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Pierre Blier, MD, Ph.D Endowed Chair and Director Mood Disorders Research Institute of Mental Health Research University of Ottawa, Ontario Canada Research Chair, Psychopharmacology The Use of Generic Medicines: A focus on Mental Health

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Page 1: Generics UOttawa2015

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

Page 2: Generics UOttawa2015

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

Page 3: Generics UOttawa2015

Total Presciptions in Canada:Brand vs Generic-2009 data

Blier, Can J Diagnosis, September 2012

Page 4: Generics UOttawa2015

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)

Page 5: Generics UOttawa2015

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

Page 6: Generics UOttawa2015

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

Page 7: Generics UOttawa2015

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

Page 8: Generics UOttawa2015

Pharmacokinetic profile

• C max: Maximum plasma concentration• AUC: Area under the curve• Tmax: Time to achieve Cmax

Page 9: Generics UOttawa2015

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

Page 10: Generics UOttawa2015

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

Page 11: Generics UOttawa2015

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

Page 12: Generics UOttawa2015

•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

Page 13: Generics UOttawa2015

• 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

Page 14: Generics UOttawa2015

Plasma levels of Budeprion XL

Jefferson, Psychiatric Times 26(5): 1-8, 2012

Cmax: equivalentAUC: equivalentTmax: different

Page 15: Generics UOttawa2015

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

Page 16: Generics UOttawa2015

Bioinequivalence of Budeprion 300 mg

Woodcock et al, New Eng J Med, Dec 24, 2012

Page 17: Generics UOttawa2015

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%

Page 18: Generics UOttawa2015

•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

Page 19: Generics UOttawa2015

•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

Page 20: Generics UOttawa2015

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

Page 21: Generics UOttawa2015

More generics: a 2012 update

Blier, Can J Diagnosis, September 2012

Page 22: Generics UOttawa2015

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.

Page 23: Generics UOttawa2015

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

Page 24: Generics UOttawa2015

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

Page 25: Generics UOttawa2015

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

Page 26: Generics UOttawa2015

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)

Page 27: Generics UOttawa2015

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…

Page 28: Generics UOttawa2015

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

Page 29: Generics UOttawa2015

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

Page 30: Generics UOttawa2015

Example of an intrapatient variabilityin a single patient

Kluznick et al, J Clin Psychiat 62(suppl 5): 14-17, 2001

Page 31: Generics UOttawa2015

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

Page 32: Generics UOttawa2015

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

Page 33: Generics UOttawa2015

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)

Page 34: Generics UOttawa2015

• 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

Page 35: Generics UOttawa2015

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

Page 36: Generics UOttawa2015

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)

Page 37: Generics UOttawa2015

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

Page 38: Generics UOttawa2015

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

Page 39: Generics UOttawa2015

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

Page 40: Generics UOttawa2015

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

Page 41: Generics UOttawa2015

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

Page 42: Generics UOttawa2015

Different sizes of granules

Effexor XR 75

Novo-venlafaxine XR 75

Page 43: Generics UOttawa2015

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

Page 44: Generics UOttawa2015

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)

Page 45: Generics UOttawa2015

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

Page 46: Generics UOttawa2015

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

Page 47: Generics UOttawa2015

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