ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
LYRICA 25 mg hard capsules
2.
Each hard capsule contains 25 mg of pregabalin.
Excipients
:
Each hard capsule also contains 35 mg lactose monohydrate.
For a full list of excipients, see section 6.1.
3.
Hard capsule
White, marked “Pfizer” on the cap and “PGN 25” on the body with black ink.
4.
Neuropathic pain
Lyrica is indicated for the treatment of peripheral and central neuropathic pain in adults.
Epilepsy
Lyrica is indicated as adjunctive therapy in adults with partial seizures with or without secondary
generalisation.
Generalised Anxiety Disorder
LYRICA is indicated for the treatment of Generalised Anxiety Disorder (GAD) in adults.
Posology
The dose range is 150 to 600 mg per day given in either two or three divided doses.
Neuropathic pain
Pregabalin treatment can be started at a dose of 150 mg per day given as two or three divided doses.
Based on individual patient response and tolerability, the dose may be increased to 300 mg per day
after an interval of 3 to 7 days, and if needed, to a maximum dose of 600 mg per day after an
additional 7-day interval.
Epilepsy
Pregabalin treatment can be started with a dose of 150 mg per day given as two or three divided doses.
Based on individual patient response and tolerability, the dose may be increased to 300 mg per day
after 1 week. The maximum dose of 600 mg per day may be achieved after an additional week.
2
Generalised Anxiety Disorder
The dose range is 150 to 600 mg per day given as two or three divided doses. The need for treatment
should be reassessed regularly.
Pregabalin treatment can be started with a dose of 150 mg per day. Based on individual patient
response and tolerability, the dose may be increased to 300 mg per day after 1 week. Following an
additional week the dose may be increased to 450 mg per day. The maximum dose of 600 mg per day
may be achieved after an additional week.
Discontinuation of pregabalin
In accordance with current clinical practice, if pregabalin has to be discontinued it is recommended
this should be done gradually over a minimum of 1 week independent of the indication (see sections
4.4 and 4.8).
Special populations
Patients with renal impairment
Pregabalin is eliminated from the systemic circulation primarily by renal excretion as unchanged drug.
As pregabalin clearance is directly proportional to creatinine clearance (see section 5.2), dose
reduction in patients with compromised renal function must be individualised according to creatinine
clearance (CLcr), as indicated in Table 1 determined using the following formula:
CL
(ml/min)
1
.
23
140
-
age
(years)
x
weight
(kg)
(
x
0.85
for
female
patients)
cr
serum
creatinine
(
mol/l)
Pregabalin is removed effectively from plasma by haemodialysis (50% of drug in 4 hours). For
patients receiving haemodialysis, the pregabalin daily dose should be adjusted based on renal function.
In addition to the daily dose, a supplementary dose should be given immediately following every 4-
hour haemodialysis treatment (see Table 1).
Table 1. Pregabalin dose adjustment based on renal function
Creatinine
clearance (CL
cr
)
(mL/min)
Total pregabalin daily dose *
Dose regimen
Starting dose
(mg/day)
Maximum dose
(mg/day)
≥ 60
150
600
BID or TID
≥30 - <60
75
300
BID or TID
≥15 - <30
25 – 50
150
Once Daily or BID
< 15
25
75
Once Daily
Supplementary dosage following haemodialysis (mg)
25
100
Single dose
+
TID = Three divided doses
BID = Two divided doses
* Total daily dose (mg/day) should be divided as indicated by dose regimen to provide mg/dose
+
Supplementary dose is a single additional dose
Use in patients with hepatic impairment
No dose adjustment is required for patients with hepatic impairment (see section 5.2).
3
Paediatric population
The safety and efficacy of Lyrica in children below the age of 12 years and in adolescents (12-17 years
of age) have not been established. No data are available.
Use in the elderly (over 65 years of age)
Elderly patients may require a dose reduction of pregabalin due to a decreased renal function (see
patients with renal impairment).
Method of administration
Lyrica may be taken with or without food.
LYRICA is for oral use only.
Hypersensitivity to the active substance or to any of the excipients.
Diabetic patients
In accordance with current clinical practice, some diabetic patients who gain weight on pregabalin
treatment may need to adjust hypoglycaemic medicinal products.
Hypersensitivity reactions
There have been reports in the postmarketing experience of hypersensitivity reactions, including cases
of angioedema. Pregabalin should be discontinued immediately if symptoms of angioedema, such as
facial, perioral, or upper airway swelling occur.
Dizziness, somnolence, loss of consciousness, confusion, and mental impairment
Pregabalin treatment has been associated with dizziness and somnolence, which could increase the
occurrence of accidental injury (fall) in the elderly population. There have also been post-marketing
reports of loss of consciousness, confusion and mental impairment. Therefore, patients should be
advised to exercise caution until they are familiar with the potential effects of the medicinal product.
Vision-related effects
In controlled trials, a higher proportion of patients treated with pregabalin reported blurred vision than
did patients treated with placebo which resolved in a majority of cases with continued dosing. In the
clinical studies where ophthalmologic testing was conducted, the incidence of visual acuity reduction
and visual field changes was greater in pregabalin-treated patients than in placebo-treated patients; the
incidence of fundoscopic changes was greater in placebo-treated patients (see section 5.1).
In the post-marketing experience, visual adverse reactions have also been reported, including loss of
vision, visual blurring or other changes of visual acuity, many of which were transient.
Discontinuation of pregabalin may result in resolution or improvement of these visual symptoms.
Renal failure
Cases of renal failure have been reported and in some cases discontinuation of pregabalin did show
reversibility of this adverse reaction.
Withdrawal of concomitant antiepileptic medicinal products
There are insufficient data for the withdrawal of concomitant antiepileptic medicinal products, once
seizure control with pregabalin in the add-on situation has been reached, in order to reach
monotherapy on pregabalin.
Withdrawal symptoms
After discontinuation of short-term and long-term treatment with pregabalin withdrawal symptoms
have been observed in some patients. The following events have been mentioned: insomnia, headache,
4
nausea, anxiety, diarrhoea, flu syndrome, nervousness, depression, pain
,
convulsion, hyperhidrosis and
dizziness. The patient should be informed about this at the start of the treatment.
Convulsions, including status epilepticus and grand mal convulsions, may occur during pregabalin use
or shortly after discontinuing pregabalin.
Concerning discontinuation of long-term treatment of pregabalin there are no data of the incidence and
severity of withdrawal symptoms in relation to duration of use and dose of pregabalin.
Congestive heart failure
There have been post-marketing reports of congestive heart failure in some patients receiving
pregabalin. These reactions are mostly seen in elderly cardiovascular compromised patients during
pregabalin treatment for a neuropathic indication. Pregabalin should be used with caution in these
patients. Discontinuation of pregabalin may resolve the reaction.
Treatment of central neuropathic pain due to spinal cord injury
In the treatment of central neuropathic pain due to spinal cord injury the incidence of adverse reactions
in general, central nervous system adverse reactions and especially somnolence was increased. This
may be attributed to an additive effect due to concomitant medicinal products (e.g. anti-spasticity
agents) needed for this condition. This should be considered when prescribing pregabalin in this
condition.
Suicidal ideation and behaviour
Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents in
several indications. A meta-analysis of randomised placebo controlled studies of anti-epileptic drugs
has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is
not known and the available data do not exclude the possibility of an increased risk for pregabalin.
Therefore patients should be monitored for signs of suicidal ideation and behaviours and appropriate
treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical
advice should signs of suicidal ideation or behaviour emerge.
Reduced lower gastrointestinal tract function
There are post-marketing reports of events related to reduced lower gastrointestinal tract function
(e.g., intestinal obstruction, paralytic ileus, constipation) when pregabalin was co-administered with
medications that have the potential to produce constipation, such as opioid analgesics. When
pregabalin and opioids will be used in combination, measures to prevent constipation may be
considered (especially in female patients and elderly).
Abuse potential
Cases of abuse have been reported. Caution should be exercised in patients with a history of substance
abuse and the patient should be monitored for symptoms of pregabalin abuse.
Encephalopathy
Cases of encephalopathy have been reported, mostly in patients with underlying conditions that may
precipitate encephalopathy.
Lactose intolerance
Lyrica contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance,
the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Since pregabalin is predominantly 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, it is unlikely to produce, or be subject to,
pharmacokinetic interactions.
5
In vivo studies and population pharmacokinetic analysis
Accordingly, in
in vivo
studies no clinically relevant pharmacokinetic interactions were observed
between pregabalin and phenytoin, carbamazepine, valproic acid, lamotrigine, gabapentin, lorazepam,
oxycodone or ethanol. Population pharmacokinetic analysis indicated that oral antidiabetics, diuretics,
insulin, phenobarbital, tiagabine and topiramate had no clinically significant effect on pregabalin
clearance.
Oral contraceptives, norethisterone and/or ethinyl oestradiol
Co-administration of pregabalin with the oral contraceptives norethisterone and/or ethinyl oestradiol
does not influence the steady-state pharmacokinetics of either substance.
Ethanol, lorazepam, oxycodone
Pregabalin may potentiate the effects of ethanol and lorazepam. In controlled clinical trials, multiple
oral doses of pregabalin co-administered with oxycodone, lorazepam, or ethanol did not result in
clinically important effects on respiration. In the postmarketing experience, there are reports of
respiratory failure and coma in patients taking pregabalin and other CNS depressant medicinal
products. Pregabalin appears to be additive in the impairment of cognitive and gross motor function
caused by oxycodone.
Interactions and the elderly
No specific pharmacodynamic interaction studies were conducted in elderly volunteers. Interaction
studies have only been performed in adults.
Women of childbearing potential / Contraception in males and females
As the potential risk for humans is unknown, effective contraception must be used in women of child
bearing potential.
Pregnancy
There are no adequate data from the use of pregabalin in pregnant women.
Studies in animals have
shown reproductive toxicity (see 5.3). The potential risk for humans is
unknown.
Lyrica should not be used during pregnancy unless clearly necessary (if the benefit to the mother
clearly outweighs the potential risk to the foetus).
Breast-feeding
It is not known if pregabalin is excreted in the breast milk of humans; however, it is present in the milk
of rats. Therefore, breast-feeding is not recommended during treatment with pregabalin.
Fertility
There are no clinical data on the effects of pregabalin on female fertility.
In a clinical trial to assess the effect of pregabalin on sperm motility, healthy male subjects were
exposed to pregabalin at a dose of 600 mg/day. After 3 months of treatment, there were no effects on
sperm motility.
A fertilty study in female rats has shown adverse reproductive effects. Fertility studies in male rats
have shown adverse reproductive and developmental effects. The clinical relevance of these findings
is unknown (see section 5.3).
Lyrica may have minor or moderate influence on the ability to drive and use machines. Lyrica may
cause dizziness and somnolence and therefore may influence the ability to drive or use machines.
6
Patients are advised not to drive, operate complex machinery or engage in other potentially hazardous
activities until it is known whether this medicinal product affects their ability to perform these
activities.
The pregabalin clinical programme involved over 8900 patients who were exposed to pregabalin, of
whom over 5600 were in double-blind placebo controlled trials. The most commonly reported adverse
reactions were dizziness and somnolence. Adverse reactions were usually mild to moderate in
intensity. In all controlled studies, the discontinuation rate due to adverse reactions was 12% for
patients receiving pregabalin and 5% for patients receiving placebo. The most common adverse
reactions resulting in discontinuation from pregabalin treatment groups were dizziness and
somnolence.
In the table below all adverse reactions, which occurred at an incidence greater than placebo and in
more than one patient, are listed by class and frequency (very common (≥1/10); common (≥1/100 to
<
1/10); uncommon (≥1/1,000 to
<
1/100); rare (≥1/10,000 to
<
1/1,000); very rare (
<
1/10,000), not
known (cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
The adverse reactions listed may also be associated with the underlying disease and / or concomitant
medicinal products.
In the treatment of central neuropathic pain due to spinal cord injury the incidence of adverse reactions
in general, CNS adverse reactions and especially somnolence was increased (See 4.4).
Additional reactions reported from post-marketing experience are included as Frequency not known in
italics in the list below.
System Organ Class
Adverse drug reactions
Infections and infestations
Uncommon Nasopharyngitis
Blood and lymphatic system disorders
Rare
Neutropenia
Immune system disorders
Frequency not known
Hypersensitivity
,
angioedema, allergic reaction
Metabolism and nutrition disorders
Common
Uncommon
Anorexia, hypoglycaemia
Psychiatric disorders
Common
Euphoric mood, confusion, irritability, libido decreased,
disorientation, insomnia
Uncommon
Hallucination, panic attack, restlessness, agitation, depression,
depressed mood, mood swings, depersonalisation, word finding
difficulty, abnormal dreams, libido increased, anorgasmia, apathy
Frequency not known
Disinhibition, elevated mood
Nervous system disorders
Very Common
Common
Ataxia, coordination abnormal, tremor, dysarthria, memory
impairment, disturbance in attention, paraesthesia, sedation, balance
disorder, lethargy
Uncommon
Syncope, stupor, myoclonus, psychomotor hyperactivity, ageusia,
dyskinesia, dizziness postural, intention tremor, nystagmus,
cognitive disorder, speech disorder, hyporeflexia, hypoaesthesia,
amnesia, hyperaesthesia, burning sensation
Rare
Hypokinesia, parosmia, dysgraphia
7
Appetite increased
Rare
Aggression
Dizziness, somnolence
Frequency not known
Loss of consciousness
,
mental impairment, convulsions, headache,
malaise
Eye disorders
Common Vision blurred, diplopia
Uncommon Visual disturbance, eye swelling, visual field defect, visual acuity
reduced, eye pain, asthenopia, dry eye, lacrimation increased
Rare Peripheral vision loss, oscillopsia, altered visual depth perception,
photopsia, eye irritation, mydriasis, strabismus, visual brightness
Frequency not known
Vision loss
,
keratitis
Ear and labyrinth disorders
Common
Uncommon
Hyperacusis
Cardiac disorders
Uncommon
Rare
Sinus tachycardia, sinus bradycardia, sinus arrhythmia
Frequency not known
Congestive heart failure, QT prolongation
Vascular disorders
Uncommon Flushing, hot flushes, hypotension, hypertension
Rare Peripheral coldness
Respiratory, thoracic and mediastinal disorders
Uncommon
Dyspnoea, nasal dryness
Frequency not known
Epistaxis, throat tightness, cough, nasal congestion, rhinitis, snoring
Gastrointestinal disorders
Common Vomiting, dry mouth, constipation, flatulence
Uncommon Abdominal distension, gastrooesophageal reflux disease, salivary
hypersecretion, hypoaesthesia oral
Rare Ascites, pancreatitis, dysphagia
Frequency not known
Swollen tongue
,
diarrhoea, nausea
Skin and subcutaneous tissue disorders
Uncommon Rash papular, hyperhidrosis
Rare Urticaria, cold sweat
Frequency not known
Stevens Johnson syndrome
,
pruritus
Musculoskeletal and connective tissue disorders
Uncommon Muscle twitching, joint swelling, muscle cramp, myalgia, arthralgia,
back pain, pain in limb, muscle stiffness
Rare Rhabdomyolysis, cervical spasm, neck pain
Renal and urinary disorders
Uncommon Urinary incontinence, dysuria
Rare Renal failure, oliguria
Frequency not known
Urinary
retention
Reproductive system and breast disorders
Common Erectile dysfunction
Uncommon Ejaculation delayed, sexual dysfunction
Rare Amenorrhoea, breast discharge, breast pain, dysmenorrhoea,
hypertrophy breast
General disorders and administration site conditions
Common
Uncommon
Fall, chest tightness, asthenia, thirst, pain, feeling abnormal, chills
Rare
Generalised oedema, pyrexia
Frequency not known
Face oedema
Investigations
Common
Uncommon
Blood creatine phosphokinase increased, alanine aminotransferase
increased, aspartate aminotransferase increased, platelet count
decreased
8
Vertigo
Tachycardia, atrioventricular block first degree
Rare
Pulmonary oedema
Gait abnormal, feeling drunk, fatigue, oedema peripheral, oedema
Weight increased
Rare
Blood glucose increased, blood potassium decreased, white blood
cell count decreased, blood creatinine increased, weight decreased
After discontinuation of short-term and long-term treatment with pregabalin withdrawal symptoms
have been observed in some patients. The following reactions have been mentioned: insomnia,
headache, nausea, anxiety, diarrhoea, flu syndrome, convulsions, nervousness, depression, pain
,
hyperhidrosis and dizziness. The patient should be informed about this at the start of the treatment.
Concerning discontinuation of long-term treatment of pregabalin there are no data of the incidence and
severity of withdrawal symptoms in relation to duration of use and dose of pregabalin.
In overdoses up to 15 g, no unexpected adverse reactions were reported.
In the post-marketing experience, the most commonly reported adverse reactions observed when
pregabalin was taken in overdose included somnolence, confusional state, agitation, and restlessness.
Treatment of pregabalin overdose should include general supportive measures and may include
haemodialysis if necessary (see section 4.2 Table 1).
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antiepileptics, other antiepileptics ATC code: N03AX16
The active substance, pregabalin, is a gamma-aminobutyric acid analogue ((S)-3-(aminomethyl)-5-
methylhexanoic acid).
Mechanism of action
Pregabalin binds to an auxiliary subunit (
2
- protein) of voltage-gated calcium channels in the central
nervous system, potently displacing [
3
H]-gabapentin.
Clinical experience
Neuropathic pain
Efficacy has been shown in trials in diabetic neuropathy, post herpetic neuralgia and spinal cord
injury. Efficacy has not been studied in other models of neuropathic pain.
Pregabalin has been studied in 10 controlled clinical trials of up to 13 weeks with twice a day dosing
(BID) and up to 8 weeks with three times a day (TID) dosing. Overall, the safety and efficacy profiles
for BID and TID dosing regimens were similar.
In clinical trials up to 12 weeks for both peripheral and central neuropathic pain, a reduction in pain
was seen by week 1 and was maintained throughout the treatment period.
In controlled clinical trials in peripheral neuropathic pain 35% of the pregabalin treated patients and
18% of the patients on placebo had a 50% improvement in pain score. For patients not experiencing
somnolence, such an improvement was observed in 33% of patients treated with pregabalin and 18%
of patients on placebo. For patients who experienced somnolence the responder rates were 48% on
pregabalin and 16% on placebo.
9
In the controlled clinical trial in central neuropathic pain 22% of the Pregabalin treated patients and
7% of the patients on placebo had a 50% improvement in pain score.
Epilepsy
Pregabalin has been studied in 3 controlled clinical trials of 12 week duration with either twice a day
dosing (BID) or three times a day (TID) dosing. Overall, the safety and efficacy profiles for BID and
TID dosing regimens were similar.
A reduction in seizure frequency was observed by Week 1.
Generalised Anxiety Disorder
Pregabalin has been studied in 6 controlled trials of 4-6 week duration, an elderly study of 8 week
duration and a long-term relapse prevention study with a double blind relapse prevention phase of 6
months duration.
Relief of the symptoms of GAD as reflected by the Hamilton Anxiety Rating Scale (HAM-A) was
observed by Week 1.
In controlled clinical trials (4-8 week duration) 52% of the pregabalin treated patients and 38% of the
patients on placebo had at least a 50% improvement in HAM-A total score from baseline to endpoint.
In controlled trials, a higher proportion of patients treated with pregabalin reported blurred vision than
did patients treated with placebo which resolved in a majority of cases with continued dosing.
Ophthamologic testing (including visual acuity testing, formal visual field testing and dilated
funduscopic examination) was conducted in over 3600 patients within controlled clinical trials. In
these patients, visual acuity was reduced in 6.5% of patients treated with pregabalin, and 4.8% of
placebo-treated patients. Visual field changes were detected in 12.4% of pregabalin-treated, and 11.7%
of placebo-treated patients. Funduscopic changes were observed in 1.7% of pregabalin-treated and
2.1% of placebo-treated patients.
5.2 Pharmacokinetic properties
Pregabalin steady-state pharmacokinetics are similar in healthy volunteers, patients with epilepsy
receiving anti-epileptic drugs and patients with chronic pain.
Absorption:
Pregabalin is rapidly absorbed when administered in the fasted state, with peak plasma concentrations
occurring within 1 hour
following both single and multiple dose administration. Pregabalin oral
bioavailability is estimated to be 90% and is independent of dose. Following repeated
administration, steady state is achieved within 24 to 48 hours. The rate of pregabalin absorption is
decreased when given with food resulting in a decrease in C
max
by approximately 25-30% and a delay
in t
max
to approximately 2.5 hours. However, administration of pregabalin with food has no clinically
significant effect on the extent of pregabalin absorption.
Distribution:
In preclinical studies, pregabalin has been shown to cross the blood brain barrier in mice, rats, and
monkeys. Pregabalin has been shown to cross the placenta in rats and is present in the milk of
lactating rats. In humans, the apparent volume of distribution of pregabalin following oral
administration is approximately 0.56 l/kg. Pregabalin is not bound to plasma proteins.
10
Biotransformation:
Pregabalin undergoes negligible metabolism in humans. Following a dose of radiolabelled pregabalin,
approximately 98% of the radioactivity recovered in the urine was 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, there was no indication of racemisation of pregabalin S-
enantiomer to the R-enantiomer.
Elimination:
Pregabalin is eliminated from the systemic circulation primarily by renal excretion as unchanged drug.
Pregabalin mean elimination half-life is 6.3 hours. Pregabalin plasma clearance and renal clearance
are directly proportional to creatinine clearance (see section 5.2 Renal impairment).
Dose adjustment in patients with reduced renal function or undergoing haemodialysis is necessary (see
Section 4.2 Table 1).
Linearity / non-linearity
:
Pregabalin pharmacokinetics are linear over the recommended daily dose range. Inter-subject
pharmacokinetic variability for pregabalin is low (<20%). Multiple dose pharmacokinetics are
predictable from single-dose data. Therefore, there is no need for routine monitoring of plasma
concentrations of pregabalin.
Pharmacokinetics in special patient groups
Gender
Clinical trials indicate that gender does not have a clinically significant influence on the plasma
concentrations of pregabalin.
Renal impairment
Pregabalin clearance is directly proportional to creatinine clearance. In addition, pregabalin is
effectively removed from plasma by haemodialysis (following a 4 hour haemodialysis treatment
plasma pregabalin concentrations are reduced by approximately 50%). Because renal elimination is
the major elimination pathway, dose reduction in patients with renal impairment and dose
supplementation following haemodialysis is necessary (see section 4.2 Table 1).
Hepatic impairment
No specific pharmacokinetic studies were carried out in patients with impaired liver function. Since
pregabalin does not undergo significant metabolism and is excreted predominantly as unchanged drug
in the urine, impaired liver function would not be expected to significantly alter pregabalin plasma
concentrations.
Elderly (over 65 years of age)
Pregabalin clearance tends to decrease with increasing age. This decrease in pregabalin oral clearance
is consistent with decreases in creatinine clearance associated with increasing age. Reduction of
pregabalin dose may be required in patients who have age related compromised renal function (see
section 4.2 Table 1).
5.3 Preclinical safety data
In conventional safety pharmacology studies in animals, pregabalin was well-tolerated at clinically
relevant doses. In repeated dose toxicity studies in rats and monkeys CNS effects were observed,
including hypoactivity, hyperactivity and ataxia. An increased incidence of retinal atrophy commonly
11
observed in aged albino rats was seen after long term exposure to pregabalin at exposures≥ 5 times the
mean human exposure at the maximum recommended clinical dose.
Pregabalin was not teratogenic in mice, rats or rabbits. Foetal toxicity in rats and rabbits occurred only
at exposures sufficiently above human exposure. In prenatal/postnatal toxicity studies, pregabalin
induced offspring developmental toxicity in rats at exposures >2 times the maximum recommended
human exposure.
Adverse effects on fertility in male and female rats were only observed at exposures sufficiently in
excess of therapeutic exposure. Adverse effects on male reproductive organs and sperm parameters
were reversible and occurred only at exposures sufficiently in excess of therapeutic exposure or were
associated with spontaneous degenerative processes in male reproductive organs in the rat. Therefore
the effects were considered of little or no clinical relevance.
Pregabalin is not genotoxic based on results of a battery of
in vitro
and
in vivo
tests.
Two-year carcinogenicity studies with pregabalin were conducted in rats and mice. No tumours were
observed in rats at exposures up to 24 times the mean human exposure at the maximum recommended
clinical dose of 600 mg/day. In mice, no increased incidence of tumours was found at exposures
similar to the mean human exposure, but an increased incidence of haemangiosarcoma was observed
at higher exposures. The non-genotoxic mechanism of pregabalin-induced tumour formation in mice
involves platelet changes and associated endothelial cell proliferation. These platelet changes were not
present in rats or in humans based on short term and limited long term clinical data. There is no
evidence to suggest an associated risk to humans.
In juvenile rats the types of toxicity do not differ qualitatively from those observed in adult rats.
However, juvenile rats are more sensitive. At therapeutic exposures, there was evidence of CNS
clinical signs of hyperactivity and bruxism and some changes in growth (transient body weight gain
suppression). Effects on the oestrus cycle were observed at 5-fold the human therapeutic exposure.
Reduced acoustic startle response was observed in juvenile rats 1-2 weeks after exposure at >2 times
the human therapeutic exposure. Nine weeks after exposure, this effect was no longer observable.
6.
6.1 List of excipients
Capsule content
:
Lactose monohydrate
Maize starch
Talc
Capsule shell
:
Gelatin
Titanium Dioxide (E171)
Sodium Laurilsulphate
Silica, colloidal anhydrous
Purified water
Printing Ink
:
Shellac
Black Iron Oxide (E172)
Propylene Glycol
Potassium Hydroxide
12
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions
6.5 Nature and contents of container
PVC/Aluminium blisters containing 14, 21, 56, 84, 100 or 112 (2 x 56) hard capsules.
100 x 1 hard capsules in PVC/Aluminium perforated unit dose blisters.
Not all pack sizes may be marketed
6.6 Special precautions for disposal and other handling
No special requirements for disposal.
7.
Pfizer Limited,
Ramsgate Road,
Sandwich,
Kent
CT13 9NJ
UK
8.
EU/1/04/279/001-005
EU/1/04/279/026
EU/1/04/279/036
9.
Date of first authorisation: 06 July 2004
Date of last renewal: 06 July 2009
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu/
13
1.
LYRICA 50 mg hard capsules
2.
Each hard capsule contains 50 mg of pregabalin.
Excipients
:
Each hard capsule also contains 70 mg lactose monohydrate.
For a full list of excipients, see section 6.1.
3.
Hard capsule
White, marked “Pfizer” on the cap and “PGN 50” on the body with black ink. The body is also
marked with a black band.
4.
Neuropathic pai
n
Lyrica is indicated for the treatment of peripheral and central neuropathic pain in adults.
Epilepsy
Lyrica is indicated as adjunctive therapy in adults with partial seizures with or without secondary
generalisation.
Generalised Anxiety Disorder
LYRICA is indicated for the treatment of Generalised Anxiety Disorder (GAD) in adults.
Posology
The dose range is 150 to 600 mg per day given in either two or three divided doses.
Neuropathic pain
Pregabalin treatment can be started at a dose of 150 mg per day given as two or three divided doses.
Based on individual patient response and tolerability, the dose may be increased to 300 mg per day
after an interval of 3 to 7 days, and if needed, to a maximum dose of 600 mg per day after an
additional 7-day interval.
Epilepsy
Pregabalin treatment can be started with a dose of 150 mg per day given as two or three divided doses.
Based on individual patient response and tolerability, the dose may be increased to 300 mg per day
after 1 week. The maximum dose of 600 mg per day may be achieved after an additional week.
14
Generalised Anxiety Disorder
The dose range is 150 to 600 mg per day given as two or three divided doses. The need for treatment
should be reassessed regularly.
Pregabalin treatment can be started with a dose of 150 mg per day. Based on individual patient
response and tolerability, the dose may be increased to 300 mg per day after 1 week. Following an
additional week the dose may be increased to 450 mg per day. The maximum dose of 600 mg per day
may be achieved after an additional week.
Discontinuation of pregabalin
In accordance with current clinical practice, if pregabalin has to be discontinued, it is recommended
this should be done gradually over a minimum of 1 week independent of the indication (see sections
4.4 and 4.8).
Special populations
Patients with renal impairment
Pregabalin is eliminated from the systemic circulation primarily by renal excretion as unchanged drug.
As pregabalin clearance is directly proportional to creatinine clearance (see section 5.2), dose
reduction in patients with compromised renal function must be individualised according to creatinine
clearance (CLcr), as indicated in Table 1 determined using the following formula:
CL
(ml/min)
1
23
140
-
age
(years)
x
weight
(kg)
(
x
0.85
for
female
patients)
cr
serum
creatinine
(
mol/l)
Pregabalin is removed effectively from plasma by haemodialysis (50% of drug in 4 hours). For
patients receiving haemodialysis, the pregabalin daily dose should be adjusted based on renal function.
In addition to the daily dose, a supplementary dose should be given immediately following every 4-
hour haemodialysis treatment (see Table 1).
Table 1. Pregabalin dose adjustment based on renal function
Creatinine
clearance (CL
cr
)
(mL/min)
Total pregabalin daily dose *
Dose regimen
Starting dose
(mg/day)
Maximum dose
(mg/day)
≥ 60
150
600
BID or TID
≥30 - <60
75
300
BID or TID
≥15 - <30
25 – 50
150
Once Daily or BID
< 15
25
75
Once Daily
Supplementary dosage following haemodialysis (mg)
25
100
Single dose
+
TID = Three divided doses
BID = Two divided doses
* Total daily dose (mg/day) should be divided as indicated by dose regimen to provide mg/dose
+
Supplementary dose is a single additional dose
Use in patients with hepatic impairment
No dose adjustment is required for patients with hepatic impairment (see section 5.2).
15
.
Paediatric population
The safety and efficacy of Lyrica in children below the age of 12 years and in adolescents (12-17 years
of age) have not been established. No data are available.
Use in the elderly (over 65 years of age)
Elderly patients may require a dose reduction of pregabalin due to a decreased renal function (see
patients with renal impairment).
Method of administration
Lyrica may be taken with or without food/
LYRICA is for oral use only.
Hypersensitivity to the active substance or to any of the excipients.
Diabetic patients
In accordance with current clinical practice, some diabetic patients who gain weight on pregabalin
treatment may need to adjust hypoglycaemic medicinal products.
Hypersensitivity reactions
There have been reports in the postmarketing experience of hypersensitivity reactions, including cases
of angioedema. Pregabalin should be discontinued immediately if symptoms of angioedema, such as
facial, perioral, or upper airway swelling occur.
Dizziness, somnolence, loss of consciousness, confusion and mental impairment
Pregabalin treatment has been associated with dizziness and somnolence, which could increase the
occurrence of accidental injury (fall) in the elderly population. There have also been post-marketing
reports of loss of consciousness, confusion and mental impairment. Therefore, patients should be
advised to exercise caution until they are familiar with the potential effects of themedicinal products.
Vision-related effects
In controlled trials, a higher proportion of patients treated with pregabalin reported blurred vision than
did patients treated with placebo which resolved in a majority of cases with continued dosing. In the
clinical studies where ophthalmologic testing was conducted, the incidence of visual acuity reduction
and visual field changes was greater in pregabalin-treated patients than in placebo-treated patients; the
incidence of fundoscopic changes was greater in placebo-treated patients (see section 5.1).
In the post-marketing experience, visual adverse reactions have also been reported, including loss of
vision, visual blurring or other changes of visual acuity, many of which were transient.
Discontinuation of pregabalin may result in resolution or improvement of these visual symptoms.
Renal failure
Cases of renal failure have been reported and in some cases discontinuation of pregabalin did show
reversibility of this adverse reaction.
Withdrawal of concomitant antiepileptic medicinal products
There are insufficient data for the withdrawal of concomitant antiepileptic medicinal products, once
seizure control with pregabalin in the add-on situation has been reached, in order to reach
monotherapy on pregabalin.
Withdrawal symptoms
After discontinuation of short-term and long-term treatment with pregabalin withdrawal symptoms
have been observed in some patients. The following events have been mentioned: insomnia, headache,
16
nausea, anxiety, diarrhoea, flu syndrome, nervousness, depression, pain
,
convulsion, hyperhidrosis and
dizziness. The patient should be informed about this at the start of the treatment.
Convulsions, including status epilepticus and grand mal convulsions, may occur during pregabalin use
or shortly after discontinuing pregabalin.
Concerning discontinuation of long-term treatment of pregabalin there are no data of the incidence and
severity of withdrawal symptoms in relation to duration of use and dose of pregabalin.
Congestive heart failure
There have been post-marketing reports of congestive heart failure in some patients receiving
pregabalin. These reactions are mostly seen in elderly cardiovascular compromised patients during
pregabalin treatment for a neuropathic indication. Pregabalin should be used with caution in these
patients. Discontinuation of pregabalin may resolve the reaction.
Treatment of central neuropathic pain due to spinal cord injury
In the treatment of central neuropathic pain due to spinal cord injury the incidence of adverse reactions
in general, central nervous system adverse reactions and especially somnolence was increased. This
may be attributed to an additive effect due to concomitant medicinal products (e.g. anti-spasticity
agents) needed for this condition. This should be considered when prescribing pregabalin in this
condition.
Suicidal ideation and behaviour
Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents in
several indications. A meta-analysis of randomised placebo controlled studies of anti-epileptic drugs
has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is
not known and the available data do not exclude the possibility of an increased risk for pregabalin.
Therefore patients should be monitored for signs of suicidal ideation and behaviours and appropriate
treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical
advice should signs of suicidal ideation or behaviour emerge.
Reduced lower gastrointestinal tract function
There are post-marketing reports of events related to reduced lower gastrointestinal tract function
(e.g., intestinal obstruction, paralytic ileus, constipation) when pregabalin was co-administered with
medications that have the potential to produce constipation, such as opioid analgesics. When
pregabalin and opioids will be used in combination, measures to prevent constipation may be
considered (especially in female patients and elderly
Abuse potential
Cases of abuse have been reported. Caution should be exercised in patients with a history of substance
abuse and the patient should be monitored for symptoms of pregabalin abuse.
Encephalopathy
Cases of encephalopathy have been reported, mostly in patients with underlying conditions that may
precipitate encephalopathy.
Lactose intolerance
Lyrica contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance,
the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Since pregabalin is predominantly 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, it is unlikely to produce, or be subject to,
pharmacokinetic interactions.
17
In vivo studies and population pharmacokinetic analysis
Accordingly, in
in vivo
studies no clinically relevant pharmacokinetic interactions were observed
between pregabalin and phenytoin, carbamazepine, valproic acid, lamotrigine, gabapentin, lorazepam,
oxycodone or ethanol. Population pharmacokinetic analysis indicated that oral antidiabetics, diuretics,
insulin, phenobarbital, tiagabine and topiramate had no clinically significant effect on pregabalin
clearance.
Oral contraceptives, norethisterone and/or ethinyl oestradiol
Co-administration of pregabalin with the oral contraceptives norethisterone and/or ethinyl oestradiol
does not influence the steady-state pharmacokinetics of either substance.
Ethanol, lorazepam, oxycodone
Pregabalin may potentiate the effects of ethanol and lorazepam. In controlled clinical trials, multiple
oral doses of pregabalin co-administered with oxycodone, lorazepam, or ethanol did not result in
clinically important effects on respiration. In the postmarketing experience, there are reports of
respiratory failure and coma in patients taking pregabalin and other CNS depressant medicinal
products. Pregabalin appears to be additive in the impairment of cognitive and gross motor function
caused by oxycodone.
Interactions and the elderly
No specific pharmacodynamic interaction studies were conducted in elderly volunteers. Interaction
studies have only been performed in adults.
Women of childbearing potential / Contraception in males and females
As the potential risk for humans is unknown, effective contraception must be used in women of child
bearing potential.
Pregnancy
There are no adequate data from the use of pregabalin in pregnant women.
Studies in animals have
shown reproductive toxicity (see 5.3). The potential risk for humans is
unknown.
Lyrica should not be used during pregnancy unless clearly necessary (if the benefit to the mother
clearly outweighs the potential risk to the foetus).
Breast-feeding
It is not known if pregabalin is excreted in the breast milk of humans; however, it is present in the milk
of rats. Therefore, breast-feeding is not recommended during treatment with pregabalin.
Fertility
There are no clinical data on the effects of pregabalin on female fertility.
In a clinical trial to assess the effect of pregabalin on sperm motility, healthy male subjects were
exposed to pregabalin at a dose of 600 mg/day. After 3 months of treatment, there were no effects on
sperm motility.
A fertility study in female rats has shown adverse reproductive effects. Fertility studies in male rats
have shown adverse reproductive and developmental effects. The clinical relevance of these findings
is unknown (see section 5.3).
Lyrica may have minor or moderate influence on the ability to drive and use machines. Lyrica may
cause dizziness and somnolence and therefore may influence the ability to drive or use machines.
18
Patients are advised not to drive, operate complex machinery or engage in other potentially hazardous
activities until it is known whether this medicinal product affects their ability to perform these
activities.
The pregabalin clinical programme involved over 8900 patients who were exposed to pregabalin, of
whom over 5600 were in double-blind placebo controlled trials. The most commonly reported adverse
reactions were dizziness and somnolence. Adverse reactions were usually mild to moderate in
intensity. In all controlled studies, the discontinuation rate due to adverse reactions was 12% for
patients receiving pregabalin and 5% for patients receiving placebo. The most common adverse
reactions resulting in discontinuation from pregabalin treatment groups were dizziness and
somnolence.
In the table below all adverse reactions, which occurred at an incidence greater than placebo and in
more than one patient, are listed by class and frequency (very common (≥1/10); common (≥1/100 to
≤1/10); uncommon (≥1/1,000 to ≤1/100); rare (≥1/10,000 to ≤1/1,000); very rare (≤1/10,000), not
known (cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
The adverse reactions listed may also be associated with the underlying disease and / or concomitant
medicinal products.
In the treatment of central neuropathic pain due to spinal cord injury the incidence of adverse reactions
in general, CNS adverse reactions and especially somnolence was increased (See 4.4).
Additional reactions reported from post-marketing experience are included as Frequency not known in
italics in the list below.
System Organ Class
Adverse drug reactions
Infections and infestations
Uncommon Nasopharyngitis
Blood and lymphatic system disorders
Rare
Neutropenia
Immune system disorders
Frequency not known
Hypersensitivity,
angioedema, allergic reaction
Metabolism and nutrition disorders
Common
Uncommon
Anorexia, hypoglycaemia
Psychiatric disorders
Common
Euphoric mood, confusion, irritability, libido decreased,
disorientation, insomnia
Uncommon
Hallucination, panic attack, restlessness, agitation, depression,
depressed mood, mood swings, depersonalisation, word finding
difficulty, abnormal dreams, libido increased, anorgasmia, apathy
Frequency not known
Disinhibition, elevated mood
Nervous system disorders
Very Common
Common
Ataxia, coordination abnormal, tremor, dysarthria, memory
impairment, disturbance in attention, paraesthesia, sedation, balance
disorder, lethargy
Uncommon
Syncope, stupor, myoclonus, psychomotor hyperactivity, ageusia,
dyskinesia, dizziness postural, intention tremor, nystagmus,
cognitive disorder, speech disorder, hyporeflexia, hypoaesthesia,
amnesia, hyperaesthesia, burning sensation
Rare
Hypokinesia, parosmia, dysgraphia
19
Appetite increased
Rare
Aggression
Dizziness, somnolence
Frequency not known
Loss of consciousness
,
mental impairment, convulsions, headache,
malaise
Eye disorders
Common
Vision blurred, diplopia
Uncommon
Visual disturbance, eye swelling, visual field defect, visual acuity
reduced, eye pain, asthenopia, dry eye, lacrimation increased
Rare
Peripheral vision loss, oscillopsia, altered visual depth perception,
photopsia, eye irritation, mydriasis, strabismus, visual brightness
Frequency not known
Vision loss
,
keratitis
Ear and labyrinth disorders
Common
Uncommon
Hyperacusis
Cardiac disorders
Uncommon
Rare
Sinus tachycardia, sinus bradycardia, sinus arrhythmia,
Frequency not known
Congestive heart failure, QT prolongation
Vascular disorders
Uncommon Flushing, hot flushes, hypotension, hypertension
Rare Peripheral coldness,
Respiratory, thoracic and mediastinal disorders
Uncommon
Dyspnoea, nasal dryness
Frequency not known
Epistaxis, throat tightness, cough, nasal congestion, rhinitis, snoring
Gastrointestinal disorders
Common Vomiting, dry mouth, constipation, flatulence
Uncommon Abdominal distension, gastrooesophageal reflux disease, salivary
hypersecretion, hypoaesthesia oral
Rare Ascites, pancreatitis, dysphagia
Frequency not known
Swollen tongue
,
diarrhoea, nausea
Skin and subcutaneous tissue disorders
Uncommon Rash papular, hyperhidrosis
Rare Urticaria, cold sweat
Frequency not known
Stevens Johnson syndrome
,
pruritus
Musculoskeletal and connective tissue disorders
Uncommon Muscle twitching, joint swelling, muscle cramp, myalgia, arthralgia,
back pain, pain in limb, muscle stiffness
Rare Rhabdomyolysis, cervical spasm, neck pain
Renal and urinary disorders
Uncommon Urinary incontinence, dysuria
Rare Renal failure, oliguria
Frequency not known
Urinary retention
Reproductive system and breast disorders
Common Erectile dysfunction
Uncommon Ejaculation delayed, sexual dysfunction
Rare Amenorrhoea, breast discharge, breast pain, dysmenorrhoea,
hypertrophy breast
General disorders and administration site conditions
Common
Uncommon
Gait abnormal, feeling drunk, fatigue, oedema peripheral, oedema
Rare
Generalised oedema,pyrexia
Frequency not known
Face oedema
Investigations
Common
Uncommon
Blood creatine phosphokinase increased, alanine aminotransferase
increased, aspartate aminotransferase increased, platelet count
decreased
20
Vertigo
Tachycardia, atrioventricular block first degree
Rare
Pulmonary oedema
Fall, chest tightness, asthenia, thirst, pain, feeling abnormal, chills
Weight increased
Rare
Blood glucose increased, blood potassium decreased, white blood
cell count decreased, blood creatinine increased, weight decreased
After discontinuation of short-term and long-term treatment with pregabalin withdrawal symptoms
have been observed in some patients. The following reactions have been mentioned: insomnia,
headache, nausea, anxiety, diarrhoea, flu syndrome, convulsions, nervousness, depression, pain
,
hyperhidrosis and dizziness. The patient should be informed about this at the start of the treatment.
Concerning discontinuation of long-term treatment of pregabalin there are no data of the incidence and
severity of withdrawal symptoms in relation to duration of use and dose of pregabalin.
In overdoses up to 15 g, no unexpected adverse reactions were reported.
In the post-marketing experience, the most commonly reported adverse reactions observed when
pregabalin was taken in overdose included somnolence, confusional state, agitation, and restlessness.
Treatment of pregabalin overdose should include general supportive measures and may include
haemodialysis if necessary (see section 4.2 Table 1).
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antiepileptics, other antiepileptics ATC code: N03AX16
The active substance, pregabalin, is a gamma-aminobutyric acid analogue ((S)-3-(aminomethyl)-5-
methylhexanoic acid).
Mechanism of action
Pregabalin binds to an auxiliary subunit (
2
- protein) of voltage-gated calcium channels in the central
nervous system, potently displacing [
3
H]-gabapentin.
Clinical experience
Neuropathic pain
Efficacy has been shown in trials in diabetic neuropathy,post herpetic neuralgia and spinal cord injury.
Efficacy has not been studied in other models of neuropathic pain.
Pregabalin has been studied in 10 controlled clinical trials of up to 13 weeks with twice a day dosing
(BID) and up to 8 weeks with three times a day (TID) dosing. Overall, the safety and efficacy profiles
for BID and TID dosing regimens were similar.
In clinical trials up to 12 weeks for both peripheral and central neuropathic pain, a reduction in pain
was seen by week 1 and was maintained throughout the treatment period.
In controlled clinical trials in peripheral neuropathic pain 35% of the pregabalin treated patients and
18% of the patients on placebo had a 50% improvement in pain score. For patients not experiencing
somnolence, such an improvement was observed in 33% of patients treated with pregabalin and 18%
of patients on placebo. For patients who experienced somnolence the responder rates were 48% on
pregabalin and 16% on placebo.
21
In the controlled clinical trial in central neuropathic pain 22% of the Pregabalin treated patients and
7% of the patients on placebo had a 50% improvement in pain score.
Epilepsy
Pregabalin has been studied in 3 controlled clinical trials of 12 week duration with either twice a day
dosing (BID) or three times a day (TID) dosing. Overall, the safety and efficacy profiles for BID and
TID dosing regimens were similar.
A reduction in seizure frequency was observed by Week 1.
Generalised Anxiety Disorder
Pregabalin has been studied in 6 controlled trials of 4-6 week duration, an elderly study of 8 week
duration and a long-term relapse prevention study with a double blind relapse prevention phase of 6
months duration.
Relief of the symptoms of GAD as reflected by the Hamilton Anxiety Rating Scale (HAM-A) was
observed by Week 1
In controlled clinical trials (4-8 week duration) 52% of the pregabalin treated patients and 38% of the
patients on placebo had at least a 50% improvement in HAM-A total score from baseline to endpoint.
In controlled trials, a higher proportion of patients treated with pregabalin reported blurred vision than
did patients treated with placebo which resolved in a majority of cases with continued dosing.
Ophthamologic testing (including visual acuity testing, formal visual field testing and dilated
funduscopic examination) was conducted in over 3600 patients within controlled clinical trials. In
these patients, visual acuity was reduced in 6.5% of patients treated with pregabalin, and 4.8% of
placebo-treated patients. Visual field changes were detected in 12.4% of pregabalin-treated, and 11.7%
of placebo-treated patients. Funduscopic changes were observed in 1.7% of pregabalin-treated and
2.1% of placebo-treated patients.
5.2 Pharmacokinetic properties
Pregabalin steady-state pharmacokinetics are similar in healthy volunteers, patients with epilepsy
receiving anti-epileptic drugs and patients with chronic pain.
Absorption
:
Pregabalin is rapidly absorbed when administered in the fasted state, with peak plasma concentrations
occurring within 1 hour
following both single and multiple dose administration. Pregabalin oral
bioavailability is estimated to be 90% and is independent of dose. Following repeated
administration, steady state is achieved within 24 to 48 hours. The rate of pregabalin absorption is
decreased when given with food resulting in a decrease in C
max
by approximately 25-30% and a delay
in t
max
to approximately 2.5 hours. However, administration of pregabalin with food has no clinically
significant effect on the extent of pregabalin absorption.
Distribution:
In preclinical studies, pregabalin has been shown to cross the blood brain barrier in mice, rats, and
monkeys. Pregabalin has been shown to cross the placenta in rats and is present in the milk of
lactating rats. In humans, the apparent volume of distribution of pregabalin following oral
administration is approximately 0.56 l/kg. Pregabalin is not bound to plasma proteins.
22
Biotransformation
:
Pregabalin undergoes negligible metabolism in humans. Following a dose of radiolabelled pregabalin,
approximately 98% of the radioactivity recovered in the urine was 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, there was no indication of racemisation of pregabalin S-
enantiomer to the R-enantiomer.
Elimination:
Pregabalin is eliminated from the systemic circulation primarily by renal excretion as unchanged drug.
Pregabalin mean elimination half-life is 6.3 hours. Pregabalin plasma clearance and renal clearance
are directly proportional to creatinine clearance (see section 5.2 Renal impairment).
Dose adjustment in patients with reduced renal function or undergoing haemodialysis is necessary (see
Section 4.2 Table 1).
Linearity / non-linearity
:
Pregabalin pharmacokinetics are linear over the recommended daily dose range. Inter-subject
pharmacokinetic variability for pregabalin is low (<20%). Multiple dose pharmacokinetics are
predictable from single-dose data. Therefore, there is no need for routine monitoring of plasma
concentrations of pregabalin.
Pharmacokinetics in special patient groups
Gender
Clinical trials indicate that gender does not have a clinically significant influence on the plasma
concentrations of pregabalin.
Renal impairment
Pregabalin clearance is directly proportional to creatinine clearance. In addition, pregabalin is
effectively removed from plasma by haemodialysis (following a 4 hour haemodialysis treatment
plasma pregabalin concentrations are reduced by approximately 50%). Because renal elimination is
the major elimination pathway, dose reduction in patients with renal impairment and dose
supplementation following haemodialysis is necessary (see section 4.2 Table 1).
Hepatic impairment
No specific pharmacokinetic studies were carried out in patients with impaired liver function. Since
pregabalin does not undergo significant metabolism and is excreted predominantly as unchanged drug
in the urine, impaired liver function would not be expected to significantly alter pregabalin plasma
concentrations.
Elderly (over 65 years of age)
Pregabalin clearance tends to decrease with increasing age. This decrease in pregabalin oral clearance
is consistent with decreases in creatinine clearance associated with increasing age. Reduction of
pregabalin dose may be required in patients who have age related compromised renal function (see
section 4.2 Table 1).
5.3 Preclinical safety data
In conventional safety pharmacology studies in animals, pregabalin was well-tolerated at clinically
relevant doses. In repeated dose toxicity studies in rats and monkeys CNS effects were observed,
including hypoactivity, hyperactivity and ataxia. An increased incidence of retinal atrophy commonly
23
observed in aged albino rats was seen after long term exposure to pregabalin at exposures≥ 5 times the
mean human exposure at the maximum recommended clinical dose.
Pregabalin was not teratogenic in mice, rats or rabbits. Foetal toxicity in rats and rabbits occurred only
at exposures sufficiently above human exposure. In prenatal/postnatal toxicity studies, pregabalin
induced offspring developmental toxicity in rats at exposures >2 times the maximum recommended
human exposure.
Adverse effects on fertility in male and female rats were only observed at exposures sufficiently in
excess of therapeutic exposure. Adverse effects on male reproductive organs and sperm parameters
were reversible and occurred only at exposures sufficiently in excess of therapeutic exposure or were
associated with spontaneous degenerative processes in male reproductive organs in the rat. Therefore
the effects were considered of little or no clinical relevance.
Pregabalin is not genotoxic based on results of a battery of
in vitro
and
in vivo
tests.
Two-year carcinogenicity studies with pregabalin were conducted in rats and mice. No tumours were
observed in rats at exposures up to 24 times the mean human exposure at the maximum recommended
clinical dose of 600 mg/day. In mice, no increased incidence of tumours was found at exposures
similar to the mean human exposure, but an increased incidence of haemangiosarcoma was observed
at higher exposures. The non-genotoxic mechanism of pregabalin-induced tumour formation in mice
involves platelet changes and associated endothelial cell proliferation. These platelet changes were not
present in rats or in humans based on short term and limited long term clinical data. There is no
evidence to suggest an associated risk to humans.
In juvenile rats the types of toxicity do not differ qualitatively from those observed in adult rats.
However, juvenile rats are more sensitive. At therapeutic exposures, there was evidence of CNS
clinical signs of hyperactivity and bruxism and some changes in growth (transient body weight gain
suppression). Effects on the oestrus cycle were observed at 5-fold the human therapeutic exposure.
Reduced acoustic startle response was observed in juvenile rats 1-2 weeks after exposure at >2 times
the human therapeutic exposure. Nine weeks after exposure, this effect was no longer observable.
6.
6.1 List of excipients
Capsule content
:
Lactose monohydrate
Maize starch
Talc
Capsule shell
:
Gelatin
Titanium Dioxide (E171)
Sodium Laurilsulphate
Silica, colloidal anhydrous
Purified water
Printing Ink
:
Shellac
Black Iron Oxide (E172)
Propylene Glycol
Potassium Hydroxide
24
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions
6.5 Nature and contents of container
PVC/Aluminium blisters containing 14, 21, 56, 84, or 100 hard capsules.
100 x 1 hard capsules in PVC/Aluminium perforated unit dose blisters.
Not all pack sizes may be marketed
6.6 Special precautions for disposal and other handling
No special requirements for disposal.
7.
Pfizer Limited,
Ramsgate Road,
Sandwich,
Kent
CT13 9NJ
UK
8.
EU/1/04/279/006-010
EU/1/04/279/037
9.
Date of first authorisation: 06 July 2004
Date of last renewal: 06 July 2009
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu/
25
1.
LYRICA 75 mg hard capsules
2.
Each hard capsule contains 75 mg of pregabalin.
Excipients
:
Each hard capsule also contains 8.25 mg lactose monohydrate.
For a full list of excipients, see section 6.1.
3.
Hard capsule
White and orange, marked “Pfizer” on the cap and “PGN 75” on the body with black ink.
4.
Neuropathic pain
Lyrica is indicated for the treatment of peripheral and central neuropathic pain in adults.
Epilepsy
Lyrica is indicated as adjunctive therapy in adults with partial seizures with or without secondary
generalisation.
Generalised Anxiety Disorder
LYRICA is indicated for the treatment of Generalised Anxiety Disorder (GAD) in adults.
Posology
The dose range is 150 to 600 mg per day given in either two or three divided doses.
Neuropathic pain
Pregabalin treatment can be started at a dose of 150 mg per day given as two or three divided doses.
Based on individual patient response and tolerability, the dose may be increased to 300 mg per day
after an interval of 3 to 7 days, and if needed, to a maximum dose of 600 mg per day after an
additional 7-day interval.
Epilepsy
Pregabalin treatment can be started with a dose of 150 mg per day given as two or three divided doses.
Based on individual patient response and tolerability, the dose may be increased to 300 mg per day
after 1 week. The maximum dose of 600 mg per day may be achieved after an additional week.
26
Generalised Anxiety Disorder
The dose range is 150 to 600 mg per day given as two or three divided doses. The need for treatment
should be reassessed regularly.
Pregabalin treatment can be started with a dose of 150 mg per day. Based on individual patient
response and tolerability, the dose may be increased to 300 mg per day after 1 week. Following an
additional week the dose may be increased to 450 mg per day. The maximum dose of 600 mg per day
may be achieved after an additional week.
Discontinuation of pregabalin
In accordance with current clinical practice, if pregabalin has to be discontinued, it is recommended
this should be done gradually over a minimum of 1 week independent of the indication (see sections
4.4 and 4.8).
Special populations
Patients with renal impairment
Pregabalin is eliminated from the systemic circulation primarily by renal excretion as unchanged drug.
As pregabalin clearance is directly proportional to creatinine clearance (see section 5.2), dose
reduction in patients with compromised renal function must be individualised according to creatinine
clearance (CLcr), as indicated in Table 1 determined using the following formula:
1
23
140
-
age
(years)
x
weight
(kg)
CL
(ml/min)
(
x
0.85
for
female
patients)
cr
serum
creatinine
(
mol/l)
Pregabalin is removed effectively from plasma by haemodialysis (50% of drug in 4 hours). For
patients receiving haemodialysis, the pregabalin daily dose should be adjusted based on renal function.
In addition to the daily dose, a supplementary dose should be given immediately following every 4-
hour haemodialysis treatment (see Table 1).
Table 1. Pregabalin dose adjustment based on renal function
Creatinine
clearance (CL
cr
)
(mL/min)
Total pregabalin daily dose *
Dose regimen
Starting dose
(mg/day)
Maximum dose
(mg/day)
≥ 60
150
600
BID or TID
≥30 - <60
75
300
BID or TID
≥15 - <30
25 – 50
150
Once Daily or BID
< 15
25
75
Once Daily
Supplementary dosage following haemodialysis (mg)
25
100
Single dose
+
TID = Three divided doses
BID = Two divided doses
* Total daily dose (mg/day) should be divided as indicated by dose regimen to provide mg/dose
+
Supplementary dose is a single additional dose
Use in patients with hepatic impairment
No dose adjustment is required for patients with hepatic impairment (see section 5.2).
27
.
Paediatric poulation
The safety and efficacy of Lyrica in children below the age of 12 years and in adolescents (12-17 years
of age) have not been established. No data are available.
Use in the elderly (over 65 years of age)
Elderly patients may require a dose reduction of pregabalin due to a decreased renal function (see
patients with renal impairment).
Method of administration
Lyrica may be taken with or without food.
LYRICA is for oral use only.
Hypersensitivity to the active substance or to any of the excipients.
Diabetic patients
In accordance with current clinical practice, some diabetic patients who gain weight on pregabalin
treatment may need to adjust hypoglycaemic medicinal products.
Hypersensitivity reactions
There have been reports in the postmarketing experience of hypersensitivity reactions, including cases
of angioedema. Pregabalin should be discontinued immediately if symptoms of angioedema, such as
facial, perioral, or upper airway swelling occur.
Dizziness, somnolence, loss of consciousness, confusion and mental impairment
Pregabalin treatment has been associated with dizziness and somnolence, which could increase the
occurrence of accidental injury (fall) in the elderly population. There have also been post-marketing
reports of loss of consciousness, confusion and mental impairment. Therefore, patients should be
advised to exercise caution until they are familiar with the potential effects of the medicinal product.
Vision-related effects
In controlled trials, a higher proportion of patients treated with pregabalin reported blurred vision than
did patients treated with placebo which resolved in a majority of cases with continued dosing. In the
clinical studies where ophthalmologic testing was conducted, the incidence of visual acuity reduction
and visual field changes was greater in pregabalin-treated patients than in placebo-treated patients; the
incidence of fundoscopic changes was greater in placebo-treated patients (see section 5.1).
In the post-marketing experience, visual adverse reactions have also been reported, including loss of
vision, visual blurring or other changes of visual acuity, many of which were transient.
Discontinuation of pregabalin may result in resolution or improvement of these visual symptoms.
Renal failure
Cases of renal failure have been reported and in some cases discontinuation of pregabalin did show
reversibility of this adverse reaction.
Withdrawal of concomitant antiepileptic medicinal products
There are insufficient data for the withdrawal of concomitant antiepileptic medicinal products, once
seizure control with pregabalin in the add-on situation has been reached, in order to reach
monotherapy on pregabalin.
Withdrawal symptoms
After discontinuation of short-term and long-term treatment with pregabalin withdrawal symptoms
have been observed in some patients. The following events have been mentioned: insomnia, headache,
28
nausea, anxiety, diarrhoea, flu syndrome, nervousness, depression, pain
,
convulsion, hyperhidrosis and
dizziness. The patient should be informed about this at the start of the treatment.
Convulsions, including status epilepticus and grand mal convulsions, may occur during pregabalin use
or shortly after discontinuing pregabalin.
Concerning discontinuation of long-term treatment of pregabalin there are no data of the incidence and
severity of withdrawal symptoms in relation to duration of use and dose of pregabalin.
Congestive heart failure
There have been post-marketing reports of congestive heart failure in some patients receiving
pregabalin. These reactions are mostly seen in elderly cardiovascular compromised patients during
pregabalin treatment for a neuropathic indication. Pregabalin should be used with caution in these
patients. Discontinuation of pregabalin may resolve the reaction.
Treatment of central neuropathic pain due to spinal cord injury
In the treatment of central neuropathic pain due to spinal cord injury the incidence of adverse reactions
in general, central nervous system adverse reactions and especially somnolence was increased. This
may be attributed to an additive effect due to concomitant medicinal products (e.g. anti-spasticity
agents) needed for this condition. This should be considered when prescribing pregabalin in this
condition.
Suicidal ideation and behaviour
Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents in
several indications. A meta-analysis of randomised placebo controlled studies of anti-epileptic drugs
has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is
not known and the available data do not exclude the possibility of an increased risk for pregabalin.
Therefore patients should be monitored for signs of suicidal ideation and behaviours and appropriate
treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical
advice should signs of suicidal ideation or behaviour emerge.
Reduced lower gastrointestinal tract function
There are post-marketing reports of events related to reduced lower gastrointestinal tract function
(e.g., intestinal obstruction, paralytic ileus, constipation) when pregabalin was co-administered with
medications that have the potential to produce constipation, such as opioid analgesics. When
pregabalin and opioids will be used in combination, measures to prevent constipation may be
considered (especially in female patients and elderly
Abuse potential
Cases of abuse have been reported. Caution should be exercised in patients with a history of substance
abuse and the patient should be monitored for symptoms of pregabalin abuse.
Encephalopathy
Cases of encephalopathy have been reported, mostly in patients with underlying conditions that may
precipitate encephalopathy.
Lactose intolerance
Lyrica contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance,
the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Since pregabalin is predominantly 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, it is unlikely to produce, or be subject to,
pharmacokinetic interactions.
29
In vivo studies and population pharmacokinetic analysis
Accordingly, in
in vivo
studies no clinically relevant pharmacokinetic interactions were observed
between pregabalin and phenytoin, carbamazepine, valproic acid, lamotrigine, gabapentin, lorazepam,
oxycodone or ethanol. Population pharmacokinetic analysis indicated that oral antidiabetics, diuretics,
insulin, phenobarbital, tiagabine and topiramate had no clinically significant effect on pregabalin
clearance.
Oral contraceptives, norethisterone and/or ethinyl oestradiol
Co-administration of pregabalin with the oral contraceptives norethisterone and/or ethinyl oestradiol
does not influence the steady-state pharmacokinetics of either substance.
Ethanol, lorazepam, oxycodone
Pregabalin may potentiate the effects of ethanol and lorazepam. In controlled clinical trials, multiple
oral doses of pregabalin co-administered with oxycodone, lorazepam, or ethanol did not result in
clinically important effects on respiration. In the postmarketing experience, there are reports of
respiratory failure and coma in patients taking pregabalin and other CNS depressant medicinal
products. Pregabalin appears to be additive in the impairment of cognitive and gross motor function
caused by oxycodone.
Interactions and the elderly
No specific pharmacodynamic interaction studies were conducted in elderly volunteers. Interaction
studies have only been performed in adults.
Women of childbearing potential / Contraception in males and females
As the potential risk for humans is unknown, effective contraception must be used in women of child
bearing potential.
Pregnancy
There are no adequate data from the use of pregabalin in pregnant women.
Studies in animals have
shown reproductive toxicity (see 5.3). The potential risk for humans is
unknown.
Lyrica should not be used during pregnancy unless clearly necessary (if the benefit to the mother
clearly outweighs the potential risk to the foetus).
Breast-feeding
It is not known if pregabalin is excreted in the breast milk of humans; however, it is present in the milk
of rats. Therefore, breast-feeding is not recommended during treatment with pregabalin.
Fertility
There are no clinical data on the effects of pregabalin on female fertility.
In a clinical trial to assess the effect of pregabalin on sperm motility, healthy male subjects were
exposed to pregabalin at a dose of 600 mg/day. After 3 months of treatment, there were no effects on
sperm motility.
A fertility study in female rats has shown adverse reproductive effects. Fertility studies in male rats
have shown adverse reproductive and developmental effects. The clinical relevance of these findings
is unknown (see section 5.3).
Lyrica may have minor or moderate influence on the ability to drive and use machines. Lyrica may
cause dizziness and somnolence and therefore may influence the ability to drive or use machines.
Patients are advised not to drive, operate complex machinery or engage in other potentially hazardous
30
activities until it is known whether this medicinal product affects their ability to perform these
activities.
The pregabalin clinical programme involved over 8900 patients who were exposed to pregabalin, of
whom over 5600 were in double-blind placebo controlled trials. The most commonly reported adverse
reactions were dizziness and somnolence. Adverse reactions were usually mild to moderate in
intensity. In all controlled studies, the discontinuation rate due to adverse reactions was 12% for
patients receiving pregabalin and 5% for patients receiving placebo. The most common adverse
reactions resulting in discontinuation from pregabalin treatment groups were dizziness and
somnolence.
In the table below all adverse reactions, which occurred at an incidence greater than placebo and in
more than one patient, are listed by class and frequency (very common (≥1/10); common (≥1/100 to
≤1/10); uncommon (≥1/1,000 to ≤1/100); rare (≥1/10,000 to ≤1/1,000); very rare (≤1/10,000), not
known (cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
The adverse reactions listed may also be associated with the underlying disease and / or concomitant
medicinal products.
In the treatment of central neuropathic pain due to spinal cord injury the incidence of adverse reactions
in general, CNS adverse reactions and especially somnolence was increased (See 4.4).
Additional reactions reported from post-marketing experience are included as Frequency not known in
italics in the list below.
System Organ Class
Adverse drug reactions
Infections and infestations
Uncommon Nasopharyngitis
Blood and lymphatic
system disorders
Rare
Neutropenia
Immune system disorders
Frequency not known
Hypersensitivity
,
angioedema, allergic reaction
Metabolism and nutrition disorders
Common
Appetite increased
Uncommon
Anorexia, hypoglycaemia
Psychiatric disorders
Common
Euphoric mood, confusion, irritability, libido decreased,
disorientation, insomnia
Uncommon
Hallucination, panic attack, restlessness, agitation, depression,
depressed mood, mood swings, depersonalisation, word finding
difficulty, abnormal dreams, libido increased, anorgasmia, apathy
Rare
Disinhibition, elevated mood
Frequency not known
Aggression
Nervous system disorders
Very Common
Dizziness, somnolence
Common
Ataxia, coordination abnormal, tremor, dysarthria, memory
impairment, disturbance in attention, paraesthesia, sedation, balance
disorder, lethargy
Uncommon
Syncope, stupor, myoclonus, psychomotor hyperactivity, ageusia,
dyskinesia, dizziness postural, intention tremor, nystagmus,
cognitive disorder, speech disorder, hyporeflexia, hypoaesthesia,
amnesia, hyperaesthesia, burning sensation
Rare
Hypokinesia, parosmia, dysgraphia
31
Frequency not known
Loss of consciousness
,
mental impairment, convulsions, headache,
malaise
Eye disorders
Common
Vision blurred, diplopia
Uncommon
Visual disturbance, eye swelling, visual field defect, visual acuity
reduced, eye pain, asthenopia, dry eye, lacrimation increased
Rare
Peripheral vision loss, oscillopsia, altered visual depth perception,
photopsia, eye irritation, mydriasis, strabismus, visual brightness
Frequency not known
Vision loss
,
keratitis
Ear and labyrinth disorders
Common
Uncommon
Hyperacusis
Cardiac disorders
Uncommon
Rare
Sinus tachycardia, sinus bradycardia, sinus arrhythmia
Frequency not known
Congestive heart failure, QT prolongation
Vascular disorders
Uncommon Flushing, hot flushes, hypotension, hypertension
Rare Peripheral coldness,
Respiratory, thoracic and mediastinal disorders
Uncommon
Dyspnoea, nasal dryness
Frequency not known
Epistaxis, throat tightness, cough, nasal congestion, rhinitis, snoring
Gastrointestinal disorders
Common Vomiting, dry mouth, constipation, flatulence
Uncommon Abdominal distension, gastrooesophageal reflux disease, salivary
hypersecretion, hypoaesthesia oral
Rare Ascites, pancreatitis, dysphagia
Frequency not known
Swollen tongue
,
diarrhoea, nausea
Skin and subcutaneous tissue disorders
Uncommon Rash papular, hyperhidrosis
Rare Urticaria, cold sweat
Frequency not known
Stevens Johnson syndrome
,
pruritus
Musculoskeletal and connective tissue disorders
Uncommon Muscle twitching, joint swelling, muscle cramp, myalgia, arthralgia,
back pain, pain in limb, muscle stiffness
Rare Rhabdomyolysis, cervical spasm, neck pain
Renal and urinary disorders
Uncommon Urinary incontinence, dysuria
Rare Renal failure, oliguria
Frequency not known
Urinary retention
Reproductive system and breast disorders
Common Erectile dysfunction
Uncommon Ejaculation delayed, sexual dysfunction
Rare Amenorrhoea, breast discharge, breast pain, dysmenorrhoea,
hypertrophy breast
General disorders and administration site conditions
Common
Uncommon
Gait abnormal, feeling drunk, fatigue, oedema peripheral, oedema,
Rare
Generalised oedema, pyrexia
Frequency not known
Face oedema
Investigations
Common
Uncommon
Blood creatine phosphokinase increased, alanine aminotransferase
increased, aspartate aminotransferase increased, platelet count
decreased
32
Vertigo
Tachycardia, atrioventricular block first degree
Rare
Pulmonary oedema
Fall, chest tightness, asthenia, thirst, pain, feeling abnormal, chills
Weight increased
Rare
Blood glucose increased, blood potassium decreased, white blood
cell count decreased, blood creatinine increased, weight decreased
After discontinuation of short-term and long-term treatment with pregabalin withdrawal symptoms
have been observed in some patients. The following reactions have been mentioned: insomnia,
headache, nausea, anxiety, diarrhoea, flu syndrome, convulsions, nervousness, depression, pain
,
hyperhidrosis, and dizziness. The patient should be informed about this at the start of the treatment.
Concerning discontinuation of long-term treatment of pregabalin there are no data of the incidence and
severity of withdrawal symptoms in relation to duration of use and dose of pregabalin.
In overdoses up to 15 g, no unexpected adverse reactions were reported.
In the post-marketing experience, the most commonly reported adverse reactions observed when
pregabalin was taken in overdose included somnolence, confusional state, agitation, and restlessness.
Treatment of pregabalin overdose should include general supportive measures and may include
haemodialysis if necessary (see section 4.2 Table 1).
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antiepileptics, other antiepileptics ATC code: N03AX16
The active substance, pregabalin, is a gamma-aminobutyric acid analogue ((S)-3-(aminomethyl)-5-
methylhexanoic acid).
Mechanism of action
Pregabalin binds to an auxiliary subunit (
2
- protein) of voltage-gated calcium channels in the central
nervous system, potently displacing [
3
H]-gabapentin.
Clinical experience
Neuropathic pain
Efficacy has been shown in trials in diabetic neuropathy,post herpetic neuralgia and spinal cord injury.
Efficacy has not been studied in other models of neuropathic pain.
Pregabalin has been studied in 10 controlled clinical trials of up to 13 weeks with twice a day dosing
(BID) and up to 8 weeks with three times a day (TID) dosing. Overall, the safety and efficacy profiles
for BID and TID dosing regimens were similar.
In clinical trials up to 12 weeks for both peripheral and central neuropathic pain, a reduction in pain
was seen by week 1 and was maintained throughout the treatment period.
In controlled clinical trials in peripheral neuropathic pain 35% of the pregabalin treated patients and
18% of the patients on placebo had a 50% improvement in pain score. For patients not experiencing
somnolence, such an improvement was observed in 33% of patients treated with pregabalin and 18%
of patients on placebo. For patients who experienced somnolence the responder rates were 48% on
pregabalin and 16% on placebo.
33
In the controlled clinical trial in central neuropathic pain 22% of the Pregabalin treated patients and
7% of the patients on placebo had a 50% improvement in pain score.
Epilepsy
Pregabalin has been studied in 3 controlled clinical trials of 12 week duration with either twice a day
dosing (BID) or three times a day (TID) dosing. Overall, the safety and efficacy profiles for BID and
TID dosing regimens were similar.
A reduction in seizure frequency was observed by Week 1.
Generalised Anxiety Disorder
Pregabalin has been studied in 6 controlled trials of 4-6 week duration, an elderly study of 8 week
duration and a long-term relapse prevention study with a double blind relapse prevention phase of 6
months duration.
Relief of the symptoms of GAD as reflected by the Hamilton Anxiety Rating Scale (HAM-A) was
observed by Week 1.
In controlled clinical trials (4-8 week duration) 52% of the pregabalin treated patients and 38% of the
patients on placebo had at least a 50% improvement in HAM-A total score from baseline to endpoint.
In controlled trials, a higher proportion of patients treated with pregabalin reported blurred vision than
did patients treated with placebo which resolved in a majority of cases with continued dosing.
Ophthamologic testing (including visual acuity testing, formal visual field testing and dilated
funduscopic examination) was conducted in over 3600 patients within controlled clinical trials. In
these patients, visual acuity was reduced in 6.5% of patients treated with pregabalin, and 4.8% of
placebo-treated patients. Visual field changes were detected in 12.4% of pregabalin-treated, and 11.7%
of placebo-treated patients. Funduscopic changes were observed in 1.7% of pregabalin-treated and
2.1% of placebo-treated patients.
5.2 Pharmacokinetic properties
Pregabalin steady-state pharmacokinetics are similar in healthy volunteers, patients with epilepsy
receiving anti-epileptic drugs and patients with chronic pain.
Absorption:
Pregabalin is rapidly absorbed when administered in the fasted state, with peak plasma concentrations
occurring within 1 hour
following both single and multiple dose administration. Pregabalin oral
bioavailability is estimated to be 90% and is independent of dose. Following repeated
administration, steady state is achieved within 24 to 48 hours. The rate of pregabalin absorption is
decreased when given with food resulting in a decrease in C
max
by approximately 25-30% and a delay
in t
max
to approximately 2.5 hours. However, administration of pregabalin with food has no clinically
significant effect on the extent of pregabalin absorption.
Distribution
:
In preclinical studies, pregabalin has been shown to cross the blood brain barrier in mice, rats, and
monkeys. Pregabalin has been shown to cross the placenta in rats and is present in the milk of
lactating rats. In humans, the apparent volume of distribution of pregabalin following oral
administration is approximately 0.56 l/kg. Pregabalin is not bound to plasma proteins.
34
Biotransformation:
Pregabalin undergoes negligible metabolism in humans. Following a dose of radiolabelled pregabalin,
approximately 98% of the radioactivity recovered in the urine was 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, there was no indication of racemisation of pregabalin S-
enantiomer to the R-enantiomer.
Elimination:
Pregabalin is eliminated from the systemic circulation primarily by renal excretion as unchanged drug.
Pregabalin mean elimination half-life is 6.3 hours. Pregabalin plasma clearance and renal clearance
are directly proportional to creatinine clearance (see section 5.2 Renal impairment).
Dose adjustment in patients with reduced renal function or undergoing haemodialysis is necessary (see
Section 4.2 Table 1).
Linearity / non-linearity:
Pregabalin pharmacokinetics are linear over the recommended daily dose range. Inter-subject
pharmacokinetic variability for pregabalin is low (<20%). Multiple dose pharmacokinetics are
predictable from single-dose data. Therefore, there is no need for routine monitoring of plasma
concentrations of pregabalin.
Pharmacokinetics in special patient group
s
Gender
Clinical trials indicate that gender does not have a clinically significant influence on the plasma
concentrations of pregabalin.
Renal impairment
Pregabalin clearance is directly proportional to creatinine clearance. In addition, pregabalin is
effectively removed from plasma by haemodialysis (following a 4 hour haemodialysis treatment
plasma pregabalin concentrations are reduced by approximately 50%). Because renal elimination is
the major elimination pathway, dose reduction in patients with renal impairment and dose
supplementation following haemodialysis is necessary (see section 4.2 Table 1).
Hepatic impairment
No specific pharmacokinetic studies were carried out in patients with impaired liver function. Since
pregabalin does not undergo significant metabolism and is excreted predominantly as unchanged drug
in the urine, impaired liver function would not be expected to significantly alter pregabalin plasma
concentrations.
Elderly (over 65 years of age)
Pregabalin clearance tends to decrease with increasing age. This decrease in pregabalin oral clearance
is consistent with decreases in creatinine clearance associated with increasing age. Reduction of
pregabalin dose may be required in patients who have age related compromised renal function (see
section 4.2 Table 1).
5.3 Preclinical safety data
In conventional safety pharmacology studies in animals, pregabalin was well-tolerated at clinically
relevant doses. In repeated dose toxicity studies in rats and monkeys CNS effects were observed,
including hypoactivity, hyperactivity and ataxia. An increased incidence of retinal atrophy commonly
35
observed in aged albino rats was seen after long term exposure to pregabalin at exposures≥ 5 times the
mean human exposure at the maximum recommended clinical dose.
Pregabalin was not teratogenic in mice, rats or rabbits. Foetal toxicity in rats and rabbits occurred only
at exposures sufficiently above human exposure. In prenatal/postnatal toxicity studies, pregabalin
induced offspring developmental toxicity in rats at exposures >2 times the maximum recommended
human exposure.
Adverse effects on fertility in male and female rats were only observed at exposures sufficiently in
excess of therapeutic exposure. Adverse effects on male reproductive organs and sperm parameters
were reversible and occurred only at exposures sufficiently in excess of therapeutic exposure or were
associated with spontaneous degenerative processes in male reproductive organs in the rat. Therefore
the effects were considered of little or no clinical relevance.
Pregabalin is not genotoxic based on results of a battery of
in vitro
and
in vivo
tests.
Two-year carcinogenicity studies with pregabalin were conducted in rats and mice. No tumours were
observed in rats at exposures up to 24 times the mean human exposure at the maximum recommended
clinical dose of 600 mg/day. In mice, no increased incidence of tumours was found at exposures
similar to the mean human exposure, but an increased incidence of haemangiosarcoma was observed
at higher exposures. The non-genotoxic mechanism of pregabalin-induced tumour formation in mice
involves platelet changes and associated endothelial cell proliferation. These platelet changes were not
present in rats or in humans based on short term and limited long term clinical data. There is no
evidence to suggest an associated risk to humans.
In juvenile rats the types of toxicity do not differ qualitatively from those observed in adult rats.
However, juvenile rats are more sensitive. At therapeutic exposures, there was evidence of CNS
clinical signs of hyperactivity and bruxism and some changes in growth (transient body weight gain
suppression). Effects on the oestrus cycle were observed at 5-fold the human therapeutic exposure.
Reduced acoustic startle response was observed in juvenile rats 1-2 weeks after exposure at >2 times
the human therapeutic exposure. Nine weeks after exposure, this effect was no longer observable.
6.
6.1 List of excipients
Capsule content
:
Lactose monohydrate
Maize starch
Talc
Capsule shell
:
Gelatin
Titanium Dioxide (E171)
Sodium Laurilsulphate
Silica, colloidal anhydrous
Purified water
Red Iron Oxide (E172)
Printing Ink
:
Shellac
Black Iron Oxide (E172)
Propylene Glycol
Potassium Hydroxide
36
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions
6.5 Nature and contents of container
PVC/Aluminium blisters containing 14, 56, 100, or 112 (2 x 56) hard capsules.
100 x 1 hard capsules in PVC/Aluminium perforated unit dose blisters.
HDPE bottle containing 200 hard capsules.
Not all pack sizes may be marketed
6.6 Special precautions for disposal and other handling
No special requirements for disposal.
7.
Pfizer Limited,
Ramsgate Road,
Sandwich,
Kent
CT13 9NJ
UK
8.
EU/1/04/279/011-013
EU/1/04/279/027
EU/1/04/279/030
EU/1/04/279/038
9.
Date of first authorisation: 06 July 2004
Date of last renewal: 06 July 2009
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu/
37
1.
FURTHER INFORMATION
What LYRICA contains
The active substance is pregabalin. Each ml contains 20 mg of pregabalin.
182
The other ingredients are: methyl parahydroxybenzoate (E218), propyl parahydroxybenzoate (E216),
sodium dihydrogen phosphate, anhydrous, disodium phosphate, anhydrous (E339), sucralose (E995),
artificial strawberry flavour (contains small amounts of ethanol (alcohol) , purified water.
What LYRICA looks like and contents of the pack
Lyrica 20 mg/ml oral solution is a clear colourless solution in a white bottle containing 473 ml of oral
solution, in a cardboard carton. The carton also contains, in a clear polyethylene wrap, a graduated
5 ml oral syringe and a press-in bottle adapter (PIBA).
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder:
Pfizer Limited, Sandwich, Kent, CT13 9NJ, UK.
Manufacturer:
Pfizer Service Company, Hoge Wei 10, B1930 Zaventem, Belgium
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
Pfizer S.A. / N.V.
Tél/Tel: +32 (0)2 554 62 11
Luxembourg/Luxemburg
Pfizer S.A.
Tél/Tel: +32 (0)2 554 62 11
България
Пфайзер Люксембург САРЛ, Клон България
Тел.: +359 2 970 4333
Magyarország
PFIZER Kft.
Tel. + 36 1 488 37 00
Česká republika
Pfizer spol s.r.o.
Tel: +420-283-004-111
Malta
V.J. Salomone Pharma Ltd.
Tel :+356 21220174
Danmark
Pfizer ApS
Tlf: +45 44 20 11 00
Nederland
Pfizer bv
Tel: +31 (0)10 406 4301
Deutschland
Pfizer Pharma GmbH
Tel: +49 (0)30 550055-51000
Norge
Pfizer AS
Tlf: +47 67 52 61 00
Eesti
Pfizer Luxembourg SARL Eesti filiaal
Tel: +372 6 405 328
Österreich
Pfizer Corporation Austria Ges.m.b.H.
Tel: +43 (0)1 521 15-0
Ελλάδα
Pfizer Hellas A.E.
Τηλ.: +30 210 67 85 800
Polska
Pfizer Polska Sp. z o.o.
Tel.: +48 22 335 61 00
España
Pfizer S.A.
Tel: +34 91 490 99 00
Portugal
Laboratórios Pfizer, Lda.
Tel: +351 21 423 5500
France
Pfizer
Tél: +33 (0)1 58 07 34 40
România
Pfizer România S.R.L.
Tel: +40 (0)21 207 28 00
183
Ireland
Pfizer Healthcare Ireland
Slovenija
Pfizer Luxembourg SARL,
Pfizer, podružnica za svetovanje s področja
farmacevtske dejavnosti, Ljubljana
Tel: +386 (0)1 52 11 400
Tel: +1800 633 363 (toll free)
Tel: +44 (0)1304 616161
Ísland
Vistor hf.
Sími: +354 535 7000
Slovenská republika
Pfizer Luxembourg SARL, organizačná zložka
Tel: +421–2–3355 5500
Italia
Pfizer Italia S.r.l.
Tel: +39 06 33 18 21
Suomi/Finland
Pfizer Oy
Puh./Tel: +358 (0)9 43 00 40
Κύπρος
GEO. PAVLIDES & ARAOUZOS LTD.
Τηλ: +35722818087
Sverige
Pfizer AB
Tel: +46 (0)8 550 520 00
Latvija
Pfizer Luxembourg SARL filiāle Latvijā
Tel: +371 670 35 775
United Kingdom
Pfizer Limited
Tel: +44 (0)1304 616161
Lietuva
Pfizer Luxembourg SARL filialas Lietuvoje
Tel. +3705 2514000
This leaflet was last approved in:
184
Source: European Medicines Agency
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