Health Canada Advisories

Health Canada advises Canadians to exercise caution when taking gabapentin or pregabalin with opioids (2019-09)

LYRICA​®
pregabalin
Analgesic Agent
Upjohn Canada ULC
DIN(s): 02268418, 02268426, 02268434, 02268450, 02268477, 02268485

Date of Revision: May 11, 2020

Summary Product Information

Route of
Administration Dosage Form/Strength All Nonmedicinal Ingredients
Oral Capsules, 25 mg, 50 mg, Lactose monohydrate, maize starch,
75 mg, 150 mg, 225 mg, and talc
300 mg Capsule shells contain gelatin and
titanium dioxide. In addition, orange
capsule shells contain red iron oxide.
White capsule shells contain sodium
lauryl sulphate and colloidal silicon
dioxide.

Indications and Clinical Use

Adults
LYRICA (pregabalin) is indicated for the management of neuropathic pain associated with:

Diabetic peripheral neuropathy and

Postherpetic neuralgia

LYRICA is indicated for the management of neuropathic pain associated with spinal cord injury.

LYRICA is indicated for the management of pain associated with fibromyalgia.

The efficacy of LYRICA in the management of pain associated with fibromyalgia for up to 6 months was
demonstrated in a placebo-controlled trial in patients who had initially responded to LYRICA during a 6-week open-
label phase.
Geriatrics (>65 years of age)
Pregabalin oral clearance tended to decrease with increasing age. This decrease in pregabalin oral clearance is
consistent with age-related decreases in creatinine clearance. Reduction of pregabalin dose may be required in
patients who have age related compromised renal function (see Warnings and Precautions, Special Populations,
Human Data, Geriatrics (>65 years of age)).

Pediatrics (<18 years of age)

The safety and efficacy of pregabalin in pediatric patients (<18 years of age) have not been established and its use
in this patient population is not recommended (see Warnings and Precautions, Special Populations, Human Data,
Pediatrics (<18 years of age)).

Contraindications
Patients who are hypersensitive to pregabalin or to any ingredient in the formulation or component of the container.

Warnings and Precautions

Serious Warnings and Precautions

Life-threatening Respiratory Depression

Concomitant use of LYRICA with opioids may result in respiratory depression, profound sedation,
syncope, and death.

Limit dosages and durations to the minimum required.

Follow patients for signs and symptoms of respiratory depression and sedation.

Angioedema
There have been post-marketing reports of angioedema in patients, some without reported previous
history/episode(s), during initial/acute and chronic treatment with LYRICA. Specific symptoms included swelling of
the face, mouth (tongue, lips, and gums), neck, throat, and larynx/upper airway. There have been reports of life-
threatening angioedema with respiratory compromise requiring emergency treatment. Some of these patients did not
have reported previous history/episode(s) of angioedema. LYRICA should be immediately discontinued in patients
with these symptoms. During the pre-marketing assessment of pregabalin in clinical trials, angioedema was reported
as a rare reaction. (See Adverse Reactions, Less Common Clinical Trial Adverse Drug Reactions (<2%) and Post-
Market Adverse Drug Reactions).

Caution should be exercised when prescribing LYRICA to patients with previous history/episode(s) of angioedema
and related events. In addition, patients who are taking other drugs associated with angioedema (e.g., ACE-
inhibitors) may be at increased risk of developing this condition.

Hypersensitivity
There have been postmarketing reports of hypersensitivity reactions (e.g., skin redness, blisters, hives, rash,
dyspnea, and wheezing). Pregabalin should be discontinued immediately if such symptoms occur. (See Adverse
Reactions, Post-Market Adverse Drug Reactions.)

Neurologic

Respiratory Depression
Pregabalin has been associated with central nervous system (CNS) depression including sedation, somnolence,
loss of consciousness as well as serious cases of respiratory depression. Patients with compromised respiratory
function, respiratory or neurological disease, renal impairment and the elderly are at higher risk of experiencing
these severe adverse effects. Concomitant use of CNS depressants with pregabalin is also a contributing factor.

Concomitant Use With Opioids

Caution is advised when prescribing LYRICA concomitantly with opioids due to risk of CNS depression.
Concomitant use of opioids with LYRICA potentiates the risk of respiratory depression, profound sedation,
syncope, and death. In an observational study of opioid users, those patients who took pregabalin concomitantly
with an opioid had an increased risk for opioid-related death compared to opioid use alone (adjusted odds ratio
[aOR], 1.68 [95% CI, 1.19 to 2.36]).

Patients who require concurrent treatment with opioids or other CNS depressants should be observed carefully
for signs and symptoms of CNS depression, and the dose of pregabalin or opioid should be reduced accordingly
(see WARNINGS AND PRECAUTIONS, Patient Counselling Information).

Dizziness and Somnolence

LYRICA may cause dizziness and somnolence. In controlled peripheral neuropathic pain and fibromyalgia
studies, pregabalin caused dizziness in 32% of patients compared to 8% in placebo. Somnolence was
experienced by 17% and 4% of the patients treated with pregabalin and placebo, respectively. These events
begin shortly after the initiation of therapy and generally occur more frequently at higher doses. In these studies,
dizziness and somnolence led to withdrawal of 5% (placebo: 0.5%) and 3% (placebo: 0.1%) of the pregabalin-
treated patients, respectively. For the remaining patients who experienced these events, dizziness and
somnolence persisted until the last dose of pregabalin in 35% and 49% of the patients, respectively (see Adverse
Reactions, Table 2, Table 4, and Table 11 and Post-Market Adverse Drug Reactions).

Accordingly, patients should be advised not to drive or operate complex machinery or engage in other hazardous
activities until they have gained sufficient experience on pregabalin to gauge whether or not it affects their mental
and/or motor performance adversely (see Patient Medication Information).

Renal Failure
In both clinical trials of various indications and post-marketing database, there are reports of patients, with or without
previous history, experiencing renal failure while receiving pregabalin alone or in combination with other medications.
Discontinuation of pregabalin should be considered as it has shown reversibility of this event in some cases. Caution
is advised when prescribing pregabalin to the elderly or those with any degree of renal impairment (see Warnings
and Precautions, Special Populations, Renal, Abrupt or Rapid Discontinuation; Adverse Reactions, Post-Market
Adverse Drug Reactions; and Dosage and Administration).

Tumorigenic Potential
In standard preclinical in vivo lifetime carcinogenicity studies of pregabalin, a high incidence of hemangiosarcoma
was identified in two different strains of mice (see Preclinical Toxicology). The clinical significance of this finding is
uncertain. Clinical experience during pregabalin's premarketing development provides no direct means to assess its
potential for inducing tumors in humans.

In clinical studies across various patient populations, comprising 6396 patient-years of exposure in 8666 patients
ranging in age from 12 to 100 years, new or worsening-preexisting tumors were reported in 57 patients. The most
common malignant tumor diagnosed was skin carcinoma (17 patients) followed by breast carcinoma (8 patients),
prostatic carcinoma (6 patients), carcinoma not otherwise specified (6 patients), and bladder carcinoma (4 patients).
Without knowledge of the background incidence and recurrence in similar populations not treated with LYRICA
(pregabalin), it is impossible to know whether the incidence seen in these cohorts is or is not affected by treatment.

Ophthalmological Effects
In controlled studies, pregabalin treatment was associated with vision-related adverse events such as blurred vision
(amblyopia) [6% pregabalin and 2% placebo] and diplopia (2% pregabalin and 0.5% placebo). Approximately 1% of
pregabalin-treated patients discontinued treatment due to vision-related adverse events (primarily blurred vision). Of
the patients who did not withdraw, the blurred vision resolved with continued dosing in approximately half of the
cases (see Adverse Reactions, Post-Market Adverse Drug Reactions).

Prospectively planned ophthalmologic testing, including visual acuity testing, formal visual field testing and dilated
funduscopic examination, was performed in over 3600 patients. In these patients, visual acuity was reduced in 7% of
patients treated with pregabalin, and 5% of placebo-treated patients. Visual field changes were detected in 13% of
pregabalin-treated, and 12% of placebo-treated patients. Funduscopic changes were observed in 2% of pregabalin-
treated and 2% of placebo-treated patients. At this time, clinical significance of the ophthalmologic findings is
unknown.

Patients should be informed that if changes in vision occur, they should notify their physician. If visual disturbance
persists, further assessment, including discontinuation of pregabalin, should be considered. More frequent
assessments should be considered for patients who are already routinely monitored for ocular conditions.

Peripheral Edema
LYRICA may cause peripheral edema. In controlled peripheral neuropathic pain and fibromyalgia clinical trials,
pregabalin treatment caused peripheral edema in 9% of patients compared with 3% of patients in the placebo group.
In these studies, 0.7% of pregabalin patients and 0.3% of placebo patients withdrew due to peripheral edema (see
Adverse Reactions, Less Common Clinical Trial Adverse Drug Reactions (<2%), Peripheral Edema).

In controlled clinical trials of up to 13 weeks in duration of patients without clinically significant heart or peripheral
vascular disease, there was no apparent association between peripheral edema and cardiovascular complications
such as hypertension or congestive heart failure. In the same trials, peripheral edema was not associated with
laboratory changes suggestive of deterioration in renal or hepatic function.

Higher frequencies of weight gain and peripheral edema were observed in patients taking both LYRICA and a
thiazolidinedione antidiabetic agent compared to patients taking either drug alone. The majority of patients using
thiazolidinedione antidiabetic agents in the overall safety database were participants in studies of pain associated
with diabetic peripheral neuropathy. In this population, peripheral edema was reported in 3% (2/60) of patients who
were using thiazolidinedione antidiabetic agents only, 8% (69/859) of patients who were treated with pregabalin only,
and 19% (23/120) of patients who were on both pregabalin and thiazolidinedione antidiabetic agents. Similarly,
weight gain was reported in 0% (0/60) of patients on thiazolidinediones only; 4% (35/859) of patients on pregabalin
only; and 7.5% (9/120) of patients on both drugs.

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 co-administering LYRICA and these agents.
Congestive Heart Failure
In controlled clinical studies, events of congestive heart failure were reported at an infrequent rate (between 0.1%
and 1%; see Adverse Reactions, Less Common Clinical Trial Adverse Drug Reactions (<2%)).

There have been post-marketing reports of congestive heart failure in some patients receiving pregabalin (see
Adverse Reactions, Post-Market Adverse Drug Reactions). Although this adverse reaction has mostly been observed
in elderly cardiovascular compromised patients during pregabalin treatment for a neuropathic pain indication, some
cases have occurred in patients without reported edema or previous history of cardiovascular disease. Pregabalin
should be used with caution in these patients. Discontinuation of pregabalin may resolve the reaction.

Serious Skin Reactions

There have been very rare post-marketing reports of serious cutaneous reactions, including Stevens-Johnson
Syndrome (SJS), Toxic Epidermal Necrolysis (TEN), dermatitis exfoliative, bullous skin reactions, and erythema
multiforme in patients treated with LYRICA (see Adverse Reactions, Post-Market Adverse Drug Reactions). Post-
market reporting rate is generally accepted to be an underestimate due to under-reporting. Most of the reports were
in patients taking concomitant medications also associated with the potential development of these serious skin
reactions. Therefore, in most cases, causality in relation to LYRICA could not be clearly established. Patients should
be advised that if they experience a skin rash, they should discontinue LYRICA treatment and contact their physician
for assessment and advice.

Gastrointestinal
There have been post-marketing reports of events related to reduced lower gastrointestinal tract function (e.g.,
intestinal obstruction, paralytic ileus, and constipation) in patients, some without reported previous history/episode(s),
during initial/acute and chronic treatment with LYRICA, primarily in combination with other medications that have the
potential to produce constipation. Some of these events were considered serious and required hospitalization. In a
number of instances, patients were taking opioid analgesics including tramadol.

Caution should be exercised when LYRICA and opioid analgesics are used in combination, and measures to prevent
constipation may be considered, especially in female patients and elderly as they may be at increased risk of
experiencing lower gastrointestinal-related events (see Adverse Reactions, Post-Market Adverse Drug Reactions).

Weight Gain
LYRICA may cause weight gain. In pregabalin-controlled peripheral neuropathic pain and fibromyalgia clinical trials
with durations of up to 14 weeks, a gain of 7% or more over baseline weight was observed in 8% of pregabalin-
treated patients and 3% of placebo-treated patients. Few patients treated with pregabalin (0.6%) withdrew from
controlled trials due to weight gain (see Adverse Reactions, Less Common Clinical Trial Adverse Drug Reactions
(<2%), Weight Gain).

Pregabalin-associated weight gain was related to dose and duration of exposure. Pregabalin-associated weight gain
did not appear to be associated with baseline BMI, gender, or age. Weight gain was not limited to patients with
edema and was not necessarily due to edema-related events (see Warnings and Precautions, Peripheral Edema).

Although weight gain was not associated with clinically important changes in blood pressure in short-term controlled
studies, the long-term cardiovascular effects of pregabalin-associated weight gain are unknown.

Among diabetic patients, pregabalin-treated patients gained an average of 1.6 kg (range: −16 to 16 kg), compared to
an average 0.3 kg (range: −10 to 9 kg) weight gain in placebo patients. In a cohort of 333 diabetic patients who
received pregabalin for at least 2 years, the average weight gain was 5.2 kg.

In the controlled fibromyalgia clinical trials, 10.7% of pregabalin-treated patients experienced weight gain of 7% or
greater compared to 4.9% of placebo-treated patients. Pregabalin-treated patients gained an average of 1.7 kg
compared to an average of 0.7 kg weight gain in placebo patients.

While the effects of pregabalin-associated weight gain on glycemic control have not been systematically assessed, in
controlled and longer-term open label clinical trials with diabetic patients, pregabalin treatment did not appear to be
associated with loss of glycemic control (as measured by HbA1C).

Abrupt or Rapid Discontinuation

Following abrupt or rapid discontinuation of pregabalin, some patients reported symptoms including insomnia,
nausea, headache, anxiety, hyperhidrosis, and diarrhea. Pregabalin should be tapered gradually over a minimum of
one week rather than discontinued abruptly (see Adverse Reactions, Clinical Trial Adverse Drug Reactions, Adverse
Events Following Abrupt or Rapid Discontinuation).

Convulsions, including status epilepticus and grand mal convulsions, have occurred in non-epileptic patients during
treatment with LYRICA or after abrupt discontinuation (see Adverse Reactions, Post-Market Adverse Drug
Reactions).

Encephalopathy
There have been serious post-marketing reports of encephalopathy, mostly in patients with underlying conditions that
may precipitate encephalopathy. Some cases were reported in patients with a history of kidney or liver disease.
Since there have been rare reports of renal failure with LYRICA, specific caution should be exercised when
prescribing LYRICA to the elderly with age-related compromised renal function and patients with kidney disease or
risk factors for renal failure (see Warnings and Precautions, Renal Failure and Adverse Reactions, Post-Market
Adverse Drug Reactions).

Suicidal Behaviour and Ideation

There have been post-marketing reports of suicide-related events, including completed suicide, suicide attempt, and
suicidal ideation in patients treated with LYRICA for a variety of indications such as neuropathic pain, fibromyalgia,
etc. In some of these reports, underlying psychiatric disorders may have contributed to the event. The mechanism of
this risk is not known. Patients should be monitored for signs of suicidal ideation and behaviours and appropriate
treatment should be considered. Patients should be encouraged to report any distressing thoughts or feelings at any
time to their healthcare professional (see Adverse Reactions, Post-Market Adverse Drug Reactions).

Sexual Function/Reproduction

Impairment of Male Fertility

Preclinical Data
In fertility studies in which male rats were orally administered pregabalin (50 to 2500 mg/kg) prior to and
during mating with untreated females, a number of adverse reproductive and developmental effects were
observed. These included decreased sperm counts and sperm motility, increased sperm abnormalities,
reduced fertility, increased preimplantation embryo loss, decreased litter size, decreased fetal body weights,
and an increased incidence of fetal abnormalities. Effects on sperm and fertility parameters were reversible in
studies of this duration (3-4 months). The no-effect dose for male reproductive toxicity in these studies (100
mg/kg) was associated with a plasma pregabalin exposure (AUC) approximately 3 times human exposure at
the maximum recommended dose (MRD) of 600 mg/day.
In addition, adverse effects on reproductive organ (testes, epididymides) histopathology were observed in
male rats exposed to pregabalin (500 to 1250 mg/kg) in general toxicology studies of four weeks or greater
duration. The no-effect dose for male reproductive organ histopathology in rats (250 mg/kg) was associated
with a plasma exposure approximately 8 times human exposure at the MRD.

In a fertility study in which female rats were given pregabalin (500, 1250, or 2500 mg/kg) orally prior to and
during mating and early gestation, disrupted estrous cyclicity and an increased number of days to mating
were seen at all doses, and embryolethality occurred at the highest dose. The low dose in this study produced
a plasma exposure approximately 9 times that in humans receiving the MRD. A no-effect dose for female
reproductive toxicity in rats was not established. The clinical significance of female fertility findings in animals
is unknown.

Human Data
In a double-blind, placebo-controlled clinical trial to assess the effect of pregabalin on sperm motility, 30
healthy male subjects were exposed to pregabalin 600 mg/day for 3 months (one complete sperm cycle).
Pregabalin did not exhibit significant detrimental effects on the reproductive function of healthy male subjects,
as measured by semen analysis, when compared with placebo (n=16). However, due to the small sample size
and short-term exposure to pregabalin (only one complete sperm cycle), no conclusions can be made
regarding possible reproductive effects of pregabalin during long-term exposure. Effects on other male
reproductive parameters in humans have not been adequately studied.

Special Populations

Renal
There have been reports of patients, with or without previous history, experiencing renal failure while receiving
pregabalin alone or in combination with other medications. Discontinuation of pregabalin showed reversibility of
this event in some cases (see Warnings and Precautions; Adverse Reactions, Post-Market Adverse Drug
Reactions; and Dosage and Administration). Because pregabalin is eliminated primarily by renal excretion, the
dose of pregabalin should be adjusted as noted for elderly patients or those with renal impairment (see Action
and Clinical Pharmacology and Dosage and Administration).

Adjustment of Dose in Renally-Impaired Patients

In patients with a medical history of significant renal insufficiency, daily dosages should be reduced accordingly
(see Table 14 in Dosage and Administration, Dosing Considerations).

Pregnancy

Preclinical Data
Pregabalin was not teratogenic in mice, rats, or rabbits. Pregabalin induced fetal toxicity in rats and rabbits at
≥39 times the mean human exposure at the maximum recommended clinical dose of 600 mg/day [AUC(0-24)
of 123 µg∙h/mL]. In the prenatal-postnatal toxicity study, pregabalin induced offspring developmental toxicity in
rats at ≥5 times the maximum recommended human exposure. No developmental effects occurred at 2 times
the maximum recommended human exposure.

Human Data
Pregnant Women
There are no adequate and well-controlled studies in pregnant women. Pregabalin should be used during
pregnancy only if the potential benefit justifies the potential risk to the fetus.

Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy
Registry if they become pregnant. This registry is collecting information about the safety of anticonvulsant
medications that can be taken by women during pregnancy to treat disorders such as epilepsy, mood
disorder, and chronic pain. The primary goal is to determine the frequency of major malformations, such as
heart defects, spina bifida and cleft lip, in the infants exposed during pregnancy to anticonvulsant drugs. To
enroll, patients can call the toll-free number, 1-888-233-2334. Information on the registry can be also found at
the website http://www.aedpregnancyregistry.org/ (see Warnings and Precautions, Information to Be Provided
to the Patient).

Labor and Delivery

The effects of pregabalin on labor and delivery in pregnant women are unknown. In the prenatal-postnatal
study in rats, pregabalin prolonged gestation and induced dystocia at exposures ≥47 times the mean human
exposure [AUC(0-24) of 123 µg∙h/mL] at the maximum recommended clinical dose of 600 mg/day.

Nursing Women
Pregabalin is excreted in the milk of lactating women. As the safety of pregabalin in infants is not known,
breast-feeding is not recommended during treatment with pregabalin. A decision must be made whether to
discontinue breast-feeding or to discontinue from pregabalin therapy taking into account the benefit of breast
feeding for the child and the benefit of therapy for the women. Patients should be advised to notify their
physician if they are breast-feeding.

The pharmacokinetics of 150 mg pregabalin given every 12 hours (300 mg daily dose) was evaluated in 10
lactating women who were at least 12 weeks postpartum. Pregabalin was excreted into breast milk with
average peak and steady-state concentrations approximately 53 and 76% of those in maternal plasma,
respectively. 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 total maternal daily dose.

Pediatrics (<18 years of age)

The safety and efficacy of pregabalin in pediatric patients (<18 years of age) have not been established.

Geriatrics (>65 years of age)

Of the 1831 patients who received pregabalin in neuropathic pain studies, 528 were 65 to 74 years of age,
and 452 were 75 years of age or older. No significant differences in efficacy were observed between these
patients and younger patients. Pregabalin oral clearance tended to decrease with increasing age. This
decrease in pregabalin oral clearance is consistent with age-related decreases in creatinine clearance.
Reduction of pregabalin dose may be required in patients who have age-related compromised renal function.
In general, the incidence of adverse events did not increase with age.

Creatine Kinase Elevations

Pregabalin treatment was associated with creatine kinase elevations. Mean changes in creatine kinase from
baseline to the maximum value were 60 U/L for pregabalin-treated patients and 28 U/L for the placebo
patients. In all controlled trials across multiple patient populations, 2% of patients on pregabalin and 1% of
placebo patients had a value of creatine kinase at least three times the upper limit of normal. Three
pregabalin-treated subjects had events reported as rhabdomyolysis in premarketing clinical trials. The
relationship between these myopathy events and pregabalin is not completely understood because the cases
had documented factors that may have caused or contributed to these events. 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 levels occur.

Laboratory Changes, Decreased Platelet Count

Pregabalin treatment was associated with a decrease in platelet count. Pregabalin-treated subjects
experienced a mean maximal decrease in platelet count of 20×10​3/µL, compared to 11×10​3/µL in placebo
patients. In the overall database of controlled trials, 2% of placebo patients and 3% of pregabalin patients
experienced a potentially clinically significant decrease in platelets, defined as 20% below baseline value and
<150×10​3/µL.

In randomized controlled trials, pregabalin was not associated with an increase in bleeding related adverse
events.

ECG Changes, PR Interval Prolongation

Pregabalin treatment was associated with mild PR interval prolongation. In analyses of clinical trial ECG data,
the mean PR interval increase was 3-6 msec at pregabalin doses ≥300 mg/day. This mean change difference
was not associated with an increased risk of PR increase ≥25% from baseline, an increased percentage of
subjects with on-treatment PR >200 msec, or an increased risk of adverse events of second or third degree
AV block.

Information to Be Provided to the Patient

Patients receiving LYRICA should be given the following instructions by the physician:

1. Angioedema: Patients should be advised that LYRICA may cause angioedema, with swelling of the face,
mouth (lip, gum, tongue) and neck (larynx and pharynx) that can lead to life-threatening respiratory
compromise. Instruct patients to discontinue LYRICA and immediately seek medical care if they experience
these symptoms.
2. Hypersensitivity: Patients should be advised that LYRICA has been associated with hypersensitivity reactions
such as wheezing, dyspnea, rash, hives, and blisters. Instruct patients to discontinue LYRICA and immediately
seek medical care if they experience these symptoms.
3. Suicidal Behaviour and Ideation: Patients, their caregivers, and families should be counselled to monitor for
signs of suicidal ideation and behaviours and should be encouraged to report any distressing thoughts or
feelings at anytime to their healthcare professional.
4. Dizziness and Somnolence: Patients should be counseled that LYRICA may cause dizziness, somnolence,
blurred vision and other CNS signs and symptoms. Accordingly, they should be advised not to drive, operate
complex machinery, or engage in other hazardous activities until they have gained sufficient experience on
pregabalin to gauge whether or not it affects their mental, visual, and/or motor performance adversely.
5. Edema and Weight Gain: Patients should be counseled that LYRICA may cause edema and weight gain.
Patients should be advised that concomitant treatment with LYRICA and a thiazolidinedione antidiabetic agent
may lead to an additive effect on edema and weight gain. For patients with preexisting cardiac conditions, this
may increase the risk of heart failure.
6. Abrupt or Rapid Discontinuation: Patients should be advised to take LYRICA as prescribed. Abrupt or rapid
discontinuation may result in insomnia, nausea, headache, anxiety, hyperhidrosis, or diarrhea.
7. Visual Disturbances: Patients should be counseled that LYRICA may cause visual disturbances. Patients
should be informed that if changes in vision occur, they should notify their physician (see Warnings and
Precautions, Ophthalmological Effects).
8. Muscle Pain, Tenderness or Weakness: Patients should be instructed to promptly report unexplained muscle
pain, tenderness, or weakness, particularly if accompanied by malaise or fever.
 9. Concomitant Treatment with CNS Depressants, Alcohol: Patients who require concomitant treatment with
central nervous system depressants such as opiates or benzodiazepines should be informed that they may
experience additive CNS side effects, such as somnolence.
In post-marketing experience, there are reports of respiratory failure, coma and deaths in patients taking
pregabalin alone or in combination with other CNS depressants, including in patients with substance use
disorders.
Patients should be told to avoid consuming alcohol while taking LYRICA, as LYRICA may potentiate the
impairment of motor skills and sedation of alcohol.
10. Pregnant Women: Patients should be instructed to notify their physician if they become pregnant or intend to
become pregnant during their therapy, and to notify their physician if they are breast-feeding or intend to breast-
feed during therapy.
Patients should be encouraged to enroll in the North American Antiepileptic Drug Pregnancy Registry (NAAED)
if they become pregnant. This registry is collecting information about the safety of anticonvulsant medications
that can be taken by women during pregnancy to treat disorders such as epilepsy, mood disorder, and chronic
pain. To enroll, patients can call the toll free number 1-888-233-2334. Information on the registry can also be
found at the website http://www.aedpregnancyregistry.org/ (see Warnings and Precautions, Special
Populations, Pregnant Women).
11. Animal Studies in Male Reproduction: Men being treated with LYRICA who plan to father a child should be
informed of the potential risk of male-mediated teratogenicity. In preclinical studies in rats, pregabalin was
associated with an increased risk of male-mediated teratogenicity (see Warnings and Precautions, Sexual
Function/Reproduction). The clinical significance of this finding is uncertain.
12. Skin: Diabetic patients should be instructed to pay particular attention to skin integrity while being treated with
LYRICA. Some animals treated with pregabalin developed skin ulcerations, although no increased incidence of
skin lesions associated with LYRICA was observed in clinical trials (see Warnings and Precautions, Preclinical
Toxicology).

Patients should be informed of the availability of a patient information leaflet, and they should be instructed to read
the leaflet prior to taking LYRICA.

Preclinical Toxicology

Carcinogenesis
A dose-dependent increase in the incidence of malignant vascular tumors (hemangiosarcomas) was observed in
two strains of mice (B6C3F1 and CD-1) given pregabalin (200, 1000, or 5000 mg/kg) in the diet for two years.
Plasma pregabalin exposure (AUC) in mice receiving the lowest dose that increased hemangiosarcomas was
approximately equal to the human exposure at the maximum recommended dose (MRD) of 600 mg/day. A no-
effect dose for induction of hemangiosarcomas in mice was not established. In an investigative study in female
B6C3F1 mice, chronic treatment (24 months) with pregabalin at 1000 mg/kg caused an increased incidence of
hemangiosarcoma, consistent with previous studies, but not at 50 or 200 mg/kg. Discontinuation of treatment
after 12 months at 1000 mg/kg did not significantly reduce the incidence of hemangiosarcoma at 24 months.
Evidence of carcinogenicity was not seen in two studies in Wistar rats following dietary administration of
pregabalin for two years at doses (50, 150, or 450 mg/kg in males and 100, 300, or 900 mg/kg in females) that
were associated with plasma exposures in males and females up to approximately 14 and 24 times, respectively,
human exposure at the MRD. The clinical significance in humans of this finding in mice is unknown.

Mutagenesis
Pregabalin is not genotoxic based on results of a battery of in vitro and in vivo tests. Pregabalin was not
mutagenic in bacteria or in mammalian cells in vitro, was not clastogenic in mammalian systems in vitro and in
vivo, and did not induce unscheduled DNA synthesis in mouse or rat hepatocytes.

Dermatopathy
Skin lesions ranging from erythema to necrosis were seen in repeated-dose toxicology studies in both rats and
monkeys. The etiology of these skin lesions is unknown. At the maximum recommended human dose (MRD) of
600 mg/day, there is a 2-fold safety margin for the dermatological lesions. The more severe dermatopathies
involving necrosis were associated with pregabalin exposures (as expressed by plasma AUCs) of approximately
3 to 8 times those achieved in humans given the MRD. No increase in incidence of skin lesions was observed in
clinical studies.

Ocular Lesions
Ocular lesions (characterized by retinal atrophy (including loss of photoreceptor cells) and/or corneal
inflammation/mineralization) were observed in two lifetime carcinogenicity studies in Wistar rats. These findings
were observed at plasma pregabalin exposures (AUC) ≥2 times those achieved in humans given the maximum
recommended dose of 600 mg/day. A no-effect dose for ocular lesions was not established. Similar lesions were
not observed in lifetime carcinogenicity studies in two strains of mice or in monkeys treated for 1 year. The clinical
significance of this finding in rats is unknown.

Monitoring and Laboratory Tests

Routine therapeutic drug monitoring or clinical laboratory testing is not required for patients treated with LYRICA
(pregabalin) (see Adverse Reactions).

Drug Interactions

Overview
Since pregabalin is predominately excreted unchanged in the urine, undergoes negligible metabolism in humans
(<2% of a dose recovered in urine as metabolites), does not inhibit drug metabolism in vitro, and is not bound to
plasma proteins, LYRICA (pregabalin) is unlikely to produce, or be subject to, pharmacokinetic interactions.

Pharmacokinetic
In Vitro Studies: In vitro drug metabolism studies revealed that pregabalin at concentrations which were, in
general, 10-fold greater than observed in Phase 2/3 clinical trials, does not inhibit human CYP1A2, CYP2A6,
CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 enzyme systems.

In Vivo Studies: The drug interaction data described in this section were obtained from studies involving healthy
adults, patients with epilepsy, and patients with chronic pain disorders.

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

Topiramate
In vitro and in vivo studies showed that LYRICA is unlikely to be involved in significant pharmacokinetic drug
interactions. Specifically, there are no clinically significant pharmacokinetic interactions between pregabalin
and the following antiepileptic drugs: carbamazepine, valproic acid, lamotrigine, phenytoin, phenobarbital, and
topiramate. Important pharmacokinetic interactions would also not be expected to occur between pregabalin
and commonly used antiepileptic drugs.

Tiagabine
The results of a population pharmacokinetic analysis indicated that in patients with partial seizures tiagabine
had no clinically significant effect on pregabalin clearance.

Gabapentin
The pharmacokinetics 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 q8h and 400 mg gabapentin
q8h. Gabapentin pharmacokinetics following single and multiple dose administration were unaltered by
pregabalin coadministration. The rate of pregabalin absorption was reduced by approximately 26% (single
dose administration) and 18% (multiple dose administration) based on lower Cmax values; however, the extent
of pregabalin absorption was unaffected by gabapentin coadministration.

Oral Contraceptives
Pregabalin coadministration (200 mg TID) had no effect on the steady state pharmacokinetics of
norethindrone and ethinyl estradiol (1 mg/35 µg, respectively) in healthy subjects.

Lorazepam
Multiple dose administration of pregabalin (300 mg BID) 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
clinically significant effect on the steady state pharmacokinetics of pregabalin.

Oxycodone
Multiple dose administration of pregabalin (300 mg BID) 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
clinically significant effect on the steady state pharmacokinetics of pregabalin.

Ethanol
Multiple dose administration of pregabalin (300 mg BID) 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
clinically significant effect on the steady state pharmacokinetics of pregabalin.

Diuretics, Oral Hypoglycemics, and Insulin

A population pharmacokinetic analysis in patients with chronic pain showed no clinically significant effect on
pregabalin clearance with the concomitant use of diuretics, oral hypoglycemics, and insulin.

Pharmacodynamic

Opioids, benzodiazepines and alcohol

Pregabalin appears to be additive in the impairment of cognitive and gross motor function caused by opioids,
benzodiazepines and alcohol.

In post-marketing experience, there are reports of respiratory failure, coma and deaths in patients taking
pregabalin alone or in combination with other CNS depressants, including in patients with substance use
disorders.

Thiazolidinedione Antidiabetic Agents

Higher frequencies of weight gain and peripheral edema were observed in patients taking both LYRICA and a
thiazolidinedione antidiabetic agent compared to patients taking either drug alone. The majority of patients
using thiazolidinedione antidiabetic agents in the overall safety database were participants in studies of pain
associated with diabetic peripheral neuropathy.

As the thiazolidinedione class of antidiabetic drugs or LYRICA can cause weight gain and/or fluid retention
alone or together, possibly exacerbating or leading to heart failure, caution should be exercised when co-
administering LYRICA and these agents (see Warnings and Precautions, Peripheral Edema).

Drug-Food Interactions
The rate of pregabalin absorption is decreased when given with food resulting in a decrease in Cmax by
approximately 25% to 30% and an increase in Tmax to approximately 3 hours. However, administration of pregabalin
with food has no clinically relevant effect on the total amount of pregabalin absorbed. Therefore, pregabalin can be
taken with or without food.

Drug-Herb Interactions
LYRICA has no known drug/herb interactions.

Drug-Laboratory Interactions
LYRICA has no known drug/laboratory test interactions.

Dosage and Administration

Dosing Considerations

Patients with Impaired Renal Function

Pregabalin is primarily eliminated from the systemic circulation by renal excretion as unchanged drug. In
some elderly patients and those with a medical history of significant renal insufficiency, daily dosages
should be reduced accordingly (see Dosage Adjustment Based on Renal Function).

In accordance with current clinical practice, if LYRICA (pregabalin) has to be discontinued, it is recommended this
should be done gradually over a minimum of 1 week (see Warnings and Precautions, Abrupt or Rapid
Discontinuation).

Adults

Neuropathic Pain Associated with Diabetic Peripheral Neuropathy

The recommended starting dose for LYRICA is 150 mg/day, given in two or three divided doses (75 mg BID or
50 mg TID), with or without food in patients with a creatinine clearance rate of at least 60 mL/min. Efficacy of
LYRICA has been demonstrated within the first week. Based on individual patient response and tolerability,
the dose may be increased to 150 mg BID (300 mg/day) after one week.

For patients who experience significant and ongoing pain and can tolerate pregabalin 300 mg/day well,
maximum daily dose of 600 mg (300 mg twice a day, BID) can be used. However, in clinical trials, LYRICA
600 mg/day did not provide additional significant efficacy and patients treated with this dose experienced
markedly higher rates of adverse events and discontinued the trial more frequently (see Adverse Reactions,
Table 1 and Table 5). Doses above 600 mg/day have not been studied and are not recommended.

Neuropathic Pain Associated with Postherpetic Neuralgia

The recommended starting dose for LYRICA is 150 mg/day, given in two or three divided doses (75 mg BID or
50 mg TID), with or without food in patients with a creatinine clearance rate of at least 60 mL/min. Efficacy of
LYRICA has been demonstrated within the first week. Based on individual patient response and tolerability,
the dose may be increased to 150 mg BID (300 mg/day) after one week.

For patients who experience significant and ongoing pain and can tolerate pregabalin 300 mg/day well,
maximum daily dose of 600 mg (300 mg twice a day, BID) can be used. However, in clinical trials, LYRICA
600 mg/day did not provide additional significant efficacy and patients treated with this dose experienced
markedly higher rates of adverse events and discontinued the trial more frequently (see Adverse Reactions,
Table 3 and Table 6). Doses above 600 mg/day have not been studied and are not recommended.

Neuropathic Pain Associated with Spinal Cord Injury

The recommended starting dose for LYRICA is 150 mg/day, given in two divided doses (75 mg BID), with or
without food in patients with a creatinine clearance rate of at least 60 mL/min. Efficacy of LYRICA has been
demonstrated within the first week. Based on individual patient response and tolerability, the dose may be
increased to 150 mg BID (300 mg/day) after one week.

For patients who experience significant and ongoing pain and can tolerate pregabalin 300 mg/day well, a
maximum daily dose of 600 mg (300 mg twice a day, BID) may be considered. Doses above 600 mg/day
have not been studied and are not recommended.

Pain Associated with Fibromyalgia

The recommended dosage is 300 to 450 mg/day, given in two divided doses. The recommended starting dose
for LYRICA is 150 mg/day, given in two divided doses (75 mg BID), with or without food in patients with a
creatinine clearance rate of at least 60 mL/min. Based on individual response and tolerability, the dose may
be increased to 150 mg BID (300 mg/day) after one week. Patients who do not experience sufficient benefit
with 300 mg/day may be further increased to 225 mg BID (450 mg/day). In some patients, efficacy of LYRICA
has been demonstrated within the first week.

For patients who experience significant and ongoing pain and can tolerate pregabalin 300 mg/day well,
maximum daily dose of 600 mg (300 mg twice a day, BID) can be used. However, in clinical trials of
fibromyalgia, LYRICA 600 mg/day did not provide additional significant efficacy and patients treated with this
dose experienced significantly higher rates of adverse events and discontinued the trial more frequently (see
Adverse Reactions, Table 7 and Table 10). In view of the dose-related adverse events, the decision to treat
patients with doses above 450 mg/day should be based on clinical judgment of the treating physician. Doses
above 600 mg/day have not been studied and are not recommended.

Dosage Adjustment Based on Renal Function

LYRICA is primarily eliminated by renal excretion. Therefore, the dose should be adjusted for patients with reduced
renal function. Pregabalin clearance is directly proportional to creatinine clearance. Therefore, dosing adjustment
should be based on creatinine clearance (CLCr), as indicated in Table 14.

To use this dosing table, an estimate of the patient's creatinine clearance (CLCr) in mL/min is needed. CLCr in
mL/min may be estimated from serum creatinine (mg/dL) determination using the Cockcroft and Gault equation:

[140 − age (years)] × weight (kg)

CLCr = (× 0.85 for female patients)
72 × serum creatinine (mg/dL)
Pregabalin is effectively removed from plasma by hemodialysis. Over a 4-hour hemodialysis treatment, plasma
pregabalin concentrations are reduced by approximately 50%. For patients receiving 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 (see Table 14).

Table 14: Pregabalin Dosage Adjustment Based on Renal Function

Total Pregabalin Daily Dose (mg/day)​[a]

Creatinine Recommended Dose Escalation​[b]
Clearance Maximum
(CLcr) Starting → Daily Dose
(mL/min) Dose up to Dose Regimen
≥60 150 300 450 600 BID or TID

30–60 75 150 225 300 BID or TID

15–30 25–50 75 100–150 150 QD or BID

<15 25 25–50 50–75 75 QD

Supplementary dosage following hemodialysis (mg)​[c]

Patients on the 25 mg QD regimen: take one supplemental dose of 25 mg or 50 mg

Patients on the 25–50 mg QD regimen: take one supplemental dose of 50 mg or 75
mg
Patients on the 50–75 mg QD regimen: take one supplemental dose of 75 mg or 100
mg
Patients on the 75 mg QD regimen: take one supplemental dose of 100 mg or 150 mg

[a]
Total daily dose (mg/day) should be divided as indicated by dose regimen to provide mg/dose.
[b]
Based on individual patient response and tolerability.
[c]
Supplementary dose is a single additional dose.
Legend:
TID=three divided doses; BID=two divided doses; QD=single daily dose.

Geriatrics (>65 years)

Pregabalin oral clearance tended to decrease with increasing age. This decrease in pregabalin oral clearance is
consistent with age-related decreases in creatinine clearance. Reduction of pregabalin dose may be required in
patients who have age-related compromised renal function.

Pediatrics (<18 years of age)

The safety and efficacy of pregabalin in pediatric patients (<18 years of age) have not been established and its
use in this patient population is not recommended.

Administration
LYRICA is given orally with or without food (see Drug Interactions, Drug-Food Interactions).

Overdosage
For management of a suspected drug overdose, contact your regional Poison Control Centre. See the eCPS
Directory section for a list of Poison Control Centres.

Signs, Symptoms and Laboratory Findings of Acute

Overdosage in Humans
The highest known dose of pregabalin received in the clinical development program in which there was no fatal
outcome was 15 000 mg in 1 patient. The types of adverse events experienced by patients who received an
overdose were not clinically different from other patients receiving recommended doses of pregabalin.

In post-marketing experience, fatal outcomes in cases in which pregabalin has been taken in combination with other
medications have been reported with a pregabalin overdose as low as 800 mg in a day. In none of these cases has
pregabalin been established as the cause of death or in pregabalin monotherapy. The lowest fatal dose with
pregabalin alone has not yet been identified.

The most commonly reported adverse events observed when pregabalin was taken in overdose (dose range from
800 mg/day up to 11 500 mg as a single dose) included affective disorder, somnolence, confusional state,
depression, agitation, and restlessness. Seizures were also reported.

Treatment or Management of Overdose

There is no specific antidote for overdose with pregabalin. If indicated, elimination of unabsorbed drug may be
attempted by emesis or gastric lavage; usual precautions should be observed to maintain the airway. General
supportive care of the patient is indicated including monitoring of vital signs and observation of the clinical status of
the patient. A Certified Poison Control Center should be contacted for up-to-date information on the management of
overdose with pregabalin.

Hemodialysis
Standard hemodialysis procedures result in significant clearance of pregabalin (approximately 50% in 4 hours) and
should be considered in cases of overdose. Although hemodialysis has not been performed in the few known cases
 of overdose, it may be indicated by the patient's clinical state or in patients with significant renal impairment.

Storage and Stability

Store at 15-30°C.

Dosage Forms, Composition and Packaging

Dosage Forms
LYRICA (pregabalin) is supplied as a hard gelatin capsule for daily oral administration.

25 mg capsules: White hard gelatin capsule printed with black ink “Pfizer” on the cap, “PGN 25” on the body.

50 mg capsules: White hard gelatin capsule printed with black ink “Pfizer” on the cap, “PGN 50” and an ink band on
the body.

75 mg capsules: White/orange hard gelatin capsule printed with black ink “Pfizer” on the cap, “PGN 75” on the body.

150 mg capsules: White hard gelatin capsule printed with black ink “Pfizer” on the cap, “PGN 150” on the body.

225 mg capsules: White/light orange hard gelatin capsule printed with black ink “Pfizer” on the cap, “PGN 225” on
the body.

300 mg capsules: White/orange hard gelatin capsule printed with black ink “Pfizer” on the cap, “PGN 300” on the
body.

Composition
Each capsule of LYRICA contains 25, 50, 75, 150, 225, or 300 mg pregabalin, lactose monohydrate, maize starch,
and talc. The capsule shells contain gelatin and titanium dioxide. In addition, the orange capsule shells contain red
iron oxide and the white capsule shells contain sodium lauryl sulfate and colloidal silicon dioxide. Colloidal silicon
dioxide is a manufacturing aid, which may not be present. The markings on the capsules are in black ink, which
contains shellac, black iron oxide, propylene glycol, potassium hydroxide and water.

Packaging
Capsules are packaged in HDPE bottles containing 60 capsules. The 25 mg and 75 mg capsules are also available
in PVC/ aluminum blisters containing 14 capsules.

This product monograph was developed by the pharmaceutical manufacturer in accordance with the requirements of Health Canada. CPhA
recommends that the full monograph be used. Partial monographs should not be provided to patients or anyone else and are for use only by clients at
their own risk. CPhA assumes no responsibility for or liability in connection with the use of this monograph. Once printed, there is no guarantee the
information is up-to-date. [Printed on: 01-27-2023 10:27 AM]
CPS, Drug Information © Canadian Pharmacists Association, 2023. All rights reserved