Pregabalin (Lyrica®)

Updated June 12, 2014
Author: UpToDate/Lexicomp

Description: Lyrica information in Pain Management, courtesy of Up To Date

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Pregabalin: Drug information

Brand Names: U.S. Lyrica

Dosing: Adult Note: When discontinuing, taper off gradually over at least 1 week.

Fibromyalgia: Oral: U.S. labeling: Initial: 150 mg daily in divided doses (75 mg twice daily); may be increased to 300 mg daily (150 mg twice daily) within 1 week based on tolerability and effect; may be further increased to 450 mg daily (225 mg twice daily). Maximum dose: 450 mg daily (dosages up to 600 mg daily were evaluated with no significant additional benefit and an increase in adverse effects)

Neuropathic pain, diabetes-associated: Oral: U.S. labeling: Initial: 150 mg daily in divided doses (50 mg 3 times daily); may be increased within 1 week based on tolerability and effect; maximum dose: 300 mg daily in 3 divided doses (dosages up to 600 mg daily were evaluated with no significant additional benefit and an increase in adverse effects)

Neuropathic pain, spinal cord injury associated: Oral: Initial: 150 mg daily in divided doses (75 mg twice daily); may be increased to 300 mg daily (150 mg twice daily) within 1 week based on tolerability and effect; further titration to 600 mg daily (300 mg twice daily) after 2-3 weeks may be considered in patients who do not experience sufficient relief of pain provided they are able to tolerate pregabalin. Maximum dose: 600 mg daily

Partial-onset seizures (adjunctive therapy): Oral: Initial: 150 mg daily in divided doses (75 mg twice daily or 50 mg 3 times daily); may be increased based on tolerability and effect (optimal titration schedule has not been defined). Maximum dose: 600 mg daily

Postherpetic neuralgia: Oral: Initial: 150 mg daily in divided doses (75 mg twice daily or 50 mg 3 times daily); may be increased to 300 mg daily within 1 week based on tolerability and effect; further titration (to 600 mg daily) after 2-4 weeks may be considered in patients who do not experience sufficient relief of pain provided they are able to tolerate pregabalin. Maximum dose: 600 mg daily

Dosing: Geriatric Refer to adult dosing.

Dosing: Renal Impairment Renal function may be estimated using the Cockcroft-Gault formula. Then determine recommended dosage regimen based on the indication-specific total daily dose for normal renal function (CrCl ≥60 mL/minute). For example, if the indication-specific daily dose is 450 mg daily for normal renal function, the daily dose should be reduced to 225 mg daily (in 2-3 divided doses) for a creatinine clearance of 30-60 mL/minute (see table).

Pregabalin Renal Impairment Dosing

CrCl (mL/minute) Total Pregabalin Daily Dose (mg/day) Dosing Frequency
≥60 (normal renal function) 150 300 450 600 2-3 divided doses
30-60 75 150 225 300 2-3 divided doses
15-30 25-50 75 100-150 150 1-2 divided doses
<15 25 25-50 50-75 75 Single daily dose
Posthemodialysis supplementary dosage (as a single additional dose): 25 mg/day schedule: Single supplementary dose of 25 mg or 50 mg 25-50 mg/day schedule: Single supplementary dose of 50 mg or 75 mg 50-75 mg/day schedule: Single supplementary dose of 75 mg or 100 mg 75 mg/day schedule: Single supplementary dose of 100 mg or 150 mg

Dosing: Hepatic Impairment No dosage adjustment provided in manufacturer’s labeling. However, no adjustment expected since undergoes minimal hepatic metabolism.

Dosage Forms: U.S. Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral: Lyrica: 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 225 mg, 300 mg

Solution, Oral: Lyrica: 20 mg/mL (473 mL) [contains methylparaben, propylparaben]

Administration May be administered with or without food.

Use Management of neuropathic pain associated with diabetic peripheral neuropathy or with spinal cord injury; management of postherpetic neuralgia; adjunctive therapy for partial-onset seizure disorder; management of fibromyalgia

Mechanism of Action Binds to alpha2-delta subunit of voltage-gated calcium channels within the CNS and modulates calcium influx at the nerve terminals, thereby inhibiting excitatory neurotransmitter release including glutamate, norepinephrine (noradrenaline), serotonin, dopamine, substance P, and calcitonin gene-related peptide (Gajraj, 2007; McKeage, 2009). Although structurally related to GABA, it does not bind to GABA or benzodiazepine receptors. Exerts antinociceptive and anticonvulsant activity. Pregabalin may also affect descending noradrenergic and serotonergic pain transmission pathways from the brainstem to the spinal cord.

Pharmacodynamics/Kinetics

Onset of action:

Pain management: Effects may be noted as early as the first week of therapy.

Distribution: Vd: 0.5 L/kg Protein binding: 0%

Metabolism: Negligible Bioavailability: >90% Half-life elimination: 6.3 hours Time to peak, plasma: 1.5 hours (3 hours with food)

Excretion: Urine (90% as unchanged drug; minor metabolites)

Adverse Reactions Significant Note: Frequency of adverse effects may be influenced by dose or concurrent therapy. In add-on trials in epilepsy, frequency of CNS and adverse effects were higher than those reported in pain management trials. Range noted below is inclusive of all trials.

>10%:
Cardiovascular: Peripheral edema (≤16%) Central nervous system: Dizziness (8% to 45%), somnolence (4% to 36%), ataxia (1% to 20%), headache (5% to 14%), fatigue (5% to 11%) Gastrointestinal: Weight gain (≤16%), xerostomia (1% to 15%) Neuromuscular & skeletal: Tremor (≤11%) Ocular: Blurred vision (1% to 12%), diplopia (≤12%) Miscellaneous: Infection (3% to 14%), accidental injury (2% to 11%)

1% to 10%:
Cardiovascular: Edema (≤8%), chest pain (1% to 4%), hypertension (2%), hypotension (2%) Central nervous system: Neuropathy (2% to 9%), thinking abnormal (≤9%), confusion (≤7%), euphoria (≤7%), speech disorder (≤7%), attention disturbance (4% to 6%), amnesia (≤6%), incoordination (≤6%), pain (2% to 5%), insomnia (4%), memory impaired (1% to 4%), vertigo (1% to 4%), hypoesthesia (2% to 3%), feeling abnormal (1% to 3%), anxiety (2%), lethargy (1% to 2%), drunk feeling (1% to 2%), disorientation (≤2%), depersonalization (≥1%), fever (≥1%), hypertonia (≥1%), sedation (≥1%), stupor (≥1%), nervousness (≤1%) Dermatologic: Decubitus ulcer (3%), facial edema (≤3%), bruising (≥1%), pruritus (≥1%) Endocrine & metabolic: Fluid retention (2% to 3%), hypoglycemia (1% to 3%), libido decreased (≥1%) Gastrointestinal: Constipation (≤10%), appetite increased (2% to 7%), nausea (5%), flatulence (≤3%), vomiting (1% to 3%), abdominal distension (2%), abdominal pain (≥1%), gastroenteritis (≥1%) Genitourinary: Incontinence (≤3%), anorgasmia (≥1%), impotence (≥1%), urinary frequency (≥1%) Hematologic: Thrombocytopenia (≥1%) Neuromuscular & skeletal: Balance disorder (2% to 9%), abnormal gait (≤8%), weakness (2% to 7%), arthralgia (3% to 6%), twitching (≤5%), muscle spasm (2% to 4%), back pain (≤4%), myoclonus (≤4%), CPK increased (3%), neck pain (3%), pain in extremity (3%), joint swelling (2%), paresthesia (2%), leg cramps (≥1%), myalgia (≥1%), myasthenia (1%) Ocular: Visual abnormalities (≤5%), eye disorder (≤2%), conjunctivitis (≥1%), nystagmus (≥1%) Otic: Otitis media (≥1%), tinnitus (≥1%) Respiratory: Nasopharyngitis (8%), sinusitis (4% to 7%), pharyngolaryngeal pain (1% to 3%), bronchitis (≤3%), dyspnea (≤3%) Miscellaneous: Flu-like syndrome (1% to 2%), allergic reaction (≥1%)

<1% (Limited to important or life-threatening):
Abnormal ejaculation, abscess, acute renal failure, addiction , agitation, albuminuria, alopecia, amenorrhea, anaphylactoid reaction, anemia, angioedema, anisocoria, apathy, aphasia, aphthous stomatitis, apnea, arthrosis, ascites, atelectasis, bladder cancer, blepharitis, blindness, bronchiolitis, cellulitis, cerebellar syndrome, cervicitis, chills, cholecystitis, cholelithiasis, chondrodystrophy, circumoral paresthesia, cogwheel rigidity, colitis, coma, corneal ulcer, crystalluria (urate), delirium, delusions, diarrhea, dry eyes, dysarthria, dysautonomia, dyskinesia, dysmenorrhea, dysphagia, dyspareunia, dystonia, dysuria, eczema, encephalopathy, eosinophilia, epididymitis, esophageal ulcer, esophagitis, exfoliative dermatitis, exophthalmos, extraocular palsy, extrapyramidal syndrome, eye hemorrhage, female lactation, gastritis, GI hemorrhage, glomerulitis, glucose tolerance decreased, granuloma, Guillain-Barré syndrome, gynecomastia, hallucinations, heart failure, hematuria, hirsutism, hostility, hyperacusis, hyperalgesia, hyperesthesia, hyper-/hypokinesia; hypersensitivity (including skin redness, blistering, hives, rash, dyspnea, and wheezing); hypotonia, intracranial hypertension, iritis, keratitis, keratoconjunctivitis, libido increased, laryngismus, leukopenia, leukorrhea, leukocytosis, lichenoid dermatitis, lung edema, lung fibrosis, lymphadenopathy, malaise, manic reaction, melanosis, melena, miosis, mouth ulcer, mydriasis, myelofibrosis, neck rigidity, nephritis, neuralgia, night blindness, ocular hemorrhage, oliguria, ophthalmoplegia, optic atrophy, pancreatitis, papilledema, paranoid reaction, parosmia, pelvic pain, periodontal abscess, peripheral neuritis, personality disorder, photophobia, photosensitivity, polycythemia, postural hypotension, prothrombin decreased, psychotic depression, ptosis, pulmonary edema, pulmonary fibrosis, purpura, pyelonephritis, rash (vesiculobullous, petechial, purpuric, pustular); rectal hemorrhage, renal calculus, retinal edema, retinal vascular disorder, retroperitoneal fibrosis, rhabdomyolysis, schizophrenic reaction, shock, skin atrophy, skin necrosis, skin nodule, skin ulcer, ST depression, Stevens-Johnson syndrome, subcutaneous nodule, suicide, suicide attempt, syncope, taste loss, taste perversion, thrombocythemia, thrombophlebitis, tongue edema, torticollis, trismus, urinary retention, urticaria, uveitis, ventricular fibrillation Contraindications Hypersensitivity to pregabalin or any component of the formulation Warnings/Precautions Concerns related to adverse effects: • Angioedema: Angioedema has been reported; may be life-threatening; use with caution in patients with a history of angioedema episodes. Concurrent use with other drugs known to cause angioedema (eg, ACE inhibitors) may increase risk. • CNS effects: Dizziness and somnolence are commonly reported; effects generally occur shortly after initiation and occur more frequently at higher doses. Patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving). • Hypersensitivity: Hypersensitivity reactions, including skin redness, blistering, hives, rash, dyspnea, and wheezing have been reported; discontinue treatment of hypersensitivity occurs. • Peripheral edema: Use may cause peripheral edema; use with caution in patients with heart failure (NYHA Class III or IV) due to limited data in this patient population. In addition, effect on weight gain/edema may be additive with the thiazolidinedione class of antidiabetic agents; use caution when coadministering these agents, particularly in patients with prior cardiovascular disease. • Platelet count: May decrease platelet count. Severe thrombocytopenia is extremely rare. • PR interval: May cause mild prolongation of PR interval. Clinical significance unknown. • Rhabdomyolysis: Has been associated with increases in CPK and rare cases of rhabdomyolysis; patients should be instructed to notify their prescriber if unexplained muscle pain, tenderness, or weakness, particularly if fever and/or malaise are associated with these symptoms. • Suicidal ideation: Pooled analysis of trials involving various antiepileptics (regardless of indication) showed an increased risk of suicidal thoughts/behavior (incidence rate: 0.43% treated patients compared to 0.24% of patients receiving placebo); risk observed as early as 1 week after initiation and continued through duration of trials (most trials ≤24 weeks). Monitor all patients for notable changes in behavior that might indicate suicidal thoughts or depression; notify healthcare provider immediately if symptoms occur. • Visual disturbances: Blurred vision, decreased acuity and visual field changes have been associated with therapy; patients should be instructed to notify their physician if these effects are noted. • Weight gain: Use may cause weight gain; weight gain generally associated with dose and duration (average weight gain was 5.2 kg for patients receiving pregabalin for ≥2 years); weight gain was not limited to patients with edema and did not appear to be associated with baseline BMI, gender, age, or loss of glycemic control in diabetic patients. Disease-related concerns: • Cardiovascular disease: Use with caution in patients with severe cardiovascular disease, including heart failure; weight gain and/or peripheral edema may occur. • Renal impairment: Use with caution in patients with renal impairment; dosage adjustment required. Concurrent drug therapy issues: • Sedatives: Effects with other sedative drugs or ethanol may be potentiated. Other warnings/precautions: • Tumorigenic potential: Increased incidence of hemangiosarcoma noted in animal studies; significance of these findings in humans is unknown. • Withdrawal: Anticonvulsants should not be discontinued abruptly because of the possibility of increasing seizure frequency; therapy should be withdrawn gradually to minimize the potential of increased seizure frequency, unless safety concerns require a more rapid withdrawal. Tapering over at least 1 week is recommended. Metabolism/Transport Effects None known.

Pregnancy Risk Factor C

Pregnancy Implications Adverse events were observed in animal reproduction studies. In addition, male-mediated teratogenicity has been observed in animal reproduction studies; implications in humans are not defined. Impaired male and female fertility has been noted in animal studies.

Lactation Excretion in breast milk unknown/not recommended

Breast-Feeding Considerations It is not known if pregabalin is excreted in breast milk. Due to the potential for serious adverse reactions in the nursing infant, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of treatment to the mother. Dietary Considerations May be taken with or without food.

Pricing: U.S.

Capsules (Lyrica Oral) 25 mg (90): $432.94 50 mg (90): $432.94 75 mg (90): $432.94 100 mg (90): $432.94 150 mg (90): $432.94 200 mg (90): $432.94 225 mg (90): $432.94 300 mg (90): $432.94

Solution (Lyrica Oral) 20 mg/mL (473 mL): $606.11