The Use of Generic Medicines:

A focus on Mental Health

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

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 / consultant

Astra 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

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
Bioequivalence
Testing

Clinical Research
Standards for New
Drugs

Steady-state conditions

No

Yes, normally

Longitudinal changes

No

Yes

Variability analysis

No

Yes

Transplant recipients

No

Yes

Patients with comorbidities

No

Yes

Pediatric patients

No

Yes

Differences between sexes

Sometimes

Yes

Differences between races

No

Yes, normally

No

Yes

No

Yes

Requirements
Pharmacokinetic
Measures

Patient characteristics

Specialized tests
Fasting/
fed Pharmacokinetic testing

Efficacy and safety tests

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

GENERICS AND BRANDS:

PHYSICOCHEMICAL REQUIREMENTS

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

Smith et al, Curr Med Res Opin 22: 709-720, 2006

GENERICS AND BRANDS:

PHYSICOCHEMICAL REQUIREMENTS
In November 2012, the FDA recalled quetiapine 25 mg tablets
produced by Dr Reddys Laboratories (DRL)

This happened after the FDA enforcement group carried out a 3month 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 Reddys sales
of Quetiapine Fumarate tablets in the US market (!)

Recall of RIVA, COBALT, SANIS-quetiapine because of trace

amount of clindamycine (May 17, 2013)

Plasma levels of Budeprion XL

Cmax:
AUC:
Tmax:

equivalent
equivalent
different

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

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 TEVAQUETIAPINE 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 t 1/2
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%

GENERICS AND BRANDS:

SYNTHESIS PROBLEMS

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
Smith et al, Curr Med Res Opin 22: 709-720, 2006

GENERICS AND BRANDS:

PRODUCTION PROBLEMS

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

Gervasoni, Clin Ther 26 : 801-802, 2004

WHICH ONE(S) ARE YOU TAKING

FROM
MONTH TO MONTH?

PHL-citalopram,
DOM-citalopram,
Citalopram-40,
Citalopram-20,
Gen-Citalopram,
Ratio-Citalopram,
Sandoz Citalopram,
Novo-Citalopram,
CO Citalopram,
PMS-Citalopram,
APO-citalopram,
RIVA-citalopram
(Health Canada,2006)

More generics: a 2012 update

Blier, Can J Diagnosis, September 2012

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 meds
due 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,

drivers 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, 2005

Qazi et al, Clin Transplant 20:313-317, 2006
www.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 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

Example of an intrapatient variability

in a single patient

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

CLOZAPINE 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

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)

CLOZAPINE AND SCHIZOPHRENIA

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

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 ( )

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
A- Citalopram

- Blood sample (t0)

- 1st medication
- Blood samples
(t 2,3,4,5 and 6)

Day
7

Day
1

Day
7

Day
1

Wash-out Period (14 days)

- 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)

- Blood sample (t0)

- 1st medication
- Blood samples
(t 2,3,4,5 and 6)

B- Venlafaxine
Day
1

Day
4

Last
medication
- Blood sample (t0)
- 1st medication
- Blood samples
(t 2,3,4,5 and 6)

Day
1

Day
5

1 Blood sample

Wash-out Period
(8 days)

Day
4

Day
5

Last
medication
- Blood sample (t0)
- 1st medication
- Blood samples
(t 2,3,4,5 and 6)

1 Blood sample

Chenu et al, J Clin Psychiat 70: 958-966, 2009

Levels of citalopram with a single dose

30

Brand
Generic: Gen-citalopram

Plasma Concentration, ng/mL

25

20

15

10

0
0

60

90

120

150

180

Time, min

Chenu et al, J Clin Psychiat 70: 958-966, 2009

Levels of citalopram at steady-state and

after an additional dose
80

Plasma Concentration, ng/mL

80

Brand
Gen-citalopram

70
60
50
40
30
20
10
0
0

60

90

120

150

180

Time, min

Chenu et al, J Clin Psychiat 70: 958-966, 2009

Levels of venlafaxine
70

Plasma Concentration, ng/mL

60

Brand
Generic: novo

***
***

50

+51%

***

40

30

20
10
0
0

120

180

240

300

360

Day 5

Time, min

Chenu et al, J Clin Psychiat 70: 958-966, 2009

Plasma Concentration, ng/mL

Levels of O-desmethyl-venlafaxine
***

80

Brand

70

Generic: novo-ven

60

***
***

50

40
30
20
10
0
0

120

180

240

300

360

Day 5

Time, min

Chenu et al, J Clin Psychiat 70: 958-966, 2009

Effexor vs novo-venlafaxine
3 X more side effects reported with novovenlafaxine
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: selfsupporting 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