Anticonvulsants, including pregabalin, are thought to carry an increased risk of depression (2%) and suicidal ideation/behavior. An analysis by the FDA of previously gathered drug data showed that patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) as patients receiving placebo (0.24%). The relative risk was higher in patients with epilepsy compared to those with other conditions. Age was not a determining factor. The increased risk of suicidal ideation and behavior occurred between 1 and 24 weeks after therapy initiation. However, a longer duration of therapy should not preclude the possibility of an association to the drug since most studies included in the analysis did not continue beyond 24 weeks. All patients beginning treatment with anticonvulsants or currently receiving such treatment should be closely monitored for emerging or worsening suicidal thoughts/behavior or depression. Patients and caregivers should be informed of the increased risk of suicidal thoughts and behaviors and should be advised to immediately report the emergence or worsening of depression, the emergence of suicidal thoughts or behavior, thoughts of self-harm, or other unusual changes in mood or behavior.[31493]

Peripheral edema occurred in roughly 27% of patients taking pregabalin doses of immediate-release pregabalin 300 to 600 mg/day and in 17% of those taking 150 mg/day.[30759] Lower incidences (3% to 16%) of peripheral edema, edema (1% to 8.2%), and fluid retention (2% to 3%) have been reported; 0.5% of pregabalin patients withdrew from therapy due to fluid retention vs. 0.2% of those on placebo.[31493] Across all clinical trials of the controlled-release tablets for pain indications, peripheral edema occurred in 5.3% of patients during single-blind phase. Peripheral edema (3.8% to 4.9%) and edema (0.4% to 1.4%) occurred during a randomized trial of the controlled-release tablets in patients with postherpetic neuralgia. Peripheral edema led to pregabalin discontinuation in 0.5% to 0.8% of patients.[62506] Pregabalin-induced edema did not appear to be associated with cardiovascular complications or renal or hepatic deterioration in short-term studies in patients without these complications. However, higher rates of peripheral edema (up to 19%) and an increase in weight (up to 7.5%) may occur in patients who concomitantly take a thiazolidinedione antidiabetic agent with pregabalin. As the thiazolidinedione class of antidiabetic drugs can cause gain in weight and/or fluid retention, possibly exacerbating or leading to heart failure, care should be taken when coadministering pregabalin and these agents.[31493] Dyspnea, which may or may not be associated with edema, has also been infrequently reported (2% vs. 1% placebo).

Adverse events not listed elsewhere that have been reported during pregabalin clinical trials in more than 1% of patients included anxiety (2%), arthralgia (3% to 6%), chest pain (unspecified) (1% to 4%), muscle spasms (2% to 4%), speech disorder or dyspraxia (1% to 7%), hypotension (2.2% or less), hypertension (2.2%), and urinary incontinence (1% to 2.7%). Other adverse reactions occurring in 1% or more of pregabalin-treated patients during clinical trials included fever, impotence (erectile dysfunction), increased urinary frequency, libido decrease, leg muscle cramps, myalgia, orgasm dysfunction (anorgasmia), and tinnitus. Infrequent (0.1% to 1%) adverse events reported during pregabalin clinical trials included albuminuria, amenorrhea, arthrosis, chills, dysmenorrhea, dysuria, ejaculation dysfunction, heart failure, hematuria, hyperacusis, leukorrhea, libido increase, menorrhagia, metrorrhagia, nephritis, oliguria, urinary retention, pelvic pain, joint stiffness, syncope, thrombo-phlebitis, orthostatic hypotension, palpitations, chest pain (unspecified), and facial edema. Rare reactions (less than 0.1%) during clinical trials included apnea, ascites, atelectasis, balanitis, bronchiolitis, cervicitis, coma, crystalluria, dyspareunia, epididymitis, granuloma, hiccups, increased intracranial pressure, lactation, laryngismus or laryngospasm, glomerulitis, ovarian disorder, parosmia, pulmonary edema, pulmonary fibrosis, pyelonephritis, renal failure (unspecified), retroperitoneal fibrosis, shock, ST depression, ventricular fibrillation, sinus tachycardia, facial pain, glycosuria, increased lipase, increased neutrophil count, proteinuria, coccydynia, myokymia, and yawning. Causality between pregabalin and these adverse events has not been definitively established.[31493] [62506] During a randomized trial of the controlled-release tablets in patients with postherpetic neuralgia, elevated hepatic enzymes (ALT 0.2% to 1.4%; AST 0.2% to 1%), arthralgia (0.7% to 1%), joint swelling (0% to 1.9%), cough (0.2% to 1%), and impotence (erectile dysfunction) (0.6% to 1.4%) occurred in pregabalin-treated patients.[62506] Although pregabalin treatment was associated with mild cardiac PR interval prolongation, no adverse events or AV heart block have been reported due to this effect. Additionally, subgroup analyses indicate that patients with baseline PR prolongation taking other PR prolonging medications do not appear to be at greater risk than the normal population, but numbers of patients in these groups were small.[31493]

In clinical trials of immediate-release pregabalin, headaches were reported in neuropathic pain studies at an incidence of 5% to 9% in pregabalin groups vs. 5% in placebo groups. In clinical trials for fibromyalgia, headache occurred more frequently in pregabalin-treated patients (10% to 14%) than in those receiving placebo (12%), leading to discontinuation in about 1% of patients.[31493] Headaches occurred in 1.9% to 3.9% of patients during a randomized trial of the controlled-release tablets in patients with postherpetic neuralgia.[62506]

In clinical trials, amnesia (1% to 6%) and memory impairment (1% to 4%) were reported by recipients of immediate-release pregabalin therapy.[31493] Across all clinical trials with immediate- and controlled-release pregabalin, amnesia was observed in 0.1% to 1% of patients.[62506]

In pregabalin clinical trials for fibromyalgia, fatigue occurred more frequently in pregabalin-treated patients (5% to 8%) than in those receiving placebo (4%), leading to discontinuation in about 1% of patients. Fibromyalgia patients receiving treatment with pregabalin also experienced a higher incidence of lethargy (1% to 2%) when compared with patients receiving placebo (0%). During clinical trials for neuropathic pain associated with spinal cord injury, fatigue was reported more frequently in pregabalin-treated patients (11%) than placebo-treated patients (4%).[31493] Fatigue (1.4% to 3.9%) also occurred during a randomized trial of the controlled-release tablets in patients with postherpetic neuralgia.[62506]

Gastrointestinal adverse events have been reported in pregabalin trials. Xerostomia, or dry mouth, is dose-related with an incidence ranging from 1% up to 15% with higher doses of immediate-release pregabalin (more than 300 mg/day). Other adverse reactions affecting the gastrointestinal tract include abdominal pain or distension (2%), appetite stimulation (2% to 7%), constipation (1% to 10%), flatulence (1% to 3%), gastroenteritis (1%), and nausea with or without vomiting (1% to 4.9%).[31493] During a clinical trial of the controlled-release tablets in patients with postherpetic neuralgia, pregabalin-treated patients experienced xerostomia (0.5% to 3.7%), nausea (3% to 3.4%), constipation (0% to 2.7%), diarrhea (1% to 1.4%), and vomiting (1.1% to 1.4%).[62506] During a placebo-controlled study in pediatric patients with partial onset seizures, increased appetite occurred in 8% of pregabalin-treated patients (n = 201) compared to 4% of placebo-treated patients (n = 94). Increased appetite occurred in 7% of patients who received a pregabalin dose of 2.5 mg/kg/day (n = 104) and 10% of patients who received a dose of 10 mg/kg/day (n = 97). Additionally, hypersalivation occurred in 2% of pregabalin-treated patients vs. 0% of placebo-treated patients. Hypersalivation occurred in 1% of patients who received a pregabalin dose of 2.5 mg/kg/day and 4% of patients who received a dose of 10 mg/kg/day.[31493] Adverse reactions infrequently (0.1% to 1%) reported by recipients of pregabalin during clinical trials included ageusia and dysgeusia, abdominal pain or distension, cholecystitis, cholelithiasis, colitis, dysphagia, esophagitis, gastritis, GI bleeding, melena, oral ulceration, pancreatitis, and rectal bleeding. Rare (less than 0.1%) reactions included aphthous stomatitis, esophageal ulceration, and periodontal abscesses. Nausea and diarrhea were reported during postmarketing use.[31493] [62506]

Myoclonus (myoclonia) has been observed in patients being treated with pregabalin for focal epilepsy and appears to be dose-related. The frequency and intensity of myoclonic jerks decreased after dose reduction of pregabalin. In some cases, the myoclonus was subtle and did not require dose reduction. Four of 19 patients in 1 review developed myoclonus, which is a similar rate to myoclonus reported in patients receiving the structurally similar anticonvulsant gabapentin. Several patients who have developed myoclonic jerks were also taking carbamazepine, which is also associated with myoclonus. Additionally, rapid dose titration of pregabalin may result in a higher frequency of myoclonus.[30761] Myoclonus was reported to occur at a mean incidence of 2% in all dose groups combined for pregabalin and 0% for placebo groups during clinical trials. In the groups receiving 150, 300, or 600 mg/day of pregabalin, myoclonus occurred at a rate of 1%, 0%, and 4%, respectively. Additionally, recipients of pregabalin have also experienced tremor (1% to 11%) and twitching (4% to 5%) during clinical trials.[31493]

Recipients of pregabalin treatment during clinical trials reported experiencing impairments in movement and sensation. These neurologic adverse reactions included ataxia (1% to 20%), abnormal gait (1% to 8%), asthenia (2% to 7%), hypertonia (1% or more), hypoesthesia (2% to 3%), incoordination (1% to 6%), myasthenia (1% to 4.9%), paresthesias (1% or more), and peripheral neuropathy (2% to 9%). Infrequent (0.1% to 1%) cases of hyperalgesia, hyperesthesia, hyperkinesis, hypokinesia, hypotonia, and neuralgia were also reported with pregabalin therapy. Balance disorders were a reason for drug discontinuation in roughly 1% of patients. Acute cerebellar syndrome, cogwheel rigidity, dysautonomia, dyskinesia, dystonic reaction, extrapyramidal syndrome, peripheral neuritis, torticollis, and trismus were rarely (less than 0.1%) reported during pregabalin clinical trials. Other musculoskeletal effects or pain symptoms reported more frequently in pregabalin-treated patients than placebo-treated patients include arthredema (2.2% vs. 0%) and musculoskeletal pain, such as back pain (1% to 4% vs. 3%), unspecified pain (3.3% vs. 1.1%), extremity pain (3.3% vs. 2.3%), and neck pain (2.7% vs. 1.1%).[31493] During studies of controlled-release pregabalin, pregabalin-treated patients experienced balance disorder (0.5% to 2.6% vs. 0% placebo). Across all clinical trials, bradykinesia, psychomotor impairment, and psychomotor hyperactivity occurred in less than 0.1% of pregabalin recipients.[62506]

In pregabalin clinical trials of immediate-release formulations of up to 14 weeks, a gain of 7% or more over baseline weight was observed in 9% of pregabalin-treated patients and 2% of placebo-treated patients. From 1% to 16% of pregabalin-treated patients experienced weight gain during clinical trials compared to 1% for placebo.[31493] Across all clinical trials of the controlled-release tablets for pain indications, weight gain occurred in 4% of patients during single-blind phase. During the double-blind phase of a randomized trial of the controlled-release tablets in patients with postherpetic neuralgia (n = 413), weight gain occurred more frequently in pregabalin-treated patients than in placebo-treated patients (3.7% vs. 1%).[62506] Few patients treated with immediate-release pregabalin (0.3%) withdrew from controlled trials due to weight gain. Increased appetite was reported in epilepsy trials (5% vs. 1% placebo) as well as trials for fibromyalgia. Pregabalin-associated weight gain was related to dose and duration of exposure, but did not appear to be associated with baseline body mass index (BMI), gender, or age. During a placebo-controlled study in pediatric patients with partial onset seizures, weight gain occurred in 8% of pregabalin-treated patients (n = 201) compared to 4% of placebo-treated patients (n = 94). Weight gain occurred in 4% of patients who received a pregabalin dose of 2.5 mg/kg/day (n = 104) and 13% of patients who received a dose of 10 mg/kg/day (n = 97). In a cohort of 333 diabetic patients who received pregabalin for at least 2 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, pregabalin treatment did not appear to be associated with loss of glycemic control (as measured by A1C) in controlled and longer-term open label clinical trials with diabetic patients. Hypoglycemia was reported in 1% to 3% of pregabalin recipients and 1% of placebo recipients during a clinical trial for diabetic peripheral neuropathy.[31493]

Hypersensitivity reactions including redness, blisters, hives or urticaria (0.1% to 1%), rash (0.1% to 1%), dyspnea (2% to 3%), and wheezing have been reported during clinical and postmarketing use of pregabalin. Angioedema of the face, mouth (lips, tongue, and gums), throat, and larynx (laryngeal edema) has occurred in up to 1% to 3% of pregabalin recipients during clinical trials. In addition, life-threatening angioedema with respiratory compromise and anaphylactoid reactions (less than 0.1%) have also been reported.[31493] [62506]

During clinical trials, pruritus (1% or more) was among the most frequent dermatologic adverse events reported by recipients of pregabalin. During clinical trials for the treatment of neuropathic pain associated with spinal cord injury, skin ulcer occurred in 2.7% of pregabalin-treated patients and 1.1% of placebo-treated patients. Skin ulcer was reported less frequently in other clinical trial evaluations (0.1% to 1%). Other less common dermatologic adverse events (0.1% to 1%) occurring during pregabalin clinical trials included alopecia, cellulitis, dry skin (xerosis), eczema, hirsutism, photosensitivity, and vesicular rash. Mucosal dryness, exfoliative dermatitis, lichenoid dermatitis, melanosis, nail disorder, petechial rash, purpuric rash, pustular rash, skin atrophy, skin necrosis, skin nodule, and Stevens-Johnson syndrome were reported rarely (less than 0.1%) by persons treated with pregabalin. Bullous rash (bullous pemphigoid) has been reported with pregabalin during postmarketing experience.[31493] [62506] Contact dermatitis occurred in 0% to 1% of patients receiving controlled-release pregabalin in a clinical trial for postherpetic neuralgia.[62506]

In controlled studies, a higher proportion of patients treated with immediate-release pregabalin reported blurred vision (1% to 12%) than did patients treated with placebo (1% to 4%), which resolved in a majority of cases with continued dosing. In epilepsy trials, blurred vision and diplopia occurred at an incidence of 12% in the 600 mg/day groups. However, less than 1% of patients discontinued pregabalin treatment due to vision-related events (primarily blurred vision).[31493] Across all clinical trials of the controlled-release tablets for pain indications, blurred vision occurred in 4.8% of patients in the single-blind phase. Blurred vision occurred in 0.5% to 3.7% of pregabalin patients during a randomized trial of the controlled-release tablets in patients with postherpetic neuralgia. Blurred vision led to pregabalin discontinuation in less than 1% of patients.[62506] Blurred vision appears to be a dose-related effect. Diplopia (double vision) has been reported in 2% to 12% of patients receiving immediate-release pregabalin and 0.5% to 1% of patients receiving controlled-release pregabalin vs. 0% to 4% of placebo-treated patients.[31493] [62506] Amblyopia (distorted vision) (1% to 12%), abnormal vision, conjunctivitis (1% or more), nystagmus (1% or more), and visual impairment (1% to 5%) have also been reported.[30759] Visual acuity and visual field changes were evaluated in clinical trials, but compared to placebo, differences appeared minor. Less frequent (0.1% to 1%) adverse reactions reported during clinical trials included accommodation abnormalities, blepharitis, ocular hemorrhage, photophobia, retinal edema, periorbital edema, and xerophthalmia or dry eyes. Anisocoria, blindness, corneal ulcer, exophthalmos, iritis, keratitis, keratoconjunctivitis, miosis, mydriasis, night blindness, ophthalmoplegia, optic atrophy, papilledema, ptosis, and uveitis were also reported rarely (less than 0.1%) with pregabalin use during clinical trials. If visual disturbance persists, further assessment should be considered. More frequent assessment should be considered for patients who are already routinely monitored for ocular conditions.[31493] [62506]

Pregabalin treatment has been associated with creatine kinase elevations. Mean changes in creatine kinase from baseline to the maximum value were 60 units/L for pregabalin-treated patients and 28 units/L for the placebo patients. During clinical trials for the treatment of neuropathic pain associated with spinal cord injury, elevated creatine phosphokinase occurred in 2.7% of patients receiving pregabalin and no patients treated with placebo. In clinical trials overall, roughly 1.5% of pregabalin patients and 0.7% of placebo patients had a value of creatine kinase at least 3 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 known. Prescribers should instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if these muscle symptoms are accompanied by malaise or pyrexia. Pregabalin treatment should be discontinued if myopathy is diagnosed or suspected or if markedly elevated creatine kinase concentrations occur.[31493]

Pregabalin treatment has been associated with a decrease in platelet count. Pregabalin-treated subjects experienced a mean maximal decrease in platelet count of 20 x 10³/microliters, compared to 11 x 10³/microliters in placebo patients during clinical trials of immediate-release formulations.[31493] During studies of controlled-release pregabalin, pregabalin-treated subjects experienced median changes from platelet baseline of 11 x 10³/mm³ (postherpetic neuralgia) and 14 x 10³/mm³ (fibromyalgia), compared to 1 x 10³/mm³ for all placebo-treated populations.[62506] In the overall database of controlled trials, 3% of pregabalin patients and 2% of placebo patients experienced a potentially clinically significant decrease in platelets, defined as 20% below baseline value and less than 150 x 10³/microliters. One patient developed severe thrombocytopenia with a platelet count less than 20 x 10³/microliters. Additionally, ecchymosis occurred in 1% or more of pregabalin recipients. Other hematologic adverse events reported in 0.1% to 1% of pregabalin-treated patients during clinical trials included anemia and hypochromic anemia, eosinophilia, leukocytosis, leukopenia, and lymphadenopathy. Rare (less than 0.1%) hematologic adverse events included myelofibrosis, polycythemia, decrease in prothrombin, purpura, and thrombocythemia. In randomized controlled trials, pregabalin was not associated with an increase in bleeding-related adverse events.[31493] [62506]

During clinical trials for fibromyalgia, patients receiving treatment with pregabalin experienced a higher incidence of sinusitis (4% to 7%) when compared with patients receiving placebo (4%). During clinical trials for neuropathic pain associated with spinal cord injury, pharyngitis (nasopharyngitis) occurred more frequently in pregabalin-treated patients (8.2%) than placebo-treated patients (4.6%). Infection (3% to 14%), bronchitis (1% to 3%), and otitis media (1% or more) were reported among pregabalin-treated patients. In pediatric trials for partial onset seizures, viral infection (4%) and pneumonia (4%) were reported in patients 1 month to 3 years.[31493] During studies of controlled-release pregabalin, pregabalin-treated patients experienced nasopharyngitis (1.4% to 1.5% vs. 0% placebo), bronchitis (0.5% to 1.4% vs. 1%), viral respiratory tract infection (0.4% to 1.4% vs. 0.5%), sinusitis (0.4% to 1% vs. 0%), urinary tract infection (1.4% vs. 0.5%), and viral gastroenteritis (0.2% to 1% vs. 0%). Across all adult clinical trials, otitis media (0.1% to 1%) and pneumonia (0.1% to 1%) were reported in pregabalin recipients.[62506]

Addiction or physiological dependence to pregabalin may develop in certain individuals. In a study of recreational drug users (n = 15) of sedative/hypnotic drugs (including alcohol), pregabalin (450 mg, single dose) received subjective ratings of 'good drug effect,' 'high,' and 'liking' to a degree that was similar to 30 mg of diazepam. In controlled clinical studies (n more than 5,500), 4% of pregabalin-treated patients and 1% of placebo-treated patients overall reported euphoria as an adverse event; however, in some patients, this reporting rate was higher and ranged from 1% to 12%. In clinical studies, after abrupt or rapid discontinuation of pregabalin, some patients reported withdrawal or a discontinuation syndrome consisting of sleeplessness, nausea, headache, or diarrhea.[31493] Pregabalin should be tapered over a week if treatment is to be stopped.

Central nervous system (CNS) adverse effects are the most common adverse effects reported with pregabalin therapy. In the majority of clinical studies of immediate-release pregabalin, the most commonly reported CNS adverse events were dizziness (8% to 45%) and somnolence (drowsiness) (4% to 35.7%). The majority (85%) of these adverse events were mild to moderate in intensity and dose dependent. Dizziness and drowsiness may not be transient drug effects. The incidence of dizziness ranges from 23% to 45% with pregabalin doses of 300 to 600 mg/day and 8% and 9% with 75 mg/day and 150 mg/day, respectively. Somnolence or drowsiness occurs in 13% to 28% with higher doses and 4% to 13% with the lower dose of pregabalin.[30759] [31493] Dizziness and somnolence are the adverse events most frequently leading to withdrawal (4% for dizziness and 3% for somnolence) from controlled studies. In pregabalin-treated patients reporting these adverse events in short-term, controlled studies, dizziness persisted until the last dose in 30% and somnolence persisted until the last dose in 42% of patients.[31493] [62506] During the single-blind phase of clinical trials of controlled-release pregabalin for pain indications, 24% of pregabalin-treated patients experienced dizziness and 15.8% of patients experienced drowsiness. Study withdrawal due to dizziness or drowsiness during a single-blind phase occurred in 2.4% and 1.2% of controlled-release pregabalin-treated patients, respectively. Dizziness and somnolence generally began shortly after treatment initiation and occurred more frequently with higher doses. During a randomized trial of controlled-release pregabalin in patients with postherpetic neuralgia, dizziness was observed in 3.4% to 17.1% of patients, and drowsiness in 0.5% to 11.4% of patients.[62506] In pediatric trials, somnolence (including the terms lethargy, sluggishness, hypersomnia) was reported in 15% to 21% of patients and occurred more frequently at higher doses. Drowsiness led to pregabalin discontinuation in 3 pediatric patients, and hallucination and worsening of epilepsy also each resulted in pregabalin discontinuation in a single patient.[31493] Other CNS adverse events reported during pregabalin clinical trials included abnormal thinking (1% to 9%), confusion (1% to 7%), insomnia (3.8%), disturbance in attention (3.8%), depersonalization (1%), disorientation (1% to 2%), drunk or hungover feeling (0.1% to 2%), nervousness (1%), stupor (1% or more), and vertigo (1% to 4%). Adverse events infrequently (0.1% to 1%) reported included abnormal dreams, agitation, apathy, aphasia, cognitive disorder, dysarthria (change in speech), hallucinations, hostility, irritability, malaise, sciatica, and sleep phase rhythm disturbance. Delirium, delusion, depressed level of consciousness, altered state of consciousness, encephalopathy, Guillain-Barre syndrome, mania, paranoia, psychosis, schizophrenic reactions, and sleep disorders were rarely (less than 0.1%) reported in recipients of pregabalin during clinical trials.[31493] [62506]

In carcinogenicity studies of pregabalin in mice, an unexpectedly high incidence of hemangiosarcoma was identified. Clinical experience during pregabalin premarketing development provides no direct means to assess its potential for inducing tumors in humans. In clinical studies covering more than 6,300 patient-years of exposure in patients 12 years and older, new or worsening pre-existing tumors were reported in 57 patients. The clinical significance of these findings is unknown; however, health care providers are advised to be aware of the potential for a new primary malignancy following treatment with pregabalin.[31493]

Breast enlargement and gynecomastia have been reported during postmarketing use of pregabalin. The frequencies are unknown and causality to the drug has not been established.[31493]

Men may experience decreased sperm concentrations and potential reproductive risk, such as infertility, with pregabalin therapy. In a randomized, double-blind, placebo-controlled, non-inferiority study to examine the effect of pregabalin on sperm characteristics, healthy male subjects received pregabalin at a daily dose of 600 mg or less (n = 111) or placebo (n = 109) for 13 weeks followed by a 13-week washout period. In the per protocol population (pregabalin, n = 65; placebo, n = 62), approximately 9% of the pregabalin group vs. 3% of the placebo group had a 50% or more reduction in mean sperm concentrations from baseline at week 26. The difference between pregabalin and placebo was within the pre-specified non-inferiority margin of 20%. Sperm concentrations were no longer reduced by 50% or more after an additional 3 months off pregabalin. However, at 9-month and 12-month follow-up visits, 1 subject did demonstrate reductions in sperm concentrations of 50% or more. There were no adverse effects on sperm morphology, sperm motility, or serum follicle-stimulating hormone or testosterone concentrations compared to placebo. The clinical significance of these data is uncertain.[31493]

Respiratory depression can occur with pregabalin alone or in combination with other central nervous system (CNS) depressants or in patients with underlying respiratory impairment. Over approximately 6 years, 49 postmarketing reports of respiratory depression with gabapentinoids were identified; gabapentin accounted for 15 cases and pregabalin for 34 cases. A respiratory risk factor, including age-related loss of lung function, or the use of a CNS depressant was reported in 92% of cases. Death occurred in 12 patients (24%). All death cases reported at least 1 risk factor for developing respiratory depression or concomitant use of a CNS depressant. Exposure to preoperative gabapentinoids increases the risk of postoperative respiratory depression. In a case-control study of more than 11,000 arthroplasty patients, the risk of respiratory depression, defined as apnea, hypopnea, oxyhemoglobin desaturation, or an episode of severe pain despite moderate to profound sedation (i.e., pain-sedation mismatch), during recovery in the postanesthesia care unit was increased 60% for patients using regional anesthesia (OR 1.60, 95% CI 1.27, 2.02) and 47% for those using general anesthesia (OR 1.47, 95% CI 1.26, 1.70) when the preoperative anesthesia regimen included gabapentin doses more than 300 mg compared to no preoperative gabapentin exposure. Preoperative gabapentin increased the risk of postoperative respiratory depression by 26% (OR 1.26, 95% CI 1.02, 1.58) compared to no preoperative exposure in another case-control study of more than 8,000 laparoscopy patients. Respiratory depression was defined as apnea, hypopnea, oxyhemoglobin desaturation, pain-sedation mismatch, naloxone administration, failure to extubate, need to reintubate, or non-invasive positive pressure ventilation (NIPPV) use in patients who were not previously prescribed such a device. Initiate pregabalin at the lowest recommended dose and monitor for symptoms of respiratory depression and sedation in elderly patients, patients with underlying pulmonary disease, or during coadministration with other CNS depressants. Management of respiratory depression should include observation, necessary supportive measures, and reduction or withdrawal of CNS depressants, including pregabalin. Taper the dose of pregabalin used for analgesia or seizure control before discontinuation.[64848]

Pregabalin is contraindicated in patients with known pregabalin hypersensitivity or with product specific ingredient hypersensitivity. It is not known if cross-hypersensitivity exists between gabapentin and pregabalin; however, the drugs are chemically and structurally similar. Use with caution in patients with a known hypersensitivity to gabapentin. There are postmarketing reports of hypersensitivity reactions (i.e., erythema, blisters, hives, rash, dyspnea, and wheezing) and life-threatening angioedema. Discontinue treatment with pregabalin immediately if these reactions occur. Caution is advised during use of pregabalin in patients with a history of angioedema. Concurrent use of other medications known to cause angioedema may increase the risk of this complication with use of pregabalin.[31493]

Antiepileptic drugs (AEDs), including pregabalin, increase the risk of suicidal ideation, thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored 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 1 of the AEDs had approximately twice the risk (adjusted RR 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients taking placebo. In these trials, which had a 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 1 case of suicidal thinking or behavior for every 530 patients treated. There were 4 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 was observed as early as 1 week after starting drug treatment 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 a 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 of age) in the clinical trials analyzed. The 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. 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, consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Closely monitor patients for emerging or worsening depression or suicidal thoughts/behavior. Inform patients and caregivers of the increased risk of suicidal thoughts and behaviors and advise them to immediately report the emergence or worsening of depression, the emergence of suicidal thoughts or behavior, thoughts of self-harm, or other unusual changes in mood or behavior.[31493]

Pregabalin commonly causes CNS depression, including dizziness and drowsiness. Patients should be advised to use caution when driving or operating machinery, or performing other tasks that require mental alertness, until they are aware of whether pregabalin adversely affects their mental and/or motor performance. Advise patients to avoid the concomitant use of ethanol and ethanol intoxication while receiving pregabalin due to the potential for additive drowsiness.[31493]

Pregabalin may cause physical and psychological dependence and should be used with extreme caution in patients with known, suspected, or a history of substance abuse. Pregabalin is not known to be active at receptor sites associated with drugs of abuse; however, as with any CNS active drug, carefully evaluate patients for history of drug abuse and observe them for signs of pregabalin misuse or abuse (e.g., development of tolerance, dose escalation, drug-seeking behavior).[31493]

Avoid abrupt discontinuation of pregabalin after prolonged use to reduce the risk for withdrawal seizures or adverse effects such as insomnia, nausea, headache, anxiety, hyperhidrosis, and diarrhea. Withdraw pregabalin slowly, using a gradual dose-tapering schedule over a minimum of 1 week.[31493]

Use pregabalin with caution in patients with renal impairment or renal failure. Pregabalin is excreted unchanged in the urine and can accumulate with decreased renal function. Dosage adjustments are recommended in patients with renal impairment.[31493]

Initiate pregabalin at the lowest recommended dose and monitor for symptoms of respiratory depression and sedation in elderly patients, patients with underlying pulmonary disease, such as chronic obstructive pulmonary disease (COPD), and during coadministration with other CNS depressants. Serious, life-threatening, and fatal respiratory depression has been reported with pregabalin. Most cases involved coadministration of another CNS depressant, particularly opioids, in patients with underlying respiratory impairment or advanced age. Respiratory depression, if left untreated, may cause respiratory arrest and death. Management of respiratory depression may include observation, necessary supportive measures, and reduction or withdrawal of CNS depressants, including pregabalin. Taper the dose of pregabalin used for analgesia or seizure control before discontinuation.[64848]

Initiate pregabalin at the lowest recommended dose and monitor for symptoms of respiratory depression and sedation in geriatric adults. Serious, life-threatening, and fatal respiratory depression has been reported with pregabalin. Most cases involved coadministration of another CNS depressant, particularly opioids, in patients with underlying respiratory impairment or advanced age. Respiratory depression, if left untreated, may cause respiratory arrest and death. Management of respiratory depression should include observation, necessary supportive measures, and reduction or withdrawal of CNS depressants, including pregabalin. Taper the dose of pregabalin used for analgesia or seizure control before discontinuation. During clinical trials for fibromyalgia, geriatric subjects more frequently reported neurologic reactions such as dizziness, blurred vision, balance disorder, tremor, confusional state, abnormal coordination, and lethargy. Pregabalin is known to be almost exclusively excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Adjust dosing based on estimated creatinine clearance; it may be useful to monitor renal function.[31493] [64848] According to the Beers Criteria, anticonvulsants such as pregabalin are considered potentially inappropriate medications (PIMs) in geriatric adults with a history of falls or fractures and should be avoided in these patient populations, except for treating seizure and mood disorders, since anticonvulsants can produce ataxia, impaired psychomotor function, syncope, and additional falls. If pregabalin must be used, consider reducing the use of other CNS-active medications that increase the risk of falls and fractures and implement strategies to reduce fall risk.[63923]

Pregabalin treatment may cause peripheral edema. Higher frequencies of weight gain and peripheral edema were observed in diabetes mellitus patients taking both pregabalin and a thiazolidinedione antidiabetic agent compared to patients taking either drug alone. 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 coadministering 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.[31493]

In controlled studies, a higher proportion of patients treated with pregabalin reported blurred vision than did patients treated with placebo, which resolved in most cases with continued dosing. Advise patients to notify their health care provider 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 disease or conditions.[31493]

Data from observational studies of pregabalin use during human pregnancy suggest a possible small increase in the incidence of overall major birth defects; there was no consistent or specific pattern of major birth defects identified. A database study reported a prevalence ratio for major malformations overall of 1.14 (95% CI: 0.96 to 1.35) for 2,700 pregnancies exposed to pregabalin monotherapy during the first trimester compared to 3,063,251 pregnancies not exposed to antiepileptic drugs (AEDs). Study limitations include the inability to control for underlying disease states or other potential confounders, in addition to a lack of verification of compliance with the AED regimen. A second database study showed no increase in the risk of major birth defects for 353 pregnancies with first trimester pregabalin monotherapy exposure when compared to 368,489 pregnancies with no AED exposure (adjusted relative risk 0.87 [95% CI 0.53 to 1.42]). A third database study suggested a small increase in the risk of major birth defects for 118 pregnancies with first trimester pregabalin monotherapy exposure when compared to 380,347 pregnancies with no AED exposure (adjusted relative risk 1.26 [95% CI 0.64 to 2.49]). Limitations consistent with previous database studies were present. Available postmarketing data on miscarriage and other maternal, fetal, and long-term developmental adverse effects were insufficient to identify risk associated with pregabalin. Pregabalin has been shown to cause animal developmental toxicity (e.g., fetal structural abnormalities and growth retardation) in rats and rabbits given oral pregabalin at doses that produced pregabalin AUC exposures 18 times or more the human exposure at the maximum recommended dose of 660 mg/day. In a study of rats given pregabalin throughout gestation and lactation, offspring growth was reduced at doses of 100 mg/kg or more, and offspring survival decreased at doses of 250 mg/kg or more. When offspring were tested as adults, neurobehavioral abnormalities (i.e., decreased auditory startle response) were observed at doses of 250 mg/kg or more, and decreased fertility and litter size were seen at doses of 1,250 mg/kg. In a prenatal-postnatal study in rats, pregabalin prolonged gestation and induced dystocia at exposures of 50 times or more the mean human exposure. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to pregabalin; information about the registry can be obtained at www.aedpregnancyregistry.org or by calling 1-888-233-2334.[31493] [62506]

Use caution with pregabalin while breast-feeding due to a potential risk of tumorigenicity. Animal data demonstrate a potential association of tumorigenicity with pregabalin exposure from breast milk, and there is not a clear conclusion regarding the risk from available human clinical studies. Small amounts of pregabalin have been found in the milk of breast-feeding women, with average breast milk steady-state concentrations of approximately 76% of those in maternal plasma. Assuming a mean milk consumption of 150 mL/kg/day, the estimated average daily infant dose of pregabalin from breast-milk was 0.31 mg/kg/day, which would be approximately 7% of the maternal dose. The effects of pregabalin on milk production or the breast-fed infant are unknown.[31493] Alternative treatment options may be preferred, including carbamazepine, divalproex, gabapentin, lamotrigine, oxcarbazepine, phenytoin, or valproic acid.[70364]

Pregabalin may be associated with reproductive risk. Advise men who plan to father a child of the potential risk of male-mediated teratogenicity. In animal fertility studies, pregabalin was associated with an increased risk of male-mediated teratogenicity; adverse reproductive and developmental effects were observed. Additionally, males may experience decreased sperm concentrations and infertility. In a randomized, double-blind, placebo-controlled, non-inferiority study to examine the effect of pregabalin on sperm characteristics, healthy male subjects received pregabalin at a daily dose of 600 mg or less (n = 111) or placebo (n = 109) for 13 weeks followed by a 13-week washout period. In the per protocol population (pregabalin, n = 65; placebo, n = 62), approximately 9% of the pregabalin group vs. 3% of the placebo group had a 50% or more reduction in mean sperm concentrations from baseline at week 26. The difference between pregabalin and placebo was within the pre-specified non-inferiority margin of 20%. Sperm concentrations were no longer reduced by 50% or more after an additional 3 months off pregabalin. However, at 9-month and 12-month follow-up visits, 1 subject did demonstrate reductions in sperm concentration of 50% or more. There were no adverse effects on sperm morphology, sperm motility, or serum follicle-stimulating hormone (FSH) or testosterone concentrations vs. placebo. The clinical significance of these data is uncertain.[31493]