385 CAN$ higher per person per year when compared to Lamictal (LeLorier et al, Cur Med Res Opin 24: 1069-81, 2008)
If there is a clinical difference:
When therapeutic failure with generic, we question:
•Compliance
•Wrong drug and wrong dose
•Drug-drug interaction
•Natural course of the disease
Physicians do not report
•Too busy
•Most often overlooked by authorities (i.e. Budeprion)
•Difficult to prove unless a re-challenge is carried out
Solutions for Canada
Have Health Canada apply the CI 90 to Cmax as in the USA and Europe
Regulatory agencies should do spot checks for physicochemical properties and fine delinquents: self-supporting financially
To guarantee that Bioequivalence = Clinical Equivalence
•Bioequivalence studies Include the type of population treated
•Clinical trials for certain medications
Pharmacists should inform patient + physician for a generic substitution for all medications
Take-home messages The use of a generic in a non-problematic condition
which acts rapidly is not a problem (i.e. ibuprofen)
If re-emergence of signs or symptoms without a specific cause, assess compliance
If compliance has been good, question if there was a change to a generic, and which one?
Consider all risks and benefit (major financial savings financial upon purchasing) before allowing a switch for each type of medication