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  • CLASSES

    Anticonvulsants, Gabapentinoids
    Neuropathic Pain and Peripheral Neuropathy Agents

    DEA CLASS

    Rx, schedule V

    DESCRIPTION

    Oral compound chemically and structurally similar to gabapentin, with antiepileptic, analgesic, and anxiolytic properties
    Used for neuropathic pain associated with diabetic peripheral neuropathy or spinal cord injury, postherpetic neuralgia, fibromyalgia, and adjunctive therapy for partial onset seizures
    Monitor for emerging or worsening depression, suicidal thoughts/behavior, or mood/behavior changes

    COMMON BRAND NAMES

    Lyrica, Lyrica CR

    HOW SUPPLIED

    Lyrica CR Oral Tab ER: 82.5mg, 165mg, 330mg
    Lyrica Oral Cap: 25mg, 50mg, 75mg, 100mg, 150mg, 200mg, 225mg, 300mg
    Lyrica Oral Sol: 1mL, 20mg

    DOSAGE & INDICATIONS

    For the symptomatic treatment of neuropathic pain.
    For pain associated with peripheral diabetic neuropathy (DPN).
    Oral dosage (immediate-release capsules and oral solution)
    Adults

    Initially, 50 mg PO 3 times a day; may increase to 100 mg PO 3 times a day in 1 week based on efficacy and tolerability. Although 600 mg/day PO has been studied, there is no evidence that this dose confers significant additional benefits over 300 mg/day, and it is less well tolerated due to dose-dependent adverse effects. In one clinical trial , 338 patients with DPN-related pain were randomized to receive pregabalin at 1 of 3 doses or placebo for 5 weeks. Treatment responders were defined as patients who experienced a 50% or greater reduction in pain from baseline. The 300- and 600-mg/day doses of pregabalin, but not the 75-mg/day dose, were significantly better than placebo at improving the average pain score at 5 weeks. The 2 higher doses of pregabalin had similar responder rates of roughly 47%, whereas the placebo rate was 18%. These doses were also tied to significant improvements in sleep and quality of life. Improvements in pain and sleep were noted within 1 week of treatment and persisted throughout the study. A total dose of 300 mg/day has also been found effective in improving pain scores, sleep interference, and other secondary outcomes.

    Oral dosage (extended-release tablets) in treatment-naive patients (i.e., patients not switching from immediate-release products)
    Adults

    Initially, 165 mg PO once daily. Increase to 330 mg PO once daily within 1 week based on patient response and tolerability. Doses greater than 330 mg/day do not confer additional benefit and may be less well tolerated. To discontinue, gradually taper the dose over a minimum of 1 week.

    Oral dosage (extended-release tablets) in patients switching from immediate-release products
    Adults

    Take the morning dose of immediate-release pregabalin as prescribed and begin extended-release pregabalin after an evening meal. Use the total daily dose of immediate-release pregabalin to convert the patient to an extended-release dose to be given once daily. Use 82.5 mg/day of the extended-release product in patients taking a total daily immediate-release dose of 75 mg/day; 165 mg/day of the extended-release product in patients taking a total daily immediate-release dose of 150 mg/day; 247.5 mg of the extended-release product in patients taking a total daily immediate-release dose of 225 mg/day; 330 mg/day of the extended-release product in patients taking a total daily immediate-release dose of 300 mg/day; 495 mg/day of the extended-release product in patients taking a total daily immediate-release dose of 450 mg/day; and 660 mg/day of the extended-release product in patients taking a total daily immediate-release dose of 600 mg/day. For patients taking less than 330 mg/day following conversion, gradually increase the dose to 330 mg/day within 1 week based on patient response and tolerability. Doses greater than 330 mg/day may not confer additional benefit and may be less well tolerated. To discontinue, gradually taper the dose over a minimum of 1 week.

    For pain associated with postherpetic neuralgia (PHN).
    Oral dosage (immediate-release capsules and oral solution)
    Adults

    Initially, 150 mg/day PO given in 2 or 3 divided doses; may increase to 300 mg/day, given in 2 or 3 divided doses, within 1 week based on efficacy and tolerability. If pain relief is not sufficient after 2 to 4 weeks but the drug is well tolerated, dose may be increased up to 600 mg/day given in 2 or 3 divided doses. Higher doses should be specifically reserved for patients without adequate pain relief, as adverse events are dose-related and significant at the 600 mg/day dose. Studies evaluating 150 or 300 mg/day PO in 3 divided doses resulted in a significant reduction of pain associated with PHN in patients who previously had responses to gabapentin doses of 1,200 mg/day or more. Although results were significant, responder rates (50% or better decrease in mean pain score) were low (pregabalin 150 mg/day, 26%; 300 mg/day, 28%; placebo group, 10%). In those patients who did have a response, an effect was seen within the first week of treatment. Sleep interference scores also improved.

    Oral dosage (extended-release tablets) in treatment-naive patients (i.e., patients not switching from immediate-release products)
    Adults

    Initially, 165 mg PO once daily. Increase to 330 mg PO once daily within 1 week based on patient response and tolerability. Reserve doses greater than 330 mg/day for patients who do not experience sufficient pain relief following 2 to 4 weeks of treatment with 330 mg/day. Doses up to 660 mg/day may be given. To discontinue, gradually taper the dose over a minimum of 1 week.

    Oral dosage (extended-release tablets) in patients switching from immediate-release products
    Adults

    Take the morning dose of immediate-release pregabalin as prescribed and begin extended-release pregabalin after an evening meal. Use the total daily dose of immediate-release pregabalin to convert the patient to an extended-release dose to be given once daily. Use 82.5 mg/day of the extended-release product in patients taking a total daily immediate-release dose of 75 mg/day; 165 mg/day of the extended-release product in patients taking a total daily immediate-release dose of 150 mg/day; 247.5 mg of the extended-release product in patients taking a total daily immediate-release dose of 225 mg/day; 330 mg/day of the extended-release product in patients taking a total daily immediate-release dose of 300 mg/day; 495 mg/day of the extended-release product in patients taking a total daily immediate-release dose of 450 mg/day; and 660 mg/day of the extended-release product in patients taking a total daily immediate-release dose of 600 mg/day. For patients taking less than 330 mg/day following conversion, gradually increase the dose to 330 mg/day within 1 week based on patient response and tolerability. Doses greater than 330 mg/day may not confer additional benefit and may be less well tolerated. To discontinue, gradually taper the dose over a minimum of 1 week.

    for pain associated with spinal cord injury.
    Oral dosage (immediate-release capsules and oral solution)
    Adults

    Initially, 75 mg PO twice daily. If needed, the dose may be increased to 150 mg twice daily within 1 week based upon efficacy and tolerability. If sufficient pain relief is not attained thereafter within 2 to 3 weeks, the dose may be increased up to a maximum of 300 mg twice daily.

    For the adjunctive treatment of partial seizures (with or without secondary generalization).
    Oral dosage (immediate-release capsules and oral solution)
    Adults

    Initially, 150 mg/day PO given in 2 or 3 divided doses; may increase the dosage weekly up to 600 mg/day, based on response and tolerability.

    Adolescents 17 years

    Initially, 150 mg/day PO given in 2 or 3 divided doses; may increase the dosage weekly up to 600 mg/day, based on response and tolerability.

    Children and Adolescents 4 to 16 years weighing 30 kg or more

    Initially, 2.5 mg/kg/day PO given in 2 or 3 divided doses; may increase the dosage weekly up to 10 mg/kg/day (Max: 600 mg/day), based on response and tolerability.

    Children and Adolescents 4 to 16 years weighing 11 to 29 kg

    Initially, 3.5 mg/kg/day PO given in 2 or 3 divided doses; may increase the dosage weekly up to 14 mg/kg/day, based on response and tolerability.

    For the treatment of fibromyalgia.
    Oral dosage (capsules and oral solution)
    Adults

    Initially, 75 mg PO twice daily; may increase to 150 mg PO twice daily within 1 week based on tolerability and response. Subsequently, the dose may be increased to 225 mg PO twice daily if needed. Total daily dosages above 450 mg/day do not provide additional benefits in efficacy and dose-related adverse reactions limit tolerability.

    For the treatment of social phobia (social anxiety disorder)†.
    Oral dosage
    Adults

    200 mg PO 3 times daily has been effective in clinical trials; doses are usually titrated to the target dose over a period of 1 week. In a placebo-controlled trial for the management of social phobia, significant improvements in the Liebowitz Social Anxiety Scale (LSAS) total score, LSAS fear and avoidance subscales, and the Brief Social Phobia Scale fear scale (BSPS) were observed in the 600 mg/day pregabalin group compared with placebo. A lower dose of pregabalin 150 mg/day PO was not significantly better than placebo on any measures. In a separate study comparing fixed daily doses of pregabalin (300 mg/day, 450 mg/day, or 600 mg/day in divided doses) to placebo, only the 600 mg/day dose resulted in a significantly greater mean reduction in the LSAS total score than placebo beginning at week 1 and continuing to the end of the study. For secondary efficacy measures, pregabalin 600 mg/day showed significant improvement over placebo for the LSAS fear subscale, LSAS avoidance subscale, Marks Fear Questionnaire (MFQ) total phobia subscale, MFQ social phobia subscale, and Clinical Global Impression-Improvement (CGI-I) scale. Pregabalin 450 mg/day showed significant improvement over placebo for MFQ total phobia and social phobia subscale, while the 300 mg/day dose showed no significant difference for any secondary outcomes. In both trials, most patients receiving pregabalin exhibited at least one adverse effect (e.g., somnolence, dizziness, abnormal thinking) which resulted in some cases of treatment discontinuation and loss of patients to follow-up.

    For the treatment of generalized anxiety disorder (GAD)†.
    Oral dosage
    Adults

    Initially, 75 mg PO twice daily. If tolerated after 1 week, the dose may be increased to 150 mg PO twice daily. Thereafter, the dose may be adjusted according to response and tolerability. Data from clinical trials indicate an effective dose range is 150 to 300 mg PO twice daily. Max: 300 mg PO twice daily. Pregablin is listed in Category A, along with several antidepressants, as having the highest level of evidence for efficacy in generalized anxiety disorder (GAD) according to the World Federation of Societies of Biological Psychiatry treatment guidelines based on significant efficacy in GAD from several clinical studies, a rapid onset of action similar to benzodiazepines, and mild to moderate side effect profile. Commonly reported side effects include headache, dizziness, dry mouth, nausea, somnolence, and weight gain. Because discontinuation symptoms (e.g., restlessness, irritability, nervousness) can occur following abrupt withdrawal of pregabalin, slow tapering after chronic pregabalin treatment is required.

    Geriatric Adults

    50 mg/day PO initially, followed by an increase to 50 mg PO twice daily on day 3, and an increase to 75 mg PO twice daily on day 5 was used in a study of geriatric adults. Thereafter, dosing was flexible in the range of 150 to 600 mg/day PO, administered in 2 or 3 divided doses. The mean dose was 270 mg/day PO. Pregablin is listed in Category A, along with several antidepressants, as having the highest level of evidence for efficacy in generalized anxiety disorder (GAD) according to the World Federation of Societies of Biological Psychiatry treatment guidelines based on significant efficacy in GAD from several clinical studies, a rapid onset of action similar to benzodiazepines, and mild to moderate side effect profile. Commonly reported side effects include headache, dizziness, dry mouth, nausea, somnolence, and weight gain. Because discontinuation symptoms (e.g., restlessness, irritability, nervousness) can occur following abrupt withdrawal of pregabalin, slow tapering after chronic pregabalin treatment is required.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    Immediate-release formulations: 300 mg/day PO for diabetic peripheral neuropathy; 600 mg/day PO for postherpetic neuralgia, neuropathic pain due to spinal cord injury, and adjunctive treatment of seizures; 450 mg/day PO for fibromyalgia.
    Extended-release tablets: 330 mg/day PO for diabetic peripheral neuropathy; 660 mg/day PO for postherpetic neuralgia.

    Geriatric

    Immediate-release formulations: 300 mg/day PO for diabetic peripheral neuropathy; 600 mg/day PO for postherpetic neuralgia, neuropathic pain due to spinal cord injury, and adjunctive treatment of seizures; 450 mg/day PO for fibromyalgia.
    Extended-release tablets: 330 mg/day PO for diabetic peripheral neuropathy; 660 mg/day PO for postherpetic neuralgia.

    Adolescents

    Immediate-release formulations:
    17 years: 600 mg/day PO for adjunctive treatment of partial seizures.
    13 to 16 years and weighing 30 kg or more: 10 mg/kg/day PO not to exceed 600 mg/day for adjunctive treatment of partial seizures.
    13 to 16 years and weighing 11 to 29 kg: 14 mg/kg/day PO for adjunctive treatment of partial seizures.
    Extended-release tablets: Safety and efficacy have not been established.

    Children

    Immediate-release formulations:
    4 to 12 years and weighing 30 kg or more: 10 mg/kg/day PO not to exceed 600 mg/day for adjunctive treatment of partial seizures.
    4 to 12 years and weighing 11 to 29 kg: 14 mg/kg/day PO for adjunctive treatment of partial seizures.
    Extended-release tablets: Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    The following recommendations have been made for adults :
    CrCl 60 mL/minute or more: No dose adjustment needed.
    CrCl 30 to 60 mL/minute: 75 to 300 mg/day PO given in 2 or 3 divided doses for immediate-release formulations; reduce dose by 50% for extended-release tablets.
    CrCl 15 to 30 mL/minute: Immediate-release formulations: 25 to 150 mg/day PO given in 1 or 2 divided doses. Use of the extended-release tablet is not recommended.
    CrCl 15 mL/minute or less: 25 to 75 mg PO once daily. Use of the extended-release tablet is not recommended.
     
    Intermittent hemodialysis
    Use of extended-release tablets is not recommended; use immediate-release formulations. Pregabalin is effectively removed by hemodialysis. Each 4 hour hemodialysis session removes 50% to 60% of the amount of drug initially present in the circulation in patients on three times weekly hemodialysis, who were administered pregabalin roughly 24 hours prior to next scheduled dialysis session. For patients undergoing hemodialysis, pregabalin daily dose should be adjusted based on renal function. In addition to the daily dose adjustment, a supplemental dose should be given immediately following every 4-hour hemodialysis treatment. For patients receiving the 25 mg once a day regimen: take one supplemental dose of 25 or 50 mg. For patients receiving the 25 to 50 mg once a day regimen: take one supplemental dose of 50 or 75 mg. For patients receiving the 75 mg once a day regimen: take one supplemental dose of 100 or 150 mg.

    ADMINISTRATION

    Oral Administration

    Immediate-release capsules and oral solution
    Both capsules and oral solution may be administered without regard to meals.
     
    Extended-release tablets
    Administer once daily after an evening meal.
    Do not split, crush, or chew the tablet.

    STORAGE

    Lyrica:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Lyrica CR:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    - Store in original container

    CONTRAINDICATIONS / PRECAUTIONS

    Angioedema

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

    Depression, suicidal ideation

    Antiepileptic drugs (AEDs), including pregabalin, increase the risk of suicidal ideation, thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to 1 of the AEDs had approximately twice the risk (adjusted RR 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients taking placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately 1 case of suicidal thinking or behavior for every 530 patients treated. There were 4 suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior was observed as early as 1 week after starting drug treatment and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years of age) in the clinical trials analyzed. The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Closely monitor patients for emerging or worsening depression or suicidal thoughts/behavior. Patients and caregivers should be informed of the increased risk of suicidal thoughts and behaviors and should be advised to immediately report the emergence or worsening of depression, the emergence of suicidal thoughts or behavior, thoughts of self-harm, or other unusual changes in mood or behavior. Pregabalin should be prescribed in the smallest quantity consistent with good patient management in order to reduce the risk of overdose.

    CNS depression, driving or operating machinery, ethanol intoxication

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

    Substance abuse

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

    Abrupt discontinuation

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

    Renal failure, renal impairment

    Pregabalin should be used with caution in patients with renal impairment or renal failure. Pregabalin is excreted unchanged in the urine and can accumulate with decreased renal function. Dosage adjustments are recommended in patients with renal impairment.

    Geriatric

    The use of pregabalin in geriatric patients may require caution. Elderly patients are more likely to have reduced renal function and doses should be adjusted in the elderly patient based on the degree of renal impairment. Reported clinical trials experience of pregabalin for epilepsy or neuropathic pain treatment have not revealed significant differences in response between geriatric patients and younger adults. Although the adverse reaction profile was similar between geriatric (n = 106) and younger adult subjects in clinical trials for fibromyalgia, geriatric subjects more frequently reported neurologic reactions such as dizziness, blurred vision, balance disorder, tremor, confusional state, abnormal coordination, and lethargy. According to the Beers Criteria, anticonvulsants are considered potentially inappropriate medications (PIMs) in geriatric patients with a history of falls or fractures and should be avoided in these patient populations, with the exception of treating seizure and mood disorders, since anticonvulsants can produce ataxia, impaired psychomotor function, syncope, and additional falls. If pregabalin must be used, consider reducing use of other CNS-active medications that increase risk of falls and fractures and implement other strategies to reduce fall risk. The Beers expert panel also recommends reducing the dose of pregabalin in geriatric patients with a creatinine clearance less than 60 mL/minute due to the potential for adverse CNS effects. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities. According to the OBRA guidelines, some anticonvulsants may be used to treat disorders other than seizures (e.g., bipolar disorder, schizoaffective disorder, chronic neuropathic pain, migraine prevention). The need for indefinite continuation in treating any condition should be based on confirmation of the condition and its potential cause(s). Determining effectiveness and tolerability through evaluation of symptoms should be used to adjust doses. Therapeutic drug monitoring is not required or available for most anticonvulsants. In addition, significant signs and symptoms of toxicity can occur at normal or low serum concentrations, and symptom control for seizures or behavior can occur at subtherapeutic serum concentrations. Obtaining serum medication concentrations may assist in identifying toxicity. High or toxic serum concentrations should become a consideration for dosage adjustments. Anticonvulsants may cause liver dysfunction, blood dyscrasias, and serious skin rashes requiring treatment discontinuation. Anticonvulsants may also cause nausea/vomiting, dizziness, ataxia, somnolence/lethargy, incoordination, blurred or double vision, restlessness, toxic encephalopathy, anorexia, and headaches; these effects can increase the risk for falls. When an anticonvulsant is being used to manage behavior, stabilize mood, or treat a psychiatric disorder, the facility should attempt periodic tapering of the medication or provide documentation of medical necessity in accordance with OBRA guidelines.

    Diabetes mellitus, heart failure

    There are limited data evaluating pregabalin in congestive heart failure patients, and pregabalin should be used cautiously in patients with New York Heart Association (NYHA) Class III or IV cardiac status. Dose-related weight gain and peripheral edema have been noted in clinical trials with pregabalin. In a cohort of 333 patients with diabetes mellitus who received pregabalin for at least 2 years, the average weight gain was 5.2 kg. In controlled and open label trials, pregabalin treatment did not appear to be associated with loss of glycemic control (as measured by A1C). As the thiazolidinedione class of antidiabetic drugs can cause weight gain and/or fluid retention, possibly exacerbating or leading to heart failure, care should be taken when coadministering pregabalin and these agents.

    Myopathy, rhabdomyolysis

    Rhabdomyolysis and creatine kinase elevations have been reported in 3 cases during premarketing clinical trials. Causality between these myopathy events and pregabalin use is not completely defined. Prescribers should instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if these muscle symptoms are accompanied by malaise or fever. Pregabalin treatment should be discontinued if myopathy is diagnosed or suspected or if markedly elevated creatine kinase concentrations occur.

    Glaucoma, ocular disease

    In controlled studies, a higher proportion of patients treated with pregabalin reported blurred vision (6%) than did patients treated with placebo (2%), which resolved in a majority of cases with continued dosing. Patients should be informed that if changes in vision occur, they should notify their health care provider. If visual disturbance persists, further assessment should be considered. More frequent assessment should be considered for patients who are already routinely monitored for ocular conditions or ocular disease (i.e., glaucoma).

    Labor, obstetric delivery, pregnancy

    There are no adequate and well-controlled studies with pregabalin during pregnancy in women. Pregabalin has been shown to cause animal developmental toxicity (e.g., fetal structural abnormalities and growth retardation) in rats and rabbits given oral pregabalin at doses that produced pregabalin AUC exposures 18 times or more the human exposure at the maximum recommended dose of 660 mg/day. In a study of rats given pregabalin throughout gestation and lactation, offspring growth was reduced at doses of 100 mg/kg or more, and offspring survival decreased at doses of 250 mg/kg or more. When offspring were tested as adults, neurobehavioral abnormalities (i.e., decreased auditory startle response) were observed at doses of 250 mg/kg or more, and decreased fertility and litter size were seen at doses of 1250 mg/kg. The effects of pregabalin on labor and obstetric delivery in pregnant women are unknown. In a prenatal-postnatal study in rats, pregabalin prolonged gestation and induced dystocia at exposures of 50 times or more the mean human exposure. Physicians are advised to recommend that pregnant patients receiving pregabalin enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry to provide information about the effects of in utero exposure to the drug. Patients must call 1-888-233-2334 to enroll in the registry.

    Breast-feeding

    Breast-feeding is not recommended during treatment with pregabalin due to a potential risk of tumorigenicity. Animal data demonstrate a potential association of tumorigenicity with pregabalin exposure from breast milk, and there is not a clear conclusion regarding the risk from available human clinical studies. Small amounts of pregabalin have been found in the milk of breast-feeding women, with average breast milk steady-state concentrations of approximately 76% of those in maternal plasma. Assuming a mean milk consumption of 150 mL/kg/day, the estimated average daily infant dose of pregabalin from breast-milk was 0.31 mg/kg/day, which would be approximately 7% of the maternal dose. The effects of pregabalin on milk production or the breast-fed infant are unknown.

    Reproductive risk

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

    ADVERSE REACTIONS

    Severe

    visual impairment / Early / 1.0-5.0
    angioedema / Rapid / 0.1-3.0
    laryngeal edema / Rapid / 0.1-3.0
    heart failure / Delayed / 0.1-1.0
    oliguria / Early / 0.1-1.0
    cholecystitis / Delayed / 0.1-1.0
    pancreatitis / Delayed / 0.1-1.0
    GI bleeding / Delayed / 0.1-1.0
    retinal edema / Delayed / 0.1-1.0
    ocular hemorrhage / Delayed / 0.1-1.0
    suicidal ideation / Delayed / 0.4-0.4
    epididymitis / Delayed / 0-0.1
    coma / Early / 0-0.1
    pulmonary edema / Early / 0-0.1
    renal failure (unspecified) / Delayed / 0-0.1
    increased intracranial pressure / Early / 0-0.1
    pulmonary fibrosis / Delayed / 0-0.1
    apnea / Delayed / 0-0.1
    ventricular fibrillation / Early / 0-0.1
    retroperitoneal fibrosis / Delayed / 0-0.1
    esophageal ulceration / Delayed / 0-0.1
    acute cerebellar syndrome / Early / 0-0.1
    torticollis / Delayed / 0-0.1
    anaphylactoid reactions / Rapid / 0-0.1
    skin necrosis / Early / 0-0.1
    Stevens-Johnson syndrome / Delayed / 0-0.1
    skin atrophy / Delayed / 0-0.1
    exfoliative dermatitis / Delayed / 0-0.1
    papilledema / Delayed / 0-0.1
    keratitis / Delayed / 0-0.1
    night blindness / Delayed / 0-0.1
    optic atrophy / Delayed / 0-0.1
    uveitis / Delayed / 0-0.1
    keratoconjunctivitis / Early / 0-0.1
    Guillain-Barre syndrome / Delayed / 0-0.1
    rhabdomyolysis / Delayed / Incidence not known
    new primary malignancy / Delayed / Incidence not known

    Moderate

    peripheral edema / Delayed / 3.0-27.0
    ataxia / Delayed / 1.0-20.0
    blurred vision / Early / 0.5-12.0
    amblyopia / Delayed / 1.0-12.0
    euphoria / Early / 1.0-12.0
    constipation / Delayed / 0-10.0
    peripheral neuropathy / Delayed / 2.0-9.0
    edema / Delayed / 0.4-8.2
    confusion / Early / 1.0-7.0
    amnesia / Delayed / 0.1-6.0
    myasthenia / Delayed / 1.0-4.9
    chest pain (unspecified) / Early / 0.1-4.0
    memory impairment / Delayed / 1.0-4.0
    myoclonia / Delayed / 1.0-4.0
    fluid retention / Delayed / 2.0-3.0
    hypoglycemia / Early / 1.0-3.0
    dyspnea / Early / 2.0-3.0
    thrombocytopenia / Delayed / 3.0-3.0
    urinary incontinence / Early / 1.0-2.7
    skin ulcer / Delayed / 0.1-2.7
    hypotension / Rapid / 0-2.2
    hypertension / Early / 2.2-2.2
    depression / Delayed / 2.0-2.0
    elevated hepatic enzymes / Delayed / 0.2-1.4
    hematuria / Delayed / 0.1-1.0
    dysuria / Early / 0.1-1.0
    orthostatic hypotension / Delayed / 0.1-1.0
    phlebitis / Rapid / 0.1-1.0
    palpitations / Early / 0.1-1.0
    ejaculation dysfunction / Delayed / 0.1-1.0
    urinary retention / Early / 0.1-1.0
    hyperacusis / Delayed / 0.1-1.0
    oral ulceration / Delayed / 0.1-1.0
    gastritis / Delayed / 0.1-1.0
    colitis / Delayed / 0.1-1.0
    melena / Delayed / 0.1-1.0
    dysphagia / Delayed / 0.1-1.0
    esophagitis / Delayed / 0.1-1.0
    cholelithiasis / Delayed / 0.1-1.0
    hypotonia / Delayed / 0.1-1.0
    hyperalgesia / Delayed / 0.1-1.0
    hyperesthesia / Delayed / 0.1-1.0
    contact dermatitis / Delayed / 0-1.0
    blepharitis / Early / 0.1-1.0
    photophobia / Early / 0.1-1.0
    lymphadenopathy / Delayed / 0.1-1.0
    eosinophilia / Delayed / 0.1-1.0
    anemia / Delayed / 0.1-1.0
    leukopenia / Delayed / 0.1-1.0
    dysarthria / Delayed / 0.1-1.0
    hostility / Early / 0.1-1.0
    aphasia / Delayed / 0.1-1.0
    hallucinations / Early / 0.1-1.0
    proteinuria / Delayed / 0-0.1
    crystalluria / Delayed / 0-0.1
    ascites / Delayed / 0-0.1
    glycosuria / Early / 0-0.1
    cervicitis / Delayed / 0-0.1
    sinus tachycardia / Rapid / 0-0.1
    dyspareunia / Delayed / 0-0.1
    stomatitis / Delayed / 0-0.1
    dyskinesia / Delayed / 0-0.1
    dystonic reaction / Delayed / 0-0.1
    trismus / Delayed / 0-0.1
    neuritis / Delayed / 0-0.1
    exophthalmos / Delayed / 0-0.1
    iritis / Delayed / 0-0.1
    polycythemia / Delayed / 0-0.1
    mania / Early / 0-0.1
    psychosis / Early / 0-0.1
    delirium / Early / 0-0.1
    encephalopathy / Delayed / 0-0.1
    impotence (erectile dysfunction) / Delayed / 0.6
    hypertonia / Delayed / 1.0
    nystagmus / Delayed / 1.0
    conjunctivitis / Delayed / 1.0
    wheezing / Rapid / Incidence not known
    myopathy / Delayed / Incidence not known
    physiological dependence / Delayed / Incidence not known
    withdrawal / Early / Incidence not known
    infertility / Delayed / Incidence not known

    Mild

    dizziness / Early / 3.4-45.0
    drowsiness / Early / 0.5-35.7
    weight gain / Delayed / 1.0-16.0
    xerostomia / Early / 0.5-15.0
    headache / Early / 1.9-14.0
    infection / Delayed / 3.0-14.0
    diplopia / Early / 0.5-12.0
    fatigue / Early / 1.4-11.0
    tremor / Early / 1.0-11.0
    appetite stimulation / Delayed / 2.0-10.0
    pharyngitis / Delayed / 1.4-8.2
    asthenia / Delayed / 2.0-7.0
    sinusitis / Delayed / 0.4-7.0
    arthralgia / Delayed / 0.7-6.0
    nausea / Early / 1.0-4.9
    lethargy / Early / 4.0-4.0
    hypersalivation / Early / 1.0-4.0
    back pain / Delayed / 1.0-4.0
    vertigo / Early / 1.0-4.0
    insomnia / Early / 3.8-3.8
    flatulence / Early / 1.0-3.0
    vomiting / Early / 1.0-3.0
    hypoesthesia / Delayed / 2.0-3.0
    anxiety / Delayed / 2.0-2.0
    abdominal pain / Early / 0.1-2.0
    diarrhea / Early / 1.0-1.4
    amenorrhea / Delayed / 0.1-1.0
    menorrhagia / Delayed / 0.1-1.0
    leukorrhea / Delayed / 0.1-1.0
    cough / Delayed / 0.2-1.0
    syncope / Early / 0.1-1.0
    dysmenorrhea / Delayed / 0.1-1.0
    chills / Rapid / 0.1-1.0
    pelvic pain / Delayed / 0.1-1.0
    libido increase / Delayed / 0.1-1.0
    dysgeusia / Early / 0.1-1.0
    hyperkinesis / Delayed / 0.1-1.0
    rash / Early / 0.1-1.0
    urticaria / Rapid / 0.1-1.0
    alopecia / Delayed / 0.1-1.0
    vesicular rash / Delayed / 0.1-1.0
    xerosis / Delayed / 0.1-1.0
    hirsutism / Delayed / 0.1-1.0
    photosensitivity / Delayed / 0.1-1.0
    xerophthalmia / Early / 0.1-1.0
    leukocytosis / Delayed / 0.1-1.0
    agitation / Early / 0.1-1.0
    irritability / Delayed / 0.1-1.0
    malaise / Early / 0.1-1.0
    hiccups / Early / 0-0.1
    yawning / Early / 0-0.1
    parosmia / Delayed / 0-0.1
    psychomotor impairment / Early / 0-0.1
    miosis / Early / 0-0.1
    ptosis / Delayed / 0-0.1
    mydriasis / Early / 0-0.1
    purpura / Delayed / 0-0.1
    paranoia / Early / 0-0.1
    orgasm dysfunction / Delayed / 1.0
    muscle cramps / Delayed / 1.0
    increased urinary frequency / Early / 1.0
    myalgia / Early / 1.0
    libido decrease / Delayed / 1.0
    fever / Early / 1.0
    tinnitus / Delayed / 1.0
    paresthesias / Delayed / 1.0
    pruritus / Rapid / 1.0
    ecchymosis / Delayed / 1.0
    breast enlargement / Delayed / Incidence not known
    gynecomastia / Delayed / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Butalbital: (Moderate) Concomitant administration of pregabalin with CNS-depressant drugs, including barbiturates, can potentiate the CNS effects of either agent. Pregabalin can cause considerable somnolence and the combined use of ethanol or other CNS depressants with pregabalin may lead to an additive drowsy effect.
    Acetaminophen; Butalbital; Caffeine: (Moderate) Concomitant administration of pregabalin with CNS-depressant drugs, including barbiturates, can potentiate the CNS effects of either agent. Pregabalin can cause considerable somnolence and the combined use of ethanol or other CNS depressants with pregabalin may lead to an additive drowsy effect.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Moderate) Concomitant administration of pregabalin with CNS-depressant drugs, including barbiturates, can potentiate the CNS effects of either agent. Pregabalin can cause considerable somnolence and the combined use of ethanol or other CNS depressants with pregabalin may lead to an additive drowsy effect. (Moderate) Concomitant use of opioid agonists with pregabalin may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking pregabalin. Limit the use of opioid pain medications with pregabalin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of opioid agonists with pregabalin may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking pregabalin. Limit the use of opioid pain medications with pregabalin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Acetaminophen; Codeine: (Moderate) Concomitant use of opioid agonists with pregabalin may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking pregabalin. Limit the use of opioid pain medications with pregabalin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Acetaminophen; Hydrocodone: (Moderate) Concomitant use of opioid agonists with pregabalin may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking pregabalin. Limit the use of opioid pain medications with pregabalin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Acetaminophen; Oxycodone: (Moderate) Concomitant use of opioid agonists with pregabalin may cause excessive sedation and somnolence. Limit the use of opioid pain medications with pregabalin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Acetaminophen; Pentazocine: (Moderate) Concomitant use of pentazocine with other CNS depressants, such as pregabalin, can potentiate respiratory depression, CNS depression, and sedation.
    Acetaminophen; Tramadol: (Moderate) Concomitant use of opioid agonists with pregabalin may cause excessive sedation and somnolence. Limit the use of opioid pain medications with pregabalin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Alfentanil: (Moderate) Concomitant use of opioid agonists with pregabalin may cause excessive sedation and somnolence. Limit the use of opioid pain medications with pregabalin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Alogliptin; Pioglitazone: (Moderate) Higher rates of peripheral edema and weight gain may occur in patients who concomitantly use thiazolidinediones with pregabalin. As the thiazolidinediones and pregabalin can both cause weight gain and/or fluid retention, possibly exacerbating or leading to heart failure, care should be taken when co-administering these agents.
    Alprazolam: (Moderate) Pregabalin can potentiate the CNS-depressant action of other drugs such as benzodiazepines. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension.
    Amitriptyline: (Moderate) Concomitant administration of pregabalin with tricyclic antidepressants can potentiate the CNS effects of either agent. Pregabalin can cause considerable somnolence and the combined use of ethanol or other CNS depressants with pregabalin may lead to an additive drowsy effect. Tricyclic antidepressants may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
    Amitriptyline; Chlordiazepoxide: (Moderate) Concomitant administration of pregabalin with tricyclic antidepressants can potentiate the CNS effects of either agent. Pregabalin can cause considerable somnolence and the combined use of ethanol or other CNS depressants with pregabalin may lead to an additive drowsy effect. Tricyclic antidepressants may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently. (Moderate) Pregabalin can potentiate the CNS-depressant action of other drugs such as benzodiazepines. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension.
    Amlodipine; Benazepril: (Major) Concomitant use of pregabalin with angiotensin converting enzyme (ACE) inhibitors should be closely monitored. Life-threatening angioedema with respiratory compromise has been reported with use of pregabalin. Angioedema of the face, mouth (lips, tongue, gums), throat, and larynx has occurred. The risk of developing this complication may be increased when pregabalin is used with ACE inhibitors or other drugs known to cause angioedema.
    Amobarbital: (Moderate) Concomitant administration of pregabalin with CNS-depressant drugs, including barbiturates, can potentiate the CNS effects of either agent. Pregabalin can cause considerable somnolence and the combined use of ethanol or other CNS depressants with pregabalin may lead to an additive drowsy effect.
    Amphetamine: (Major) Patients who are taking anticonvulsants for epilepsy/seizure control should use amphetamines with caution. Amphetamines may decrease the seizure threshold and may increase the risk of seizures. If seizures occur, amphetamine discontinuation may be necessary. Additionally, amphetamines may delay the intestinal absorption of ethosuximide, ethotoin (hydantoin), phenobarbital, and phenytoin, the extent of absorption of these seizure medications is not known to be affected.
    Amphetamine; Dextroamphetamine: (Major) Patients who are taking anticonvulsants for epilepsy/seizure control should use amphetamines with caution. Amphetamines may decrease the seizure threshold and may increase the risk of seizures. If seizures occur, amphetamine discontinuation may be necessary. Additionally, amphetamines may delay the intestinal absorption of ethosuximide, ethotoin (hydantoin), phenobarbital, and phenytoin, the extent of absorption of these seizure medications is not known to be affected.
    Amphetamines: (Major) Patients who are taking anticonvulsants for epilepsy/seizure control should use amphetamines with caution. Amphetamines may decrease the seizure threshold and may increase the risk of seizures. If seizures occur, amphetamine discontinuation may be necessary. Additionally, amphetamines may delay the intestinal absorption of ethosuximide, ethotoin (hydantoin), phenobarbital, and phenytoin, the extent of absorption of these seizure medications is not known to be affected.
    Angiotensin-converting enzyme inhibitors: (Major) Concomitant use of pregabalin with angiotensin converting enzyme (ACE) inhibitors should be closely monitored. Life-threatening angioedema with respiratory compromise has been reported with use of pregabalin. Angioedema of the face, mouth (lips, tongue, gums), throat, and larynx has occurred. The risk of developing this complication may be increased when pregabalin is used with ACE inhibitors or other drugs known to cause angioedema.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Concomitant administration of pregabalin with CNS-depressant drugs, including barbiturates, can potentiate the CNS effects of either agent. Pregabalin can cause considerable somnolence and the combined use of ethanol or other CNS depressants with pregabalin may lead to an additive drowsy effect.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Concomitant administration of pregabalin with CNS-depressant drugs, including barbiturates, can potentiate the CNS effects of either agent. Pregabalin can cause considerable somnolence and the combined use of ethanol or other CNS depressants with pregabalin may lead to an additive drowsy effect. (Moderate) Concomitant use of opioid agonists with pregabalin may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking pregabalin. Limit the use of opioid pain medications with pregabalin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of opioid agonists with pregabalin may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking pregabalin. Limit the use of opioid pain medications with pregabalin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of opioid agonists with pregabalin may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking pregabalin. Limit the use of opioid pain medications with pregabalin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Aspirin, ASA; Oxycodone: (Moderate) Concomitant use of opioid agonists with pregabalin may cause excessive sedation and somnolence. Limit the use of opioid pain medications with pregabalin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Atropine; Difenoxin: (Moderate) Concurrent administration of diphenoxylate/difenoxin with pregabalin can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration.
    Atropine; Diphenoxylate: (Moderate) Concurrent administration of diphenoxylate/difenoxin with pregabalin can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Moderate) Concomitant administration of pregabalin with CNS-depressant drugs, including barbiturates, can potentiate the CNS effects of either agent. Pregabalin can cause considerable somnolence and the combined use of ethanol or other CNS depressants with pregabalin may lead to an additive drowsy effect.
    Azelastine: (Moderate) An enhanced CNS depressant effect may occur when azelastine is combined with other CNS depressants including pregabalin.
    Azelastine; Fluticasone: (Moderate) An enhanced CNS depressant effect may occur when azelastine is combined with other CNS depressants including pregabalin.
    Barbiturates: (Moderate) Concomitant administration of pregabalin with CNS-depressant drugs, including barbiturates, can potentiate the CNS effects of either agent. Pregabalin can cause considerable somnolence and the combined use of ethanol or other CNS depressants with pregabalin may lead to an additive drowsy effect.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Moderate) Concomitant administration of pregabalin with CNS-depressant drugs, including barbiturates, can potentiate the CNS effects of either agent. Pregabalin can cause considerable somnolence and the combined use of ethanol or other CNS depressants with pregabalin may lead to an additive drowsy effect.
    Belladonna; Opium: (Moderate) Concomitant use of opioid agonists with pregabalin may cause excessive sedation and somnolence. Limit the use of opioid pain medications with pregabalin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Benazepril: (Major) Concomitant use of pregabalin with angiotensin converting enzyme (ACE) inhibitors should be closely monitored. Life-threatening angioedema with respiratory compromise has been reported with use of pregabalin. Angioedema of the face, mouth (lips, tongue, gums), throat, and larynx has occurred. The risk of developing this complication may be increased when pregabalin is used with ACE inhibitors or other drugs known to cause angioedema.
    Benazepril; Hydrochlorothiazide, HCTZ: (Major) Concomitant use of pregabalin with angiotensin converting enzyme (ACE) inhibitors should be closely monitored. Life-threatening angioedema with respiratory compromise has been reported with use of pregabalin. Angioedema of the face, mouth (lips, tongue, gums), throat, and larynx has occurred. The risk of developing this complication may be increased when pregabalin is used with ACE inhibitors or other drugs known to cause angioedema.
    Benzodiazepines: (Moderate) Pregabalin can potentiate the CNS-depressant action of other drugs such as benzodiazepines. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension.
    Benzphetamine: (Major) Patients who are taking anticonvulsants for epilepsy/seizure control should use amphetamines with caution. Amphetamines may decrease the seizure threshold and may increase the risk of seizures. If seizures occur, amphetamine discontinuation may be necessary. Additionally, amphetamines may delay the intestinal absorption of ethosuximide, ethotoin (hydantoin), phenobarbital, and phenytoin, the extent of absorption of these seizure medications is not known to be affected.
    Brompheniramine; Carbetapentane; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants inlcuding pregabalin.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Concomitant use of opioid agonists with pregabalin may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking pregabalin. Limit the use of opioid pain medications with pregabalin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with pregabalin may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking pregabalin. Limit the use of opioid pain medications with pregabalin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Buprenorphine: (Moderate) Concomitant use of buprenorphine with other CNS depressants can lead to additive CNS depressive effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur; examples of other CNS depressants can include pregabalin. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A dose reduction of one or both drugs may be warranted. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Buprenorphine; Naloxone: (Moderate) Concomitant use of buprenorphine with other CNS depressants can lead to additive CNS depressive effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur; examples of other CNS depressants can include pregabalin. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A dose reduction of one or both drugs may be warranted. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Buspirone: (Moderate) Concomitant administration of pregabalin with CNS depressant drugs, including buspirone, can potentiate the CNS effects of either agent.
    Butabarbital: (Moderate) Concomitant administration of pregabalin with CNS-depressant drugs, including barbiturates, can potentiate the CNS effects of either agent. Pregabalin can cause considerable somnolence and the combined use of ethanol or other CNS depressants with pregabalin may lead to an additive drowsy effect.
    Butorphanol: (Moderate) Concomitant use of butorphanol with other CNS depressants, such as pregabalin, can potentiate the effects of butorphanol on respiratory depression, CNS depression, and sedation.
    Cannabidiol: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cannabidiol and pregabalin. CNS depressants can potentiate the effects of cannabidiol.
    Captopril: (Major) Concomitant use of pregabalin with angiotensin converting enzyme (ACE) inhibitors should be closely monitored. Life-threatening angioedema with respiratory compromise has been reported with use of pregabalin. Angioedema of the face, mouth (lips, tongue, gums), throat, and larynx has occurred. The risk of developing this complication may be increased when pregabalin is used with ACE inhibitors or other drugs known to cause angioedema.
    Captopril; Hydrochlorothiazide, HCTZ: (Major) Concomitant use of pregabalin with angiotensin converting enzyme (ACE) inhibitors should be closely monitored. Life-threatening angioedema with respiratory compromise has been reported with use of pregabalin. Angioedema of the face, mouth (lips, tongue, gums), throat, and larynx has occurred. The risk of developing this complication may be increased when pregabalin is used with ACE inhibitors or other drugs known to cause angioedema.
    Carbetapentane; Chlorpheniramine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants inlcuding pregabalin.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants inlcuding pregabalin.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants inlcuding pregabalin.
    Carbetapentane; Guaifenesin: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants inlcuding pregabalin.
    Carbetapentane; Guaifenesin; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants inlcuding pregabalin.
    Carbetapentane; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants inlcuding pregabalin.
    Carbetapentane; Phenylephrine; Pyrilamine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants inlcuding pregabalin.
    Carbetapentane; Pseudoephedrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants inlcuding pregabalin.
    Carbetapentane; Pyrilamine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants inlcuding pregabalin.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of opioid agonists with pregabalin may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking pregabalin. Limit the use of opioid pain medications with pregabalin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with pregabalin may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking pregabalin. Limit the use of opioid pain medications with pregabalin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Chlordiazepoxide: (Moderate) Pregabalin can potentiate the CNS-depressant action of other drugs such as benzodiazepines. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension.
    Chlordiazepoxide; Clidinium: (Moderate) Pregabalin can potentiate the CNS-depressant action of other drugs such as benzodiazepines. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension.
    Chlorpheniramine; Codeine: (Moderate) Concomitant use of opioid agonists with pregabalin may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking pregabalin. Limit the use of opioid pain medications with pregabalin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of opioid agonists with pregabalin may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking pregabalin. Limit the use of opioid pain medications with pregabalin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with pregabalin may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking pregabalin. Limit the use of opioid pain medications with pregabalin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with pregabalin may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking pregabalin. Limit the use of opioid pain medications with pregabalin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Chlorpheniramine; Hydrocodone: (Moderate) Concomitant use of opioid agonists with pregabalin may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking pregabalin. Limit the use of opioid pain medications with pregabalin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of opioid agonists with pregabalin may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking pregabalin. Limit the use of opioid pain medications with pregabalin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with pregabalin may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking pregabalin. Limit the use of opioid pain medications with pregabalin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Chlorpromazine: (Moderate) Concomitant administration of pregabalin with CNS-depressant drugs, including phenothiazines, can potentiate the CNS effects of either agent. Pregabalin can cause considerable somnolence and the combined use of ethanol or other CNS depressants with pregabalin may lead to an additive drowsy effect.
    Clobazam: (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Potentiation of CNS effects (e..g, increased sedation) may occur when clobazam is combined with other CNS depressants such as pregabalin.
    Clomipramine: (Moderate) Concomitant administration of pregabalin with tricyclic antidepressants can potentiate the CNS effects of either agent. Pregabalin can cause considerable somnolence and the combined use of ethanol or other CNS depressants with pregabalin may lead to an additive drowsy effect. Tricyclic antidepressants may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
    Clonazepam: (Moderate) Pregabalin can potentiate the CNS-depressant action of other drugs such as benzodiazepines. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension.
    Clorazepate: (Moderate) Pregabalin can potentiate the CNS-depressant action of other drugs such as benzodiazepines. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension.
    Codeine: (Moderate) Concomitant use of opioid agonists with pregabalin may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking pregabalin. Limit the use of opioid pain medications with pregabalin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Codeine; Guaifenesin: (Moderate) Concomitant use of opioid agonists with pregabalin may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking pregabalin. Limit the use of opioid pain medications with pregabalin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant administration of pregabalin with CNS-depressant drugs, including promethazine, can potentiate the CNS effects (e.g., increased sedation) of either agent. Additive effects on cognitive and gross motor functioning were seen when pregabalin was coadministered with alcohol and certain other medications; however, no pharmacokinetic changes or clinically important effects on respiration were noted. Because promethazine causes pronounced sedation, an enhanced CNS depressant effect or additive drowsiness may occur. (Moderate) Concomitant use of opioid agonists with pregabalin may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking pregabalin. Limit the use of opioid pain medications with pregabalin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Codeine; Promethazine: (Moderate) Concomitant administration of pregabalin with CNS-depressant drugs, including promethazine, can potentiate the CNS effects (e.g., increased sedation) of either agent. Additive effects on cognitive and gross motor functioning were seen when pregabalin was coadministered with alcohol and certain other medications; however, no pharmacokinetic changes or clinically important effects on respiration were noted. Because promethazine causes pronounced sedation, an enhanced CNS depressant effect or additive drowsiness may occur. (Moderate) Concomitant use of opioid agonists with pregabalin may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking pregabalin. Limit the use of opioid pain medications with pregabalin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    COMT inhibitors: (Moderate) Concomitant administration of pregabalin with CNS-depressant drugs, including COMT inhibitors, can potentiate the CNS effects of either agent.
    Desipramine: (Moderate) Concomitant administration of pregabalin with tricyclic antidepressants can potentiate the CNS effects of either agent. Pregabalin can cause considerable somnolence and the combined use of ethanol or other CNS depressants with pregabalin may lead to an additive drowsy effect. Tricyclic antidepressants may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
    Deutetrabenazine: (Moderate) Concurrent use of deutetrabenazine and drugs that can cause CNS depression, such as pregabalin, may have additive effects and worsen drowsiness or sedation. Advise patients about worsened somnolence and not to drive or perform other tasks requiring mental alertness until they know how deutetrabenazine affects them.
    Dextroamphetamine: (Major) Patients who are taking anticonvulsants for epilepsy/seizure control should use amphetamines with caution. Amphetamines may decrease the seizure threshold and may increase the risk of seizures. If seizures occur, amphetamine discontinuation may be necessary. Additionally, amphetamines may delay the intestinal absorption of ethosuximide, ethotoin (hydantoin), phenobarbital, and phenytoin, the extent of absorption of these seizure medications is not known to be affected.
    Dextromethorphan; Promethazine: (Moderate) Concomitant administration of pregabalin with CNS-depressant drugs, including promethazine, can potentiate the CNS effects (e.g., increased sedation) of either agent. Additive effects on cognitive and gross motor functioning were seen when pregabalin was coadministered with alcohol and certain other medications; however, no pharmacokinetic changes or clinically important effects on respiration were noted. Because promethazine causes pronounced sedation, an enhanced CNS depressant effect or additive drowsiness may occur.
    Diazepam: (Moderate) Pregabalin can potentiate the CNS-depressant action of other drugs such as benzodiazepines. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with pregabalin may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking pregabalin. Limit the use of opioid pain medications with pregabalin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of opioid agonists with pregabalin may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking pregabalin. Limit the use of opioid pain medications with pregabalin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Doxepin: (Moderate) Concomitant administration of pregabalin with tricyclic antidepressants can potentiate the CNS effects of either agent. Pregabalin can cause considerable somnolence and the combined use of ethanol or other CNS depressants with pregabalin may lead to an additive drowsy effect. Tricyclic antidepressants may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
    Dronabinol: (Moderate) Concomitant use of dronabinol with other CNS depressants can potentiate the effects of dronabinol on respiratory depression. Pregabalin can cause considerable somnolence and the combined use of ethanol or other CNS depressants with pregabalin may lead to an additive drowsy effect.
    Droperidol: (Moderate) Concomitant administration of pregabalin with CNS-depressant drugs, including droperidol, can potentiate the CNS effects of either agent.
    Enalapril, Enalaprilat: (Major) Concomitant use of pregabalin with angiotensin converting enzyme (ACE) inhibitors should be closely monitored. Life-threatening angioedema with respiratory compromise has been reported with use of pregabalin. Angioedema of the face, mouth (lips, tongue, gums), throat, and larynx has occurred. The risk of developing this complication may be increased when pregabalin is used with ACE inhibitors or other drugs known to cause angioedema.
    Enalapril; Felodipine: (Major) Concomitant use of pregabalin with angiotensin converting enzyme (ACE) inhibitors should be closely monitored. Life-threatening angioedema with respiratory compromise has been reported with use of pregabalin. Angioedema of the face, mouth (lips, tongue, gums), throat, and larynx has occurred. The risk of developing this complication may be increased when pregabalin is used with ACE inhibitors or other drugs known to cause angioedema.
    Enalapril; Hydrochlorothiazide, HCTZ: (Major) Concomitant use of pregabalin with angiotensin converting enzyme (ACE) inhibitors should be closely monitored. Life-threatening angioedema with respiratory compromise has been reported with use of pregabalin. Angioedema of the face, mouth (lips, tongue, gums), throat, and larynx has occurred. The risk of developing this complication may be increased when pregabalin is used with ACE inhibitors or other drugs known to cause angioedema.
    Estazolam: (Moderate) Pregabalin can potentiate the CNS-depressant action of other drugs such as benzodiazepines. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension.
    Eszopiclone: (Moderate) A reduction in the dose of eszopiclone and concomitantly administered CNS depressants, such as pregabalin, should be considered to minimize additive sedative effects. In addition, the risk of next-day psychomotor impairment is increased during co-administration of eszopiclone and other CNS depressants, which may decrease the ability to perform tasks requiring full mental alertness such as driving.
    Ethanol: (Moderate) Concomitant administration of pregabalin with alcohol can potentiate the CNS effects of either agent.
    Ezogabine: (Moderate) Due to the CNS effects of ezogabine, an enhanced CNS depressant effect may occur during concurrent use of other centrally-acting medications such as pregabalin. Patients should be monitored for excessive somnolence during concurrent therapy with this agent.
    Fentanyl: (Moderate) Concomitant use of opioid agonists with pregabalin may cause excessive sedation and somnolence. Limit the use of opioid pain medications with pregabalin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Fluphenazine: (Moderate) Concomitant administration of pregabalin with CNS-depressant drugs, including phenothiazines, can potentiate the CNS effects of either agent. Pregabalin can cause considerable somnolence and the combined use of ethanol or other CNS depressants with pregabalin may lead to an additive drowsy effect.
    Flurazepam: (Moderate) Pregabalin can potentiate the CNS-depressant action of other drugs such as benzodiazepines. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension.
    Fosinopril: (Major) Concomitant use of pregabalin with angiotensin converting enzyme (ACE) inhibitors should be closely monitored. Life-threatening angioedema with respiratory compromise has been reported with use of pregabalin. Angioedema of the face, mouth (lips, tongue, gums), throat, and larynx has occurred. The risk of developing this complication may be increased when pregabalin is used with ACE inhibitors or other drugs known to cause angioedema.
    Fosinopril; Hydrochlorothiazide, HCTZ: (Major) Concomitant use of pregabalin with angiotensin converting enzyme (ACE) inhibitors should be closely monitored. Life-threatening angioedema with respiratory compromise has been reported with use of pregabalin. Angioedema of the face, mouth (lips, tongue, gums), throat, and larynx has occurred. The risk of developing this complication may be increased when pregabalin is used with ACE inhibitors or other drugs known to cause angioedema.
    General anesthetics: (Moderate) Concomitant administration of pregabalin with CNS depressant drugs, including general anesthetics, can potentiate the CNS effects of either agent.
    Glimepiride; Pioglitazone: (Moderate) Higher rates of peripheral edema and weight gain may occur in patients who concomitantly use thiazolidinediones with pregabalin. As the thiazolidinediones and pregabalin can both cause weight gain and/or fluid retention, possibly exacerbating or leading to heart failure, care should be taken when co-administering these agents.
    Glimepiride; Rosiglitazone: (Moderate) Higher rates of peripheral edema and weight gain may occur in patients who concomitantly use thiazolidinediones with pregabalin. As the thiazolidinediones and pregabalin can both cause weight gain and/or fluid retention, possibly exacerbating or leading to heart failure, care should be taken when co-administering these agents.
    Guaifenesin; Hydrocodone: (Moderate) Concomitant use of opioid agonists with pregabalin may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking pregabalin. Limit the use of opioid pain medications with pregabalin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with pregabalin may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking pregabalin. Limit the use of opioid pain medications with pregabalin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Homatropine; Hydrocodone: (Moderate) Concomitant use of opioid agonists with pregabalin may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking pregabalin. Limit the use of opioid pain medications with pregabalin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Hydrochlorothiazide, HCTZ; Lisinopril: (Major) Concomitant use of pregabalin with angiotensin converting enzyme (ACE) inhibitors should be closely monitored. Life-threatening angioedema with respiratory compromise has been reported with use of pregabalin. Angioedema of the face, mouth (lips, tongue, gums), throat, and larynx has occurred. The risk of developing this complication may be increased when pregabalin is used with ACE inhibitors or other drugs known to cause angioedema.
    Hydrochlorothiazide, HCTZ; Moexipril: (Major) Concomitant use of pregabalin with angiotensin converting enzyme (ACE) inhibitors should be closely monitored. Life-threatening angioedema with respiratory compromise has been reported with use of pregabalin. Angioedema of the face, mouth (lips, tongue, gums), throat, and larynx has occurred. The risk of developing this complication may be increased when pregabalin is used with ACE inhibitors or other drugs known to cause angioedema.
    Hydrochlorothiazide, HCTZ; Quinapril: (Major) Concomitant use of pregabalin with angiotensin converting enzyme (ACE) inhibitors should be closely monitored. Life-threatening angioedema with respiratory compromise has been reported with use of pregabalin. Angioedema of the face, mouth (lips, tongue, gums), throat, and larynx has occurred. The risk of developing this complication may be increased when pregabalin is used with ACE inhibitors or other drugs known to cause angioedema.
    Hydrocodone: (Moderate) Concomitant use of opioid agonists with pregabalin may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking pregabalin. Limit the use of opioid pain medications with pregabalin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Hydrocodone; Ibuprofen: (Moderate) Concomitant use of opioid agonists with pregabalin may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking pregabalin. Limit the use of opioid pain medications with pregabalin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Hydrocodone; Phenylephrine: (Moderate) Concomitant use of opioid agonists with pregabalin may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking pregabalin. Limit the use of opioid pain medications with pregabalin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Concomitant use of opioid agonists with pregabalin may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking pregabalin. Limit the use of opioid pain medications with pregabalin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with pregabalin may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking pregabalin. Limit the use of opioid pain medications with pregabalin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with pregabalin may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking pregabalin. Limit the use of opioid pain medications with pregabalin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Hydromorphone: (Moderate) Concomitant use of opioid agonists with pregabalin may cause excessive sedation and somnolence. Limit the use of opioid pain medications with pregabalin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Hydroxychloroquine: (Moderate) Caution is warranted with the coadministration of hydroxychloroquine and antiepileptic drugs, such as pregabalin. Hydroxychloroquine can lower the seizure threshold; therefore, the activity of antiepileptic drugs may be impaired with concomitant use.
    Ibuprofen; Oxycodone: (Moderate) Concomitant use of opioid agonists with pregabalin may cause excessive sedation and somnolence. Limit the use of opioid pain medications with pregabalin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Imipramine: (Moderate) Concomitant administration of pregabalin with tricyclic antidepressants can potentiate the CNS effects of either agent. Pregabalin can cause considerable somnolence and the combined use of ethanol or other CNS depressants with pregabalin may lead to an additive drowsy effect. Tricyclic antidepressants may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
    Levorphanol: (Moderate) Concomitant use of opioid agonists with pregabalin may cause excessive sedation and somnolence. Limit the use of opioid pain medications with pregabalin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Lisdexamfetamine: (Major) Patients who are taking anticonvulsants for epilepsy/seizure control should use amphetamines with caution. Amphetamines may decrease the seizure threshold and may increase the risk of seizures. If seizures occur, amphetamine discontinuation may be necessary. Additionally, amphetamines may delay the intestinal absorption of ethosuximide, ethotoin (hydantoin), phenobarbital, and phenytoin, the extent of absorption of these seizure medications is not known to be affected.
    Lisinopril: (Major) Concomitant use of pregabalin with angiotensin converting enzyme (ACE) inhibitors should be closely monitored. Life-threatening angioedema with respiratory compromise has been reported with use of pregabalin. Angioedema of the face, mouth (lips, tongue, gums), throat, and larynx has occurred. The risk of developing this complication may be increased when pregabalin is used with ACE inhibitors or other drugs known to cause angioedema.
    Lorazepam: (Moderate) Pregabalin can potentiate the CNS-depressant action of other drugs such as benzodiazepines. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension.
    Meperidine: (Moderate) Concomitant use of opioid agonists with pregabalin may cause excessive sedation and somnolence. Limit the use of opioid pain medications with pregabalin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Meperidine; Promethazine: (Moderate) Concomitant administration of pregabalin with CNS-depressant drugs, including promethazine, can potentiate the CNS effects (e.g., increased sedation) of either agent. Additive effects on cognitive and gross motor functioning were seen when pregabalin was coadministered with alcohol and certain other medications; however, no pharmacokinetic changes or clinically important effects on respiration were noted. Because promethazine causes pronounced sedation, an enhanced CNS depressant effect or additive drowsiness may occur. (Moderate) Concomitant use of opioid agonists with pregabalin may cause excessive sedation and somnolence. Limit the use of opioid pain medications with pregabalin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Mephobarbital: (Moderate) Concomitant administration of pregabalin with CNS-depressant drugs, including barbiturates, can potentiate the CNS effects of either agent. Pregabalin can cause considerable somnolence and the combined use of ethanol or other CNS depressants with pregabalin may lead to an additive drowsy effect.
    Meprobamate: (Moderate) The CNS-depressant effects of meprobamate can be potentiated with concomitant administration of other drugs known to cause CNS depression including pregabalin.
    Mesoridazine: (Moderate) Concomitant administration of pregabalin with CNS-depressant drugs, including phenothiazines, can potentiate the CNS effects of either agent. Pregabalin can cause considerable somnolence and the combined use of ethanol or other CNS depressants with pregabalin may lead to an additive drowsy effect.
    Metformin; Pioglitazone: (Moderate) Higher rates of peripheral edema and weight gain may occur in patients who concomitantly use thiazolidinediones with pregabalin. As the thiazolidinediones and pregabalin can both cause weight gain and/or fluid retention, possibly exacerbating or leading to heart failure, care should be taken when co-administering these agents.
    Metformin; Rosiglitazone: (Moderate) Higher rates of peripheral edema and weight gain may occur in patients who concomitantly use thiazolidinediones with pregabalin. As the thiazolidinediones and pregabalin can both cause weight gain and/or fluid retention, possibly exacerbating or leading to heart failure, care should be taken when co-administering these agents.
    Methadone: (Moderate) Concomitant use of opioid agonists with pregabalin may cause excessive sedation and somnolence. Limit the use of opioid pain medications with pregabalin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Methamphetamine: (Major) Patients who are taking anticonvulsants for epilepsy/seizure control should use amphetamines with caution. Amphetamines may decrease the seizure threshold and may increase the risk of seizures. If seizures occur, amphetamine discontinuation may be necessary. Additionally, amphetamines may delay the intestinal absorption of ethosuximide, ethotoin (hydantoin), phenobarbital, and phenytoin, the extent of absorption of these seizure medications is not known to be affected.
    Methohexital: (Moderate) Concomitant administration of pregabalin with CNS-depressant drugs, including barbiturates, can potentiate the CNS effects of either agent. Pregabalin can cause considerable somnolence and the combined use of ethanol or other CNS depressants with pregabalin may lead to an additive drowsy effect.
    Midazolam: (Moderate) Pregabalin can potentiate the CNS-depressant action of other drugs such as benzodiazepines. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension.
    Moexipril: (Major) Concomitant use of pregabalin with angiotensin converting enzyme (ACE) inhibitors should be closely monitored. Life-threatening angioedema with respiratory compromise has been reported with use of pregabalin. Angioedema of the face, mouth (lips, tongue, gums), throat, and larynx has occurred. The risk of developing this complication may be increased when pregabalin is used with ACE inhibitors or other drugs known to cause angioedema.
    Morphine: (Moderate) Concomitant use of opioid agonists with pregabalin may cause excessive sedation and somnolence. Limit the use of opioid pain medications with pregabalin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Morphine; Naltrexone: (Moderate) Concomitant use of opioid agonists with pregabalin may cause excessive sedation and somnolence. Limit the use of opioid pain medications with pregabalin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Nabilone: (Moderate) Concomitant use of nabilone with other CNS depressants can potentiate the effects of nabilone on respiratory depression. Pregabalin can cause considerable somnolence and the combined use of ethanol or other CNS depressants with pregabalin may lead to an additive drowsy effect.
    Nalbuphine: (Moderate) Concomitant use of nalbuphine with other CNS depressants can potentiate the effects of nalbuphine on respiratory depression, CNS depression, and sedation.
    Nortriptyline: (Moderate) Concomitant administration of pregabalin with tricyclic antidepressants can potentiate the CNS effects of either agent. Pregabalin can cause considerable somnolence and the combined use of ethanol or other CNS depressants with pregabalin may lead to an additive drowsy effect. Tricyclic antidepressants may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
    Oxazepam: (Moderate) Pregabalin can potentiate the CNS-depressant action of other drugs such as benzodiazepines. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension.
    Oxycodone: (Moderate) Concomitant use of opioid agonists with pregabalin may cause excessive sedation and somnolence. Limit the use of opioid pain medications with pregabalin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Oxymorphone: (Moderate) Concomitant use of opioid agonists with pregabalin may cause excessive sedation and somnolence. Limit the use of opioid pain medications with pregabalin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Pentazocine: (Moderate) Concomitant use of pentazocine with other CNS depressants, such as pregabalin, can potentiate respiratory depression, CNS depression, and sedation.
    Pentazocine; Naloxone: (Moderate) Concomitant use of pentazocine with other CNS depressants, such as pregabalin, can potentiate respiratory depression, CNS depression, and sedation.
    Pentobarbital: (Moderate) Concomitant administration of pregabalin with CNS-depressant drugs, including barbiturates, can potentiate the CNS effects of either agent. Pregabalin can cause considerable somnolence and the combined use of ethanol or other CNS depressants with pregabalin may lead to an additive drowsy effect.
    Perampanel: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as pregabalin.
    Perindopril: (Major) Concomitant use of pregabalin with angiotensin converting enzyme (ACE) inhibitors should be closely monitored. Life-threatening angioedema with respiratory compromise has been reported with use of pregabalin. Angioedema of the face, mouth (lips, tongue, gums), throat, and larynx has occurred. The risk of developing this complication may be increased when pregabalin is used with ACE inhibitors or other drugs known to cause angioedema.
    Perindopril; Amlodipine: (Major) Concomitant use of pregabalin with angiotensin converting enzyme (ACE) inhibitors should be closely monitored. Life-threatening angioedema with respiratory compromise has been reported with use of pregabalin. Angioedema of the face, mouth (lips, tongue, gums), throat, and larynx has occurred. The risk of developing this complication may be increased when pregabalin is used with ACE inhibitors or other drugs known to cause angioedema.
    Perphenazine: (Moderate) Concomitant administration of pregabalin with CNS-depressant drugs, including phenothiazines, can potentiate the CNS effects of either agent. Pregabalin can cause considerable somnolence and the combined use of ethanol or other CNS depressants with pregabalin may lead to an additive drowsy effect.
    Perphenazine; Amitriptyline: (Moderate) Concomitant administration of pregabalin with CNS-depressant drugs, including phenothiazines, can potentiate the CNS effects of either agent. Pregabalin can cause considerable somnolence and the combined use of ethanol or other CNS depressants with pregabalin may lead to an additive drowsy effect. (Moderate) Concomitant administration of pregabalin with tricyclic antidepressants can potentiate the CNS effects of either agent. Pregabalin can cause considerable somnolence and the combined use of ethanol or other CNS depressants with pregabalin may lead to an additive drowsy effect. Tricyclic antidepressants may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
    Phenobarbital: (Moderate) Concomitant administration of pregabalin with CNS-depressant drugs, including barbiturates, can potentiate the CNS effects of either agent. Pregabalin can cause considerable somnolence and the combined use of ethanol or other CNS depressants with pregabalin may lead to an additive drowsy effect.
    Phenothiazines: (Moderate) Concomitant administration of pregabalin with CNS-depressant drugs, including phenothiazines, can potentiate the CNS effects of either agent. Pregabalin can cause considerable somnolence and the combined use of ethanol or other CNS depressants with pregabalin may lead to an additive drowsy effect.
    Phentermine; Topiramate: (Moderate) Concurrent use of topiramate and drugs that cause thrombocytopenia such as the anticonvulsant pregabalin, may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Phenylephrine; Promethazine: (Moderate) Concomitant administration of pregabalin with CNS-depressant drugs, including promethazine, can potentiate the CNS effects (e.g., increased sedation) of either agent. Additive effects on cognitive and gross motor functioning were seen when pregabalin was coadministered with alcohol and certain other medications; however, no pharmacokinetic changes or clinically important effects on respiration were noted. Because promethazine causes pronounced sedation, an enhanced CNS depressant effect or additive drowsiness may occur.
    Pioglitazone: (Moderate) Higher rates of peripheral edema and weight gain may occur in patients who concomitantly use thiazolidinediones with pregabalin. As the thiazolidinediones and pregabalin can both cause weight gain and/or fluid retention, possibly exacerbating or leading to heart failure, care should be taken when co-administering these agents.
    Primidone: (Moderate) Concomitant administration of pregabalin with CNS-depressant drugs, including barbiturates, can potentiate the CNS effects of either agent. Pregabalin can cause considerable somnolence and the combined use of ethanol or other CNS depressants with pregabalin may lead to an additive drowsy effect.
    Prochlorperazine: (Moderate) Concomitant administration of pregabalin with CNS-depressant drugs, including phenothiazines, can potentiate the CNS effects of either agent. Pregabalin can cause considerable somnolence and the combined use of ethanol or other CNS depressants with pregabalin may lead to an additive drowsy effect.
    Promethazine: (Moderate) Concomitant administration of pregabalin with CNS-depressant drugs, including promethazine, can potentiate the CNS effects (e.g., increased sedation) of either agent. Additive effects on cognitive and gross motor functioning were seen when pregabalin was coadministered with alcohol and certain other medications; however, no pharmacokinetic changes or clinically important effects on respiration were noted. Because promethazine causes pronounced sedation, an enhanced CNS depressant effect or additive drowsiness may occur.
    Protriptyline: (Moderate) Concomitant administration of pregabalin with tricyclic antidepressants can potentiate the CNS effects of either agent. Pregabalin can cause considerable somnolence and the combined use of ethanol or other CNS depressants with pregabalin may lead to an additive drowsy effect. Tricyclic antidepressants may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
    Quazepam: (Moderate) Pregabalin can potentiate the CNS-depressant action of other drugs such as benzodiazepines. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension.
    Quinapril: (Major) Concomitant use of pregabalin with angiotensin converting enzyme (ACE) inhibitors should be closely monitored. Life-threatening angioedema with respiratory compromise has been reported with use of pregabalin. Angioedema of the face, mouth (lips, tongue, gums), throat, and larynx has occurred. The risk of developing this complication may be increased when pregabalin is used with ACE inhibitors or other drugs known to cause angioedema.
    Ramelteon: (Moderate) The concomitant use of pregabalin with ramelteon may augment the CNS depressant effect of pregabalin and/or ramelteon.
    Ramipril: (Major) Concomitant use of pregabalin with angiotensin converting enzyme (ACE) inhibitors should be closely monitored. Life-threatening angioedema with respiratory compromise has been reported with use of pregabalin. Angioedema of the face, mouth (lips, tongue, gums), throat, and larynx has occurred. The risk of developing this complication may be increased when pregabalin is used with ACE inhibitors or other drugs known to cause angioedema.
    Remifentanil: (Moderate) Concomitant use of opioid agonists with pregabalin may cause excessive sedation and somnolence. Limit the use of opioid pain medications with pregabalin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Rosiglitazone: (Moderate) Higher rates of peripheral edema and weight gain may occur in patients who concomitantly use thiazolidinediones with pregabalin. As the thiazolidinediones and pregabalin can both cause weight gain and/or fluid retention, possibly exacerbating or leading to heart failure, care should be taken when co-administering these agents.
    Secobarbital: (Moderate) Concomitant administration of pregabalin with CNS-depressant drugs, including barbiturates, can potentiate the CNS effects of either agent. Pregabalin can cause considerable somnolence and the combined use of ethanol or other CNS depressants with pregabalin may lead to an additive drowsy effect.
    Sedating H1-blockers: (Moderate) Concomitant administration of pregabalin with CNS-depressant drugs, including sedating H1-blockers, can potentiate the CNS effects of either agent. Pregabalin can cause considerable somnolence and the combined use of ethanol or other CNS depressants with pregabalin may lead to an additive drowsy effect.
    Sufentanil: (Moderate) Concomitant use of opioid agonists with pregabalin may cause excessive sedation and somnolence. Limit the use of opioid pain medications with pregabalin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Suvorexant: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of the CNS depressant may be needed in some cases.
    Tapentadol: (Moderate) Concomitant use of opioid agonists with pregabalin may cause excessive sedation and somnolence. Limit the use of opioid pain medications with pregabalin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Temazepam: (Moderate) Pregabalin can potentiate the CNS-depressant action of other drugs such as benzodiazepines. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension.
    Thiazolidinediones: (Moderate) Higher rates of peripheral edema and weight gain may occur in patients who concomitantly use thiazolidinediones with pregabalin. As the thiazolidinediones and pregabalin can both cause weight gain and/or fluid retention, possibly exacerbating or leading to heart failure, care should be taken when co-administering these agents.
    Thiethylperazine: (Moderate) Concomitant administration of pregabalin with CNS-depressant drugs, including phenothiazines, can potentiate the CNS effects of either agent. Pregabalin can cause considerable somnolence and the combined use of ethanol or other CNS depressants with pregabalin may lead to an additive drowsy effect.
    Thiopental: (Moderate) Concomitant administration of pregabalin with CNS-depressant drugs, including barbiturates, can potentiate the CNS effects of either agent. Pregabalin can cause considerable somnolence and the combined use of ethanol or other CNS depressants with pregabalin may lead to an additive drowsy effect.
    Thioridazine: (Moderate) Concomitant administration of pregabalin with CNS-depressant drugs, including phenothiazines, can potentiate the CNS effects of either agent. Pregabalin can cause considerable somnolence and the combined use of ethanol or other CNS depressants with pregabalin may lead to an additive drowsy effect.
    Topiramate: (Moderate) Concurrent use of topiramate and drugs that cause thrombocytopenia such as the anticonvulsant pregabalin, may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Tramadol: (Moderate) Concomitant use of opioid agonists with pregabalin may cause excessive sedation and somnolence. Limit the use of opioid pain medications with pregabalin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Trandolapril: (Major) Concomitant use of pregabalin with angiotensin converting enzyme (ACE) inhibitors should be closely monitored. Life-threatening angioedema with respiratory compromise has been reported with use of pregabalin. Angioedema of the face, mouth (lips, tongue, gums), throat, and larynx has occurred. The risk of developing this complication may be increased when pregabalin is used with ACE inhibitors or other drugs known to cause angioedema.
    Trandolapril; Verapamil: (Major) Concomitant use of pregabalin with angiotensin converting enzyme (ACE) inhibitors should be closely monitored. Life-threatening angioedema with respiratory compromise has been reported with use of pregabalin. Angioedema of the face, mouth (lips, tongue, gums), throat, and larynx has occurred. The risk of developing this complication may be increased when pregabalin is used with ACE inhibitors or other drugs known to cause angioedema.
    Trazodone: (Moderate) Trazodone can lower the seizure threshold of anticonvulsants, although the overall risk is low at therapeutic doses. Patients may require increased concentrations of anticonvulsants to achieve equivalent effects if trazodone is added. Drowsiness may be additive between trazodone and other anticonvulsants.
    Triazolam: (Moderate) Pregabalin can potentiate the CNS-depressant action of other drugs such as benzodiazepines. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension.
    Tricyclic antidepressants: (Moderate) Concomitant administration of pregabalin with tricyclic antidepressants can potentiate the CNS effects of either agent. Pregabalin can cause considerable somnolence and the combined use of ethanol or other CNS depressants with pregabalin may lead to an additive drowsy effect. Tricyclic antidepressants may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
    Trifluoperazine: (Moderate) Concomitant administration of pregabalin with CNS-depressant drugs, including phenothiazines, can potentiate the CNS effects of either agent. Pregabalin can cause considerable somnolence and the combined use of ethanol or other CNS depressants with pregabalin may lead to an additive drowsy effect.
    Trimipramine: (Moderate) Concomitant administration of pregabalin with tricyclic antidepressants can potentiate the CNS effects of either agent. Pregabalin can cause considerable somnolence and the combined use of ethanol or other CNS depressants with pregabalin may lead to an additive drowsy effect. Tricyclic antidepressants may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
    Zaleplon: (Moderate) Concomitant administration of pregabalin with CNS-depressant drugs, including zaleplon, can potentiate the CNS effects (e.g., increased sedation) of either agent. In clinical studies, pregabalin was co-administered with oxycodone, lorazepam, or ethanol. Additive effects on cognitive and gross motor functioning were seen when pregabalin was coadministered with these drugs. Pregabalin can cause considerable somnolence and the combined use of other CNS depressants with pregabalin may lead to an additive drowsy effect.
    Zolpidem: (Moderate) Sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and ethanol or other CNS depressants, like pregabalin, than with zolpidem alone. Pregabalin may also have cumulative sedative effects when administered concurrently and should be used cautiously with zolpidem. A reduction in dose of the CNS depressant may be needed in some cases. A dosage reduction of the Intermezzo brand of sublingual zolpidem tablets to 1.75 mg/night is recommended in patients receiving concomitant CNS depressants. A reduction in dose of the CNS depressant may also be needed.

    PREGNANCY AND LACTATION

    Pregnancy

    There are no adequate and well-controlled studies with pregabalin during pregnancy in women. Pregabalin has been shown to cause animal developmental toxicity (e.g., fetal structural abnormalities and growth retardation) in rats and rabbits given oral pregabalin at doses that produced pregabalin AUC exposures 18 times or more the human exposure at the maximum recommended dose of 660 mg/day. In a study of rats given pregabalin throughout gestation and lactation, offspring growth was reduced at doses of 100 mg/kg or more, and offspring survival decreased at doses of 250 mg/kg or more. When offspring were tested as adults, neurobehavioral abnormalities (i.e., decreased auditory startle response) were observed at doses of 250 mg/kg or more, and decreased fertility and litter size were seen at doses of 1250 mg/kg. The effects of pregabalin on labor and obstetric delivery in pregnant women are unknown. In a prenatal-postnatal study in rats, pregabalin prolonged gestation and induced dystocia at exposures of 50 times or more the mean human exposure. Physicians are advised to recommend that pregnant patients receiving pregabalin enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry to provide information about the effects of in utero exposure to the drug. Patients must call 1-888-233-2334 to enroll in the registry.

    MECHANISM OF ACTION

    Mechanism of Action: Pregabalin is a structural analogue of gamma-aminobutyric acid (GABA) and has anxiolytic, analgesic, and antiepileptic properties. Pregabalin is structurally related to gabapentin, but pregabalin has shown greater potency than gabapentin in pain and seizure disorders (3- to 10-times more potent in animal studies). The exact mechanism of action of pregabalin as an antiseizure agent has not been determined. Pregabalin does not show direct GABA-mimetic effects, but increases neuronal GABA levels as well as produces a dose-dependent increase in glutamic acid decarboxylase activity. Pregabalin reduces neuronal calcium currents by binding to the alpha-2-delta subunit of calcium channels, and this particular mechanism may be responsible for effects in neuropathic pain, anxiety, and other pain syndromes. Pregabalin does not bind directly to GABAA, GABAB, or benzodiazepine receptors, does not block sodium channels, is not active at opiate receptors, and does not alter cyclooxygenase enzyme activity. It is inactive at serotonin and dopamine receptors and does not inhibit dopamine, serotonin, or noradrenaline reuptake.

    PHARMACOKINETICS

    Pregabalin is administered orally. Pregabalin does not bind to plasma proteins and shows negligible hepatic metabolism. The volume of distribution is 0.5 L/kg. Although human data are not available, pregabalin has been shown to cross into the blood-brain barrier, placenta, and breast milk in animal studies. The primary route of elimination is renal excretion, with 90% to 98% of an administered dose eliminated unchanged in the urine. Pregabalin clearance by the kidneys is directly proportional to CrCl in patients not on dialysis. Mean renal clearance is roughly 67 to 81 mL/minute in young, healthy subjects. Because pregabalin is not bound to plasma proteins, this clearance rate indicates that renal tubular reabsorption is involved. Pregabalin undergoes minimal metabolism. The elimination half-life has been reported to be roughly 6 hours.
     
    Affected cytochrome P450 isoenzymes: none
    In vitro studies suggest that pregabalin does not inhibit CYP isoenzymes including 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4 or induce isoenzymes 1A2 or 3A4.

    Oral Route

    Oral bioavailability of pregabalin is roughly 90% and is independent of dose. Oral formulations are rapidly absorbed. The immediate-release oral solution and capsules are bioequivalent dissolving at a rate of more than 85% within 30 minutes. Pregabalin displays linear pharmacokinetics. The median Tmax for immediate-release formulations is 0.7 hours (0.7 to 1.5 hours), and for extended-release tablets is 8 hours (5 to 12 hours). After multiple oral doses, steady state concentrations are achieved within 1 to 2 days for immediate-release formulations and 2 to 3 days for extended-release formulations. Food delays the rate but not the extent of absorption of immediate-release formulations. Administration of the extended-release tablets once daily after an evening meal has an equivalent AUC and lower Cmax compared to administration of immediate-release formulations without food twice daily.