PREGABALIN Dailymed

7 Drug Interactions

Since pregabalin is predominantly excreted unchanged in the urine, undergoes negligible metabolism in humans (less than 2% of a dose recovered in urine as metabolites), and does not bind to plasma proteins, its pharmacokinetics are unlikely to be affected by other agents through metabolic interactions or protein binding displacement. In vitro studies showed that pregabalin is unlikely to be involved in significant pharmacokinetic drug interactions [see Clinical Pharmacology (12)].

The interactions of pregabalin extended-release tablets with co-administration of other drugs have not been systematically evaluated. Co-administration of the prokinetic drug erythromycin with pregabalin extended-release tablets did not result in any clinically important changes in the pharmacokinetics of pregabalin extended-release tablets [see Clinical Pharmacology (12)].

Additional studies have been performed with pregabalin. No pharmacokinetic interactions were observed between pregabalin and carbamazepine, gabapentin, lamotrigine, oral contraceptive, phenobarbital, phenytoin, topiramate, and valproic acid. A similar lack of pharmacokinetic interactions would be expected to occur with pregabalin extended-release tablets.

Pharmacodynamics

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

8 Use In Specific Populations

• Pregnancy: May cause fetal harm. Advise of potential risk to the fetus. (8.1)
• Lactation: Breastfeeding is not recommended. (8.2)

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to pregabalin during pregnancy. To provide information regarding the effects of in utero exposure to pregabalin extended-release tablets, physicians are advised to recommend that pregnant patients taking pregabalin extended-release tablets enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.

Risk Summary

There are no adequate and well-controlled studies with pregabalin extended-release tablets in pregnant women.

However, in animal reproduction studies, increased incidences of fetal structural abnormalities and other manifestations of developmental toxicity, including skeletal malformations, retarded ossification, and decreased fetal body weight were observed in the offspring of rats and rabbits given pregabalin orally during organogenesis, at doses that produced plasma pregabalin exposures (AUC) greater than or equal to 18 times human exposure at the maximum recommended dose (MRD) of 660 mg/day [see Data]. In an animal development study, lethality, growth retardation, and nervous and reproductive system functional impairment were observed in the offspring of rats given pregabalin during gestation and lactation. The no-effect dose for developmental toxicity was approximately twice the human exposure at MRD. The background risk of major birth defects and miscarriage for the indicated populations are unknown. However, the background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies. Advise pregnant women of the potential risk to a fetus.

Data

Animal Data

When pregnant rats were given pregabalin (500, 1,250, or 2,500 mg/kg) orally throughout the period of organogenesis, incidences of specific skull alterations attributed to abnormally advanced ossification (premature fusion of the jugal and nasal sutures) were increased at greater than or equal to 1,250 mg/kg, and incidences of skeletal variations and retarded ossification were increased at all doses. Fetal body weights were decreased at the highest dose. The low dose in this study was associated with a plasma exposure (AUC) approximately 18 times human exposure at the MRD of 660 mg/day. A no-effect dose for rat embryo-fetal developmental toxicity was not established.

When pregnant rabbits were given pregabalin (250, 5,00, or 1,250 mg/kg) orally throughout the period of organogenesis, decreased fetal body weight and increased incidences of skeletal malformations, visceral variations, and retarded ossification were observed at the highest dose. The no-effect dose for developmental toxicity in rabbits (500 mg/kg) was associated with a plasma exposure approximately 17 times human exposure at the MRD.

In a study in which female rats were dosed with pregabalin (50, 100, 250, 1,250, or 2,500 mg/kg) throughout gestation and lactation, offspring growth was reduced at greater than or equal to 100 mg/kg and offspring survival was decreased at greater than or equal to 250 mg/kg. The effect on offspring survival was pronounced at doses greater than or equal to 1,250 mg/kg, with 100% mortality in high-dose litters. When offspring were tested as adults, neurobehavioral abnormalities (decreased auditory startle responding) were observed at greater than or equal to 250 mg/kg and reproductive impairment (decreased fertility and litter size) was seen at 1,250 mg/kg. The no-effect dose for pre- and postnatal developmental toxicity in rats (50 mg/kg) produced a plasma exposure approximately 2 times human exposure at the MRD.

In the prenatal-postnatal study in rats, pregabalin prolonged gestation and induced dystocia at exposures greater than or equal to 50 times the mean human exposure (AUC _(0–24) of 123 µg∙hr/mL) at the MRD.

8.2Lactation

Risk Summary

Small amounts of pregabalin have been detected in the milk of lactating women. A pharmacokinetic study in lactating women detected pregabalin in breast milk at average steady state concentrations approximately 76% of those in maternal plasma. The estimated average daily infant dose of pregabalin from breast milk (assuming mean milk consumption of 150 mL/kg/day) was 0.31 mg/kg/day, which on a mg/kg basis would be approximately 7% of the maternal dose [see Data]. The study did not evaluate the effects of pregabalin on milk production or the effects of pregabalin on the breastfed infant.

Based on animal studies, there is a potential risk of tumorigenicity with pregabalin exposure via breast milk to the breastfed infant [see Nonclinical Toxicology (13.1)]. Available clinical study data in patients greater than 12 years of age do not provide a clear conclusion about the potential risk of tumorigenicity with pregabalin [see Warnings and Precautions (5.9)]. Because of the potential risk of tumorigenicity, breastfeeding is not recommended during treatment with pregabalin extended-release tablets.

Data

A pharmacokinetic study in ten lactating women, who were at least 12 weeks postpartum, evaluated the concentrations of pregabalin in plasma and breast milk. Pregabalin 150 mg oral capsule was given every 12 hours (300 mg daily dose) for a total of 4 doses. Pregabalin was detected in breast milk at average steady-state concentrations approximately 76% of those in maternal plasma. The estimated average daily infant dose of pregabalin from breast milk (assuming mean milk consumption of 150 mL/kg/day) was 0.31 mg/kg/day, which on a mg/kg basis would be approximately 7% of the maternal dose. The study did not evaluate the effects of pregabalin on milk production. Infants did not receive breast milk obtained during the dosing period, therefore, the effects of pregabalin on the breastfed infant were not evaluated.

8.3Females and Males of Reproductive Potential

Infertility

Males

8.4 Pediatric Use

The safety and effectiveness of pregabalin extended-release tablets in pediatric patients have not been established.

Juvenile Animal Toxicity Data

In studies in which pregabalin (50 to 500 mg/kg) was orally administered to young rats from early in the postnatal period (Postnatal Day 7) through sexual maturity, neurobehavioral abnormalities (deficits in learning and memory, altered locomotor activity, decreased auditory startle responding and habituation) and reproductive impairment (delayed sexual maturation and decreased fertility in males and females) were observed at doses greater than or equal to 50 mg/kg. The neurobehavioral changes of acoustic startle persisted at greater than or equal to 250 mg/kg and locomotor activity and water maze performance at greater than or equal to 500 mg/kg in animals tested after cessation of dosing and, thus, were considered to represent long-term effects. The low effect dose for developmental neurotoxicity and reproductive impairment in juvenile rats (50 mg/kg) was associated with a plasma pregabalin exposure (AUC) approximately equal to human exposure at the maximum recommended dose of 660 mg/day. A no-effect dose was not established.

8.5 Geriatric Use

In controlled clinical studies of pregabalin in neuropathic pain associated with diabetic peripheral neuropathy, 246 patients were 65 to 74 years of age, and 73 patients were 75 years of age or older.

In controlled clinical studies of pregabalin in neuropathic pain associated with postherpetic neuralgia, 282 patients were 65 to 74 years of age, and 379 patients were 75 years of age or older.

In the pregabalin extended-release tablets neuropathic pain associated with postherpetic neuralgia study, 422 patients 65 years of age and older received pregabalin.

No overall differences in safety and effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Pregabalin is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. See Dosage and Administration (2.5) for recommendations for dosing in patients with renal impairment.

Pregabalin extended-release tablets are for oral use and contain pregabalin. Pregabalin is described chemically as (S)-3-(aminomethyl)-5-methylhexanoic acid. The molecular formula is C₈H₁₇NO₂ and the molecular weight is 159.23. The chemical structure of pregabalin is:



Pregabalin is a white to off-white, crystalline solid with a pK _a1 of 4.2 and a pK _a2 of 10.6. It is freely soluble in water and both basic and acidic aqueous solutions. The log of the partition coefficient (n-octanol/0.05M phosphate buffer) at pH 7.4 is – 1.35.

Pregabalin extended-release tablets are administered orally and contain 82.5, 165, or 330 mg of pregabalin, along with Kollidon SR (polyvinyl acetate, povidone, sodium lauryl sulphate, and silica), microcrystalline cellulose, polyethylene oxide, carbomer, magnesium stearate, polyvinyl alcohol, titanium dioxide, talc, macrogol/PEG, and colorants ( FD&C Blue #2/Indigo carmine aluminum lake (82.5 mg), Iron Oxide Yellow & Iron Oxide Red (165 mg & 330 mg) and Black Iron Oxide (330 mg)) as inactive ingredients.

12 Clinical Pharmacology

12.1 Mechanism of Action

Pregabalin binds with high affinity to the alpha₂-delta site (an auxiliary subunit of voltage-gated calcium channels) in central nervous system tissues. Although the mechanism of action of pregabalin has not been fully elucidated, results with genetically modified mice and with compounds structurally related to pregabalin (such as gabapentin) suggest that binding to the alpha₂-delta subunit may be involved in pregabalin's anti-nociceptive and antiseizure effects in animals. In animal models of nerve damage, pregabalin has been shown to reduce calcium-dependent release of pro-nociceptive neurotransmitters in the spinal cord, possibly by disrupting alpha₂-delta containing-calcium channel trafficking and/or reducing calcium currents. Evidence from other animal models of nerve damage and persistent pain suggest the anti-nociceptive activities of pregabalin may also be mediated through interactions with descending noradrenergic and serotonergic pathways originating from the brainstem that modulate pain transmission in the spinal cord.

While pregabalin is a structural derivative of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), it does not bind directly to GABA_A, GABA_B, or benzodiazepine receptors, does not augment GABA_A responses in cultured neurons, does not alter rat brain GABA concentration or have acute effects on GABA uptake or degradation. However, in cultured neurons prolonged application of pregabalin increases the density of GABA transporter protein and increases the rate of functional GABA transport. Pregabalin 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.

12.3 Pharmacokinetics

Pregabalin extended-release tablets have linear pharmacokinetics with dose-proportional increases in maximum plasma concentration (C_max) and area under the plasma concentration-time curve (AUC) from 82.5 mg/day to 660 mg/day. Following repeated administration, steady state is achieved within approximately 48 hours to 72 hours.

Pregabalin extended-release tablets administered once daily following an evening meal has equivalent AUC and lower C_max relative to a comparative dose of pregabalin capsules administered without food twice daily (Table 5). Variability in C_max and AUC for pregabalin extended-release tablets is less than or equal to 25%.

Table 5. Steady-State Pharmacokinetics for LYRICA Pregabalin Extended-Release Tablets 165 mg Once Daily and Pregabalin Capsules 75 mg Twice Daily

	Pregabalin Extended-Release TabletsOnce Daily	Pregabalin CapsulesBID
Note: Geometric mean (%CV) for AUC24, Cmax, Cmin; median (range) for Tmax.Abbreviations: AUC24=area under the curve over 24 hours; BID=every 12 hours; Cmax=peak concentrations; Cmin=minimum concentrations; N=Number of subjects ; Tmax=time to peak concentrations.
N	24	24
Cmax (µg/mL)	2.0 (17)	3.2 (21)
Tmax (h)	8.0 (5.0 to 12.0)	0.7 (0.7 to 1.5)
AUC24 (µg∙h/mL)	29.4 (17)	31.5 (18)
Cmin (µg/mL)	0.44 (24)	0.59 (25)

Absorption

Pregabalin is absorbed from the small intestine and proximal colon. Pregabalin extended-release tablets absorption is linear and dose proportional.

The bioavailability of pregabalin extended-release tablets is reduced if taken on an empty stomach. The AUC is approximately 30% lower when pregabalin extended-release tablets are administered fasted relative to following an evening meal.

When pregabalin extended-release tablets are administered following a 600 to 750 calorie (50% carbohydrates, 20% protein, 30% fat) evening meal, peak plasma concentrations occur within approximately 8 to 10 hours and AUC is approximately 93% to 97% relative to a comparative dose of pregabalin capsules or oral solution. The rate and extent of pregabalin extended-release tablets are absorption is similar when administered following a 400 to 500 calorie, 30% fat or an 800 to 1,000 calorie, 15%, 30%, or 50% fat evening meal.

When pregabalin extended-release tablets are administered following an 800 to 1,000 calorie (50% carbohydrates, 20% protein, 30% fat) morning meal, peak plasma concentrations occur within approximately 12 hours and AUC is 99% relative to a comparative dose of pregabalin capsules or oral solution. AUC decreases approximately 13% to 25% when pregabalin extended-release tablets are administered following a 400 to 500 calorie or 600 to 750 calorie (50% carbohydrates, 20% protein, 30% fat) morning meal relative to the 800 to 1,000 calorie meal, while C_max remains the same.

Distribution

Pregabalin does not bind to plasma proteins. The apparent volume of distribution of pregabalin following oral administration is approximately 0.5 L/kg. Pregabalin is a substrate for system L transporter which is responsible for the transport of large amino acids across the blood brain barrier. Although there are no data in humans, pregabalin has been shown to cross the blood brain barrier in mice, rats, and monkeys. In addition, pregabalin has been shown to cross the placenta in rats and is present in the milk of lactating rats.

Elimination

Metabolism

Pregabalin undergoes negligible metabolism in humans. Following a dose of radiolabeled pregabalin, approximately 90% of the administered dose was recovered in the urine as unchanged pregabalin. The N-methylated derivative of pregabalin, the major metabolite of pregabalin found in urine, accounted for 0.9% of the dose. In preclinical studies, pregabalin (S-enantiomer) did not undergo racemization to the R-enantiomer in mice, rats, rabbits, or monkeys.

Excretion

Pregabalin is eliminated from the systemic circulation primarily by renal excretion as unchanged drug with a mean elimination half-life of 6.3 hours in subjects with normal renal function. Mean renal clearance was estimated to be 67.0 to 80.9 mL/min in young healthy subjects. Because pregabalin is not bound to plasma proteins this clearance rate indicates that renal tubular reabsorption is involved. Pregabalin elimination is nearly proportional to CLcr [see Dosage and Administration (2.5)].

Specific Populations

Age: Geriatric Patients

Pregabalin oral clearance tended to decrease with increasing age. This decrease in pregabalin oral clearance is consistent with age-related decreases in CLcr. Reduction of pregabalin dose may be required in patients who have age-related compromised renal function [see Dosage and Administration (2.5)].

Sex

Population pharmacokinetic analyses of the clinical studies showed that the relationship between daily dose and pregabalin extended-release tablets drug exposure is similar between genders.

Race/Ethnicity

In population pharmacokinetic analyses of the clinical studies of pregabalin capsules or oral solution and pregabalin extended-release tablets, the pharmacokinetics of pregabalin were not significantly affected by race (Caucasians, Blacks, and Hispanics).

Renal Impairment

Pregabalin clearance is nearly proportional to CLcr. Dosage reduction in patients with reduced renal function is necessary. Pregabalin is effectively removed from plasma by hemodialysis. Following a 4-hour hemodialysis treatment, plasma pregabalin concentrations are reduced by approximately 50%. For patients on hemodialysis, treatment with pregabalin extended-release tablets is not recommended [see Dosage and Administration (2.5)].

Drug Interaction Studies

In Vitro Studies

In vitro studies showed that pregabalin is unlikely to be involved in significant pharmacokinetic drug interactions. Pregabalin, at concentrations that were, in general, 10-times those attained in clinical trials, does not inhibit human CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 enzyme systems. In vitro drug interaction studies demonstrate that pregabalin does not induce CYP1A2 or CYP3A4 activity. Therefore, an increase in the metabolism of co-administered CYP1A2 substrates (e.g., theophylline, caffeine) or CYP3A4 substrates (e.g., midazolam, testosterone) is not anticipated.

In Vivo Studies

With the exception of erythromycin, the interactions of pregabalin extended-release tablets with co-administration of other drugs have not been systematically evaluated.

Additional studies have been performed with pregabalin [see Drug Interactions (7)]. No pharmacokinetic interactions were observed between pregabalin and carbamazepine, ethanol, gabapentin, lamotrigine, lorazepam, oral contraceptive, oxycodone, phenobarbital, phenytoin, topiramate, and valproic acid. A similar lack of pharmacokinetic interactions would be expected to occur with pregabalin extended-release tablets.

The drug interaction studies described in this section were conducted in healthy adults, and across various patient populations.

Erythromycin

Multiple-dose administration of erythromycin (500 mg every 6 hours for 18 hours) in healthy subjects resulted in a 17% decrease in AUC of pregabalin extended-release tablets (330 mg single dose).

Ethanol

Multiple-dose administration of pregabalin (300 mg twice a day) in healthy subjects had no effect on the rate and extent of ethanol single-dose pharmacokinetics and single-dose administration of ethanol (0.7 g/kg) had no effect on the steady-state pharmacokinetics of pregabalin. Additive effects on cognitive and gross motor functioning were seen when pregabalin was co-administered with ethanol. No clinically important effects on respiration were seen [see Drug Interactions (7)].

Gabapentin

The pharmacokinetic interactions of pregabalin and gabapentin were investigated in 12 healthy subjects following concomitant single-dose administration of 100-mg pregabalin and 300-mg gabapentin and in 18 healthy subjects following concomitant multiple-dose administration of 200-mg pregabalin every 8 hours and 400-mg gabapentin every 8 hours. Gabapentin pharmacokinetics following single- and multiple-dose administration were unaltered by pregabalin co-administration. The extent of pregabalin absorption was unaffected by gabapentin co-administration, although there was a small reduction in rate of absorption.

Lorazepam

Multiple-dose administration of pregabalin (300 mg twice a day) in healthy subjects had no effect on the rate and extent of lorazepam single-dose pharmacokinetics and single-dose administration of lorazepam (1 mg) had no effect on the steady-state pharmacokinetics of pregabalin. Additive effects on cognitive and gross motor functioning were seen when pregabalin was co-administered with lorazepam. No clinically important effects on respiration were seen [see Drug Interactions (7)].

Oral Contraceptive

Pregabalin co-administration (200 mg 3 times a day) had no effect on the steady-state pharmacokinetics of norethindrone and ethinyl estradiol (1 mg/35 µg, respectively) in healthy subjects.

Oxycodone

Multiple-dose administration of pregabalin (300 mg twice a day) in healthy subjects had no effect on the rate and extent of oxycodone single-dose pharmacokinetics. Single-dose administration of oxycodone (10 mg) had no effect on the steady-state pharmacokinetics of pregabalin. Additive effects on cognitive and gross motor functioning were seen when pregabalin was co-administered with oxycodone. No clinically important effects on respiration were seen [see Drug Interactions (7)].

Carbamazepine, Lamotrigine, Phenobarbital, Phenytoin, Topiramate and Valproic Acid

Steady-state trough plasma concentrations of phenytoin, carbamazepine, and carbamazepine 10,11 epoxide, valproic acid, and lamotrigine were not affected by concomitant pregabalin (200 mg 3 times a day) administration.

Population pharmacokinetic analyses in patients treated with pregabalin and various concomitant medications suggest the following:

Therapeutic class	Specific concomitant drug studied
Concomitant drug has no effect on the pharmacokinetics of pregabalin
Hypoglycemics	Glyburide, insulin, metformin
Diuretics	Furosemide
Antiepileptic Drugs	Tiagabine
Concomitant drug has no effect on the pharmacokinetics of pregabalin and pregabalin has no effect on the pharmacokinetics of concomitant drug
Antiepileptic Drugs	Carbamazepine, lamotrigine, phenobarbital, phenytoin, topiramate, valproic acid