ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following serious adverse reactions are described elsewhere in the labeling:oAngioedema [see Warnings and Precautions (5.1)] oHypersensitivity [see Warnings and Precautions (5.2)] oSuicidal Behavior and Ideation [see Warnings and Precautions (5.3)]oIncreased Risk of Adverse Reactions with Abrupt or Rapid Discontinuation [see Warnings and Precautions (5.4)] oRespiratory Depression [see Warnings and Precautions (5.5) ]oDizziness and Somnolence [see Warnings and Precautions (5.6) ]oPeripheral Edema [see Warnings and Precautions (5.7)] oWeight Gain [see Warnings and Precautions (5.8)] oTumorigenic Potential [see Warnings and Precautions (5.9)]oOphthalmological Effects [see Warnings and Precautions (5.10)] oCreatine Kinase Elevations [see Warnings and Precautions (5.11)] oDecreased Platelet Count [see Warnings and Precautions (5.12)] oPR Interval Prolongation [see Warnings and Precautions (5.13)]. oAngioedema [see Warnings and Precautions (5.1)] oHypersensitivity [see Warnings and Precautions (5.2)] oSuicidal Behavior and Ideation [see Warnings and Precautions (5.3)]. oIncreased Risk of Adverse Reactions with Abrupt or Rapid Discontinuation [see Warnings and Precautions (5.4)] oRespiratory Depression [see Warnings and Precautions (5.5) ]. oDizziness and Somnolence [see Warnings and Precautions (5.6) ]. oPeripheral Edema [see Warnings and Precautions (5.7)] oWeight Gain [see Warnings and Precautions (5.8)] oTumorigenic Potential [see Warnings and Precautions (5.9)]. oOphthalmological Effects [see Warnings and Precautions (5.10)] oCreatine Kinase Elevations [see Warnings and Precautions (5.11)] oDecreased Platelet Count [see Warnings and Precautions (5.12)] oPR Interval Prolongation [see Warnings and Precautions (5.13)]. Most common adverse reactions (greater than or equal to 5% and twice placebo) in adults are dizziness, somnolence, dry mouth, edema, blurred vision, weight gain, and thinking abnormal (primarily difficulty with concentration/attention). (6.1)Most common adverse reactions (greater than or equal to 5% and twice placebo) in pediatric patients for the treatment of partial-onset seizures are increased weight and increased appetite. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Rising Pharma Holdings, Inc. at 1-844-874-7464 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 pregabalin, more than 10,000 patients have received pregabalin. Approximately 5,000 patients were treated for months or more, over 3,100 patients were treated for year or longer, and over 1,400 patients were treated for at least years.Adverse Reactions Most Commonly Leading to Discontinuation in All Premarketing Controlled Clinical Studies In premarketing controlled trials of all adult populations combined, 14% of patients treated with pregabalin and 7% of patients treated with placebo discontinued prematurely due to adverse reactions. In the pregabalin treatment group, the adverse reactions most frequently leading to discontinuation were dizziness (4%) and somnolence (4%). In the placebo group, 1% of patients withdrew due to dizziness and less than 1% withdrew due to somnolence. Other adverse reactions that led to discontinuation from controlled trials more frequently in the pregabalin 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 Controlled Clinical Studies in Adults In premarketing controlled trials of all adult patient populations combined (including DPN, PHN, and adult patients with partial-onset seizures), 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 pregabalin than by subjects treated with placebo (greater than or equal to 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 adults with neuropathic pain associated with diabetic peripheral neuropathy, 9% of patients treated with pregabalin and 4% 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 (3%) and somnolence (2%). In comparison, less than 1% of placebo patients withdrew due to dizziness and somnolence. Other reasons for discontinuation from the trials, occurring with greater frequency in the pregabalin 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 lists all adverse reactions, regardless of causality, occurring in greater than or equal to 1% of patients with neuropathic pain associated with diabetic neuropathy in the combined pregabalin group for which the incidence was greater in this combined pregabalin group than in the placebo group. majority of pregabalin-treated patients in clinical studies had adverse reactions with maximum intensity of mild or moderate. Table 4. Adverse Reaction Incidence in Controlled Trials in Neuropathic Pain Associated with Diabetic Peripheral Neuropathy Body system Preferred term75 mg/day [N=77]%150 mg/day [N=212]%300 mg/day [N=321]%600 mg/day [N=369]%All PGB [N=979]%Placebo[N=459]%Body as wholeAsthenia424752Accidental injury522643Back pain021220Chest pain411221Face edema011210Digestive systemDry mouth325751Constipation024642Flatulence302321Metabolic and nutritional disordersPeripheral edema4691292Weight gain044640Edema024220Hypoglycemia132121Nervous systemDizziness892329215Somnolence461316123Neuropathy922543Ataxia612431Vertigo122431Confusion012321Euphoria003220Incoordination102220Thinking abnormal+101320Tremor111210Abnormal gait101310Amnesia310210Nervousness011110Respiratory systemDyspnea302221Special sensesBlurry vision313642Abnormal vision101110 PGB: pregabalin Thinking abnormal primarily consists of events related to difficulty with concentration/attention but also includes events related to cognition and language problems and slowed thinking. Investigator term; summary level term is amblyopiaControlled Studies in Postherpetic NeuralgiaAdverse Reactions Leading to DiscontinuationIn clinical trials in adults with postherpetic neuralgia, 14% of patients treated with pregabalin and 7% 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 (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 pregabalin group than in the placebo group, were confusion (2%), as well as peripheral edema, asthenia, ataxia, and abnormal gait (1% each).Most Common Adverse ReactionsTable lists all adverse reactions, regardless of causality, occurring in greater than or equal to 1% of patients with neuropathic pain associated with postherpetic neuralgia in the combined pregabalin group for which the incidence was greater in this combined pregabalin group than in the placebo group. In addition, an event is included, even if the incidence in the all pregabalin 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. majority of pregabalin-treated patients in clinical studies had adverse reactions with maximum intensity of mild or moderate. Overall, 12.4% of all pregabalin-treated patients and 9.0% of all placebo-treated patients had at least one severe event while 8% of pregabalin-treated patients and 4.3% of placebo-treated patients had at least one severe treatment-related adverse event.Table 5. Adverse Reaction Incidence in Controlled Trials in Neuropathic Pain Associated with Postherpetic NeuralgiaBody system Preferred term75 mg/d [N=84]%150 mg/d [N=302]%300 mg/d [N=312]%600 mg/d [N=154]%All PGB [N=852]%Placebo [N=398]%Body as wholeInfection1486374Headache595875Pain545554Accidental injury433532Flu syndrome122121Face edema021321Digestive systemDry mouth7761583Constipation455552Flatulence212321Vomiting113321Metabolic and nutritional disordersPeripheral edema081616124Weight gain125740Edema012621Musculoskeletal systemMyasthenia111110Nervous systemDizziness11183137269Somnolence8121825165Ataxia125951Abnormal gait024841Confusion123730Thinking abnormal+021622Incoordination221320Amnesia011420Speech disorder001310Respiratory systemBronchitis011311Special sensesBlurry vision155953Diplopia022420Abnormal vision012520Eye Disorder011210Urogenital SystemUrinary Incontinence011210 PGB: pregabalin+ Thinking abnormal primarily consists of events related to difficulty with concentration/attention but also includes events related to cognition and language problems and slowed thinking. Investigator term; summary level term is amblyopia Controlled Studies of Adjunctive Therapy for Partial-Onset Seizures in Adult Patients Adverse Reactions Leading to Discontinuation Approximately 15% of patients receiving pregabalin and 6% of patients receiving placebo in trials of adjunctive therapy for partial-onset seizures discontinued prematurely due to adverse reactions. In the pregabalin treatment group, the adverse reactions most frequently leading to discontinuation were dizziness (6%), ataxia (4%), and somnolence (3%). In comparison, less than 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 pregabalin 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 lists all dose-related adverse reactions occurring in at least 2% of all pregabalin-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 pregabalin and 294 patients received placebo for up to 12 weeks. majority of pregabalin-treated patients in clinical studies had adverse reactions with maximum intensity of mild or moderate. Table 6. Dose-related Adverse Reaction Incidence in Controlled Trials of Adjunctive Therapy for Partial-Onset Seizures in Adult Patients Body System Preferred Term150 mg/d[N 185]%300 mg/d[N 90]%600 mg/d[N 395]%All PGB [N 670]+ %Placebo[N 294]%Body as WholeAccidental Injury7111095Pain32543Digestive SystemIncreased Appetite23651Dry Mouth12641Constipation11742Metabolic and Nutritional DisordersWeight Gain5716121Peripheral Edema33652Nervous SystemDizziness1831383211Somnolence1118282211Ataxia61020154Tremor371184Thinking Abnormal48982Amnesia32652Speech Disorder12751Incoordination13641Abnormal Gait13540Twitching04541Confusion12542Myoclonus10420Special SensesBlurred Vision5812104Diplopia571294Abnormal Vision31541 PGB: pregabalin Excludes patients who received the 50 mg dose in Study E1. Thinking abnormal primarily consists of events related to difficulty with concentration/attention but also includes events related to cognition and language problems and slowed thinking. Investigator term; summary level term is amblyopia.Controlled Study of Adjunctive Therapy for Partial-Onset Seizures in Patients to Less Than 17 Years of Age Adverse Reactions Leading to Discontinuation Approximately 2.5% of patients receiving pregabalin and no patients receiving placebo in trials of adjunctive therapy for partial-onset seizures discontinued prematurely due to adverse reactions. In the pregabalin treatment group, the adverse reactions leading to discontinuation were somnolence (3 patients), worsening of epilepsy (1 patient), and hallucination (1 patient). Most Common Adverse Reactions Table lists all dose-related adverse reactions occurring in at least 2% of all pregabalin-treated patients. Dose-relatedness was defined as an incidence of the adverse event in the 10 mg/kg/day group that was at least 2% greater than the rate in both the placebo and 2.5 mg/kg/day groups. In this study, 201 patients received pregabalin and 94 patients received placebo for up to 12 weeks. majority of pregabalin-treated patients in the clinical study had adverse reactions with maximum intensity of mild or moderate. Table 7. Dose-related Adverse Reaction Incidence in Controlled Trial in Adjunctive Therapy for Partial-Onset Seizures in Patients to Less Than 17 Years of Age Body System Preferred Term2.5 mg/kg/daya [N=104] %10 mg/kg/dayb [N=97] %All PGB [N=201] Placebo [N=94] Gastrointestinal disordersSalivary hypersecretion 420InvestigationsWeight increased4 1384Metabolism and nutrition disordersIncreased appetite 71084Nervous system disordersSomnolence17262114Abbreviations: N=number of patients; PGB pregabalin. a. 2.5 mg/kg/day: Maximum dose 150 mg/day. Includes patients less than 30 kg for whom dose was adjusted to 3.5 mg/kg/day. b. 10 mg/kg/day: Maximum dose 600 mg/day. Includes patients less than 30 kg for whom dose was adjusted to 14 mg/kg/day. Controlled Study of Adjunctive Therapy for Partial-Onset Seizures in Patients Month to Less Than Years of Age Most Common Adverse Reactions Table lists all dose-related adverse reactions occurring in at least 2% of all pregabalin-treated patients. Dose-relatedness was defined as an incidence of the adverse event in the 14 mg/kg/day group that was at least 2% greater than the rate in both the placebo and mg/kg/day groups. In this study, 105 patients received pregabalin and 70 patients received placebo for up to 14 days. Table 8. Dose-related Adverse Reaction Incidence in Controlled Trial in Adjunctive Therapy for Partial-Onset Seizures in Patients Month to Less Than Years of Age Body System Preferred Term7 mg/kg/day [N=71] %14 mg/kg/day [N=34] %All PGB [N=105] %Placebo [N=70] %Nervous system disordersSomnolence 13 21 15 9Infections and infestationsPneumonia 9 0Viral infection 6 3Abbreviations: N=number of patients; PGB=pregabalin. includes related terms including lethargy, sluggishness, and hypersomnia.Controlled Studies with FibromyalgiaAdverse Reactions Leading to Discontinuation In clinical trials of patients with fibromyalgia, 19% of patients treated with pregabalin (150 to 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, less than 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 lists all adverse reactions, regardless of causality, occurring in greater than or equal to 2% of patients with fibromyalgia in the all pregabalin treatment group for which the incidence was greater than in the placebo treatment group. majority of pregabalin-treated patients in clinical studies experienced adverse reactions with maximum intensity of mild or moderate.Table 9. Adverse Reaction Incidence in Controlled Trials in FibromyalgiaSystem Organ Class Preferred term150mg/d [N=132]%300mg/d [N=502]%450mg/d [N=505]%600mg/d [N=378]%All PGB[N=1,517]%Placebo[N=505]%Ear and Labyrinth DisordersVertigo222120Eye DisordersVision blurred8771281Gastrointestinal DisordersDry mouth769982Constipation4471072Vomiting233232Flatulence112221Abdominal distension222221General Disorders and Administrative Site ConditionsFatigue576874Edema peripheral556962Chest pain211221Feeling abnormal132220Edema121221Feeling drunk121220Infections and InfestationsSinusitis457554InvestigationsWeight increased8101014112Metabolism and Nutrition DisordersIncreased appetite435751Fluid retention233221Musculoskeletal and Connective Tissue DisordersArthralgia433642Muscle spasms244442Back pain234333Nervous System DisordersDizziness23314345389Somnolence13182222204Headache111214101212Disturbance in attention446651Balance disorder236950Memory impairment134430Coordination abnormal212221Hypoesthesia223221Lethargy221220Tremor013220Psychiatric DisordersEuphoric Mood256761Confusional state023430Anxiety222221Disorientation102120Depression222222Respiratory, Thoracic and Mediastinal DisordersPharyngolaryngeal pain213322 PGB: pregabalin Controlled Studies in Neuropathic Pain Associated with Spinal Cord Injury Adverse Reactions Leading to DiscontinuationIn clinical trials of adults with neuropathic pain associated with spinal cord injury, 13% of patients treated with pregabalin 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 somnolence (3%) and edema (2%). In comparison, none of the placebo-treated patients withdrew due to somnolence and edema. Other reasons for discontinuation from the trials, occurring with greater frequency in the pregabalin treatment group than in the placebo treatment group, were fatigue and balance disorder. Each of these adverse reactions led to withdrawal in less than 2% of patients.Most Common Adverse ReactionsTable 10 lists all adverse reactions, regardless of causality, occurring in greater than or equal to 2% of patients for which the incidence was greater than in the placebo treatment group with neuropathic pain associated with spinal cord injury in the controlled trials. majority of pregabalin-treated patients in clinical studies experienced adverse reactions with maximum intensity of mild or moderate. Table 10. Adverse Reaction Incidence in Controlled Trials in Neuropathic Pain Associated with Spinal Cord Injury System Organ ClassPreferred termPGB (N=182)Placebo (N=174)%%Ear and labyrinth disordersVertigo2.71.1Eye disordersVision blurred6.61.1Gastrointestinal disordersDry mouth11.02.9Constipation8.25.7Nausea4.94.0Vomiting2.71.1General disorders and administration site conditionsFatigue11.04.0Edema peripheral10.45.2Edema8.21.1Pain3.31.1Infections and infestationsNasopharyngitis8.24.6InvestigationsWeight increased3.31.1Blood creatine phosphokinase increased2.70Musculoskeletal and connective tissue disordersMuscular weakness4.91.7Pain in extremity3.32.3Neck pain2.71.1Back pain2.21.7Joint swelling2.20Nervous system disordersSomnolence35.711.5Dizziness20.96.9Disturbance in attention3.80Memory impairment3.31.1Paresthesia2.20.6Psychiatric disordersInsomnia3.82.9Euphoric mood2.20.6Renal and urinary disordersUrinary incontinence2.71.1Skin and subcutaneous tissue disordersDecubitus ulcer2.71.1Vascular disordersHypertension2.21.1Hypotension2.20 PGB: Pregabalin Other Adverse Reactions Observed During the Clinical Studies of Pregabalin Following is list of treatment-emergent adverse reactions reported by patients treated with pregabalin 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 drug cause was remote, those events which were so general as to be uninformative, and those events reported only once which did not have 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 1/1,000 patients; rare reactions are those occurring in fewer than 1/1,000 patients. Events of major clinical importance are described in the Warnings and Precautions section (5).Body as 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, ShockCardiovascular System Infrequent: Deep thrombophlebitis, Heart failure, Hypotension, Postural hypotension, Retinal vascular disorder, Syncope; Rare: ST Depressed, Ventricular FibrillationDigestive 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 abscessHemic and Lymphatic System Frequent: Ecchymosis; Infrequent: Anemia, Eosinophilia, Hypochromic anemia, Leukocytosis, Leukopenia, Lymphadenopathy, Thrombocytopenia; Rare: Myelofibrosis, Polycythemia, Prothrombin decreased, Purpura, Thrombocythemia, Alanine aminotransferase increased, Aspartate aminotransferase increasedMetabolic and Nutritional Disorders Rare: Glucose Tolerance Decreased, Urate CrystalluriaMusculoskeletal System Frequent: Arthralgia, Leg cramps, Myalgia, Myasthenia; Infrequent: Arthrosis; Rare: Chondrodystrophy, Generalized SpasmNervous System Frequent: Anxiety, Depersonalization, Hypertonia, Hypoesthesia, Libido decreased, Nystagmus, Paresthesia, Sedation, 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-Barre syndrome, Hypalgesia, Intracranial hypertension, Manic reaction, Paranoid reaction, Peripheral neuritis, Personality disorder, Psychotic depression, Schizophrenic reaction, Sleep disorder, Torticollis, TrismusRespiratory System Rare: Apnea, Atelectasis, Bronchiolitis, Hiccup, Laryngismus, Lung edema, Lung fibrosis, YawnSkin 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 noduleSpecial 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, UveitisUrogenital 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, PyelonephritisComparison of Gender and RaceThe overall adverse event profile of pregabalin was similar between women and men. There are insufficient data to support statement regarding the distribution of adverse experience reports by race. 6.2 Postmarketing Experience. The following adverse reactions have been identified during postapproval use of pregabalin. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Nervous System Disorders HeadacheGastrointestinal Disorders Nausea, DiarrheaReproductive System and Breast Disorders Gynecomastia, Breast Enlargement Skin and subcutaneous tissue disorders Bullous pemphigoid There are postmarketing reports of life-threatening or fatal respiratory depression in patients taking pregabalin with opioids or other CNS depressants, or in the setting of underlying respiratory impairment. In addition, there are postmarketing reports of events related to reduced lower gastrointestinal tract function (e.g., intestinal obstruction, paralytic ileus, constipation) when pregabalin was co-administered with medications that have the potential to produce constipation, such as opioid analgesics.There are postmarketing reports of withdrawal symptoms after discontinuation of pregabalin. Reported adverse reactions include, but are not limited to, seizures, depression, suicidal ideation and behavior, agitation, confusion, disorientation, psychotic symptoms, anxiety, insomnia, nausea, pain, sweating, tremor, headache, dizziness, malaise, and diarrhea.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Pregabalin binds with high affinity to the alpha2-delta site (an auxiliary subunit of voltage-gated calcium channels) in central nervous system tissues. Although the mechanism of action of pregabalin has not been fully elucidated, results with genetically modified mice and with compounds structurally related to pregabalin (such as gabapentin) suggest that binding to the alpha2-delta subunit may be involved in pregabalins anti-nociceptive and antiseizure effects in animals. In animal models of nerve damage, pregabalin has been shown to reduce calcium-dependent release of pro-nociceptive neurotransmitters in the spinal cord, possibly by disrupting alpha2-delta containing-calcium channel trafficking and/or reducing calcium currents. Evidence from other animal models of nerve damage and persistent pain suggest the anti-nociceptive activities of pregabalin may also be mediated through interactions with descending noradrenergic and serotonergic pathways originating from the brainstem that modulate pain transmission in the spinal cord.While pregabalin is structural derivative of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), it does not bind directly to GABAA, GABAB, or benzodiazepine receptors, does not augment GABAA responses in cultured neurons, does not alter rat brain GABA concentration or have acute effects on GABA uptake or degradation. However, in cultured neurons prolonged application of pregabalin increases the density of GABA transporter protein and increases the rate of functional GABA transport. Pregabalin does not block sodium channels, is not active at opiate receptors, and does not alter cyclooxygenase enzyme activity. It is inactive at serotonin and dopamine receptors and does not inhibit dopamine, serotonin, or noradrenaline reuptake.. 12.3 Pharmacokinetics. Pregabalin is well absorbed after oral administration, is eliminated largely by renal excretion, and has an elimination half-life of about hours.. Absorption and DistributionFollowing oral administration of pregabalin capsules under fasting conditions, peak plasma concentrations occur within 1.5 hours. Pregabalin oral bioavailability is greater than or equal to 90% and is independent of dose. Following single- (25 to 300 mg) and multiple-dose (75 to 900 mg/day) administration, maximum plasma concentrations (Cmax) and area under the plasma concentration-time curve (AUC) values increase linearly. Following repeated administration, steady state is achieved within 24 to 48 hours. Multiple-dose pharmacokinetics can be predicted from single-dose data.The rate of pregabalin absorption is decreased when given with food, resulting in decrease in Cmax of approximately 25% to 30% and an increase in Tmax to approximately hours. However, administration of pregabalin with food has no clinically relevant effect on the total absorption of pregabalin. Therefore, pregabalin can be taken with or without food.Pregabalin does not bind to plasma proteins. The apparent volume of distribution of pregabalin following oral administration is approximately 0.5 L/kg. Pregabalin is substrate for system transporter which is responsible for the transport of large amino acids across the blood brain barrier. Although there are no data in humans, pregabalin has been shown to cross the blood brain barrier in mice, rats, and monkeys. In addition, pregabalin has been shown to cross the placenta in rats and is present in the milk of lactating rats.. Metabolism and EliminationPregabalin undergoes negligible metabolism in humans. Following dose of radiolabeled pregabalin, approximately 90% of the administered dose was recovered in the urine as unchanged pregabalin. The N-methylated derivative of pregabalin, the major metabolite of pregabalin found in urine, accounted for 0.9% of the dose. In preclinical studies, pregabalin (S-enantiomer) did not undergo racemization to the R-enantiomer in mice, rats, rabbits, or monkeys.Pregabalin is eliminated from the systemic circulation primarily by renal excretion as unchanged drug with mean elimination half-life of 6.3 hours in subjects with normal renal function. Mean renal clearance was estimated to be 67.0 to 80.9 mL/min in young healthy subjects. Because pregabalin is not bound to plasma proteins this clearance rate indicates that renal tubular reabsorption is involved. Pregabalin elimination is nearly proportional to creatinine clearance (CLcr) [see Dosage and Administration (2.7)].. Pharmacokinetics in Specific Populations. RaceIn population pharmacokinetic analyses of the clinical studies in various populations, the pharmacokinetics of pregabalin were not significantly affected by race (Caucasians, Blacks, and Hispanics).. GenderPopulation pharmacokinetic analyses of the clinical studies showed that the relationship between daily dose and pregabalin drug exposure is similar between genders.. Renal Impairment and HemodialysisPregabalin clearance is nearly proportional to creatinine clearance (CLcr). Dosage reduction in patients with renal dysfunction is necessary. Pregabalin is effectively removed from plasma by hemodialysis. Following 4-hour hemodialysis treatment, plasma pregabalin concentrations are reduced by approximately 50%. For patients on hemodialysis, dosing must be modified [see Dosage and Administration (2.7) ].. ElderlyPregabalin oral clearance tended to decrease with increasing age. This decrease in pregabalin oral clearance is consistent with age-related decreases in CLcr. Reduction of pregabalin dose may be required in patients who have age-related compromised renal function [see Dosage and Administration (2.7)].Pediatric PharmacokineticsPediatric Patients (3 months to less than 17 years of age)Pregabalin pharmacokinetics were evaluated in 358 pediatric patients months to less than 17 years of age with partial-onset seizures at dose levels of 2.5, 5, 10, and 15 mg/kg/day after single and multiple oral administration of pregabalin. Following oral administration, pregabalin reaches peak plasma concentration at 0.5 hours to hours in the fasted state. Both apparent clearance (CL/F) and apparent volume of distribution increase as body weight increases. weight-based dosing regimen is necessary to achieve pregabalin exposures in pediatric patients month to less than 17 years of age similar to those observed in adults treated for partial-onset seizures at effective doses [see Dosage and Administration (2.4)]. The mean t1/2 is to hours in pediatric subjects up to years of age, and to hours in those years of age and older. Pregabalin CL/F is nearly proportional to CLcr (mL/min). The relationship is similar in pediatric and adult subjects. When normalized per body weight, CL/F (mL/min/kg) in pediatric subjects weighing less than 30 kg is approximately 40% higher in comparison to subjects weighing greater than or equal to 30 kg [see Dosage and Administration (2.4)]. Drug Interactions. In Vitro StudiesPregabalin, at concentrations that were, in general, 10-times those attained in clinical trials, does not inhibit human CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 enzyme systems. In vitro drug interaction studies demonstrate that pregabalin does not induce CYP1A2 or CYP3A4 activity. Therefore, an increase in the metabolism of coadministered CYP1A2 substrates (e.g. theophylline, caffeine) or CYP 3A4 substrates (e.g., midazolam, testosterone) is not anticipated.. In Vivo StudiesThe drug interaction studies described in this section were conducted in healthy adults, and across various patient populations.. GabapentinThe pharmacokinetic interactions of pregabalin and gabapentin were investigated in 12 healthy subjects following concomitant single-dose administration of 100-mg pregabalin and 300-mg gabapentin and in 18 healthy subjects following concomitant multiple-dose administration of 200-mg pregabalin every hours and 400-mg gabapentin every hours. Gabapentin pharmacokinetics following single- and multiple-dose administration were unaltered by pregabalin coadministration. The extent of pregabalin absorption was unaffected by gabapentin coadministration, although there was small reduction in rate of absorption.. Oral Contraceptive Pregabalin coadministration (200 mg three times day) had no effect on the steady-state pharmacokinetics of norethindrone and ethinyl estradiol (1 mg/35 mcg, respectively) in healthy subjects.. LorazepamMultiple-dose administration of pregabalin (300 mg twice day) in healthy subjects had no effect on the rate and extent of lorazepam single-dose pharmacokinetics and single-dose administration of lorazepam (1 mg) had no effect on the steady-state pharmacokinetics of pregabalin.. Oxycodone Multiple-dose administration of pregabalin (300 mg twice day) in healthy subjects had no effect on the rate and extent of oxycodone single-dose pharmacokinetics. Single-dose administration of oxycodone (10 mg) had no effect on the steady-state pharmacokinetics of pregabalin.. Ethanol Multiple-dose administration of pregabalin (300 mg twice day) in healthy subjects had no effect on the rate and extent of ethanol single-dose pharmacokinetics and single-dose administration of ethanol (0.7 g/kg) had no effect on the steady-state pharmacokinetics of pregabalin.. Phenytoin, carbamazepine, valproic acid, and lamotrigine Steady-state trough plasma concentrations of phenytoin, carbamazepine and carbamazepine 10,11 epoxide, valproic acid, and lamotrigine were not affected by concomitant pregabalin (200 mg three times day) administration.Population pharmacokinetic analyses in patients treated with pregabalin and various concomitant medications suggest the following:Therapeutic classSpecific concomitant drug studiedConcomitant drug has no effect on the pharmacokinetics of pregabalinHypoglycemicsGlyburide, insulin, metforminDiureticsFurosemideAntiepileptic DrugsTiagabineConcomitant drug has no effect on the pharmacokinetics of pregabalin and pregabalin has no effect on the pharmacokinetics of concomitant drugAntiepileptic DrugsCarbamazepine, lamotrigine, phenobarbital, phenytoin, topiramate, valproic acid.

CLINICAL STUDIES SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 pregabalin, more than 10,000 patients have received pregabalin. Approximately 5,000 patients were treated for months or more, over 3,100 patients were treated for year or longer, and over 1,400 patients were treated for at least years.Adverse Reactions Most Commonly Leading to Discontinuation in All Premarketing Controlled Clinical Studies In premarketing controlled trials of all adult populations combined, 14% of patients treated with pregabalin and 7% of patients treated with placebo discontinued prematurely due to adverse reactions. In the pregabalin treatment group, the adverse reactions most frequently leading to discontinuation were dizziness (4%) and somnolence (4%). In the placebo group, 1% of patients withdrew due to dizziness and less than 1% withdrew due to somnolence. Other adverse reactions that led to discontinuation from controlled trials more frequently in the pregabalin 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 Controlled Clinical Studies in Adults In premarketing controlled trials of all adult patient populations combined (including DPN, PHN, and adult patients with partial-onset seizures), 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 pregabalin than by subjects treated with placebo (greater than or equal to 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 adults with neuropathic pain associated with diabetic peripheral neuropathy, 9% of patients treated with pregabalin and 4% 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 (3%) and somnolence (2%). In comparison, less than 1% of placebo patients withdrew due to dizziness and somnolence. Other reasons for discontinuation from the trials, occurring with greater frequency in the pregabalin 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 lists all adverse reactions, regardless of causality, occurring in greater than or equal to 1% of patients with neuropathic pain associated with diabetic neuropathy in the combined pregabalin group for which the incidence was greater in this combined pregabalin group than in the placebo group. majority of pregabalin-treated patients in clinical studies had adverse reactions with maximum intensity of mild or moderate. Table 4. Adverse Reaction Incidence in Controlled Trials in Neuropathic Pain Associated with Diabetic Peripheral Neuropathy Body system Preferred term75 mg/day [N=77]%150 mg/day [N=212]%300 mg/day [N=321]%600 mg/day [N=369]%All PGB [N=979]%Placebo[N=459]%Body as wholeAsthenia424752Accidental injury522643Back pain021220Chest pain411221Face edema011210Digestive systemDry mouth325751Constipation024642Flatulence302321Metabolic and nutritional disordersPeripheral edema4691292Weight gain044640Edema024220Hypoglycemia132121Nervous systemDizziness892329215Somnolence461316123Neuropathy922543Ataxia612431Vertigo122431Confusion012321Euphoria003220Incoordination102220Thinking abnormal+101320Tremor111210Abnormal gait101310Amnesia310210Nervousness011110Respiratory systemDyspnea302221Special sensesBlurry vision313642Abnormal vision101110 PGB: pregabalin Thinking abnormal primarily consists of events related to difficulty with concentration/attention but also includes events related to cognition and language problems and slowed thinking. Investigator term; summary level term is amblyopiaControlled Studies in Postherpetic NeuralgiaAdverse Reactions Leading to DiscontinuationIn clinical trials in adults with postherpetic neuralgia, 14% of patients treated with pregabalin and 7% 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 (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 pregabalin group than in the placebo group, were confusion (2%), as well as peripheral edema, asthenia, ataxia, and abnormal gait (1% each).Most Common Adverse ReactionsTable lists all adverse reactions, regardless of causality, occurring in greater than or equal to 1% of patients with neuropathic pain associated with postherpetic neuralgia in the combined pregabalin group for which the incidence was greater in this combined pregabalin group than in the placebo group. In addition, an event is included, even if the incidence in the all pregabalin 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. majority of pregabalin-treated patients in clinical studies had adverse reactions with maximum intensity of mild or moderate. Overall, 12.4% of all pregabalin-treated patients and 9.0% of all placebo-treated patients had at least one severe event while 8% of pregabalin-treated patients and 4.3% of placebo-treated patients had at least one severe treatment-related adverse event.Table 5. Adverse Reaction Incidence in Controlled Trials in Neuropathic Pain Associated with Postherpetic NeuralgiaBody system Preferred term75 mg/d [N=84]%150 mg/d [N=302]%300 mg/d [N=312]%600 mg/d [N=154]%All PGB [N=852]%Placebo [N=398]%Body as wholeInfection1486374Headache595875Pain545554Accidental injury433532Flu syndrome122121Face edema021321Digestive systemDry mouth7761583Constipation455552Flatulence212321Vomiting113321Metabolic and nutritional disordersPeripheral edema081616124Weight gain125740Edema012621Musculoskeletal systemMyasthenia111110Nervous systemDizziness11183137269Somnolence8121825165Ataxia125951Abnormal gait024841Confusion123730Thinking abnormal+021622Incoordination221320Amnesia011420Speech disorder001310Respiratory systemBronchitis011311Special sensesBlurry vision155953Diplopia022420Abnormal vision012520Eye Disorder011210Urogenital SystemUrinary Incontinence011210 PGB: pregabalin+ Thinking abnormal primarily consists of events related to difficulty with concentration/attention but also includes events related to cognition and language problems and slowed thinking. Investigator term; summary level term is amblyopia Controlled Studies of Adjunctive Therapy for Partial-Onset Seizures in Adult Patients Adverse Reactions Leading to Discontinuation Approximately 15% of patients receiving pregabalin and 6% of patients receiving placebo in trials of adjunctive therapy for partial-onset seizures discontinued prematurely due to adverse reactions. In the pregabalin treatment group, the adverse reactions most frequently leading to discontinuation were dizziness (6%), ataxia (4%), and somnolence (3%). In comparison, less than 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 pregabalin 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 lists all dose-related adverse reactions occurring in at least 2% of all pregabalin-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 pregabalin and 294 patients received placebo for up to 12 weeks. majority of pregabalin-treated patients in clinical studies had adverse reactions with maximum intensity of mild or moderate. Table 6. Dose-related Adverse Reaction Incidence in Controlled Trials of Adjunctive Therapy for Partial-Onset Seizures in Adult Patients Body System Preferred Term150 mg/d[N 185]%300 mg/d[N 90]%600 mg/d[N 395]%All PGB [N 670]+ %Placebo[N 294]%Body as WholeAccidental Injury7111095Pain32543Digestive SystemIncreased Appetite23651Dry Mouth12641Constipation11742Metabolic and Nutritional DisordersWeight Gain5716121Peripheral Edema33652Nervous SystemDizziness1831383211Somnolence1118282211Ataxia61020154Tremor371184Thinking Abnormal48982Amnesia32652Speech Disorder12751Incoordination13641Abnormal Gait13540Twitching04541Confusion12542Myoclonus10420Special SensesBlurred Vision5812104Diplopia571294Abnormal Vision31541 PGB: pregabalin Excludes patients who received the 50 mg dose in Study E1. Thinking abnormal primarily consists of events related to difficulty with concentration/attention but also includes events related to cognition and language problems and slowed thinking. Investigator term; summary level term is amblyopia.Controlled Study of Adjunctive Therapy for Partial-Onset Seizures in Patients to Less Than 17 Years of Age Adverse Reactions Leading to Discontinuation Approximately 2.5% of patients receiving pregabalin and no patients receiving placebo in trials of adjunctive therapy for partial-onset seizures discontinued prematurely due to adverse reactions. In the pregabalin treatment group, the adverse reactions leading to discontinuation were somnolence (3 patients), worsening of epilepsy (1 patient), and hallucination (1 patient). Most Common Adverse Reactions Table lists all dose-related adverse reactions occurring in at least 2% of all pregabalin-treated patients. Dose-relatedness was defined as an incidence of the adverse event in the 10 mg/kg/day group that was at least 2% greater than the rate in both the placebo and 2.5 mg/kg/day groups. In this study, 201 patients received pregabalin and 94 patients received placebo for up to 12 weeks. majority of pregabalin-treated patients in the clinical study had adverse reactions with maximum intensity of mild or moderate. Table 7. Dose-related Adverse Reaction Incidence in Controlled Trial in Adjunctive Therapy for Partial-Onset Seizures in Patients to Less Than 17 Years of Age Body System Preferred Term2.5 mg/kg/daya [N=104] %10 mg/kg/dayb [N=97] %All PGB [N=201] Placebo [N=94] Gastrointestinal disordersSalivary hypersecretion 420InvestigationsWeight increased4 1384Metabolism and nutrition disordersIncreased appetite 71084Nervous system disordersSomnolence17262114Abbreviations: N=number of patients; PGB pregabalin. a. 2.5 mg/kg/day: Maximum dose 150 mg/day. Includes patients less than 30 kg for whom dose was adjusted to 3.5 mg/kg/day. b. 10 mg/kg/day: Maximum dose 600 mg/day. Includes patients less than 30 kg for whom dose was adjusted to 14 mg/kg/day. Controlled Study of Adjunctive Therapy for Partial-Onset Seizures in Patients Month to Less Than Years of Age Most Common Adverse Reactions Table lists all dose-related adverse reactions occurring in at least 2% of all pregabalin-treated patients. Dose-relatedness was defined as an incidence of the adverse event in the 14 mg/kg/day group that was at least 2% greater than the rate in both the placebo and mg/kg/day groups. In this study, 105 patients received pregabalin and 70 patients received placebo for up to 14 days. Table 8. Dose-related Adverse Reaction Incidence in Controlled Trial in Adjunctive Therapy for Partial-Onset Seizures in Patients Month to Less Than Years of Age Body System Preferred Term7 mg/kg/day [N=71] %14 mg/kg/day [N=34] %All PGB [N=105] %Placebo [N=70] %Nervous system disordersSomnolence 13 21 15 9Infections and infestationsPneumonia 9 0Viral infection 6 3Abbreviations: N=number of patients; PGB=pregabalin. includes related terms including lethargy, sluggishness, and hypersomnia.Controlled Studies with FibromyalgiaAdverse Reactions Leading to Discontinuation In clinical trials of patients with fibromyalgia, 19% of patients treated with pregabalin (150 to 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, less than 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 lists all adverse reactions, regardless of causality, occurring in greater than or equal to 2% of patients with fibromyalgia in the all pregabalin treatment group for which the incidence was greater than in the placebo treatment group. majority of pregabalin-treated patients in clinical studies experienced adverse reactions with maximum intensity of mild or moderate.Table 9. Adverse Reaction Incidence in Controlled Trials in FibromyalgiaSystem Organ Class Preferred term150mg/d [N=132]%300mg/d [N=502]%450mg/d [N=505]%600mg/d [N=378]%All PGB[N=1,517]%Placebo[N=505]%Ear and Labyrinth DisordersVertigo222120Eye DisordersVision blurred8771281Gastrointestinal DisordersDry mouth769982Constipation4471072Vomiting233232Flatulence112221Abdominal distension222221General Disorders and Administrative Site ConditionsFatigue576874Edema peripheral556962Chest pain211221Feeling abnormal132220Edema121221Feeling drunk121220Infections and InfestationsSinusitis457554InvestigationsWeight increased8101014112Metabolism and Nutrition DisordersIncreased appetite435751Fluid retention233221Musculoskeletal and Connective Tissue DisordersArthralgia433642Muscle spasms244442Back pain234333Nervous System DisordersDizziness23314345389Somnolence13182222204Headache111214101212Disturbance in attention446651Balance disorder236950Memory impairment134430Coordination abnormal212221Hypoesthesia223221Lethargy221220Tremor013220Psychiatric DisordersEuphoric Mood256761Confusional state023430Anxiety222221Disorientation102120Depression222222Respiratory, Thoracic and Mediastinal DisordersPharyngolaryngeal pain213322 PGB: pregabalin Controlled Studies in Neuropathic Pain Associated with Spinal Cord Injury Adverse Reactions Leading to DiscontinuationIn clinical trials of adults with neuropathic pain associated with spinal cord injury, 13% of patients treated with pregabalin 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 somnolence (3%) and edema (2%). In comparison, none of the placebo-treated patients withdrew due to somnolence and edema. Other reasons for discontinuation from the trials, occurring with greater frequency in the pregabalin treatment group than in the placebo treatment group, were fatigue and balance disorder. Each of these adverse reactions led to withdrawal in less than 2% of patients.Most Common Adverse ReactionsTable 10 lists all adverse reactions, regardless of causality, occurring in greater than or equal to 2% of patients for which the incidence was greater than in the placebo treatment group with neuropathic pain associated with spinal cord injury in the controlled trials. majority of pregabalin-treated patients in clinical studies experienced adverse reactions with maximum intensity of mild or moderate. Table 10. Adverse Reaction Incidence in Controlled Trials in Neuropathic Pain Associated with Spinal Cord Injury System Organ ClassPreferred termPGB (N=182)Placebo (N=174)%%Ear and labyrinth disordersVertigo2.71.1Eye disordersVision blurred6.61.1Gastrointestinal disordersDry mouth11.02.9Constipation8.25.7Nausea4.94.0Vomiting2.71.1General disorders and administration site conditionsFatigue11.04.0Edema peripheral10.45.2Edema8.21.1Pain3.31.1Infections and infestationsNasopharyngitis8.24.6InvestigationsWeight increased3.31.1Blood creatine phosphokinase increased2.70Musculoskeletal and connective tissue disordersMuscular weakness4.91.7Pain in extremity3.32.3Neck pain2.71.1Back pain2.21.7Joint swelling2.20Nervous system disordersSomnolence35.711.5Dizziness20.96.9Disturbance in attention3.80Memory impairment3.31.1Paresthesia2.20.6Psychiatric disordersInsomnia3.82.9Euphoric mood2.20.6Renal and urinary disordersUrinary incontinence2.71.1Skin and subcutaneous tissue disordersDecubitus ulcer2.71.1Vascular disordersHypertension2.21.1Hypotension2.20 PGB: Pregabalin Other Adverse Reactions Observed During the Clinical Studies of Pregabalin Following is list of treatment-emergent adverse reactions reported by patients treated with pregabalin 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 drug cause was remote, those events which were so general as to be uninformative, and those events reported only once which did not have 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 1/1,000 patients; rare reactions are those occurring in fewer than 1/1,000 patients. Events of major clinical importance are described in the Warnings and Precautions section (5).Body as 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, ShockCardiovascular System Infrequent: Deep thrombophlebitis, Heart failure, Hypotension, Postural hypotension, Retinal vascular disorder, Syncope; Rare: ST Depressed, Ventricular FibrillationDigestive 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 abscessHemic and Lymphatic System Frequent: Ecchymosis; Infrequent: Anemia, Eosinophilia, Hypochromic anemia, Leukocytosis, Leukopenia, Lymphadenopathy, Thrombocytopenia; Rare: Myelofibrosis, Polycythemia, Prothrombin decreased, Purpura, Thrombocythemia, Alanine aminotransferase increased, Aspartate aminotransferase increasedMetabolic and Nutritional Disorders Rare: Glucose Tolerance Decreased, Urate CrystalluriaMusculoskeletal System Frequent: Arthralgia, Leg cramps, Myalgia, Myasthenia; Infrequent: Arthrosis; Rare: Chondrodystrophy, Generalized SpasmNervous System Frequent: Anxiety, Depersonalization, Hypertonia, Hypoesthesia, Libido decreased, Nystagmus, Paresthesia, Sedation, 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-Barre syndrome, Hypalgesia, Intracranial hypertension, Manic reaction, Paranoid reaction, Peripheral neuritis, Personality disorder, Psychotic depression, Schizophrenic reaction, Sleep disorder, Torticollis, TrismusRespiratory System Rare: Apnea, Atelectasis, Bronchiolitis, Hiccup, Laryngismus, Lung edema, Lung fibrosis, YawnSkin 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 noduleSpecial 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, UveitisUrogenital 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, PyelonephritisComparison of Gender and RaceThe overall adverse event profile of pregabalin was similar between women and men. There are insufficient data to support statement regarding the distribution of adverse experience reports by race.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. oFor adult indications, begin dosing at 150 mg/day. For partial-onset seizure dosing in pediatric patients month of age and older, refer to section 2.4. (2.2, 2.3, 2.4, 2.5, 2.6)oDosing recommendations:INDICATION Dosing Regimen Maximum Dose DPN Pain (2.2) divided doses per day 300 mg/day within week PHN (2.3) or divided doses per day 300 mg/day within week. Maximum dose of 600 mg/day.Adjunctive Therapy for Partial-Onset Seizures in Pediatric and Adult Patients Weighing 30 kg or More (2.4) or divided doses per day Maximum dose of 600 mg/day.Adjunctive Therapy for Partial-Onset Seizures in Pediatric Patients Weighing Less than 30 kg (2.4) month to less than years: divided doses per day years and older: or divided doses per day 14 mg/kg/day.Fibromyalgia (2.5) divided doses per day 300 mg/day within week. Maximum dose of 450 mg/day.Neuropathic Pain Associated with Spinal Cord Injury (2.6) divided doses per day 300 mg/day within week. Maximum dose of 600 mg/day.oDose should be adjusted in adult patients with reduced renal function. (2.7). oFor adult indications, begin dosing at 150 mg/day. For partial-onset seizure dosing in pediatric patients month of age and older, refer to section 2.4. (2.2, 2.3, 2.4, 2.5, 2.6). oDosing recommendations:. oDose should be adjusted in adult patients with reduced renal function. (2.7). 2.1 Important Administration Instructions. Pregabalin capsules are given orally with or without food.When discontinuing pregabalin capsules, taper gradually over minimum of week [see Warnings and Precautions (5.4)]. Because pregabalin is eliminated primarily by renal excretion, adjust the dose in adult patients with reduced renal function [see Dosage and Administration (2.7)].. 2.2 Neuropathic Pain Associated with Diabetic Peripheral Neuropathy in Adults. The maximum recommended dose of pregabalin capsules is 100 mg three times day (300 mg/day) in patients with creatinine clearance of at least 60 mL/min. Begin dosing at 50 mg three times day (150 mg/day). The dose may be increased to 300 mg/day within week based on efficacy and tolerability.Although pregabalin was also studied at 600 mg/day, there is no evidence that this dose confers additional significant benefit and this dose was less well tolerated. In view of the dose-dependent adverse reactions, treatment with doses above 300 mg/day is not recommended [see Adverse Reactions (6.1)].. 2.3 Postherpetic Neuralgia in Adults. The recommended dose of pregabalin capsules is 75 to 150 mg two times day, or 50 to 100 mg three times day (150 to 300 mg/day) in patients with creatinine clearance of at least 60 mL/min. Begin dosing at 75 mg two times day, or 50 mg three times day (150 mg/day). The dose may be increased to 300 mg/day within week based on efficacy and tolerability.Patients who do not experience sufficient pain relief following to weeks of treatment with 300 mg/day, and who are able to tolerate pregabalin, may be treated with up to 300 mg two times day, or 200 mg three times day (600 mg/day). In view of the dose-dependent adverse reactions and the higher rate of treatment discontinuation due to adverse reactions, reserve dosing above 300 mg/day for those patients who have on-going pain and are tolerating 300 mg daily [see Adverse Reactions (6.1)].. 2.4 Adjunctive Therapy for Partial-Onset Seizures in Patients Month of Age and Older. The recommended dosages for adults and pediatric patients month of age and older are included in Table 1. Administer the total daily dosage orally in two or three divided doses as indicated in Table 1. In pediatric patients, the recommended dosing regimen is dependent upon body weight. Based on clinical response and tolerability, dosage may be increased, approximately weekly.Table 1. Recommended Dosage for Adults and Pediatric Patients Month and OlderAge and Body WeightRecommended Initial Dosage Recommended Maximum DosageFrequency of AdministrationAdults (17 years and older)150 mg/day 600 mg/day2 or divided dosesPediatric patients weighing 30 kg or more2.5 mg/kg/day10 mg/kg/day (not to exceed 600 mg/day)2 or divided dosesPediatric patients weighing less than 30 kg3.5 mg/kg/day14 mg/kg/day1 month to less than years of age: divided doses years of age and older: or divided dosesBoth the efficacy and adverse event profiles of pregabalin have been shown to be dose-related. The effect of dose escalation rate on the tolerability of pregabalin has not been formally studied. The efficacy of adjunctive pregabalin in patients taking gabapentin has not been evaluated in controlled trials. Consequently, dosing recommendations for the use of pregabalin with gabapentin cannot be offered.. 2.5 Management of Fibromyalgia in Adults. The recommended dose of pregabalin capsules for fibromyalgia is 300 to 450 mg/day. Begin dosing at 75 mg two times day (150 mg/day). The dose may be increased to 150 mg two times day (300 mg/day) within week based on efficacy and tolerability. Patients who do not experience sufficient benefit with 300 mg/day may be further increased to 225 mg two times day (450 mg/day). Although pregabalin was also studied at 600 mg/day, there is no evidence that this dose confers additional benefit and this dose was less well tolerated. In view of the dose-dependent adverse reactions, treatment with doses above 450 mg/day is not recommended [see Adverse Reactions (6.1)].. 2.6 Neuropathic Pain Associated with Spinal Cord Injury in Adults. The recommended dose range of pregabalin capsules for the treatment of neuropathic pain associated with spinal cord injury is 150 to 600 mg/day. The recommended starting dose is 75 mg two times day (150 mg/day). The dose may be increased to 150 mg two times day (300 mg/day) within week based on efficacy and tolerability. Patients who do not experience sufficient pain relief after to weeks of treatment with 150 mg two times day and who tolerate pregabalin may be treated with up to 300 mg two times day [see Clinical Studies (14.5)].. 2.7 Dosing for Adult Patients with Renal Impairment. In view of dose-dependent adverse reactions and since pregabalin is eliminated primarily by renal excretion, adjust the dose in adult patients with reduced renal function. The use of pregabalin capsules in pediatric patients with compromised renal function has not been studied. Base the dose adjustment in patients with renal impairment on creatinine clearance (CLcr), as indicated in Table 2. To use this dosing table, an estimate of the patients CLcr in mL/min is needed. CLcr in mL/min may be estimated from serum creatinine (mg/dL) determination using the Cockcroft and Gault equation:Next, refer to the Dosage and Administration section to determine the recommended total daily dose based on indication, for patient with normal renal function (CLcr greater than or equal to 60 mL/min). Then refer to Table to determine the corresponding renal adjusted dose. (For example: patient initiating pregabalin therapy for postherpetic neuralgia with normal renal function (CLcr greater than or equal to 60 mL/min), receives total daily dose of 150 mg/day pregabalin. Therefore, renal impaired patient with CLcr of 50 mL/min would receive total daily dose of 75 mg/day pregabalin administered in two or three divided doses.)For patients undergoing hemodialysis, adjust the pregabalin daily dose based on renal function. In addition to the daily dose adjustment, administer supplemental dose immediately following every 4-hour hemodialysis treatment (see Table 2).Table 2. Pregabalin Dosage Adjustment Based on Renal Function Creatinine Clearance (CLcr) (mL/min) Total Pregabalin Daily Dose (mg/day) Dose Regimen Greater than or equal to 60 150 300 450 600 BID or TID 30 to 60 75 150 225 300 BID or TID 15 to 30 25 to 50 75 100 to 150 150 QD or BID Less than 15 25 25 to 50 50 to 75 75 QD Supplementary dosage following hemodialysis (mg)+ Patients on the 25 mg QD regimen: take one supplemental dose of 25 mg or 50 mg Patients on the 25 to 50 mg QD regimen: take one supplemental dose of 50 mg or 75 mg Patients on the 50 to 75 mg QD regimen: take one supplemental dose of 75 mg or 100 mg Patients on the 75 mg QD regimen: take one supplemental dose of 100 mg or 150 mg TID Three divided doses; BID Two divided doses; QD Single daily dose. Total daily dose (mg/day) should be divided as indicated by dose regimen to provide mg/dose. Supplementary dose is single additional dose.. pregabalin-equation.jpg.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Medication Guide).AngioedemaAdvise patients that pregabalin capsules may cause angioedema, with swelling of the face, mouth (lip, gum, tongue) and neck (larynx and pharynx) that can lead to life-threatening respiratory compromise. Instruct patients to discontinue pregabalin capsules and immediately seek medical care if they experience these symptoms [see Warnings and Precautions (5.1) ].HypersensitivityAdvise patients that pregabalin capsules has been associated with hypersensitivity reactions such as wheezing, dyspnea, rash, hives, and blisters. Instruct patients to discontinue pregabalin capsules and immediately seek medical care if they experience these symptoms [see Warnings and Precautions (5.2) ].Suicidal Thinking and BehaviorCounsel patients, their caregivers, and families that AEDs, including pregabalin, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Instruct patients, caregivers, and families to report behaviors of concern immediately to healthcare providers. Also inform patients who plan to or have discontinued pregabalin that suicidal thoughts and behavior can appear even after the drug is stopped[see Warnings and Precautions (5.3) ].Respiratory DepressionInform patients about the risk of respiratory depression. Include information that the risk is greatest for those using concomitant central nervous system (CNS) depressants (such as opioid analgesics) or in those with underlying respiratory impairment. Teach patients how to recognize respiratory depression and advise them to seek medical attention immediately if it occurs [see Warnings and Precautions (5.5) ].Dizziness and SomnolenceCounsel patients that pregabalin capsules may cause dizziness, somnolence, blurred vision and other CNS signs and symptoms. Accordingly, advise patients not to drive, operate complex machinery, or engage in other hazardous activities until they have gained sufficient experience on pregabalin to gauge whether or not it affects their mental, visual, and/or motor performance adversely [see Warnings and Precautions (5.6) ].CNS DepressantsInform patients who require concomitant treatment with central nervous system depressants such as opiates or benzodiazepines that they may experience additive CNS side effects, such as respiratory depression, somnolence, and dizziness [see Warnings and Precautions (5.5, 5.6) and Drug Interactions (7) ]. Advise patients to avoid consuming alcohol while taking pregabalin capsules, as pregabalin may potentiate the impairment of motor skills and sedating effects of alcohol.Adverse Reactions with Abrupt or Rapid DiscontinuationAdvise patients to take pregabalin capsules as prescribed. Abrupt or rapid discontinuation may result in increased seizure frequency in patients with seizure disorders, and insomnia, nausea, headache, anxiety, hyperhidrosis, or diarrhea [see Warnings and Precautions (5.4) ].Missed DoseCounsel patients if they miss dose, they should take it as soon as they remember. If it is almost time for the next dose, they should skip the missed dose and take the next dose at their regularly scheduled time. Instruct patients not to take two doses at the same time.Weight Gain and EdemaCounsel patients that pregabalin capsules may cause edema and weight gain. Advise patients that concomitant treatment with pregabalin and thiazolidinedione antidiabetic agent may lead to an additive effect on edema and weight gain. For patients with preexisting cardiac conditions, this may increase the risk of heart failure [see Warnings and Precautions (5.7, 5.8) ].Ophthalmological EffectsCounsel patients that pregabalin capsules may cause visual disturbances. Inform patients that if changes in vision occur, they should notify their physician [see Warnings and Precautions (5.10) ].Creatine Kinase ElevationsInstruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever [see Warnings and Precautions (5.11) ].Use in PregnancyInstruct patients to inform their healthcare provider if they are pregnant or intend to become pregnant during therapy, and to notify their physician if they are breast feeding or intend to breast feed during therapy [see Use in Specific Populations (8.1) and (8.2)].Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll-free number 1-888-233- 2334 [see Use in Specific Populations (8.1) ].LactationAdvise nursing mothers that breastfeeding is not recommended during treatment with pregabalin [see Use in Specific Populations (8.2) ].Male FertilityInform men being treated with pregabalin who plan to father child of the potential risk of male-mediated teratogenicity. In preclinical studies in rats, pregabalin was associated with an increased risk of male-mediated teratogenicity. The clinical significance of this finding is uncertain [see Nonclinical Toxicology (13.1) and Use in Specific Populations (8.3) ].DermatopathyInstruct diabetic patients to pay particular attention to skin integrity while being treated with pregabalin and to inform their healthcare provider about any sores or skin problems. Some animals treated with pregabalin developed skin ulcerations, although no increased incidence of skin lesions associated with pregabalin was observed in clinical trials [see Nonclinical Toxicology (13.2) ].Dispense with Medication Guide available at: https://risingpharma.com/Medguides/PregabalinCapsulesMG.pdf.

SPL MEDGUIDE SECTION.

Medication Guide Pregabalin (pree gab lin)Capsules, CVRead this Medication Guide before you start taking pregabalin capsules and each time you get refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. If you have any questions about pregabalin capsules, ask your healthcare provider or pharmacist. What is the most important information should know about pregabalin capsules Pregabalin capsules may cause serious side effects including:o serious, even life-threatening, allergic reactionsosuicidal thoughts or actionsoserious breathing problemsoswelling of your hands, legs and feetodizziness and sleepiness These serious side effects are described below:o Serious, even life-threatening, allergic reactions.Stop taking pregabalin capsules and call your healthcare provider right away if you have any of these signs of serious allergic reaction: oswelling of your face, mouth, lips, gums, tongue, throat or neckotrouble breathingorash, hives (raised bumps) or blistersoLike other antiepileptic drugs, pregabalin capsules may cause suicidal thoughts or actions in very small number of people, about in 500. This can happen while you take Pregabalin capsules or after stopping. Call healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:othoughts about suicide or dyingoattempts to commit suicideonew or worse depressiononew or worse anxietyofeeling agitated or restlessopanic attacksotrouble sleeping (insomnia)onew or worse irritabilityoacting aggressive, being angry, or violentoacting on dangerous impulsesoan extreme increase in activity and talking (mania)oother unusual changes in behavior or moodIf you have suicidal thoughts or actions, do not stop pregabalin capsules without first talking to healthcare provider.oStopping pregabalin capsules suddenly can cause serious problems.oSuicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes.How can watch for early symptoms of suicidal thoughts and actionsoPay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.oKeep all follow-up visits with your healthcare provider as scheduled.oCall your healthcare provider between visits as needed, especially if you are worried about symptoms.oSerious breathing problems can occur when pregabalin capsules are taken with other medicines that can cause severe sleepiness or decreased awareness, or when it is taken by someone who already has breathing problems. Watch for increased sleepiness or decreased breathing when starting pregabalin capsules or when the dose is increased. Get help right away if breathing problems occur.oSwelling of your hands, legs and feet. This swelling can be serious problem for people with heart problems.oDizziness and sleepiness. Do not drive car, work with machines, or do other dangerous activities until you know how pregabalin capsules affect you. Ask your healthcare provider about when it will be okay to do these activities.What are pregabalin capsulesPregabalin capsules are prescription medicine used in adults, 18 years of age and older to treat:opain from damaged nerves (neuropathic pain) that happens with diabetesopain from damaged nerves (neuropathic pain) that follows healing of shinglesofibromyalgia (pain all over your body)opain from damaged nerves (neuropathic pain) that follows spinal cord injuryIt is not known if pregabalin capsules are safe and effective in people under 18 years of age for the treatment of fibromyalgia and neuropathic pain with diabetes, shingles, or spinal cord injury. Pregabalin capsules are prescription medicine used in people month of age and older to treat: opartial-onset seizures when taken together with other seizure medicines.For the treatment of partial-onset seizures when taken together with other seizure medicines, it is not known if pregabalin capsules are safe and effective in children under month of age.Who should not take pregabalin capsules Do not take pregabalin capsules if you are allergic to pregabalin or any of the ingredients in pregabalin capsules.See What is the most important information should know about pregabalin capsules for the signs of an allergic reaction. See the end of this Medication Guide for complete list of ingredients in pregabalin capsules.What should tell my healthcare provider before taking pregabalin capsulesBefore taking pregabalin capsules, tell your healthcare provider about all your medical conditions, including if you:ohave or have had depression, mood problems or suicidal thoughts or behavior.ohave breathing problems.ohave kidney problems or get kidney dialysis.ohave heart problems including heart failure.ohave bleeding problem or low blood platelet count.ohave abused prescription medicines, street drugs, or alcohol in the past.ohave ever had swelling of your face, mouth, tongue, lips, gums, neck, or throat (angioedema).oplan to father child. Animal studies have shown that pregabalin, the active ingredient in pregabalin capsules, made male animals less fertile and caused sperm to change. Also, in animal studies, birth defects were seen in the offspring (babies) of male animals treated with pregabalin. It is not known if these problems can happen in people who take pregabalin capsules.o are pregnant or plan to become pregnant. Pregabalin may harm your unborn baby. You and your healthcare provider will decide if you should take pregabalin capsules while you are pregnant.oIf you become pregnant while taking pregabalin capsules, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy. Information about the registry can also be found at the website, http://www.aedpregnancyregistry.org/.oare breastfeeding or plan to breastfeed. Pregabalin passes into your breast milk. It is not known if pregabalin capsules can harm your baby. Talk to your healthcare provider about the best way to feed your baby if you take pregabalin capsules. Breastfeeding is not recommended while taking pregabalin capsules.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins or herbal supplements. Pregabalin capsules and other medicines may affect each other causing side effects. Especially tell your healthcare provider if you take:oangiotensin converting enzyme (ACE) inhibitors, which are used to treat many conditions, including high blood pressure. You may have higher chance for swelling and hives if these medicines are taken with pregabalin capsules.oAvandia (rosiglitazone) or Actos (pioglitazone) for diabetes. You may have higher chance of weight gain or swelling of your hands or feet if these medicines are taken with pregabalin capsules.oany opioid pain medicine (such as oxycodone), or medicines for anxiety (such as lorazepam) or insomnia (such as zolpidem). You may have higher chance for dizziness, sleepiness or serious breathing problems if these medicines are taken with pregabalin capsules.oany medicines that make you sleepy.Know the medicines you take. Keep list of them with you to show your healthcare provider and pharmacist each time you get new medicine. Do not start new medicine without talking with your healthcare provider.How should take pregabalin capsulesoTake pregabalin capsules exactly as prescribed. Your healthcare provider will tell you how much pregabalin capsules to take and when to take it.oPregabalin capsules may be taken with or without food.oYour healthcare provider may change your dose. Do not change your dose without talking to your healthcare provider.oDo not stop taking pregabalin capsules without talking to your healthcare provider. If you stop taking pregabalin capsules suddenly you may have headaches, nausea, diarrhea, trouble sleeping, increased sweating, or you may feel anxious. If you have epilepsy and you stop taking pregabalin capsules suddenly, you may have seizures more often. Talk with your healthcare provider about how to stop pregabalin capsules slowly.oIf you miss dose, take it as soon as you remember. If it is almost time for your next dose, just skip the missed dose. Take the next dose at your regular time. Do not take doses at the same time.oIf you take too much pregabalin capsules, call your healthcare provider or poison control center, or go to the nearest emergency room right away.What should avoid while taking pregabalin capsulesoDo not drive car, work with machines, or do other dangerous activities until you know how pregabalin capsules affect you.oDo not drink alcohol while taking pregabalin capsules. Pregabalin capsules and alcohol can affect each other and increase side effects such as sleepiness and dizziness.What are the possible side effects of pregabalin capsulesPregabalin capsules may cause serious side effects, including:oSee What is the most important information should know about pregabalin capsuleso Muscle problems, muscle pain, soreness, or weakness. If you have these symptoms, especially if you feel sick and have fever, tell your healthcare provider right away.oProblems with your eyesight, including blurry vision. Call your healthcare provider if you have any changes in your eyesight.oWeight gain. If you have diabetes, weight gain may affect the management of your diabetes. Weight gain can also be serious problem for people with heart problems.oFeeling high.The most common side effects of pregabalin capsules in adults are:odizzinessoblurry visionodry mouthoweight gainosleepinessotrouble concentratingoswelling of hands and feetThe most common side effects of pregabalin capsules in children are weight gain, increase in appetite, and sleepiness.Pregabalin capsules caused skin sores in animal studies. Skin sores did not happen in studies in people. If you have diabetes, you should pay attention to your skin while taking pregabalin capsules and tell your healthcare provider about any sores or skin problems. Tell your healthcare provider about any side effect that bothers you or that does not go away. These are not all the possible side effects of pregabalin capsules. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store pregabalin capsulesoStore pregabalin capsules at room temperature between 68F to 77F (20C to 25C) in its original package.oSafely throw away any pregabalin capsules that are out of date or no longer needed. Keep pregabalin capsules and all medicines out of the reach of children.General information about the safe and effective use of pregabalin capsulesMedicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use pregabalin capsules for condition for which it was not prescribed. Do not give pregabalin capsules to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for information about pregabalin capsules that is written for health professionals.For more information call Rising Pharma Holdings, Inc. at 1-844-874-7464.What are the ingredients in pregabalin capsulesActive ingredient: pregabalinInactive ingredients:Pregabalin capsules: pregelatinized starch, talcCapsule shell: gelatin, sodium lauryl sulfate and titanium dioxide; Orange Red capsule shell: red iron oxide; Imprinting ink: shellac, black iron oxide, propylene glycol, potassium hydroxide. This Medication Guide has been approved by the U.S. Food and Drug Administration. Dispense with Medication Guide available at:https://risingpharma.com/Medguides/PregabalinCapsulesMG.pdfManufactured for:Rising Pharma Holdings, Inc.East Brunswick, NJ 08816 Manufactured by:Laurus Labs LimitedAnakapalli-531011IndiaPackaged and Distributed by:MAJOR(R) PHARMACEUTICALSIndianapolis, IN 46268 USARefer to package label for Distributors NDC Number M. L. No.: 16/VSP/AP/2015/F&B/CC Revised: 05/2025 MGR41710-03. serious, even life-threatening, allergic reactions. osuicidal thoughts or actions. oserious breathing problems. oswelling of your hands, legs and feet. odizziness and sleepiness. Serious, even life-threatening, allergic reactions.. oswelling of your face, mouth, lips, gums, tongue, throat or neck. otrouble breathing. orash, hives (raised bumps) or blisters. oLike other antiepileptic drugs, pregabalin capsules may cause suicidal thoughts or actions in very small number of people, about in 500. This can happen while you take Pregabalin capsules or after stopping. Call healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:. othoughts about suicide or dying. oattempts to commit suicide. onew or worse depression. onew or worse anxiety. ofeeling agitated or restless. opanic attacks. otrouble sleeping (insomnia). onew or worse irritability. oacting aggressive, being angry, or violent. oacting on dangerous impulses. oan extreme increase in activity and talking (mania). oother unusual changes in behavior or mood. oStopping pregabalin capsules suddenly can cause serious problems.. oSuicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes.. oPay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.. oKeep all follow-up visits with your healthcare provider as scheduled.. oCall your healthcare provider between visits as needed, especially if you are worried about symptoms.. oSerious breathing problems can occur when pregabalin capsules are taken with other medicines that can cause severe sleepiness or decreased awareness, or when it is taken by someone who already has breathing problems. Watch for increased sleepiness or decreased breathing when starting pregabalin capsules or when the dose is increased. Get help right away if breathing problems occur.. oSwelling of your hands, legs and feet. This swelling can be serious problem for people with heart problems.. oDizziness and sleepiness. Do not drive car, work with machines, or do other dangerous activities until you know how pregabalin capsules affect you. Ask your healthcare provider about when it will be okay to do these activities.. opain from damaged nerves (neuropathic pain) that happens with diabetes. opain from damaged nerves (neuropathic pain) that follows healing of shingles. ofibromyalgia (pain all over your body). opain from damaged nerves (neuropathic pain) that follows spinal cord injury. opartial-onset seizures when taken together with other seizure medicines.. ohave or have had depression, mood problems or suicidal thoughts or behavior.. ohave breathing problems.. ohave kidney problems or get kidney dialysis.. ohave heart problems including heart failure.. ohave bleeding problem or low blood platelet count.. ohave abused prescription medicines, street drugs, or alcohol in the past.. ohave ever had swelling of your face, mouth, tongue, lips, gums, neck, or throat (angioedema).. oplan to father child. Animal studies have shown that pregabalin, the active ingredient in pregabalin capsules, made male animals less fertile and caused sperm to change. Also, in animal studies, birth defects were seen in the offspring (babies) of male animals treated with pregabalin. It is not known if these problems can happen in people who take pregabalin capsules.. are pregnant or plan to become pregnant. Pregabalin may harm your unborn baby. You and your healthcare provider will decide if you should take pregabalin capsules while you are pregnant.oIf you become pregnant while taking pregabalin capsules, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy. Information about the registry can also be found at the website, http://www.aedpregnancyregistry.org/.. oIf you become pregnant while taking pregabalin capsules, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy. Information about the registry can also be found at the website, http://www.aedpregnancyregistry.org/.. oare breastfeeding or plan to breastfeed. Pregabalin passes into your breast milk. It is not known if pregabalin capsules can harm your baby. Talk to your healthcare provider about the best way to feed your baby if you take pregabalin capsules. Breastfeeding is not recommended while taking pregabalin capsules.. oangiotensin converting enzyme (ACE) inhibitors, which are used to treat many conditions, including high blood pressure. You may have higher chance for swelling and hives if these medicines are taken with pregabalin capsules.. oAvandia (rosiglitazone) or Actos (pioglitazone) for diabetes. You may have higher chance of weight gain or swelling of your hands or feet if these medicines are taken with pregabalin capsules.. oany opioid pain medicine (such as oxycodone), or medicines for anxiety (such as lorazepam) or insomnia (such as zolpidem). You may have higher chance for dizziness, sleepiness or serious breathing problems if these medicines are taken with pregabalin capsules.. oany medicines that make you sleepy.. oTake pregabalin capsules exactly as prescribed. Your healthcare provider will tell you how much pregabalin capsules to take and when to take it.. oPregabalin capsules may be taken with or without food.. oYour healthcare provider may change your dose. Do not change your dose without talking to your healthcare provider.. oDo not stop taking pregabalin capsules without talking to your healthcare provider. If you stop taking pregabalin capsules suddenly you may have headaches, nausea, diarrhea, trouble sleeping, increased sweating, or you may feel anxious. If you have epilepsy and you stop taking pregabalin capsules suddenly, you may have seizures more often. Talk with your healthcare provider about how to stop pregabalin capsules slowly.. oIf you miss dose, take it as soon as you remember. If it is almost time for your next dose, just skip the missed dose. Take the next dose at your regular time. Do not take doses at the same time.. oIf you take too much pregabalin capsules, call your healthcare provider or poison control center, or go to the nearest emergency room right away.. oDo not drive car, work with machines, or do other dangerous activities until you know how pregabalin capsules affect you.. oDo not drink alcohol while taking pregabalin capsules. Pregabalin capsules and alcohol can affect each other and increase side effects such as sleepiness and dizziness.. oSee What is the most important information should know about pregabalin capsules. Muscle problems, muscle pain, soreness, or weakness. If you have these symptoms, especially if you feel sick and have fever, tell your healthcare provider right away.. oProblems with your eyesight, including blurry vision. Call your healthcare provider if you have any changes in your eyesight.. oWeight gain. If you have diabetes, weight gain may affect the management of your diabetes. Weight gain can also be serious problem for people with heart problems.. oFeeling high.. odizziness. oblurry vision. odry mouth. oweight gain. osleepiness. otrouble concentrating. oswelling of hands and feet. oStore pregabalin capsules at room temperature between 68F to 77F (20C to 25C) in its original package.. oSafely throw away any pregabalin capsules that are out of date or no longer needed.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. oLactation: Breastfeeding is not recommended. (8.2). oLactation: Breastfeeding is not recommended. (8.2). 8.1 Pregnancy. Pregnancy Exposure RegistryThere is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to pregabalin during pregnancy. To provide information regarding the effects of in utero exposure to pregabalin, physicians are advised to recommend that pregnant patients taking pregabalin capsules enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves.Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/. Risk SummaryObservational studies on the use of pregabalin during pregnancy suggest possible small increase in the rate of overall major birth defects, but there was no consistent or specific pattern of major birth defects identified (see Data). Available postmarketing data on miscarriage and other maternal, fetal, and long term developmental adverse effects were insufficient to identify risk associated with pregabalin.Postmarketing data suggest that extended gabapentinoid use with opioids close to delivery may increase the risk of neonatal withdrawal versus opioids alone (see Clinical Considerations). There are no comparative epidemiologic studies evaluating this association. Therefore, it is not known whether exposure to pregabalin alone late in pregnancy may cause withdrawal signs and symptoms.In animal reproduction studies, increased incidences of fetal structural abnormalities and other manifestations of developmental toxicity, including skeletal malformations, retarded ossification, and decreased fetal body weight were observed in the offspring of rats and rabbits given pregabalin orally during organogenesis, at doses that produced plasma pregabalin exposures (AUC) greater than or equal to 16 times human exposure at the maximum recommended dose (MRD) of 600 mg/day (see Data). In an animal development study, lethality, growth retardation, and nervous and reproductive system functional impairment were observed in the offspring of rats given pregabalin during gestation and lactation. The no-effect dose for developmental toxicity was approximately twice the human exposure at MRD.The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively.. Clinical ConsiderationsFetal/Neonatal Adverse ReactionsNeonatal withdrawal syndrome has been reported in newborns exposed to gabapentinoids in utero for an extended period of time when also exposed to opioids close to delivery. Neonatal withdrawal signs and symptoms reported have included tachypnea, vomiting, diarrhea, hypertonia, irritability, sneezing, poor feeding, hyperactivity, abnormal sleep pattern, and tremor. Reported signs and symptoms that may also be related to withdrawal include tongue thrusting, wandering eye movements while awake, back arching, and continuous extremity movements. Observe neonates exposed to pregabalin and opioids for signs and symptoms of neonatal withdrawal and manage accordingly.. DataHuman DataOne database study, which included over 2,700 pregnancies exposed to pregabalin (monotherapy) during the first trimester compared to 3,063,251 pregnancies unexposed to antiepileptics demonstrated prevalence ratios for major malformations overall of 1.14 (CI 95% 0.96 to 1.35) for pregabalin, 1.29 (CI 95% 1.01 to 1.65) for lamotrigine, 1.39 (CI 95% 1.07 to 1.82) for duloxetine, and 1.24 (CI 95% 1.00 to 1.54) for exposure to either lamotrigine or duloxetine. Important study limitations include uncertainty of whether women who filled prescription took the medication and inability to adequately control for the underlying disease and other potential confounders.A published study included results from two separate databases. One database, which included 353 pregnancies exposed to pregabalin (monotherapy) during the first trimester compared to 368,489 pregnancies unexposed to antiepileptics, showed no increase in risk of major birth defects; adjusted relative risk 0.87 (CI 95% 0.53 to 1.42). The second database, which included 118 pregnancies exposed to pregabalin (monotherapy) during the first trimester compared to 380,347 pregnancies unexposed to antiepileptics, suggested small increase in risk of major birth defects; adjusted relative risk 1.26 (CI 95% 0.64 to 2.49). The risk estimates crossed the null, and the study had limitations similar to the prior study.Other published epidemiologic studies reported inconsistent findings. No specific pattern of birth defects was identified across studies. All of the studies had limitations due to their retrospective design.. Animal DataWhen pregnant rats were given pregabalin (500, 1,250, or 2,500 mg/kg) orally throughout the period of organogenesis, incidences of specific skull alterations attributed to abnormally advanced ossification (premature fusion of the jugal and nasal sutures) were increased at greater than or equal to 1,250 mg/kg, and incidences of skeletal variations and retarded ossification were increased at all doses. Fetal body weights were decreased at the highest dose. The low dose in this study was associated with plasma exposure (AUC) approximately 17 times human exposure at the MRD of 600 mg/day. no-effect dose for rat embryo-fetal developmental toxicity was not established.When pregnant rabbits were given pregabalin (250, 500, or 1,250 mg/kg) orally throughout the period of organogenesis, decreased fetal body weight and increased incidences of skeletal malformations, visceral variations, and retarded ossification were observed at the highest dose. The no-effect dose for developmental toxicity in rabbits (500 mg/kg) was associated with plasma exposure approximately 16 times human exposure at the MRD.In study in which female rats were dosed with pregabalin (50, 100, 250, 1,250, or 2,500 mg/kg) throughout gestation and lactation, offspring growth was reduced at greater than or equal to 100 mg/kg and offspring survival was decreased at greater than or equal to 250 mg/kg. The effect on offspring survival was pronounced at doses greater than or equal to 1,250 mg/kg, with 100% mortality in high-dose litters. When offspring were tested as adults, neurobehavioral abnormalities (decreased auditory startle responding) were observed at greater than or equal to 250 mg/kg and reproductive impairment (decreased fertility and litter size) was seen at 1,250 mg/kg. The no-effect dose for pre- and postnatal developmental toxicity in rats (50 mg/kg) produced plasma exposure approximately times human exposure at the MRD.In the prenatal-postnatal study in rats, pregabalin prolonged gestation and induced dystocia at exposures greater than or equal to 50 times the mean human exposure (AUC (0 to 24) of 123 mcghr/mL) at the MRD.. 8.2 Lactation. Risk SummarySmall amounts of pregabalin have been detected in the milk of lactating women. pharmacokinetic study in lactating women detected pregabalin in breast milk at average steady state concentrations approximately 76% of those in maternal plasma. The estimated average daily infant dose of pregabalin from breast milk (assuming mean milk consumption of 150 mL/kg/day) was 0.31 mg/kg/day, which on mg/kg basis would be approximately 7% of the maternal dose (see Data). The study did not evaluate the effects of pregabalin on milk production or the effects of pregabalin on the breastfed infant.Based on animal studies, there is potential risk of tumorigenicity with pregabalin exposure via breast milk to the breastfed infant [see Nonclinical Toxicology (13.1)]. Available clinical study data in patients greater than 12 years of age do not provide clear conclusion about the potential risk of tumorigenicity with pregabalin [see Warnings and Precautions (5.9)]. Because of the potential risk of tumorigenicity, breastfeeding is not recommended during treatment with pregabalin.. DataA pharmacokinetic study in ten lactating women, who were at least 12 weeks postpartum, evaluated the concentrations of pregabalin in plasma and breast milk. Pregabalin 150 mg oral capsule was given every 12 hours (300 mg daily dose) for total of four doses. Pregabalin was detected in breast milk at average steady-state concentrations approximately 76% of those in maternal plasma. The estimated average daily infant dose of pregabalin from breast milk (assuming mean milk consumption of 150 mL/kg/day) was 0.31 mg/kg/day, which on mg/kg basis would be approximately 7% of the maternal dose. The study did not evaluate the effects of pregabalin on milk production. Infants did not receive breast milk obtained during the dosing period, therefore, the effects of pregabalin on the breast fed infant were not evaluated.. 8.3 Females and Males of Reproductive Potential. Infertility. Males. Effects on SpermatogenesisIn randomized, double-blind, placebo-controlled non-inferiority study to assess the effect of pregabalin on sperm characteristics, healthy male subjects received pregabalin at daily dose up to 600 mg (n=111) or placebo (n=109) for 13 weeks (one complete sperm cycle) followed by 13-week washout period (off-drug). total of 65 subjects in the pregabalin group (59%) and 62 subjects in the placebo group (57%) were included in the per protocol (PP) population. These subjects took study drug for at least weeks, had appropriate timing of semen collections and did not have any significant protocol violations. Among these subjects, approximately 9% of the pregabalin group (6/65) vs. 3% in the placebo group (2/62) had greater than or equal to 50% reduction in mean sperm concentrations from baseline at Week 26 (the primary endpoint). The difference between pregabalin and placebo was within the pre-specified non-inferiority margin of 20%. There were no adverse effects of pregabalin on sperm morphology, sperm motility, serum FSH or serum testosterone levels as compared to placebo. In subjects in the PP population with greater than or equal to 50% reduction in sperm concentration from baseline, sperm concentrations were no longer reduced by greater than or equal to 50% in any affected subject after an additional months off-drug. In one subject, however, subsequent semen analyses demonstrated reductions from baseline of greater than or equal to 50% at and 12 months off-drug. The clinical relevance of these data is unknown.In the animal fertility study with pregabalin in male rats, adverse reproductive and developmental effects were observed [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use. Neuropathic Pain Associated with Diabetic Peripheral Neuropathy, Postherpetic Neuralgia, and Neuropathic Pain Associated with Spinal Cord InjurySafety and effectiveness in pediatric patients have not been established.FibromyalgiaSafety and effectiveness in pediatric patients have not been established. 15-week, placebo-controlled trial was conducted with 107 pediatric patients with fibromyalgia, ages 12 through 17 years, at pregabalin total daily doses of 75 to 450 mg per day. The primary efficacy endpoint of change from baseline to Week 15 in mean pain intensity (derived from an 11-point numeric rating scale) showed numerically greater improvement for the pregabalin-treated patients compared to placebo-treated patients, but did not reach statistical significance. The most frequently observed adverse reactions in the clinical trial included dizziness, nausea, headache, weight increased, and fatigue. The overall safety profile in adolescents was similar to that observed in adults with fibromyalgia.Adjunctive Therapy for Partial-Onset SeizuresSafety and effectiveness in pediatric patients below the age of month have not been established.4 to Less Than 17 Years of Age with Partial-Onset Seizures The safety and effectiveness of pregabalin as adjunctive treatment for partial-onset seizures in pediatric patients to less than 17 years of age have been established in 12-week, double-blind, placebo-controlled study (n=295) [see Clinical Studies (14.3)]. Patients treated with pregabalin 10 mg/kg/day had, on average, 21.0% greater reduction in partial-onset seizures than patients treated with placebo (p=0.0185). Patients treated with pregabalin 2.5 mg/kg/day had, on average, 10.5% greater reduction in partial-onset seizures than patients treated with placebo, but the difference was not statistically significant (p=0.2577). Responder rates (50% or greater reduction in partial-onset seizure frequency) were key secondary efficacy parameter and showed numerical improvement with pregabalin compared with placebo: the responder rates were 40.6%, 29.1%, and 22.6%, for pregabalin 10 mg/kg/day, pregabalin 2.5 mg/kg/day, and placebo, respectively. The most common adverse reactions (>=5%) with pregabalin in this study were somnolence, weight increased, and increased appetite [see Adverse Reactions (6.1)]. The use of pregabalin 2.5 mg/kg/day in pediatric patients is further supported by evidence from adequate and well-controlled studies in adults with partial-onset seizures and pharmacokinetic data from adult and pediatric patients [see Clinical Pharmacology (12.3)]. Month to Less than Years of Age with Partial-Onset Seizures The safety and effectiveness of pregabalin as adjunctive treatment for partial-onset seizures in pediatric patients month to less than years of age have been established in 14-day double-blind, placebo-controlled study (N=175) [see Clinical Studies (14.3)]. The youngest subject evaluated was months of age; use in patients month to less than months of age is supported by additional pharmacokinetic analyses. Patients treated with pregabalin 14 mg/kg/day had, on average, 43.9% greater reduction in partial-onset seizures than patients treated with placebo (p=0.0223). In addition, pediatric patients treated with pregabalin 14 mg/kg/day showed numerical improvement in responder rates (>=50% reduction in partial-onset seizure frequency) compared with placebo (53.6% versus 41.5%). Patients treated with pregabalin mg/kg/day did not show improvement relative to placebo for either endpoint. The most common dose-related adverse reactions (>5%) with pregabalin in this study were somnolence, pneumonia, and viral infection [see Adverse Reactions (6.1)]. Juvenile Animal DataIn studies in which pregabalin (50 to 500 mg/kg) was orally administered to young rats from early in the postnatal period (Postnatal Day 7) through sexual maturity, neurobehavioral abnormalities (deficits in learning and memory, altered locomotor activity, decreased auditory startle responding and habituation) and reproductive impairment (delayed sexual maturation and decreased fertility in males and females) were observed at doses greater than or equal to 50 mg/kg. The neurobehavioral changes of acoustic startle persisted at greater than or equal to 250 mg/kg and locomotor activity and water maze performance at greater than or equal to 500 mg/kg in animals tested after cessation of dosing and, thus, were considered to represent long-term effects. The low effect dose for developmental neurotoxicity and reproductive impairment in juvenile rats (50 mg/kg) was associated with plasma pregabalin exposure (AUC) approximately equal to human exposure at the maximum recommended dose of 600 mg/day. no-effect dose was not established. 8.5 Geriatric Use. In controlled clinical studies of pregabalin in neuropathic pain associated with diabetic peripheral neuropathy, 246 patients were 65 to 74 years of age, and 73 patients were 75 years of age or older.In controlled clinical studies of pregabalin in neuropathic pain associated with postherpetic neuralgia, 282 patients were 65 to 74 years of age, and 379 patients were 75 years of age or older.In controlled clinical studies of pregabalin in epilepsy, there were only 10 patients 65 to 74 years of age, and patients who were 75 years of age or older.No overall differences in safety and efficacy were observed between these patients and younger patients.In controlled clinical studies of pregabalin in fibromyalgia, 106 patients were 65 years of age or older. Although the adverse reaction profile was similar between the two age groups, the following neurological adverse reactions were more frequent in patients 65 years of age or older: dizziness, vision blurred, balance disorder, tremor, confusional state, coordination abnormal, and lethargy.Pregabalin is known to be substantially excreted by the kidney, and the risk of toxic reactions to pregabalin may be greater in patients with impaired renal function. Because pregabalin is eliminated primarily by renal excretion, adjust the dose for elderly patients with renal impairment [see Dosage and Administration (2.7)].. 8.6 Renal Impairment. Pregabalin is eliminated primarily by renal excretion and dose adjustment is recommended for adult patients with renal impairment [see Dosage and Administration (2.7) and Clinical Pharmacology (12.3) ]. The use of pregabalin in pediatric patients with compromised renal function has not been studied.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oAngioedema (e.g., swelling of the throat, head, and neck) can occur, and may be associated with life-threatening respiratory compromise requiring emergency treatment. Discontinue pregabalin immediately in these cases. (5.1)oHypersensitivity reactions (e.g., hives, dyspnea, and wheezing) can occur. Discontinue pregabalin immediately in these patients. (5.2)oAntiepileptic drugs, including pregabalin, the active ingredient in pregabalin capsules, increase the risk of suicidal thoughts or behavior. (5.3)oAbrupt or rapid discontinuation may increase the risk for seizures. Withdrawal symptoms or suicidal behavior and ideation have been observed after discontinuation. Taper pregabalin gradually over minimum of week. (5.4)oRespiratory depression: May occur with pregabalin, when used with concomitant CNS depressants or in the setting of underlying respiratory impairment. Monitor patients and adjust dosage as appropriate. (5.5)oPregabalin may cause dizziness and somnolence and impair patients ability to drive or operate machinery. (5.6)oPregabalin may cause peripheral edema. Exercise caution when co-administering pregabalin and thiazolidinedione antidiabetic agents.(5.7). oAngioedema (e.g., swelling of the throat, head, and neck) can occur, and may be associated with life-threatening respiratory compromise requiring emergency treatment. Discontinue pregabalin immediately in these cases. (5.1). oHypersensitivity reactions (e.g., hives, dyspnea, and wheezing) can occur. Discontinue pregabalin immediately in these patients. (5.2). oAntiepileptic drugs, including pregabalin, the active ingredient in pregabalin capsules, increase the risk of suicidal thoughts or behavior. (5.3). oAbrupt or rapid discontinuation may increase the risk for seizures. Withdrawal symptoms or suicidal behavior and ideation have been observed after discontinuation. Taper pregabalin gradually over minimum of week. (5.4). oRespiratory depression: May occur with pregabalin, when used with concomitant CNS depressants or in the setting of underlying respiratory impairment. Monitor patients and adjust dosage as appropriate. (5.5). oPregabalin may cause dizziness and somnolence and impair patients ability to drive or operate machinery. (5.6). oPregabalin may cause peripheral edema. Exercise caution when co-administering pregabalin and thiazolidinedione antidiabetic agents.(5.7). 5.1 Angioedema. There have been postmarketing reports of angioedema in patients during initial and chronic treatment with pregabalin. Specific symptoms included swelling of the face, mouth (tongue, lips, and gums), and neck (throat and larynx). There were reports of life-threatening angioedema with respiratory compromise requiring emergency treatment. Discontinue pregabalin immediately in patients with these symptoms.Exercise caution when prescribing pregabalin to patients who have had previous episode of angioedema. In addition, patients who are taking other drugs associated with angioedema (e.g., angiotensin converting enzyme inhibitors [ACE-inhibitors]) may be at increased risk of developing angioedema.. 5.2 Hypersensitivity. There have been postmarketing reports of hypersensitivity in patients shortly after initiation of treatment with pregabalin. Adverse reactions included skin redness, blisters, hives, rash, dyspnea, and wheezing. Discontinue pregabalin immediately in patients with these symptoms.. 5.3 Suicidal Behavior and Ideation. Antiepileptic drugs (AEDs), including pregabalin, the active ingredient in pregabalin, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Suicidal behavior and ideation have also been reported in patients after discontinuation of pregabalin [see Warnings and Precautions (5.4) ]. Monitor patients treated with any AED for any indication for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed.Table shows absolute and relative risk by indication for all evaluated AEDs.Table 3. Risk by Indication for Antiepileptic Drugs in the Pooled Analysis IndicationPlacebo Patients with Events Per 1,000 PatientsDrug Patients with Events Per 1,000 PatientsRelative Risk: Incidence of Events in Drug Patients/Incidence in Placebo PatientsRisk Difference: Additional Drug Patients with Events Per 1,000 PatientsEpilepsy Psychiatric Other Total1.05.71.02.43.48.51.84.33.51.51.91.82.42.90.91.9The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing pregabalin or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.. 5.4 Increased Risk of Adverse Reactions with Abrupt or Rapid Discontinuation. As with all antiepileptic drugs (AEDs), withdraw pregabalin gradually to minimize the potential of increased seizure frequency in patients with seizure disorders.Following abrupt or rapid discontinuation of pregabalin, some patients reported symptoms including insomnia, nausea, headache, anxiety, hyperhidrosis, and diarrhea [see Adverse Reactions (6.2), Drug Abuse and Dependence (9.3)]. Suicidal behavior and ideation have also been reported in patients after discontinuation of pregabalin [see Warnings and Precautions (5.3) ].If pregabalin is discontinued, taper the drug gradually over minimum of week rather than discontinue the drug abruptly.. 5.5 Respiratory Depression. There is evidence from case reports, human studies, and animal studies associating pregabalin with serious, life-threatening, or fatal respiratory depression when co-administered with central nervous system (CNS) depressants, including opioids, or in the setting of underlying respiratory impairment. When the decision is made to co-prescribe pregabalin with another CNS depressant, particularly an opioid, or to prescribe pregabalin to patients with underlying respiratory impairment, monitor patients for symptoms of respiratory depression and sedation, and consider initiating pregabalin at low dose. The management of respiratory depression may include close observation, supportive measures, and reduction or withdrawal of CNS depressants (including pregabalin).There is more limited evidence from case reports, animal studies, and human studies associating pregabalin with serious respiratory depression, without co-administered CNS depressants or without underlying respiratory impairment.. 5.6 Dizziness and Somnolence. Pregabalin may cause dizziness and somnolence. Inform patients that pregabalin-related dizziness and somnolence may impair their ability to perform tasks such as driving or operating machinery [see Patient Counseling Information (17)].In the pregabalin controlled trials in adult patients, dizziness was experienced by 30% of pregabalin-treated patients compared to 8% of placebo-treated patients; somnolence was experienced by 23% of pregabalin-treated patients compared to 8% of placebo-treated patients. Dizziness and somnolence generally began shortly after the initiation of pregabalin therapy and occurred more frequently at higher doses. Dizziness and somnolence were the adverse reactions most frequently leading to withdrawal (4% each) from controlled studies. In pregabalin-treated patients reporting these adverse reactions in short-term, controlled studies, dizziness persisted until the last dose in 30% and somnolence persisted until the last dose in 42% of patients [see Drug Interactions (7)].In the pregabalin controlled trials in pediatric patients to less than 17 years of age and month to less than years of age for the treatment of partial-onset seizures, somnolence was reported in 21% and 15% of pregabalin-treated patients compared to 14% and 9% of placebo-treated patients, respectively, and occurred more frequently at higher doses. For patients month to less than years of age, somnolence includes related terms lethargy, sluggishness, and hypersomnia.. 5.7 Peripheral Edema. Pregabalin treatment may cause peripheral edema. In short-term trials of patients without clinically significant heart or peripheral vascular disease, there was no apparent association between peripheral edema and cardiovascular complications such as hypertension or congestive heart failure. Peripheral edema was not associated with laboratory changes suggestive of deterioration in renal or hepatic function.In controlled clinical trials in adult patients, the incidence of peripheral edema was 6% in the pregabalin group compared with 2% in the placebo group. In controlled clinical trials, 0.5% of pregabalin patients and 0.2% placebo patients withdrew due to peripheral edema.Higher frequencies of weight gain and peripheral edema were observed in patients taking both pregabalin and thiazolidinedione antidiabetic agent compared to patients taking either drug alone. The majority of patients using thiazolidinedione antidiabetic agents in the overall safety database were participants in studies of pain associated with diabetic peripheral neuropathy. In this population, peripheral edema was reported in 3% (2/60) of patients who were using thiazolidinedione antidiabetic agents only, 8% (69/859) of patients who were treated with pregabalin only, and 19% (23/120) of patients who were on both pregabalin and thiazolidinedione antidiabetic agents. Similarly, weight gain was reported in 0% (0/60) of patients on thiazolidinediones only; 4% (35/859) of patients on pregabalin only; and 7.5% (9/120) of patients on both drugs.As the thiazolidinedione class of antidiabetic drugs can cause weight gain and/or fluid retention, possibly exacerbating or leading to heart failure, exercise caution when co-administering pregabalin and these agents.Because there are limited data on congestive heart failure patients with New York Heart Association (NYHA) Class III or IV cardiac status, exercise caution when using pregabalin in these patients.. 5.8 Weight Gain. Pregabalin treatment may cause weight gain. In pregabalin controlled clinical trials in adult patients of up to 14 weeks, gain of 7% or more over baseline weight was observed in 9% of pregabalin-treated patients and 2% of placebo-treated patients. Few patients treated with pregabalin (0.3%) withdrew from controlled trials due to weight gain. Pregabalin associated weight gain was related to dose and duration of exposure but did not appear to be associated with baseline BMI, gender, or age. Weight gain was not limited to patients with edema [see Warnings and Precautions (5.7)].Although weight gain was not associated with clinically important changes in blood pressure in short-term controlled studies, the long-term cardiovascular effects of pregabalin-associated weight gain are unknown.Among diabetic patients, pregabalin-treated patients gained an average of 1.6 kg (range: -16 to 16 kg), compared to an average 0.3 kg (range: -10 to kg) weight gain in placebo patients. In cohort of 333 diabetic patients who received pregabalin for at least years, the average weight gain was 5.2 kg.While the effects of pregabalin-associated weight gain on glycemic control have not been systematically assessed, in controlled and longer-term open label clinical trials with diabetic patients, pregabalin treatment did not appear to be associated with loss of glycemic control (as measured by HbA1C).. 5.9 Tumorigenic Potential. In standard preclinical in vivo lifetime carcinogenicity studies of pregabalin, an unexpectedly high incidence of hemangiosarcoma was identified in two different strains of mice [see Nonclinical Toxicology (13.1)]. The clinical significance of this finding is unknown. Clinical experience during pregabalins premarketing development provides no direct means to assess its potential for inducing tumors in humans.In clinical studies across various patient populations, comprising 6,396 patient-years of exposure in patients greater than 12 years of age, new or worsening-preexisting tumors were reported in 57 patients. Without knowledge of the background incidence and recurrence in similar populations not treated with pregabalin, it is impossible to know whether the incidence seen in these cohorts is or is not affected by treatment.. 5.10 Ophthalmological Effects. In controlled studies in adult patients, higher proportion of patients treated with pregabalin reported blurred vision (7%) than did patients treated with placebo (2%), which resolved in majority of cases with continued dosing. Less than 1% of patients discontinued pregabalin treatment due to vision-related events (primarily blurred vision).Prospectively planned ophthalmologic testing, including visual acuity testing, formal visual field testing and dilated funduscopic examination, was performed in over 3,600 patients. In these patients, visual acuity was reduced in 7% of patients treated with pregabalin, and 5% of placebo-treated patients. Visual field changes were detected in 13% of pregabalin-treated, and 12% of placebo-treated patients. Funduscopic changes were observed in 2% of pregabalin-treated and 2% of placebo-treated patients.Although the clinical significance of the ophthalmologic findings is unknown, inform patients to notify their physician if changes in vision occur. If visual disturbance persists, consider further assessment. Consider more frequent assessment for patients who are already routinely monitored for ocular conditions [see Patient Counseling Information (17)].. 5.11 Creatine Kinase Elevations. Pregabalin treatment was associated with creatine kinase elevations. Mean changes in creatine kinase from baseline to the maximum value were 60 U/L for pregabalin-treated patients and 28 U/L for the placebo patients. In all controlled trials in adult patients across multiple patient populations, 1.5% of patients on pregabalin and 0.7% of placebo patients had value of creatine kinase at least three times the upper limit of normal. Three pregabalin-treated subjects had events reported as rhabdomyolysis in premarketing clinical trials. The relationship between these myopathy events and pregabalin is not completely understood because the cases had documented factors that may have caused or contributed to these events. Instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if these muscle symptoms are accompanied by malaise or fever. Discontinue treatment with pregabalin if myopathy is diagnosed or suspected or if markedly elevated creatine kinase levels occur.. 5.12 Decreased Platelet Count. Pregabalin treatment was associated with decrease in platelet count. Pregabalin-treated subjects experienced mean maximal decrease in platelet count of 20 103/uL, compared to 11 103/uL in placebo patients. In the overall database of controlled trials in adult patients, 2% of placebo patients and 3% of pregabalin patients experienced potentially clinically significant decrease in platelets, defined as 20% below baseline value and less than 150 103/uL. single pregabalin-treated subject developed severe thrombocytopenia with platelet count less than 20 103/ uL. In randomized controlled trials, pregabalin was 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 in adult patients, the mean PR interval increase was to 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.