Side Effects of Lyrica (pregabalin)

Lyrica (pregabalin) is an anti-epileptic drug (anticonvulsant) chemically related to gabapentin (Gralise, Neurontin) used to treat nerve pain associated with diabetic peripheral neuropathy or postherpetic neuralgia, spinal cord injury, in combination with other drugs to treat partial onset seizures in adults, and fibromyalgia.

Drug interactions of Lyrica include alcohol, drugs that cause sedation, pioglitazone, and rosiglitazone.

There are no adequate studies of Lyrica in pregnant women. It is not known whether Lyrica is excreted in breast milk.

WARNING

Antiepileptic medications have been associated with increased risk of suicidal thinking and behavior. Anyone considering the use of antiepileptic drugs must balance this risk of suicide with the clinical need. Patients who are started on therapy should be closely observed for clinical worsening, suicidal thoughts, or unusual changes in behavior.

What are the common side effects of Lyrica?

Common side effects of Lyrica include

• dizziness,
• drowsiness,
• dry mouth,
• fluid retention (edema),
• blurred vision,
• double vision,
• weight gain,
• fatigue/tiredness,
• abnormal gait,
• tremor,
• difficulty concentrating,
• constipation,
• increased appetite,
• nausea,
• vomiting, and
• gas.

What are the serious side effects of Lyrica?

Serious side effects of Lyrica include

• amnesia,
• disorientation,
• myoclonus (sudden, involuntary jerking of a muscle or muscle groups),
• heart failure,
• low blood pressure,
• reduced blood platelet counts,
• increased blood creatinine kinase levels, and
• angioedema (swelling of the face, tongue, lips, and gums, throat and larynx).

Controlled Substance

Lyrica is a Schedule V controlled substance.

Lyrica is not known to be active at receptor sites associated with drugs of abuse. As with any CNS active drug, carefully evaluate patients for history of drug abuse and observe them for signs of Lyrica misuse or abuse (e.g., development of tolerance, dose escalation, drug-seeking behavior).

Abuse

In a study of recreational users (N=15) of sedative/hypnotic drugs, including alcohol, Lyrica (450 mg, single dose) received subjective ratings of “good drug effect,” “high” and “liking” to a degree that was similar to diazepam (30 mg, single dose). In controlled clinical studies in over 5500 patients, 4 % of Lyrica-treated patients and 1 % of placebo-treated patients overall reported euphoria as an adverse reaction, though in some patient populations studied, this reporting rate was higher and ranged from 1 to 12%.

Dependence

In clinical studies, following abrupt or rapid discontinuation of Lyrica, some patients reported symptoms including insomnia, nausea, headache or diarrhea, consistent with physical dependence. In the postmarketing experience, in addition to these reported symptoms there have also been reported cases of anxiety and hyperhidrosis.

Since Lyrica is predominantly excreted unchanged in the urine, undergoes negligible metabolism in humans (less than 2% of a dose recovered in urine as metabolites), and does not bind to plasma proteins, its pharmacokinetics are unlikely to be affected by other agents through metabolic interactions or protein binding displacement. In vitro and in vivo studies showed that Lyrica is unlikely to be involved in significant pharmacokinetic drug interactions. Specifically, there are no pharmacokinetic interactions between pregabalin and the following antiepileptic drugs: carbamazepine, valproic acid, lamotrigine, phenytoin, phenobarbital, and topiramate. Important pharmacokinetic interactions would also not be expected to occur between Lyrica and commonly used antiepileptic drugs.

Pharmacodynamics

Multiple oral doses of Lyrica were co-administered with oxycodone, lorazepam, or ethanol. Although no pharmacokinetic interactions were seen, additive effects on cognitive and gross motor functioning were seen when Lyrica was co-administered with these drugs. No clinically important effects on respiration were seen.

The following serious adverse reactions are described elsewhere in the labeling:

• Angioedema
• Hypersensitivity
• Increased Risk of Adverse Reactions with Abrupt or Rapid Discontinuation
• Suicidal Behavior and Ideation
• Peripheral Edema
• Dizziness and Somnolence
• Weight Gain
• Tumorigenic Potential
• Ophthalmological Effects
• Creatine Kinase Elevations
• Decreased Platelet Count
• PR Interval Prolongation

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In all controlled and uncontrolled trials across various patient populations during the premarketing development of Lyrica, more than 10,000 patients have received Lyrica. Approximately 5000 patients were treated for 6 months or more, over 3100 patients were treated for 1 year or longer, and over 1400 patients were treated for at least 2 years.

Adverse Reactions Most Commonly Leading To Discontinuation In All Premarketing Controlled Clinical Studies

In premarketing controlled trials of all adult populations combined, 14% of patients treated with Lyrica and 7% of patients treated with placebo discontinued prematurely due to adverse reactions. In the Lyrica treatment group, the adverse reactions most Frequently leading to discontinuation were dizziness (4%) and somnolence (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 Lyrica group compared to the placebo group were ataxia, confusion, asthenia, thinking abnormal, blurred vision, incoordination, and peripheral edema (1% each).

Most Common Adverse Reactions In All 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 Lyrica 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 patients with neuropathic pain associated with diabetic peripheral neuropathy, 9% of patients treated with Lyrica and 4% of patients treated with placebo discontinued prematurely due to adverse reactions. In the Lyrica treatment group, the most common reasons for discontinuation due to adverse reactions were dizziness (3%) and somnolence (2%). In comparison, 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 Lyrica group than in the placebo group, were asthenia, confusion, and peripheral edema. Each of these events led to withdrawal in approximately 1% of patients.

Most Common Adverse Reactions

Table 4 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 Lyrica group for which the incidence was greater in this combined Lyrica group than in the placebo group. A majority of pregabalin-treated patients in clinical studies had adverse reactions with a maximum intensity of “mild” or “moderate”.

Table 4: Adverse Reaction Incidence in Controlled Trials in Neuropathic Pain Associated with Diabetic Peripheral Neuropathy

Controlled Studies In Postherpetic Neuralgia

Adverse Reactions Leading To Discontinuation

In clinical trials in patients with postherpetic neuralgia, 14% of patients treated with Lyrica and 7% of patients treated with placebo discontinued prematurely due to adverse reactions. In the Lyrica treatment group, the most common reasons for discontinuation due to adverse reactions were dizziness (4%) and somnolence (3%). In comparison, less than 1% of placebo patients withdrew due to dizziness and somnolence. Other reasons for discontinuation from the trials, occurring in greater frequency in the Lyrica group than in the placebo group, were confusion (2%), as wellas peripheraledema, asthenia, ataxia, and abnormal gait(1% each).

Most Common Adverse Reactions

Table 5 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 Lyrica group for which the incidence was greater in this combined Lyrica group than in the placebo group. In addition, an event is included, even if the incidence in the all Lyrica group is not greater than in the placebo group, if the incidence of the event in the 600 mg/day group is more than twice that in the placebo group. A majority of pregabalin-treated patients in clinical studies had adverse reactions with a maximum intensity of “mild” or “moderate”. 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 Neuralgia

Controlled Studies Of Adjunctive Therapy For Partial Onset Seizures In Adult Patients

Adverse Reactions Leading To Discontinuation

Approximately 15% of patients receiving Lyrica and 6% of patients receiving placebo in trials of adjunctive therapy for partial onset seizures discontinued prematurely due to adverse reactions. In the Lyrica treatment group, the adverse reactions most Frequently leading to discontinuation were dizziness (6%), ataxia (4%), and somnolence (3%). In comparison, 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 Lyrica group and at least twice as Frequently compared to the placebo group were asthenia, diplopia, blurred vision, thinking abnormal, nausea, tremor, vertigo, headache, and confusion (which each led to withdrawal in 2% or less of patients).

Most Common Adverse Reactions

Table 6 lists all dose-related adverse reactions occurring in at least 2% of all Lyrica-treated patients. Dose-relatedness was defined as the incidence of the adverse event in the 600 mg/day group was at least 2% greater than the rate in both the placebo and 150 mg/day groups. In these studies, 758 patients received Lyrica and 294 patients received placebo for up to 12 weeks. A majority of pregabalin-treated patients in clinical studies had adverse reactions with a maximum intensity of “mild” or “moderate”.

Table 6: Dose-related Adverse Reaction Incidencein ControlledTrials ofAdjunctive Therapy for Partial Onset Seizures in Adult Patients

Controlled Study Of Adjunctive Therapy For Partial Onset Seizures In Patients 4 To Less Than 17 Years Of Age

Adverse Reactions Leading To Discontinuation

Approximately 2.5% of patients receiving Lyrica and no patients receiving placebo in trials of adjunctive therapy for partial onset seizures discontinued prematurely due to adverse reactions. In the Lyrica 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 7 lists all dose-related adverse reactions occurring in at least 2% of all Lyrica-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 Lyrica and 94 patients received placebo for up to 12 weeks. A majority of pregabalin-treated patients in the clinical study had adverse reactions with a maximum intensity of “mild” or “moderate”.

Table 7: Dose-related Adverse Reaction Incidence in a ControlledTrial in Adjunctive Therapy for Partial Onset Seizures in Patients 4 to Less Than 17 Years of Age

Controlled Studies With Fibromyalgia

Adverse Reactions Leading To Discontinuation

In clinical trials of patients with fibromyalgia, 19% of patients treated with pregabalin (150-600 mg/day) and 10% of patients treated with placebo discontinued prematurely due to adverse reactions. In the pregabalin treatment group, the most common reasons for discontinuation due to adverse reactions were dizziness (6%) and somnolence (3%). In comparison, 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 8 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. A majority of pregabalin-treated patients in clinical studies experienced adverse reactions with a maximum intensity of “mild” or “moderate”.

Table 8: Adverse Reaction Incidence in Controlled Trials in Fibromyalgia

Controlled Studies In Neuropathic Pain Associated With Spinal Cord Injury

Adverse Reactions Leading To Discontinuation

In clinical trials of patients 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 Reactions

Table 9 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 painassociated with spinal cord injuryin thecontrolled trials. Amajorityof pregabalin-treated patients in clinical studies experienced adverse reactions with a maximum intensity of “mild” or “moderate”.

Table 9: Adverse Reaction Incidence in Controlled Trials in Neuropathic Pain Associated with Spinal Cord Injury

Other Adverse Reactions Observed During The Clinical Studies Of Lyrica

Following is a list of treatment-emergent adverse reactions reported by patients treated with Lyrica during all clinical trials. The listing does not include those events already listed in the previous tables or elsewhere in labeling, those events for which a drug cause was remote, those events which were so general as to be uninformative, and those events reported only once which did not have a substantial probability of being acutely life-threatening.

Events are categorized by body system and listed in order of decreasing frequency according to the following definitions: Frequent adverse reactions are those occurring on one or more occasions in at least 1/100 patients; inFrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; Rare reactions are those occurring in fewer than 1/1000 patients. Events of major clinical importance are described in the Warnings and Precautions section (5).

Body as a Whole - Frequent: Abdominal pain, Allergic reaction, Fever, Infrequent: Abscess, Cellulitis, Chills, Malaise, Neck rigidity, Overdose, Pelvic pain, Photosensitivity reaction, Rare: Anaphylactoid reaction, Ascites, Granuloma, Hangover effect, Intentional Injury, Retroperitoneal Fibrosis, Shock

Cardiovascular System - Infrequent: Deep thrombophlebitis, Heart failure, Hypotension, Postural hypotension, Retinal vascular disorder, Syncope; Rare: ST Depressed, Ventricular Fibrillation

Digestive System - Frequent: Gastroenteritis, Increased appetite; Infrequent: Cholecystitis, Cholelithiasis, Colitis, Dysphagia, Esophagitis, Gastritis, Gastrointestinal hemorrhage, Melena, Mouth ulceration, Pancreatitis, Rectal hemorrhage, Tongue edema; Rare: Aphthous stomatitis, Esophageal Ulcer, Periodontal abscess

Hemic and Lymphatic System - Frequent: Ecchymosis; Infrequent: Anemia, Eosinophilia, Hypochromic anemia, Leukocytosis, Leukopenia, Lymphadenopathy, Thrombocytopenia; Rare: Myelofibrosis, Polycythemia, Prothrombin decreased, Purpura, Thrombocythemia, Alanine aminotransferase increased, Aspartate aminotransferase increased

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

Musculoskeletal System - Frequent: Arthralgia, Leg cramps, Myalgia, Myasthenia; Infrequent: Arthrosis; Rare: Chondrodystrophy, Generalized Spasm

Nervous System - Frequent: Anxiety, Depersonalization, Hypertonia, 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, Trismus

Respiratory System - Rare: Apnea, Atelectasis, Bronchiolitis, Hiccup, Laryngismus, Lung edema, Lung fibrosis, Yawn

Skin and Appendages - Frequent: Pruritus, Infrequent: Alopecia, Dry skin, Eczema, Hirsutism, Skin ulcer, Urticaria, Vesiculobullous rash; Rare: Angioedema, Exfoliative dermatitis, Lichenoid dermatitis, Melanosis, Nail Disorder, Petechial rash, Purpuric rash, Pustular rash, Skin atrophy, Skin necrosis, Skin nodule, Stevens-Johnson syndrome, Subcutaneous nodule

Special senses - Frequent: Conjunctivitis, Diplopia, Otitis media, Tinnitus; Infrequent: Abnormality of accommodation, Blepharitis, Dry eyes, Eye hemorrhage, Hyperacusis, Photophobia, Retinal edema, Taste loss, Taste perversion; Rare: Anisocoria, Blindness, Corneal ulcer, Exophthalmos, Extraocular palsy, Iritis, Keratitis, Keratoconjunctivitis, Miosis, Mydriasis, Night blindness, Ophthalmoplegia, Optic atrophy, Papilledema, Parosmia, Ptosis, Uveitis

Urogenital System - Frequent: Anorgasmia, Impotence, Urinary frequency, Urinary incontinence; Infrequent: Abnormal ejaculation, Albuminuria, Amenorrhea, Dysmenorrhea, Dysuria, Hematuria, Kidney calculus, Leukorrhea, Menorrhagia, Metrorrhagia, Nephritis, Oliguria, Urinary retention, Urine abnormality; Rare: Acute kidney failure, Balanitis, Bladder Neoplasm, Cervicitis, Dyspareunia, Epididymitis, Female lactation, Glomerulitis, Ovarian disorder, Pyelonephritis

Comparison Of Gender And Race

The overall adverse event profile of pregabalin was similar between women and men. There are insufficient data to support a statement regarding the distribution of adverse experience reports by race.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Lyrica. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Nervous System Disorders - Headache

Gastrointestinal Disorders - Nausea, Diarrhea

Reproductive System and Breast Disorders - Gynecomastia, Breast Enlargement

In addition, there are postmarketing reports of events related to reduced lower gastrointestinal tract function (e.g., intestinal obstruction, paralytic ileus, constipation) when Lyrica was co-administered with medications that have the potential to produce constipation, such as opioid analgesics. There are also postmarketing reports of respiratory failure and coma in patients taking pregabalin and other CNS depressant medications.