AHFS Class:

• GABA-mediated Anticonvulsants 28:12.28

Generic Name(s):

• Pregabalin

Chemical Name:

• (S)-3-(aminomethyl)-5-methylhexanoic acid

Molecular Formula:

• C₈H₁₇NO₂

Pregabalin is an anticonvulsant structurally related to the inhibitory CNS neurotransmitter γ-aminobutyric acid (GABA); the drug also possesses analgesic activity.1,2,3,5,6,8,18

Seizure Disorders

Pregabalin is used as adjunctive therapy (i.e., in combination with other anticonvulsant agents) for the management of partial seizures in adults1,13,16,36 and pediatric patients 1 month of age or older.1,2,3,4,12,35 Clinical studies establishing efficacy of pregabalin for this indication were conducted with conventional (immediate-release) preparations of the drug; efficacy of the extended-release preparation has not been established in patients with partial seizures.1,15,36

Efficacy of pregabalin conventional preparations for adjunctive therapy of partial seizures in adults was established in three 12-week, multicenter, randomized, double-blind, placebo-controlled studies in patients with refractory partial onset seizures with or without secondary generalization who were receiving a regimen of 1-3 anticonvulsants, but were continuing to have seizures (based on a prespecified number of partial seizures experienced during a baseline period).1,2,3,4 In these studies, patients receiving pregabalin 150, 300, or 600 mg daily (administered in 2 or 3 divided doses as conventional preparations) experienced a median decrease in seizure frequency of 17-35, 37, or 36-51%, respectively, while those receiving placebo experienced no appreciable change in seizure frequency.1 In one study, 31, 40, or 51% of patients receiving pregabalin 150, 300, or 600 mg daily, respectively, and 14% of those receiving placebo experienced at least a 50% reduction in seizure frequency;1,2 in another study, 43 or 49% of those receiving pregabalin 600 mg daily in 2 or 3 divided doses, respectively, and 9% of those receiving placebo experienced at least a 50% reduction in seizure frequency.1,4

Efficacy of pregabalin conventional preparations for adjunctive therapy of partial seizures in pediatric patients was established in 2 multicenter, randomized, double-blind, placebo-controlled studies (one 12-week study in patients 4-16 years of age and one 14-day study in patients 1 month to less than 4 years of age).1,35 Both studies included patients with partial onset seizures with or without secondary generalization who were receiving 1-3 concurrent anticonvulsant agents at baseline, but were continuing to have seizures (based on a prespecified number of partial-onset seizures experienced during a baseline period).1,35 In the 12-week study, patients were randomized to receive pregabalin 2.5 mg/kg daily (maximum of 150 mg daily), pregabalin 10 mg/kg daily (maximum of 600 mg daily), or placebo in 2 divided doses.1 Because of higher clearance in patients weighing less than 30 kg, the daily dosage of pregabalin for these patients was increased to 3.5 or 14 mg/kg daily.1,35 In this study, patients receiving pregabalin 10 mg/kg daily experienced a 21% greater reduction in partial seizure frequency relative to placebo.1 Although patients receiving the 2.5-mg/kg daily dosage had a reduction in partial seizure frequency of about 10.5% compared with placebo, the difference was not statistically significant.1 Approximately 41 or 29% of patients receiving pregabalin 10 or 2.5 mg/kg daily, respectively, and 23% of those receiving placebo in this study experienced at least a 50% reduction in seizure frequency.1 In the 14-day study, patients were randomized to receive pregabalin (7 or 14 mg/kg daily in 3 divided doses) or placebo.1 Pregabalin 14 mg/kg daily reduced partial seizure frequency by 43.9% compared with placebo.1 Approximately 54% of patients receiving pregabalin 14 mg/kg daily experienced at least a 50% reduction in seizure frequency compared with 42% of those receiving placebo.1 The 7-mg/kg daily dosage of pregabalin was not more effective than placebo in this study.1

Neuropathic Pain

Postherpetic Neuralgia

Pregabalin is used for the management of postherpetic neuralgia (PHN) in adults.1,5,6,13,15,16

Efficacy of pregabalin conventional preparations for the management of PHN has been established in 3 multicenter, double-blind, placebo-controlled studies in adults with neuralgia persisting for at least 3 months following healing of herpes zoster rash.1,5,6 In these studies, mean pain scores (assessed on an 11-point numerical rating scale) at the end of 8 or 13 weeks of treatment were improved in patients receiving pregabalin compared with those receiving placebo; in addition, a greater proportion of patients receiving pregabalin, compared with those receiving placebo, achieved at least a 50% reduction in pain score from baseline.1,5,6,10 In these studies, pregabalin was administered at dosages of 150 or 300 mg daily in patients with renal impairment (i.e., creatinine clearance of 30-60 mL/minute) and at dosages of 150, 300, or 600 mg daily in patients with normal renal function (i.e., creatinine clearance greater than 60 mL/minute).1,5,6

Efficacy of extended-release pregabalin for the management of PHN is based on studies conducted with conventional preparations of the drug in addition to a randomized withdrawal study in adults with persistent pain for more than 3 months after healing of their herpes zoster rash.15,37 In the randomized withdrawal study, pregabalin daily doses of 82.5, 165, 247.5, 330, 495, and 660 mg as extended-release tablets were compared with placebo.15,37 Patients who experienced at least a 50% reduction in mean pain scores during a 6-week single-blind treatment phase were randomized to receive pregabalin or placebo.15,37 Mean pain scores were substantially improved in patients receiving pregabalin compared with those receiving placebo; in addition, a greater proportion of patients receiving pregabalin, compared with those receiving placebo, achieved at least a 50% reduction in pain scores from baseline.15,37

Pregabalin is considered by many experts to be one of several first-line therapies for PHN; although the drug has been shown to be more effective than placebo in reducing pain associated with PHN, the evidence suggests that only a small proportion of patients will derive a clinically meaningful benefit from the drug.27,67,89 Other drugs that have been recommended for the management of PHN include gabapentin, tricyclic antidepressants, and topical lidocaine.67,89 When selecting an appropriate regimen, clinicians should consider the relative efficacy and safety of the specific drugs as well as individual patient-related factors (e.g., age, preference, tolerability, contraindications, comorbid conditions, concomitant medications).67,68

Diabetic Neuropathy

Pregabalin is used for the management of pain associated with diabetic peripheral neuropathy (DPN) in adults.1,7,8,13,15,16

Efficacy of pregabalin conventional preparations for the management of DPN has been established in 3 multicenter, double-blind, placebo-controlled studies in adults with type 1 or 2 diabetes mellitus and painful distal symmetrical sensorimotor polyneuropathy of 1-5 years' duration.1,7,8 In 2 studies that excluded patients with renal impairment (i.e., creatinine clearance of 60 mL/minute or less), treatment with pregabalin 300 mg daily (given in 3 divided doses) for 5 or 8 weeks improved the mean pain score (assessed on an 11-point numeric rating scale) compared with placebo; in addition, a greater proportion of patients receiving pregabalin 300 mg daily, compared with those receiving placebo, achieved at least a 50% reduction in pain score from baseline.1,7,8 One of these studies also evaluated pregabalin at dosages of 75 and 600 mg daily. 1,7 The 600-mg daily dosage did not provide additional benefit, but was associated with an increased risk of dose-dependent adverse effects when compared with the 300-mg daily dosage.1,7 The 75-mg daily dosage was not effective.1,7

Efficacy of extended-release pregabalin for the management of DPN is based on studies conducted with conventional preparations of the drug in addition to a randomized withdrawal study in adults with PHN.15,37 (See Postherpetic Neuralgia under Uses: Neuropathic Pain.)

Pregabalin also has been evaluated in other randomized controlled studies for the management of DPN.25,26,27,28,29,94,95 The overall evidence indicates that the drug is more effective than placebo in relieving pain associated with DPN, but the effect size is small and not all studies found a benefit with the drug.25,29,94,95 A dose-related effect has been observed in which higher dosages of pregabalin are associated with greater efficacy and a more rapid onset of pain relief, but the increase in efficacy is accompanied by an increased risk of adverse effects.25,94

Although pregabalin is considered by many experts to be one of several first-line therapies for DPN, the evidence suggests that only a small proportion of patients will derive a clinically meaningful benefit from the drug.27,67,89,91,94,95,96 Other drugs that have been recommended for the management of DPN include gabapentin, tricyclic antidepressants, and serotonin- and norepinephrine-reuptake inhibitors (e.g., duloxetine, venlafaxine).67,91,94,95,96,105 When selecting an appropriate regimen, clinicians should consider the relative efficacy, safety, pharmacokinetics, drug interaction potential, and cost of the specific drugs in addition to individual patient-related factors (e.g., contraindications, comorbid conditions, concomitant medications).67,94,96

Neuropathic Pain Associated with Spinal Cord Injury

Pregabalin is used for the management of neuropathic pain associated with spinal cord injury in adults.1,13,16,23,24 Clinical studies establishing efficacy of pregabalin for this indication were conducted with conventional (immediate-release) preparations of the drug.1

Efficacy of pregabalin for neuropathic pain associated with spinal cord injury was established in 2 multicenter, double-blind, placebo-controlled studies in adults with such pain that persisted continuously for at least 3 months or relapsed/remitted for at least 6 months.1,23,24 Patients were randomized to receive flexible-dose pregabalin in the range of 150-600 mg daily or placebo for 12 or 16 weeks.1,23,24 Patients were allowed to continue their existing pain management therapy (e.g., opiates, nonopiate analgesics, anticonvulsants, muscle relaxants, antidepressants) if the dosages were stable for at least 30 days prior to screening; acetaminophen and nonsteroidal anti-inflammatory drugs could be used as needed during the studies.1,23,24

In both studies, treatment with pregabalin 150-600 mg daily substantially improved weekly mean pain scores.1,23,24 In addition, the percentages of patients achieving at least a 30 or 50% reduction in pain scores from baseline were substantially greater in the pregabalin compared with placebo groups.1,23,24 Some patients experienced a decrease in pain as early as 1 week, which was sustained throughout the studies.1,23,24

Other Types of Neuropathic Pain

Pregabalin also has been evaluated for the management of other types of neuropathic pain, including central post-stroke pain†,30,100 HIV-related peripheral neuropathy†,27,31,32 and cancer-related neuropathy.33,99 Although the majority of studies evaluating gabapentinoids (i.e., gabapentin and pregabalin) for chronic neuropathic pain were conducted in patients with PHN or DPN, the evidence is often extrapolated to other neuropathic pain conditions and many experts recommend these drugs as first-line agents for all types of neuropathic pain (except for trigeminal neuralgia).67,87,88,89,90,92,93,94,100,101 However, controlled studies generally have shown only limited benefit or no benefit of pregabalin for these other neuropathic conditions.27,31,32,100

Fibromyalgia

Pregabalin is used for the management of fibromyalgia in adults.1,17,18,19,20,34 Clinical studies establishing efficacy of pregabalin for this indication were conducted with conventional (immediate-release) preparations of the drug; efficacy of the extended-release preparation has not been established in patients with fibromyalgia.1,15

Efficacy of pregabalin conventional preparations for the management of fibromyalgia has been established in a 14-week multicenter, randomized, double-blind, placebo-controlled study and a 6-month, randomized, withdrawal study in adults with a diagnosis of fibromyalgia based on the American College of Rheumatology (ACR) classification criteria (i.e., history of widespread pain for 3 months and pain present at 11 or more of the 18 specific tender point sites).1,17,20 In the 14-week study, treatment with pregabalin 300, 450, or 600 mg daily (administered in 2 divided doses) improved the mean end-of-treatment pain score compared with placebo; in addition, a greater proportion of patients receiving pregabalin at all 3 dosages, compared with those receiving placebo, achieved at least a 30 and 50% reduction in pain score from baseline.1,20 However, the 600-mg daily dosage did not appear to provide additional improvement in pain scores when compared with the 450-mg daily dosage, but dose-dependent adverse effects were observed.1

In the 6-month withdrawal study, patients who responded to treatment with pregabalin 300, 450, or 600 mg daily (i.e., at least 50% reduction in pain score and a self-rating of overall improvement on the Patient Global Impression of Change [PGIC] scale of “much improved” or “very much improved”) during a 6-week, open-label, dose optimization period were randomized to a 26-week, double-blind treatment period to remain on their optimal pregabalin dosage or receive placebo.1,17 In the double-blind treatment period, patients receiving pregabalin had a longer time to loss of therapeutic response than did those receiving placebo.1,17

Results of a systematic review of 5 randomized controlled studies indicated that treatment with pregabalin (at dosages of 300-600 mg daily over 12-26 weeks) provided substantial benefit (i.e., reduction in pain intensity by at least 50%) in about 22-24% of patients who received the drug compared with 14% of those who received placebo; a moderate benefit (i.e., reduction in pain intensity by at least 30%) was reported in 39-43% of patients who received the drug compared with 28% of those who received placebo.34 The majority of patients in these studies experienced adverse effects from pregabalin.34 Overall findings from these studies suggest that pregabalin may be effective in reducing pain in a small proportion of patients with fibromyalgia.34

Administration

Pregabalin is administered orally as conventional (immediate-release) capsules or oral solution.1,13,16 The drug also is available as extended-release tablets for the treatment of postherpetic neuralgia (PHN) or diabetic peripheral neuropathy (DPN) in adults; efficacy of this preparation has not been established for other indications.15 Pregabalin capsules and oral solution are administered orally without regard to food;1 the extended-release tablets should be administered once daily after the evening meal.15 The extended-release tablets should be swallowed whole and not split, crushed, or chewed.15

When switching from conventional preparations of pregabalin to the extended-release tablets, patients should take their usual morning dose of conventional capsules or oral solution, and initiate therapy with the extended-release tablets after the evening meal.15 The appropriate dose conversion should be performed according to the table below (see Table 1).15

When discontinuing therapy, pregabalin should be withdrawn gradually by tapering the dosage over at least 1 week.1,15 (See Discontinuance of Therapy under Cautions: Warnings/Precautions.)

Patients currently receiving or beginning therapy with pregabalin and/or any other anticonvulsant for any indication should be closely monitored for the emergence or worsening of depression, suicidal thoughts or behavior (suicidality), and/or any unusual changes in mood or behavior.1,21 (See Suicidality Risk under Cautions: Warnings/Precautions.)

Dosage

Seizure Disorders

For adjunctive therapy of partial seizures in adults, pregabalin therapy generally is initiated at a dosage of 150 mg daily, administered in 2 or 3 divided doses as conventional preparations;1,2,3,12,13,16 based on individual patient response and tolerability, dosage may be increased at approximately weekly intervals up to a maximum daily dosage of 600 mg.1,2,3,4,12,13,16 Dosage adjustments are required in patients with renal impairment.1 (See Dosage and Administration: Special Populations.)

Dosage of pregabalin for adjunctive therapy of partial seizures in pediatric patients is based on body weight.1 In pediatric patients 1 month of age or older who weigh less than 30 kg, the recommended initial dosage of pregabalin as conventional preparations is 3.5 mg/kg daily (administered in 3 divided doses for patients 1 month to less than 4 years of age, or in 2 or 3 divided doses for patients 4 years of age or older); dosage may be increased at approximately weekly intervals based on individual patient response and tolerability up to a maximum of 14 mg/kg daily.1 In pediatric patients 1 month of age or older who weigh 30 kg or more, the recommended initial dosage of pregabalin is 2.5 mg/kg daily (administered in 2 or 3 divided doses as conventional preparations); dosage may be increased at approximately weekly intervals based on individual patient response and tolerability up to a maximum of 10 mg/kg daily (not to exceed 600 mg daily).1 In clinical studies, the 2.5-mg/kg daily dosage of pregabalin was not substantially more effective than placebo in reducing seizure frequency; however, additional support for this dosage can be derived from adult studies and pharmacokinetic data.1

Both the efficacy and adverse effects of pregabalin are dose related,1,2,3 but the effect of the dosage escalation rate on tolerability of the drug has not been specifically studied.1,10

The manufacturer states that dosage recommendations for the use of pregabalin in conjunction with gabapentin are not available because such regimens have not been evaluated in controlled clinical studies.1

Neuropathic Pain

Postherpetic Neuralgia

For the management of PHN in adults, the recommended dosage range of pregabalin (as conventional preparations) is 150-300 mg daily, administered in 2 or 3 divided doses.1,6,13,16 Therapy is generally initiated at a dosage of 150 mg daily (75 mg twice daily or 50 mg 3 times daily); dosage may be increased to 300 mg daily (administered in 2 or 3 divided doses) within 1 week based on efficacy and tolerability.1,5,13,16 In patients who are tolerating the drug but not experiencing adequate pain relief following 2-4 weeks of treatment with pregabalin 300 mg daily as conventional tablets, dosage may be increased up to a maximum of 600 mg daily (administered in 2 or 3 divided doses).1,5,13,16 Because of dose-dependent adverse reactions, dosages exceeding 300 mg daily should be reserved for patients who have continuing pain and are tolerating the drug.1,13,16

If the extended-release tablets are used, the recommended initial adult dosage is 165 mg once daily after the evening meal; dosage may be increased to 330 mg once daily within 1 week based on individual patient response and tolerability.15 In patients who are tolerating the drug but not experiencing adequate pain relief following 2-4 weeks of treatment with pregabalin 330 mg daily as extended-release tablets, dosage may be increased up to a maximum of 660 mg once daily.15 Because of dose-dependent adverse reactions, dosages exceeding 330 mg daily should be reserved for patients who have continuing pain and are tolerating the 330-mg daily dosage.15

Dosage adjustments are required in patients with renal impairment.1 (See Dosage and Administration: Special Populations.)

When switching from conventional to extended-release preparations of pregabalin, the manufacturer's dose conversion guidelines in Table 1 should be followed.15 (See Dosage and Administration: Administration.)

Diabetic Neuropathy

For the management of pain associated with DPN in adults, the initial dosage of pregabalin (as conventional preparations) is 150 mg daily administered in 3 divided doses; dosage may be increased within 1 week based on efficacy and tolerability to the maximum recommended daily dosage of 300 mg.1,7,8,13,16 If the extended-release tablets are used, the recommended initial adult dosage is 165 mg once daily after the evening meal; dosage may be increased to the maximum recommended dosage of 330 mg once daily within 1 week based on individual patient response and tolerability.15 Although higher dosages of pregabalin (e.g., 600 mg daily) were evaluated in clinical studies, there is no evidence that these dosages provide additional benefit and may increase the risk of adverse effects.1,7,15

Dosage adjustments are required in patients with renal impairment.1 (See Dosage and Administration: Special Populations.)

When switching from conventional to extended-release preparations of pregabalin, the manufacturer's dose conversion guidelines in Table 1 should be followed.15 (See Dosage and Administration: Administration.)

Neuropathic Pain Associated with Spinal Cord Injury

For the management of neuropathic pain associated with spinal cord injury in adults, the recommended dosage range of pregabalin is 150-600 mg daily (administered in 2 divided doses as conventional preparations).1,13,16 An initial dosage of 150 mg daily (75 mg twice daily) is recommended; dosage may be increased to 300 mg daily (150 mg twice daily) within 1 week based on efficacy and tolerability.1 In patients who are tolerating the drug but not experiencing adequate pain relief after 2-3 weeks of treatment with a dosage of 300 mg daily, dosage may be further increased to 600 mg daily (300 mg twice daily).1

Dosage adjustments are required in patients with renal impairment.1 (See Dosage and Administration: Special Populations.)

Fibromyalgia

For the management of fibromyalgia in adults, the recommended dosage of pregabalin is 300-450 mg daily (as conventional preparations).1,13,16 An initial dosage of 150 mg daily (administered as 75 mg twice daily) is recommended; dosage may be increased to 300 mg daily (150 mg twice daily) within 1 week based on efficacy and tolerability.1,13,16 Patients who do not experience adequate benefit with pregabalin 300 mg daily may have their dosage further increased to the maximum recommended dosage of 450 mg daily (225 mg twice daily).1,13,16 Clinical studies in patients with fibromyalgia indicate that higher pregabalin dosages (e.g., 600 mg daily) provide no additional benefit but may increase the risk of adverse effects; therefore, dosages exceeding 450 mg daily are not recommended.1,13,16

Dosage adjustments are required in patients with renal impairment.1 (See Dosage and Administration: Special Populations.)

Special Populations

In patients with renal impairment (creatinine clearance of less than 60 mL/minute), dosage of pregabalin should be modified based on creatinine clearance (see Tables 2 or 3 based on the preparation of drug used).1,13,15,16 Patients with a creatinine clearance of less than 30 mL/minute or who are undergoing hemodialysis should not receive the extended-release formulation of pregabalin; in these patients, conventional preparations of the drug should be used.15

Because pregabalin is removed by hemodialysis, in addition to the adjusted daily dosage, patients undergoing hemodialysis should receive a supplemental dose of the drug (as a conventional [immediate-release] preparation) immediately following each 4-hour dialysis session.1 Individuals receiving the 25-mg once daily dosage regimen should receive a supplemental dose of 25 or 50 mg, those receiving the 25- to 50-mg once daily dosage regimen should receive a supplemental dose of 50 or 75 mg, those receiving the 50- to 75-mg once daily dosage regimen should receive a supplemental dose of 75 or 100 mg, and those receiving the 75-mg once daily dosage regimen should receive a supplemental dose of 100 or 150 mg.1 The extended-release preparation of pregabalin is not recommended in patients undergoing hemodialysis.15

Contraindications

Known hypersensitivity to pregabalin or any ingredient in the formulation.1,15

Warnings/Precautions

Sensitivity Reactions

Angioedema

Angioedema, including life-threatening cases with respiratory compromise requiring emergency treatment, has been reported during postmarketing surveillance in patients receiving initial and chronic pregabalin therapy.1,15 Specific symptoms included swelling of the face, mouth (e.g., tongue, lips, gums), and neck (e.g., throat, larynx).1 Pregabalin should be immediately discontinued in patients with these symptoms.1 Caution is advised if the drug is used in patients who have had a previous episode of angioedema.1 Patients receiving concomitant drugs associated with angioedema (e.g., angiotensin-converting enzyme [ACE] inhibitors) may be at increased risk of developing angioedema.1

Hypersensitivity Reactions

Hypersensitivity reactions (i.e., skin redness, blisters, hives, rash, dyspnea, wheezing) have been reported during postmarketing surveillance in patients shortly after initiation of pregabalin therapy.1,15 Pregabalin should be immediately discontinued in patients with symptoms of hypersensitivity.1

Suicidality Risk

An increased risk of suicidality (suicidal behavior or ideation) has been observed in an analysis of studies using various anticonvulsants, including pregabalin, compared with placebo.1,15,21 The analysis of suicidality reports from placebo-controlled studies involving 11 anticonvulsants (i.e., carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, zonisamide) in patients with epilepsy, psychiatric disorders (e.g., bipolar disorder, depression, anxiety), and other conditions (e.g., migraine, neuropathic pain) found that patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) compared with patients receiving placebo (0.24%).1 This increased suicidality risk was consistent among anticonvulsants with varying mechanisms of action and across a range of indications, and was observed as early as 1 week after beginning therapy.1 Because most of these studies did not extend beyond 24 weeks, the suicidality risk beyond 24 weeks is not known.1 Although patients treated with an anticonvulsant for epilepsy, psychiatric disorders, and other conditions were all found to have an increased suicidality risk compared with those receiving placebo, the relative suicidality risk was higher for patients with epilepsy compared to those receiving anticonvulsants for other conditions.1

Clinicians should inform patients, their families, and caregivers of the potential for an increased risk of suicidality with anticonvulsant therapy.1 All patients currently receiving or beginning therapy with any anticonvulsant should be closely monitored for notable changes that may indicate the emergence or worsening of suicidal thoughts or behavior or depression.1,21

Clinicians who prescribe pregabalin or any other anticonvulsant should balance the risk of suicidality with the risk of untreated illness.1 Epilepsy and many other illnesses for which anticonvulsants are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior.1,21 If suicidal thoughts or behavior emerge during anticonvulsant therapy, the clinician should consider whether these symptoms may be related to the illness being treated.1,21 (See Advice to Patients.)

Respiratory Depression

Serious, life-threatening, or fatal respiratory depression has been reported in patients receiving gabapentinoids (i.e., gabapentin and pregabalin).1,15,106 In the majority of cases, the drugs were used in combination with an opiate analgesic (or other CNS depressant), in patients with preexisting respiratory risk factors (e.g., COPD), or in geriatric patients.1,106,107,108,109,110 During a 5-year period between 2012 and 2017, 49 cases of respiratory depression associated with gabapentinoid use (15 cases with gabapentin and 34 cases with pregabalin) were reported to the FDA, including 12 fatalities.106 Most of the cases (92%) reported either concomitant use of another CNS depressant or a respiratory risk factor, including age-related decreases in lung function.106 In all of the fatal cases, patients had at least one risk factor for developing respiratory depression or were receiving a CNS depressant concomitantly.106 In addition, there is evidence from small randomized studies in healthy individuals and observational studies in postoperative patients suggesting that use of gabapentinoids alone or in conjunction with opiate analgesics may increase the risk of respiratory depression.106,107,108,109,110 Although findings from these studies as well as animal data suggest that gabapentinoids may have an independent respiratory depressant effect, there is less evidence supporting the risk of serious respiratory complications when these drugs are used alone in otherwise healthy individuals.106,107,108

Because of the risk of respiratory depression when gabapentinoids are used in combination with opiate analgesics or other CNS depressants (e.g., benzodiazepines) or in the setting of underlying respiratory impairment, patients should be monitored for respiratory depression and sedation in these situations.1,15,106 Consideration should be given to initiating pregabalin therapy at the lowest dosage and titrating the dosage carefully; appropriate dosage adjustments should be made in patients with renal impairment and those undergoing hemodialysis.1,106 (See Dosage and Administration: Special Populations.) Patients should be advised to seek immediate medical attention if signs or symptoms of respiratory depression occur.1,106 (See Advice to Patients.) Management of respiratory depression may include supportive measures and reduction or withdrawal of CNS depressants, including pregabalin.1,106 If the decision is made to discontinue pregabalin, dosage should be reduced gradually.106 (See Discontinuance of Therapy under Cautions: Warnings/Precautions.)

Dizziness and Somnolence

Pregabalin may cause dizziness and somnolence. 1,15 (See Advice to Patients.) In controlled studies, approximately 24-30% of adults who received pregabalin experienced dizziness and approximately 16-23% of the patients experienced somnolence.1,15 Dizziness and somnolence were the most frequent adverse effects requiring discontinuance of the drug in these studies.1,10,15 In controlled studies in pediatric patients with partial seizures, somnolence was reported in 15-21% of the patients who received pregabalin.1 These adverse effects occurred more frequently at higher doses and, in some cases, persisted throughout therapy.1,15

Discontinuance of Therapy

As with all anticonvulsant agents, there is a potential for increased seizure frequency when pregabalin therapy is withdrawn abruptly.1,15 When discontinuing pregabalin therapy, dosage should be reduced gradually over at least 1 week.1,15 Abrupt or rapid discontinuance of pregabalin has been associated with symptoms suggestive of physical dependence (e.g., insomnia, nausea, headache, anxiety, hyperhidrosis, diarrhea).1

Peripheral Edema

Pregabalin may cause peripheral edema.1,15 In short-term clinical trials of patients without clinically important cardiac or peripheral vascular disease, there was no apparent association between peripheral edema and cardiovascular complications (e.g., hypertension, congestive heart failure).1 Peripheral edema was not associated with deterioration of renal or hepatic function.1 In controlled clinical studies, peripheral edema was reported in about 5-6% of adults receiving pregabalin.1,15

Concomitant use of pregabalin with a thiazolidinedione antidiabetic agent has been associated with a greater risk of developing weight gain and peripheral edema than use of either drug alone.1 (See Drug Interactions: Antidiabetic Agents.)

Because there are limited data regarding use of pregabalin in patients with New York Heart Association (NYHA) class III or IV heart failure, the drug should be used with caution in these patients.1

Weight Gain

Pregabalin may cause weight gain.1,15 Pregabalin-associated weight gain appeared to be related to dosage and duration of exposure; however, weight gain did not appear to be associated with baseline body mass index (BMI), gender, or age and was not limited to patients with edema.1

Although weight gain was not associated with clinically important changes in blood pressure in short-term controlled studies, the long-term cardiovascular effects of such weight gain have not been elucidated.1 In addition, 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 in diabetic patients, pregabalin therapy did not appear to be associated with loss of glycemic control.1

Carcinogenicity

Possible carcinogenicity of pregabalin (e.g., hemangiosarcoma) has been demonstrated in animals.1,15

In clinical studies across various patient populations, comprising 6396 patient-years of exposure in those 12 years of age or older, new or worsening-preexisting tumors were reported in 57 patients; however, a causal relationship to the drug has not been established.1

Ocular Effects

In controlled studies in adults, blurred vision was reported in about 5-7% of patients receiving pregabalin and resolved in the majority of cases with continued dosing.1,15 In addition, decreased visual acuity was reported in 7% of patients receiving pregabalin, while visual field and funduscopic changes were detected in 13 and 2%, respectively, of patients receiving the drug.1 However, these ocular effects occurred at a similar incidence to placebo and the clinical importance of these findings has not been elucidated.1,15

Patients receiving pregabalin should inform their clinician if any changes in vision occur. 1,15 If visual disturbance persists, further ophthalmologic assessment should be considered, while more frequent assessment should be considered in patients who already are monitored for ocular conditions.1

Creatine Kinase Elevations

In clinical trials in adults, increases in serum creatinine kinase (CK, creatine phosphokinase, CPK) concentrations at least 3 times the upper limit of normal have been reported in 1.5 or 0.7% of patients receiving pregabalin or placebo, respectively.1,15

Rhabdomyolysis has been reported rarely in premarketing clinical trials.1 However, a definite causal relationship between these musculoskeletal effects and the drug has not been fully elucidated because the cases had documented factors that may have caused or contributed to these events.1

Pregabalin treatment should be discontinued if myopathy is diagnosed or suspected or if markedly elevated CK (CPK) concentrations occur.1

Thrombocytopenia

In controlled clinical trials in adults, potentially clinically important decreases in platelet count (thrombocytopenia; defined as 20% below baseline value and less than 150,000/mm³) have been reported in 3 or 2% of patients receiving pregabalin or placebo, respectively.1,15 Pregabalin-treated patients experienced a mean maximal decrease in platelet count of 20,000/mm³ compared with 11,000/mm³ in placebo recipients.1 Severe thrombocytopenia with a platelet count less than 20,000/mm³ has been reported in at least one patient who received pregabalin.1 In randomized controlled trials, pregabalin was not associated with an increase in bleeding-related adverse effects.1

PR Interval Prolongation

Prolongation of the PR interval (mean increase: 3-6 msec) has been reported in adults receiving pregabalin dosages of at least 300 mg daily.1,15 Subgroup analyses in a limited number of patients suggest that those with preexisting PR prolongation at baseline or those receiving drugs that prolong the PR interval do not appear to have an increased risk for developing prolongation of the PR interval.1

Abuse Potential and Dependence

In controlled clinical studies using conventional pregabalin, 4 or 1% of patients receiving the drug or placebo, respectively, reported euphoria as an adverse event;1,12 in some patient populations studied, the rate of euphoria was higher and ranged from 1-12%.1,15 In clinical studies, abrupt or rapid discontinuance of pregabalin has resulted in withdrawal symptoms (e.g., insomnia, nausea, headache, diarrhea).1 (See Discontinuance of Therapy under Cautions: Warnings/Precautions.)

Pregabalin is not known to be active at receptor sites associated with drugs of abuse.1 However, the drug is subject to control as a schedule V (C-V) drug.9,12

As with any CNS active drug, clinicians should carefully evaluate patients for a history of drug abuse and observe them for signs of pregabalin misuse or abuse (e.g., development of tolerance, dose escalation, drug-seeking behavior).1

Specific Populations

Pregnancy

Women who are pregnant while receiving pregabalin should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry at 888-233-2334 (for patients); registry information also is available on the website [Web].1

There are no adequate and well-controlled studies of pregabalin in pregnant women; however, based on animal studies, pregabalin may cause fetal harm.1 In animal reproductive studies, pregabalin produced developmental toxicity (e.g., fetal structural abnormalities, skeletal malformations, retarded ossification, decreased fetal body weight) when administered orally to pregnant animals during the period of organogenesis at exposure levels 16 times higher than those associated with the maximum recommended human dosage of 600 mg daily.1 When pregabalin was administered to female rats throughout the period of gestation and lactation, growth retardation, impairment to the nervous and reproductive systems, and decreased survival were observed in the offspring.1

Lactation

Pregabalin is distributed into human milk at steady-state concentrations approximately 76% of those in maternal plasma.1 Following administration of maternal dosages of 300 mg daily, the estimated average infant dose of pregabalin from breast milk is 0.31 mg/kg daily (approximately 7% of the maternal dose).1 Because of the potential for tumorigenicity (see Carcinogenicity under Cautions: Warnings/Precautions), breastfeeding is not recommended during pregabalin therapy.1

Pediatric Use

Safety and efficacy of pregabalin conventional preparations for adjunctive treatment of partial seizures have not been established in children younger than 1 month of age.1 Use of conventional pregabalin in older children is supported by evidence from 2 randomized placebo-controlled studies.1 (See Uses: Seizure Disorders.) Although the youngest patient evaluated in these studies was 3 months of age, use of pregabalin in infants 1-3 months of age can be supported by additional pharmacokinetic data.1

Clearance of pregabalin (normalized for body weight) is approximately 40% higher in patients weighing less than 30 kg.1,22 For children weighing less than 30 kg, a dosage increase is required to achieve comparable exposure to those weighing 30 kg or more.1,22

Safety and efficacy of pregabalin for the treatment of fibromyalgia, diabetic peripheral neuropathy (DPN), postherpetic neuralgia (PHN), or neuropathic pain associated with spinal cord injury have not been established in pediatric patients.1

Safety and efficacy of pregabalin extended-release tablets have not been established in pediatric patients.15

Geriatric Use

The manufacturer states that no substantial differences in safety and efficacy have been observed in geriatric patients relative to younger adults; however, increased sensitivity to pregabalin in certain individuals cannot be ruled out.1,15 In controlled clinical studies of patients with fibromyalgia, neurological adverse reactions including dizziness, blurred vision, balance disorder, tremor, confusional state, abnormal coordination, and lethargy occurred more frequently in patients 65 years of age and older than in younger adults.1 In addition, FDA warns that geriatric patients receiving gabapentinoids are at increased risk of potentially serious, life-threatening, or fatal respiratory depression; pregabalin therapy should be initiated at the lowest dosage and titrated carefully with close monitoring in such patients.106

It should be considered that pregabalin is substantially excreted by the kidneys, and the risk of adverse reactions to the drug may be increased in patients with impaired renal function.1 The dosage should be adjusted for geriatric patients with renal impairment.1 Monitoring renal function in geriatric patients may be helpful.15 (See Dosage and Administration: Special Populations.)

Renal Impairment

Pregabalin is eliminated renally.1 Dosage of pregabalin should be modified in adults according to the degree of renal impairment.1 (See Dosage and Administration: Special Populations.) The drug has not been evaluated in pediatric patients with renal impairment.1

Pregabalin is removed from plasma by hemodialysis.1 Plasma pregabalin concentrations are reduced by approximately 50% following a 4-hour hemodialysis treatment.1 (See Dosage and Administration: Special Populations.)

Common Adverse Effects

The most common adverse effects in adults receiving conventional pregabalin preparations across indications in clinical trials (occurring in 5% or more of patients and more frequently than placebo) include dizziness, somnolence, dry mouth, edema, blurred vision, weight gain, and abnormal thinking (primarily difficulty with concentration/attention).1 The most common adverse effects in pediatric patients receiving conventional pregabalin for the treatment of partial seizures (occurring in 5% or more of patients and more frequently than placebo) include somnolence, weight gain, and increased appetite.1

The most common adverse effects in adults receiving extended-release pregabalin in clinical studies include dizziness, somnolence, headache, fatigue, peripheral edema, nausea, blurred vision, dry mouth, and weight gain.15

Other adverse effects commonly reported in adults receiving conventional pregabalin in combination with other anticonvulsant agents in the management of partial seizures include ataxia,1,2,3,4,12 tremor,1,2,3 amnesia,1 speech disorder,1 increased appetite,1 peripheral edema,1,12 diplopia,1,3,4 and accidental injury.1,2

Other adverse effects commonly reported in adults receiving conventional pregabalin for the management of PHN include headache,1,5,6 ataxia,1,5 constipation,1 peripheral edema,1,5,6 infection,1,6 and pain.1

Other adverse effects commonly reported in adults receiving conventional pregabalin for the management of DPN include asthenia1,7,8 and peripheral edema.1,7,8

Other adverse effects commonly reported in adults receiving conventional pregabalin for the management of fibromyalgia include headache,1 euphoric mood,1 attention disturbance,1 balance disorder,1 constipation,1 fatigue,1 peripheral edema,1 increased appetite,1 and sinusitis.1

Other adverse effects commonly reported in adults receiving conventional pregabalin for the management of neuropathic pain associated with spinal cord injury include fatigue,1 peripheral edema,1 constipation,1 nasopharyngitis,1 and muscle weakness.1

Specific drug interaction studies conducted with pregabalin extended-release tablets are limited; the information presented below is derived principally from studies with conventional preparations of pregabalin.1,15 Similar pharmacokinetic interactions are expected with the various preparations of pregabalin.15

Drugs Affecting Hepatic Microsomal Enzymes

Based on results of in vitro studies, pregabalin does not appear to inhibit cytochrome P-450 (CYP) isoenzymes 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4 or induce CYP1A2 or CYP3A4.1,10

The manufacturer states that increased metabolism of concomitantly administered CYP1A2 substrates (e.g., caffeine, theophylline) or CYP3A4 substrates (e.g., midazolam, testosterone) is not anticipated.1

Since pregabalin undergoes negligible metabolism in humans, pharmacokinetics of the drug are unlikely to be affected by other agents through metabolic interactions.1

Drugs that Cause Constipation

Concomitant use of pregabalin and drugs that can cause constipation (e.g., opiate analgesics) has been associated with adverse events related to reduced lower GI tract function (e.g., intestinal obstruction, paralytic ileus, constipation).1

Protein-bound Drugs

Because pregabalin does not bind to plasma proteins, pharmacokinetic interactions with drugs that are highly protein bound are unlikely.1

Alcohol

Although a pharmacokinetic interaction has not been observed with pregabalin and alcohol, additive effects on cognitive and gross motor functioning have occurred; however, concomitant use of pregabalin and alcohol did not result in any clinically important effects on respiration.1 Use of alcohol should be avoided in patients receiving pregabalin.1

Angiotensin-converting Enzyme Inhibitors

Potential pharmacologic interaction with angiotensin-converting enzyme (ACE) inhibitors (e.g., increased risk of developing angioedema).1

Anticonvulsants

Pharmacokinetic interactions have not been observed when pregabalin was used concomitantly with phenytoin, carbamazepine, valproate, lamotrigine, phenobarbital, or topiramate.1

Concomitant administration of gabapentin with pregabalin did not alter pharmacokinetics of gabapentin, although the rate, but not extent, of absorption of pregabalin was decreased slightly.1

Tiagabine does not appear to affect the pharmacokinetics of pregabalin.1

Antidiabetic Agents

Glyburide, insulin, and metformin do not appear to affect the pharmacokinetics of pregabalin.1

Concomitant use of pregabalin and thiazolidinediones may increase the risk of weight gain and peripheral edema, possibly exacerbating or causing heart failure.1 Caution is advised when these drugs are used concomitantly.1

CNS Depressants

Additive CNS and respiratory depressant effects can occur with concurrent use of pregabalin and CNS depressants, including opiates and benzodiazepines.1,15,106 If pregabalin is used concomitantly with other CNS depressants, pregabalin should be initiated with the lowest dosage and titrated carefully.1,106 (See Respiratory Depression under Cautions: Warnings/Precautions.)

Erythromycin

Concomitant administration of a single dose of pregabalin (as the extended-release tablet) and erythromycin resulted in a 17% decrease in systemic exposure of pregabalin.15

Furosemide

Furosemide does not appear to affect the pharmacokinetics of pregabalin.1

Lorazepam

Although a pharmacokinetic interaction has not been observed, additive effects on cognitive and gross motor functioning have occurred when pregabalin was administered concomitantly with lorazepam; concomitant use of these drugs did not result in any clinically important effects on respiration.1 (See Drug Interactions: CNS Depressants.)

Opiates

Additive CNS and respiratory depressant effects can occur with concurrent use of pregabalin and opiates.1,15,106 If pregabalin is used concomitantly with opiates, pregabalin should be initiated with the lowest dosage and titrated carefully.1,106 (See Respiratory Depression under Cautions: Warnings/Precautions.)

In addition, events related to reduced lower GI function (e.g., intestinal obstruction, paralytic ileus, constipation) have been reported during postmarketing experience in patients taking pregabalin concomitantly with drugs that have the potential to produce constipation, such as opiates.1,15

Oxycodone

Although a pharmacokinetic interaction has not been observed, additive effects on cognitive and gross motor functioning have occurred when pregabalin was administered concomitantly with oxycodone; concomitant use of these drugs did not result in any clinically important effects on respiration.1

Oral Contraceptives

Concomitant administration of pregabalin and an oral contraceptive containing norethindrone and ethinyl estradiol in healthy individuals did not affect the pharmacokinetics of either component of the oral contraceptive.1

Description

Pregabalin is an anticonvulsant that is structurally related to the inhibitory CNS neurotransmitter γ-aminobutyric acid (GABA). 1,18 Pregabalin also has demonstrated analgesic activity.1,2,3,5,6,8,18 Although pregabalin was developed as a structural analog of GABA, the drug does not bind directly to GABA_A, GABA_B, or benzodiazepine receptors; does not augment GABA_A responses in cultured neurons; and does not alter brain concentrations of GABA in rats or affect GABA uptake or degradation.1,2,18 However, in cultured neurons, prolonged application of pregabalin increases the density of GABA transporter protein and increases the rate of functional GABA transport.1,18

Pregabalin binds with high affinity to the α₂-δ site (an auxiliary subunit of voltage-gated calcium channels) in CNS tissues.1,2,3,5,6,7,8,18 Although the exact mechanism of action of pregabalin has not been elucidated, binding to the α₂-δ subunit may be involved in pregabalin's analgesic and anticonvulsant effects.1,2,3,5,6,8,18 In vitro, pregabalin reduces the calcium-dependent release of several neurotransmitters, including glutamate, norepinephrine, calcitonin gene-related peptide, and substance P, possibly by modulation of calcium channel function.1,2,3,4,6,7,8

Pregabalin is well absorbed following oral administration and exhibits linear pharmacokinetics; peak plasma concentrations are attained within 1.5 or 12 hours with conventional or extended-release preparations, respectively.1,15 Steady-state concentrations are achieved within 24-48 hours following repeated administration of conventional pregabalin and within 48-72 hours following repeated administration of the extended-release tablets.1,15 In pediatric patients receiving conventional pregabalin, peak plasma concentrations of the drug are achieved within 0.5-2 hours in the fasted state.1 The oral bioavailability of pregabalin (administered as the conventional preparation) is at least 90% and is independent of dose.1 Bioavailability of the extended-release tablets administered once daily following an evening meal is equivalent to that of comparable doses of the conventional preparation administered without food twice daily.15 Administration of conventional preparations of pregabalin with food has been shown to delay the time to peak concentration and decrease peak plasma concentrations of the drug by approximately 25-30%, but does not affect the extent of absorption.1 Administration of the extended-release tablets in the fasted state reduces systemic exposure of pregabalin by approximately 30% compared with administration following an evening meal.15 Pregabalin is not appreciably metabolized.1,18 Following administration of a single radiolabeled dose of pregabalin, approximately 90% of the administered dose was recovered in urine as unchanged drug.1,18 Clearance of pregabalin is nearly proportional to creatinine clearance in both adults and pediatric patients.1 In pediatric patients, the weight-normalized clearance of pregabalin is approximately 40% higher in those weighing less than 30 kg.1,22 (See Pediatric Use under Warnings/Precautions: Specific Populations, in Cautions.) The mean elimination half-life of pregabalin is 6.3 hours in adults with normal renal function, 3-4 hours in children up to 6 years of age, and 4-6 hours in children 7 years of age or older.1

Advice to Patients

Importance of advising patients or caregivers to read the manufacturer's patient information (medication guide) before the start of therapy and each time the prescription is refilled.1

Importance of patients, family members, and caregivers being aware that anticonvulsants, including pregabalin, may increase the risk of having suicidal thoughts or actions in a very small number of people (about 1 in 500).1,21 Advise patients, family members, and caregivers to pay close attention to any day-to-day changes in mood, behavior, and actions; these changes can happen very quickly.1 They also should be aware of common warning signs that may signal suicide risk (e.g., talking or thinking about wanting to hurt oneself or end one's life, withdrawing from friends and family, becoming depressed or experiencing worsening of existing depression, becoming preoccupied with death and dying, giving away prized possessions).1 Advise patients, family members, and caregivers to contact the responsible clinician immediately if these or any other new and worrisome behaviors occur.1

Risk of angioedema (e.g., swelling of the face, mouth [e.g., tongue, lips, gums], and neck [e.g., throat, larynx] with or without life-threatening respiratory compromise) and other hypersensitivity reactions (e.g., wheezing, dyspnea, rash, hives, blisters); importance of discontinuing the drug and seeking immediate medical attention if such reactions occur.1 Concomitant administration with an angiotensin-converting enzyme (ACE) inhibitor may increase such risk.1

Importance of taking pregabalin only as prescribed.1 Importance of advising patients or caregivers to consult their clinician before changing the dosage of or abruptly discontinuing the drug.1 Patients or caregivers should be informed that abrupt or rapid discontinuance of pregabalin can result in increased risk of seizures in patients with epilepsy or withdrawal symptoms such as insomnia, nausea, headache, anxiety, hyperhidrosis, or diarrhea.1

Risk of respiratory depression; concomitant use of CNS depressants (e.g., opiates) increases the risk.1,106 Risk also is increased in patients with underlying respiratory impairment and in geriatric patients.1,106 Importance of patients seeking immediate medical attention if signs or symptoms of respiratory depression occur (e.g., slow, shallow, or difficult breathing; confusion or disorientation; unusual dizziness or lightheadedness; extreme sleepiness or lethargy; bluish-colored or tinted skin, especially on the lips, fingers, and toes; unresponsiveness).1,106

Risk of dizziness, somnolence, blurred vision, and other neuropsychiatric effects.1 Avoid driving or operating machinery while taking pregabalin until experience is gained with the drug's effects.1

Inform patients that concomitant use of CNS depressants and pregabalin (e.g., opiates or benzodiazepines) may result in additive CNS effects such as respiratory depression, somnolence, and dizziness.1,106

Avoid alcohol-containing beverages or products; pregabalin may potentiate impairment of motor skills and sedation associated with ingestion of alcohol.1

Advise patients that if a dose of pregabalin (as conventional preparations) is missed, the missed dose should be taken as soon as possible; if it is almost time for the next dose, the missed dose should be skipped and the next dose should be taken at the regularly scheduled time.1 Patients should not take 2 doses at the same time.1

Advise patients that if a dose of pregabalin (as extended-release tablets) is missed after an evening meal, the dose should be taken prior to bedtime following a snack.15 If they miss the dose prior to bedtime, then they should take their usual dose the next morning following breakfast.15 If they miss taking the dose following the morning meal, they should take their usual dose at the regularly scheduled time after the evening meal.15

Risk of edema and weight gain; concomitant administration with a thiazolidinedione antidiabetic agent may increase such risk.1 In patients with preexisting cardiac conditions, risk of heart failure may be increased.1

Risk of visual disturbances.1 Importance of informing clinician if changes in vision occur.1

Importance of patients promptly informing clinicians of any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever.1

Advise diabetic patients to watch for skin damage while receiving pregabalin therapy, since increased risk of skin ulcerations associated with pregabalin therapy has been observed in animal studies.1

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Importance of clinicians informing women about the existence of and encouraging enrollment in the North American Antiepileptic Drug Pregnancy Registry (see Pregnancy under Warnings/Precautions: Specific Populations, in Cautions).1 Women should be advised that breastfeeding is not recommended during treatment with pregabalin.1

Advise patients of male-mediated teratogenicity.1 Importance of men informing clinicians if they plan to father a child.1

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1 Potential for additive CNS effects if used concomitantly with other CNS depressants (e.g., opiates, benzodiazepines).1

Importance of informing patients of other important precautionary information.1 (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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