Pregabalin Extended Release (Page 4 of 9)

5.12 Decreased Platelet Count

Both pregabalin extended-release tablets and pregabalin treatment were associated with a decrease in platelet count. In the double-blind phase of controlled studies for pain indication, pregabalin extended-release tablets-treated patients experienced a median change from baseline in platelet count of 11 × 103 /mm3 (for the PHN population) and 14 × 103 /mm3 (for the FM population) as compared to 1 × 103 /mm3 in placebo-treated patients (for both populations). Pregabalin-treated patients experienced a mean maximal decrease in platelet count of 20 × 103 /µL, compared to 11 × 103 /µL in placebo patients. In the overall database of controlled trials, 2% of placebo patients and 3% of pregabalin patients experienced a potentially clinically significant decrease in platelets, defined as 20% below baseline value and less than 150 × 103 /µL. A single pregabalin-treated subject developed severe thrombocytopenia with a platelet count less than 20 × 103 /µL. In randomized controlled trials, pregabalin or pregabalin extended-release tablets were not associated with an increase in bleeding-related adverse reactions.

5.13 PR Interval Prolongation

Pregabalin treatment was associated with PR interval prolongation. In analyses of clinical trial ECG data, the mean PR interval increase was 3 to 6 msec at pregabalin doses greater than or equal to 300 mg/day. This mean change difference was not associated with an increased risk of PR increase greater than or equal to 25% from baseline, an increased percentage of subjects with on-treatment PR greater than 200 msec, or an increased risk of adverse reactions of second or third degree AV block.

Subgroup analyses did not identify an increased risk of PR prolongation in patients with baseline PR prolongation or in patients taking other PR prolonging medications. However, these analyses cannot be considered definitive because of the limited number of patients in these categories.

6 ADVERSE REACTIONS

The following adverse reactions are described elsewhere in the labeling:

  • Angioedema [see Warnings and Precautions (5.1)]
  • Hypersensitivity Reactions [see Warnings and Precautions (5.2)]
  • Suicidal Behavior and Ideation [see Warnings and Precautions (5.3)]
  • Respiratory Depression [see Warnings and Precautions (5.4)]
  • Dizziness and Somnolence [see Warnings and Precautions (5.5)]
  • Risks Associated with Abrupt or Rapid Discontinuation [see Warnings and Precautions (5.6)]
  • Peripheral Edema [see Warnings and Precautions (5.7)]
  • Weight Gain [see Warnings and Precautions (5.8)]
  • Ophthalmological Effects [see Warnings and Precautions (5.10)]
  • Creatine Kinase Elevations [see Warnings and Precautions (5.11)]
  • Decreased Platelet Count [see Warnings and Precautions (5.12)]

6.1 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.

Two randomized placebo-controlled clinical trials were conducted in patients with postherpetic neuralgia and fibromyalgia in which a total of 1,242 patients received pregabalin extended-release tablets. Both studies were randomized withdrawal design where a 6-week single-blind, dose optimization phase was followed by a 13-week double-blind phase. The most common adverse events leading to discontinuation from the single-blind phase of the study occurring in greater than or equal to 0.3% of patients were dizziness, somnolence, peripheral edema, fatigue, blurred vision, and increased weight. Sixty-four percent of patients experienced adverse events during the single-blind phase, with the most common adverse events occurring in greater than or equal to 4% of patients being dizziness, somnolence, headache, fatigue, peripheral edema, nausea, blurred vision, dry mouth, and weight gain.

Controlled Study in Postherpetic Neuralgia

Adverse Reactions Leading to Discontinuation

In a clinical trial in patients with postherpetic neuralgia, 8.9% of patients treated with pregabalin extended-release tablets discontinued prematurely during the single-blind phase due to adverse reactions. The most common reasons for discontinuation due to adverse reactions were dizziness (2.1%), somnolence (0.87%), and peripheral edema (0.50%).

Most Common Adverse Reactions

Table 4 lists all adverse reactions, regardless of causality, occurring in greater than or equal to 1% of patients with postherpetic neuralgia who received pregabalin extended-release tablets, regardless of the phase of the study.

Table 4. Incidence of Adverse Reactions Reported in Greater Than or Equal to 1% of Subjects in Any Phase of the Pregabalin Extended-Release Tablets Study in Patients With Postherpetic Neuralgia *
System Organ ClassPreferred Term Single-Blind Phase Double-Blind Phase
Pregabalin Extended-Release Tablets[N=801]n (%) Pregabalin Extended-Release Tablets[N=208]n (%) Placebo[N=205]n (%)
*
Table is limited to adverse reactions that occurred with higher incidence in pregabalin extended-release tablets-treated patients than in placebo-treated patients for the DB Phase of the study.
Ear and labyrinth disorders
Vertigo 31 (3.9) 2 (1.0) 1 (0.5)
Eye disorders
Vision blurred 30 (3.7) 1 (0.5) 0
Diplopia 8 (1.0) 1 (0.5) 0
Gastrointestinal disorders
Dry mouth 30 (3.7) 1 (0.5) 0
Nausea 24 (3.0) 7 (3.4) 0
Constipation 22 (2.7) 0 0
Diarrhea 11 (1.4) 2 (1.0) 1 (0.5)
Vomiting 9 (1.1) 3 (1.4) 1 (0.5)
General disorders and administration site conditions
Edema peripheral 39 (4.9) 8 (3.8) 1 (0.5)
Fatigue 31 (3.9) 3 (1.4) 2 (1.0)
Edema 3 (0.4) 3 (1.4) 0
Infections and infestations
Nasopharyngitis 12 (1.5) 3 (1.4) 0
Urinary tract infection 11 (1.4) 3 (1.4) 1 (0.5)
Bronchitis 4 (0.5) 3 (1.4) 2 (1.0)
Respiratory tract infection viral 3 (0.4) 3 (1.4) 1 (0.5)
Sinusitis 3 (0.4) 2 (1.0) 0
Gastroenteritis viral 2 (0.2) 2 (1.0) 0
Investigations
Weight increased 20 (2.5) 8 (3.8) 2 (1.0)
Alanine aminotransferase increased 2 (0.2) 3 (1.4) 0
Aspartate aminotransferase increased 2 (0.2) 2 (1.0) 0
Musculoskeletal and connective tissue disorders
Arthralgia 6 (0.7) 2 (1.0) 1 (0.5)
Joint swelling 0 4 (1.9) 0
Nervous system disorders
Dizziness 137 (17.1) 7 (3.4) 1 (0.5)
Somnolence 91 (11.4) 1 (0.5) 0
Headache 31 (3.9) 4 (1.9) 1 (0.5)
Balance disorder 21 (2.6) 1 (0.5) 0
Reproductive system and breast disorders
Erectile dysfunction 2 (0.6) 1 (1.4) 0
Respiratory, thoracic, and mediastinal disorders
Cough 2 (0.2) 2 (1.0) 1 (0.5)
Skin and subcutaneous tissue disorders
Dermatitis contact 0 2 (1.0) 0

Other Adverse Reactions Observed During Clinical Studies with Pregabalin and Pregabalin Extended-Release Tablets

In addition to the adverse reactions reported during the controlled studies with pregabalin extended-release tablets in postherpetic neuralgia, the following adverse reactions have been reported in patients treated with pregabalin and pregabalin extended-release tablets during all clinical studies. This listing does not include those adverse reactions already listed above. The adverse reactions are categorized by system organ class and listed in order of decreasing frequency according to the following definitions: frequent adverse reactions are those occurring on 1 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. Adverse reactions of major clinical importance are described in the Warnings and Precautions section (5).

Cardiac Disorders – Infrequent: Palpitations, Deep thrombophlebitis, Heart failure, Hypotension, Postural hypotension, Retinal vascular disorder, Syncope; Rare: Cardiac failure, Tachycardia

Eye Disorders – Infrequent: Periorbital edema

Gastrointestinal Disorders – Frequent: Increased appetite; Infrequent: Abdominal distension, Abdominal pain, Dysphagia, Pancreatitis, Tongue edema

General Disorders – Frequent: Fever; Infrequent: Chest pain, Face edema; Rare: Facial pain, Mucosal dryness

Hemic and Lymphatic System Disorders – Frequent: Ecchymosis; Infrequent: Anemia, Eosinophilia, Hypochromic anemia, Leukocytosis, Leukopenia, Lymphadenopathy, Thrombocytopenia; Rare: Myelofibrosis, Polycythemia, Prothrombin decreased, Purpura, Thrombocythemia

Infections and Infestations – Infrequent: Otitis media, Pneumonia

Investigations – Rare: Glucose urine present, Lipase increased, Neutrophil count increased, Proteinuria

Metabolic and Nutritional Disorders – Rare: Glucose Tolerance Decreased, Urate Crystalluria

Musculoskeletal and Connective Tissue Disorders – Frequent: Leg cramps, Myalgia, Myasthenia; Infrequent: Joint stiffness; Rare: Coccydynia, Myokymia

Nervous System Disorders – Frequent: Anxiety, Depersonalization, Hypertonia, Hypoesthesia, Libido decreased, Nystagmus, Paresthesia, Sedation, Stupor, Twitching; Infrequent: Coordination abnormal, Abnormal dreams, Agitation, Amnesia, Apathy, Aphasia, Circumoral paresthesia, Cognitive disorder, Dysarthria, Dysgeusia, Hallucinations, Hostility, Hyperalgesia, Hyperesthesia, Hyperkinesia, Hypokinesia, Hypotonia, Libido increased, Myoclonus, Neuralgia, Sciatica, Sleep phase rhythm disturbance; Rare: Addiction, Altered state of consciousness, Bradykinesia, Cerebellar syndrome, Cogwheel rigidity, Coma, Delirium, Delusions, Depressed level of consciousness, Dysautonomia, Dyskinesia, Dystonia, Encephalopathy, Extrapyramidal syndrome, Psychomotor hyperactivity, Psychomotor skills impaired

Psychiatric Disorders – Infrequent: Irritability

Respiratory System Disorders – Rare: Lung edema

Skin Disorders – Frequent: Pruritus; Rare: Stevens-Johnson syndrome

Special Senses – Frequent: Conjunctivitis, Tinnitus

Urogenital System Disorders – Frequent: Anorgasmia, Impotence, Urinary frequency, Urinary incontinence; Infrequent: Abnormal ejaculation, Albuminuria, Dysuria, Hematuria, Kidney calculus, Leukorrhea, Nephritis, Oliguria, Urinary retention

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