Rationale for Study Drug Selection
Levetiracetam
Levetiracetam is a second-generation antiepileptic drug approved for the adjunctive treatment of
partial-onset seizures [1]. As a drug class, antiepileptic drugs are characterized by narrow
therapeutic ranges and/or pharmacokinetic variability. This characteristic means switching to the
generic may lead to changes in the AE profile or overall efficacy, a concern also potentially
associated with biosimilars. For example, generic versions of this small-molecule drug have
shown variable therapeutic equivalence to the branded reference product [2,3], which may lead
to poor clinical outcomes [4]. Loss of drug efficacy in epileptic patients switching from branded
to generic levetiracetam, as measured by an increased incidence of seizures, has been observed
[3]. Levetiracetam is considered a narrow therapeutic index (NTI) drug by certain insurers,
including Medicaid [5]. For levetiracetam, the drug names containing the name “KEPPRA” and
“LEVETIRACETAM” were considered as branded and generic, respectively.
Enoxaparin Sodium
Enoxaparin sodium, a low molecular weight heparin (LMWH), is an injectable anticoagulant
with a complex chemical structure composed of a mixture of oligosaccharides (small sugar
chains) that vary in structure and size [6,7]. The European Medicines Agency considers the
follow-on version of enoxaparin sodium to be a biosimilar, because of the potential for
considerable heterogeneity in the structure-effect relationship [8]. Similar to biologics, LMWHs
are sensitive to source materials and manufacturing processes. The manufacturing process can
affect a product’s molecular and, consequently, clinical attributes [9]. Further, the relationship
between pharmacodynamic evidence and clinical outcomes for LMWHs is not clear [10]. For
enoxaparin sodium, the drug names containing the name “LOVENOX” and “ENOXAPARIN
SODIUM” were considered as branded and generic, respectively.
Data Descriptions
The FAERS database contains AEs and medication errors reported voluntarily by health care
professionals, patients, and other individuals, as well as mandatorily reported from product
manufacturers. FAERS data were used to estimate monthly reported AEs attributed to the
branded or generic products of interest. Minimum data elements for a FAERS submission are an
identifiable patient, an identifiable reporter, a reaction or event, and a suspect drug [11].
Information about the suspect drug would preferably include, at minimum, both the proprietary
name (when a product uses a proprietary name) and the nonproprietary name; however, FAERS
reports are accepted for processing if only one of these identifiers (brand or nonproprietary
name) is reported.
Additional Methodologic Detail
Continuous possession was determined based on the number of days of supply of the branded or
generic drug, allowing for up to a 30-day gap, and ended with discontinuation of the branded or
generic drug or a switch from one drug type (branded or generic) to the other. If a patient was in
simultaneous possession of both the branded and generic drug, then it was assumed that the
patient finished the days of supply of the earliest filled product before switching to the other
product. AE claims filed while a patient was in continuous possession of the branded drug or
generic drug were attributed to the branded drug or generic drug, respectively. AEs filed during
periods of non-continuous possession were excluded.
To capture MarketScan claims AEs in the way in which those AEs would have been reported to
FAERS, only 1 AE per patient per AE category was counted for the time period when a patient
had evidence of receiving only the branded or generic drug. If a patient switched from the brand
to generic (or vice versa) and experienced an AE in the same category as an AE experienced
while on the previous product, however, that new AE was counted. Patient-level counts of
branded- or generic-attributed AEs were then summed to calculate total monthly branded- or
generic-attributed MarketScan AE counts. Patient-level counts of drug prescriptions filled were
also summed by month to calculate total monthly branded or generic MarketScan prescription
counts.
Because the study aimed to investigate AE trends over time, it was necessary to identify the
month and year associated with AEs. The approximate AE date for each report was identified via
the event date variable; for reports with no event date available, the earliest date associated with
the AE report (eg, date of submission of AE report) was used in an attempt to most accurately
reflect when the event likely took place [12].
Table S1. List of generic products, manufacturers, market entry dates, therapeutic equivalence ratings, and
application numbers
First
Therapeutic
Generic
Market
Equivalence
ANDA
Entry Date Manufacturer
Entry
Ratingb
Number
Datea
11/4/2008
Mylan Pharmaceuticals Inc
11/4/2008
AB
76919
Generic
levetiracetam
Actavis Mid Atlantic LLC
1/15/2009
AA
78976
Aurobindo Pharma Ltd
1/15/2009
AB
78993
Aurobindo Pharma USA Inc
1/15/2009
AA
79063
Dr Reddys Laboratories Ltd
1/15/2009
AB
78904
Dr Reddys Laboratories Ltd
1/15/2009
AB
76920
Invagen Pharmaceuticals Inc
1/15/2009
AB
78234
Lupin Ltd
1/15/2009
AB
90025
Lupin Ltd
1/15/2009
AB
78154
Orchid Healthcare
1/15/2009
AB
78526
Roxane Laboratories Inc
1/15/2009
AA
78582
Roxane Laboratories Inc
1/15/2009
AB
78042
Sandoz Inc
1/15/2009
AB
77324
Teva Pharmaceuticals USA
1/15/2009
AB
78101
Tolmar Inc
1/15/2009
AA
79107
Torrent Pharmaceuticals Ltd
1/15/2009
AB
78858
Watson Laboratories Inc
1/15/2009
AB
78797
Wockhardt Ltd
1/15/2009
AB
79042
Breckenridge Pharmaceutical Inc
1/16/2009
AA
79120
Mylan Pharmaceuticals Inc
2/10/2009
Not available
78731
Prinston Pharmaceutical Inc
2/10/2009
AB
78106
Taro Pharmaceutical Industries Ltd
2/10/2009
AA
78774
Watson Laboratories Inc Florida
3/2/2009
Not available
77408
Apotex Inc
3/13/2009
AB
78869
Boca Pharmacal LLC
3/20/2009
AB
77319
Silarx Pharmaceuticals Inc
4/3/2009
AA
90263
Zydus Pharmaceuticals USA Inc
4/29/2009
AB
78918
Amneal Pharmaceuticals
10/27/2009
AA
90992
Mylan Pharmaceuticals Inc
12/8/2009
AB
90261
Taro Pharmaceutical Industries Ltd
2/1/2010
AB
78960
Wockhardt EU Operations (Swiss) AG
3/3/2010
AA
90028
Fresenius Kabi USA LLC
5/26/2010
AP
90813
Sun Pharmaceutical Industries Ltd
6/16/2010
AP
90754
Methapharm Inc
7/28/2010
AB
90767
Orchid Healthcare
8/5/2010
AB
90484
Tris Pharma Inc
9/30/2010
AA
90461
Hetero Labs Ltd Unit III
10/8/2010
AB
90515
Lotus Pharmaceutical Co Ltd
11/5/2010
AB
90906
7/23/2010
Sandoz Inc
7/23/2010
AP
77857
Generic
enoxaparin
Amphastar Pharmaceutical Inc
9/19/2011
AP
76684
sodium
Sandoz Inc
11/28/2011
AB
78660
a
Date of final regulatory approval was used as a proxy for market entry date.
b
AA = therapeutically equivalent products in conventional dosage forms not presenting bioequivalence problems;
AB = therapeutically equivalent products meeting necessary bioequivalence requirements; AP = therapeutically
equivalent injectable aqueous solutions.
Table S2. Adverse event categories and corresponding MedDRA terms and ICD-9-CM codes for levetiracetam
AE Category
MedDRA Term(s)
ICD-9 Code(s)
Abnormal liver function
Liver function test abnormal
794.8
test
Amnesia, memory impairment, transient global
437.7, 780.93
Amnesia
amnesia
Anxiety
Anxiety
300.0X
Convulsion/seizure
780.31, 780.32, 780.39
Convulsion, febrile convulsion, partial seizures,
petit mal epilepsy, simple partial seizures, status
epilepticus
Depression and suicidal
behavior
Diplopia
Erythematous conditions
Completed suicide, depression, depression
suicidal, major depression, suicidal behaviour,
suicidal ideation, suicide attempt
Diplopia
Erythema multiforme, Stevens-Johnson
syndrome, toxic epidermal necrolysis
Gastroenteritis
Hallucination
Hepatic failure, autoimmune hepatitis, cytolytic
hepatitis, hepatitis, hepatitis acute
296.2X, 296.3X, 296.82, 311,
E95.XX, V62.84
368.2
695.10, 695.11, 695.12, 695.13,
695.14, 695.15, 695.19
558.2, 558.9
292.12, 293.82, 780.1
570, 571.42, 573.3
Gastroenteritis
Hallucination
Hepatic failure and
hepatitis
Leukopenia and
288.00, 288.03, 288.09, 288.50,
Granulocytopenia, leukopenia, neutropenia
neutropenia
288.59
Movement disorders
Ataxia, dyskinesia, tardive dyskinesia
333.82, 333.85, 334.3, 781.3
Pancreatitis
Pancreatitis, pancreatitis acute
577.0
Pancytopenia
Pancytopenia
284.12, 284.19
Pregnancy-related
Abortion spontaneous, premature labor
634.XX, 644.2X
Thrombocytopenia
Thrombocytopenia
287.30, 287.39, 287.49, 287.5
AE, adverse event; ICD-9-CM, International Classification of Diseases, Ninth Revision; MedDRA, Medical
Dictionary for Regulatory Activities.
Table S3. Adverse event categories and corresponding MedDRA terms and ICD-9-CM codes for enoxaparin
sodium
AE Category
MedDRA Term(s)
ICD-9 Code(s)
Anaphylactic/anaphylactoid
Anaphylactic reaction
995.0
reactions
Anaemia, hemorrhagic anaemia, iron deficiency
280.0, 280.1, 280.9, 281.9,
Anemia
anaemia
285.1, 285.9
Atrial fibrillation
Atrial fibrillation
427.31
Cellulitis
Cellulitis
681.00, 681.10, 682.X
Cerebrovascular accident
Cerebrovascular accident
434.01, 434.91, 977.02
Convulsion
Convulsion
780.31, 780.32, 780.39
Edema
Edema, edema peripheral
782.3
Eosinophilia
Eosinophilia
288.3
Hematemesis
Hematemesis
578.0
Cardiac failure, cardiac failure congestive,
428.0, 428.1, 428.20, 428.21,
cardiogenic shock, cardiopulmonary failure
428.23, 428.30, 428.31, 428.33,
Heart failure
428.40, 428.41, 428.43, 428.9,
785.51, 799.1
Abdominal wall hemorrhage, arterial
360.43, 376.32, 379.23, 430,
hemorrhage, cerebellar hemorrhage, cerebral
431, 432.0, 432.1, 432.9, 459.0,
hemorrhage, diverticulum intestinal hemorrhagic, 530.82, 532.00, 532.01, 562.02,
duodenal ulcer hemorrhage, eye hemorrhage,
562.03, 562.12, 562.13, 569.3,
gastric hemorrhage, gastrointestinal hemorrhage,
578.9, 719.1X, 729.92, 998.12
hemarthrosis, hemorrhage intracranial, intraabdominal hemorrhage, lower gastrointestinal
hemorrhage, oesophageal hemorrhage,
Hemorrhage and hematoma pericardial hemorrhage, peritoneal hemorrhage,
rectal hemorrhage, retroperitoneal hemorrhage,
skin hemorrhage, subarachnoid hemorrhage,
thalamus hemorrhage, thoracic hemorrhage,
upper gastrointestinal hemorrhage, vitreous
hemorrhage, abdominal wall hematoma,
extradural hematoma, post procedural hematoma,
spinal hematoma, subdural hematoma, vessel
puncture site hematoma
Hematuria
Hematuria
599.7X
Hyperkalemia
Hyperkalemia
276.7
Hyperlipidemia
Hyperlipidemia
272.0, 272.1, 272.2, 272.3, 272.4
458.0, 458.29, 459.8, 458.9,
Hypotension
Hypotension
796.3
Lung edema
Pulmonary edema, acute pulmonary edema
518.4
Osteoporosis
Osteoporosis
733.00, 733.02, 733.09
Pneumonia, pneumonia staphylococcal
480.9, 482.4X, 482.9, 483.8,
Pneumonia
484.8, 486, 514, 518.3
Pulmonary embolism
Pulmonary embolism
415.1X
Renal failure acute
Renal failure acute
584.X
Tachycardia
Tachycardia
427.0, 427.1, 427.2, 785.0
Thrombocytopenia, heparin-induced
287.30, 287.39, 287.49, 287.5,
Thrombocytopenia
thrombocytopenia, heparin-induced
289.84
thrombocytopenia test positive
Cerebral thrombosis, cerebral venous thrombosis, 434.0X, 437.6, 453.81, 453.83,
Thrombosis
intracranial venous sinus thrombosis, thrombosis
453.85, 453.87, 453.9
AE, adverse event; ICD-9-CM, International Classification of Diseases, Ninth Revision; MedDRA, Medical
Dictionary for Regulatory Activities.
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