ADVERSE REACTIONS
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction
rates observed in the clinical trials of a drug cannot be directly compared to rates
in the clinical trials of another drug and may not reflect the rates observed in
practice.
In all controlled and uncontrolled trials across various patient populations during
the premarketing development of LYRICA, more than 10,000 patients have received
LYRICA. Approximately 5000 patients were treated for 6 months or more, over 3100
patients were treated for 1 year or longer, and over 1400 patients were treated
for at least 2 years.
Adverse Reactions Most Commonly Leading to Discontinuation in All Premarketing Controlled
Clinical Studies
In premarketing controlled trials of all populations combined, 14% of patients treated
with LYRICA and 7% of patients treated with placebo discontinued prematurely
due to adverse reactions. In the LYRICA treatment group, the adverse reactions most
frequently leading to discontinuation were dizziness (4%) and somnolence (3%). In
the placebo group, 1% of patients withdrew due to dizziness and <1% withdrew
due to somnolence. Other adverse reactions that led to discontinuation from controlled
trials more frequently in the LYRICA group compared to the placebo group were ataxia,
confusion, asthenia, thinking abnormal, blurred vision, incoordination, and peripheral
edema (1% each).
Most Common Adverse Reactions in All Premarketing Controlled Clinical Studies
In premarketing controlled trials of all patient populations combined, dizziness,
somnolence, dry mouth, edema, blurred vision, weight gain, and "thinking abnormal"
(primarily difficulty with concentration/attention) were more commonly reported
by subjects treated with LYRICA than by subjects treated with placebo (≥5% and twice
the rate of that seen in placebo).
Controlled Studies with Neuropathic Pain Associated with Diabetic Peripheral Neuropathy
Adverse Reactions Leading to Discontinuation
In clinical trials in patients with neuropathic pain associated with diabetic peripheral
neuropathy, 9% of patients treated with LYRICA and 4% of patients treated with placebo
discontinued prematurely due to adverse reactions. In the LYRICA treatment group,
the most common reasons for discontinuation due to adverse reactions were dizziness
(3%) and somnolence (2%). In comparison, <1% of placebo patients withdrew due
to dizziness and somnolence. Other reasons for discontinuation from the trials,
occurring with greater frequency in the LYRICA group than in the placebo group,
were asthenia, confusion, and peripheral edema. Each of these events led to withdrawal
in approximately 1% of patients.
Most Common Adverse Reactions
Table 3 lists all adverse reactions, regardless of causality, occurring in ≥1% of
patients with neuropathic pain associated with diabetic neuropathy in the combined
LYRICA group for which the incidence was greater in this combined LYRICA group than
in the placebo group. A majority of pregabalin-treated patients in clinical studies
had adverse reactions with a maximum intensity of "mild" or "moderate".
Table 3: Treatment-emergent adverse reaction incidence in controlled trials in Neuropathic
Pain Associated with Diabetic Peripheral Neuropathy (Events in at least 1% of all
LYRICA-treated patients and at least numerically more in all LYRICA than in the
placebo group)
Controlled Studies in Postherpetic Neuralgia
Adverse Reactions Leading to Discontinuation
In clinical trials in patients with postherpetic neuralgia, 14% of patients treated
with LYRICA and 7% of patients treated with placebo discontinued prematurely due
to adverse reactions. In the LYRICA treatment group, the most common reasons for
discontinuation due to adverse reactions were dizziness (4%) and somnolence (3%).
In comparison, less than 1% of placebo patients withdrew due to dizziness and somnolence.
Other reasons for discontinuation from the trials, occurring in greater frequency
in the LYRICA group than in the placebo group, were confusion (2%), as well as peripheral
edema, asthenia, ataxia, and abnormal gait (1% each).
Most Common Adverse Reactions
Table 4 lists all adverse reactions, regardless of causality, occurring in ≥ 1% of
patients with neuropathic pain associated with postherpetic neuralgia in the combined
LYRICA group for which the incidence was greater in this combined LYRICA group than
in the placebo group. In addition, an event is included, even if the incidence in
the all LYRICA group is not greater than in the placebo group, if the incidence
of the event in the 600 mg/day group is more than twice that in the placebo group.
A majority of pregabalin-treated patients in clinical studies had adverse reactions
with a maximum intensity of "mild" or "moderate".
Table 4: Treatment-emergent adverse reaction incidence in controlled trials in Neuropathic
Pain Associated with Postherpetic Neuralgia (Events in at least 1% of all LYRICA-treated
patients and at least numerically more in all LYRICA than in the placebo group)
Controlled Add-On Studies in Adjunctive Therapy for Adult Patients with Partial Onset
Seizures
Adverse Reactions Leading to Discontinuation
Approximately 15% of patients receiving LYRICA and 6% of patients receiving placebo
in add-on epilepsy trials discontinued prematurely due to adverse reactions. In
the LYRICA treatment group, the adverse reactions most frequently leading to discontinuation
were dizziness (6%), ataxia (4%), and somnolence (3%). In comparison, <1% of
patients in the placebo group withdrew due to each of these events. Other adverse
reactions that led to discontinuation of at least 1% of patients in the LYRICA group
and at least twice as frequently compared to the placebo group were asthenia, diplopia,
blurred vision, thinking abnormal, nausea, tremor, vertigo, headache, and confusion
(which each led to withdrawal in 2% or less of patients).
Most Common Adverse Reactions
Table 5 lists all dose-related adverse reactions occurring in at least 2% of all
LYRICA-treated patients. Dose-relatedness was defined as the incidence of the adverse
event in the 600 mg/day group was at least 2% greater than the rate in both the
placebo and 150 mg/day groups. In these studies, 758 patients received LYRICA and
294 patients received placebo for up to 12 weeks. Because patients were also treated
with 1 to 3 other AEDs, it is not possible to determine whether the following adverse
reactions can be ascribed to LYRICA alone, or the combination of LYRICA and other
AEDs. A majority of pregabalin-treated patients in clinical studies had adverse reactions
with a maximum intensity of "mild" or "moderate".
Table 5: Dose-related treatment-emergent adverse reaction incidence in controlled
trials in adjunctive therapy for adult patients with partial onset seizures (Events
in at least 2% of all LYRICA-treated patients and the adverse reaction in the 600
mg/day group was ≥2% the rate in both the placebo and 150 mg/day groups)
Controlled Studies with Fibromyalgia
Adverse Reactions Leading to Discontinuation
In clinical trials of patients with fibromyalgia, 19% of patients treated with pregabalin
(150–600 mg/day) and 10% of patients treated with placebo discontinued prematurely
due to adverse reactions. In the pregabalin treatment group, the most common reasons
for discontinuation due to adverse reactions were dizziness (6%) and somnolence
(3%). In comparison, <1% of placebo-treated patients withdrew due to dizziness
and somnolence. Other reasons for discontinuation from the trials, occurring with
greater frequency in the pregabalin treatment group than in the placebo treatment
group, were fatigue, headache, balance disorder, and weight increased. Each of these
adverse reactions led to withdrawal in approximately 1% of patients.
Most Common Adverse Reactions
Table 6 lists all adverse reactions, regardless of causality, occurring in ≥2% of
patients with fibromyalgia in the ‘all pregabalin’ treatment group for which the
incidence was greater than in the placebo treatment group. A majority of pregabalin-treated
patients in clinical studies experienced adverse reactions with a maximum intensity
of "mild" or "moderate".
Table 6: Treatment-emergent adverse reaction incidence in controlled trials in Fibromyalgia
(Events in at least 2% of all LYRICA-treated patients and occurring more frequently
in the all pregabalin-group than in the placebo treatment group)
Other Adverse Reactions Observed During the Clinical Studies of LYRICA
Following is a list of treatment-emergent adverse reactions reported by patients
treated with LYRICA during all clinical trials. The listing does not include those
events already listed in the previous tables or elsewhere in labeling, those events
for which a drug cause was remote, those events which were so general as to be uninformative,
and those events reported only once which did not have a substantial probability
of being acutely life-threatening.
Events are categorized by body system and listed in order of decreasing frequency
according to the following definitions: frequent adverse reactions are those
occurring on one or more occasions in at least 1/100 patients; infrequent
adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions
are those occurring in fewer than 1/1000 patients. Events of major clinical importance
are described in the Warnings and Precautions section.
Body as a Whole – Frequent: Abdominal pain, Allergic reaction, Fever, Infrequent:
Abscess, Cellulitis, Chills, Malaise, Neck rigidity, Overdose, Pelvic pain, Photosensitivity
reaction, Rare: Anaphylactoid reaction, Ascites, Granuloma,
Hangover effect, Intentional Injury, Retroperitoneal Fibrosis, Shock
Cardiovascular System – Infrequent: Deep thrombophlebitis, Heart failure,
Hypotension, Postural hypotension, Retinal vascular disorder, Syncope; Rare:
ST Depressed, Ventricular Fibrillation
Digestive System – Frequent: Gastroenteritis, Increased appetite; Infrequent:
Cholecystitis, Cholelithiasis, Colitis, Dysphagia, Esophagitis, Gastritis, Gastrointestinal
hemorrhage, Melena, Mouth ulceration, Pancreatitis, Rectal hemorrhage, Tongue edema;
Rare: Aphthous stomatitis, Esophageal Ulcer, Periodontal abscess
Hemic and Lymphatic System – Frequent: Ecchymosis; Infrequent: Anemia,
Eosinophilia, Hypochromic anemia, Leukocytosis, Leukopenia, Lymphadenopathy, Thrombocytopenia;
Rare: Myelofibrosis, Polycythemia, Prothrombin decreased, Purpura, Thrombocythemia
Metabolic and Nutritional Disorders – Rare: Glucose Tolerance Decreased,
Urate Crystalluria
Musculoskeletal System – Frequent: Arthralgia, Leg cramps, Myalgia, Myasthenia;
Infrequent: Arthrosis; Rare: Chondrodystrophy,
Generalized Spasm
Nervous System – Frequent: Anxiety, Depersonalization, Hypertonia, Hypesthesia,
Libido decreased, Nystagmus, Paresthesia, Stupor, Twitching; Infrequent:
Abnormal dreams, Agitation, Apathy, Aphasia, Circumoral paresthesia, Dysarthria,
Hallucinations, Hostility, Hyperalgesia, Hyperesthesia, Hyperkinesia, Hypokinesia,
Hypotonia, Libido increased, Myoclonus, Neuralgia, Rare: Addiction, Cerebellar
syndrome, Cogwheel rigidity, Coma, Delirium, Delusions, Dysautonomia, Dyskinesia,
Dystonia, Encephalopathy, Extrapyramidal syndrome, Guillain-Barré syndrome, Hypalgesia,
Intracranial hypertension, Manic reaction, Paranoid reaction, Peripheral neuritis,
Personality disorder, Psychotic depression, Schizophrenic reaction,
Sleep disorder, Torticollis,
Trismus
Respiratory System – Rare: Apnea, Atelectasis, Bronchiolitis, Hiccup, Laryngismus,
Lung edema, Lung fibrosis, Yawn
Skin and Appendages – Frequent: Pruritus, Infrequent: Alopecia, Dry
skin, Eczema, Hirsutism, Skin ulcer, Urticaria, Vesiculobullous rash; Rare:
Angioedema, Exfoliative dermatitis, Lichenoid dermatitis, Melanosis, Nail Disorder,
Petechial rash, Purpuric rash, Pustular rash, Skin atrophy, Skin necrosis, Skin
nodule, Stevens-Johnson syndrome, Subcutaneous nodule
Special senses – Frequent: Conjunctivitis, Diplopia, Otitis media, Tinnitus;
Infrequent: Abnormality of accommodation, Blepharitis, Dry eyes, Eye hemorrhage,
Hyperacusis, Photophobia, Retinal edema, Taste loss, Taste perversion; Rare:
Anisocoria, Blindness, Corneal ulcer, Exophthalmos, Extraocular palsy, Iritis, Keratitis,
Keratoconjunctivitis, Miosis, Mydriasis, Night blindness, Ophthalmoplegia, Optic
atrophy, Papilledema, Parosmia, Ptosis, Uveitis
Urogenital System – Frequent: Anorgasmia, Impotence, Urinary
frequency, Urinary incontinence; Infrequent: Abnormal ejaculation, Albuminuria, Amenorrhea,
Dysmenorrhea, Dysuria, Hematuria, Kidney calculus, Leukorrhea, Menorrhagia, Metrorrhagia,
Nephritis, Oliguria, Urinary retention, Urine abnormality; Rare: Acute kidney
failure, Balanitis, Bladder Neoplasm, Cervicitis, Dyspareunia, Epididymitis, Female
lactation, Glomerulitis, Ovarian disorder, Pyelonephritis
Comparison of Gender and Race
The overall adverse event profile of pregabalin
was similar between women and men. There are insufficient data to support a statement
regarding the distribution of adverse experience reports by race.
Post-marketing Experience
The following adverse reactions have been identified during postapproval use of
LYRICA. Because these reactions are reported voluntarily from a population of uncertain
size, it is not always possible to reliably estimate their frequency or establish
a causal relationship to drug exposure.
Nervous System Disorders – Headache
Gastrointestinal Disorders – Nausea, Diarrhea