MacGabalin

COMPOSITION

Mac GABALIN
Each hard gelatin capsule contains:
Pregabalin Ph.Eur 75 mg
Approved colors used in gelatin capsule shell.

DESCRIPTION
Pregabalin is chemically described as (S)-3-(aminomethyl)-5-methylhexanoic acid. The molecular formula is CaH11NO2 and
the molecular weight is 159.23.
The chemical structure of pregabalin is:

PHARMACODYNAMIC AND PHARMACOKINETIC PROPERTIES

• Pharroacodynaroic properties

  Pharmacotherapeutic group: Anticonvulsants, other Anticonvulsants. 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 subumit ( 2-b protein) of voltage-gated calcium channels in
  the central nervous
  system,

• 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 TIO
  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 patient’s 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.
  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

• Adjunctive Treatment

  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.

• Monotherapy (newly diagnosed patients)

  Pregabalin has been studied in 1 controlled clinical trial of 56 week
  duration with twice a day dosing (BIO).
  Pregabalin did not achieve non-inferiority to lamotrigine based on the 6-month seizure freedom endpoint.
  Pregabalin and lamotrigine were similarly safe and well tolerated.

• 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.

• Pharmacokinetic properties

  Pregabalin steady-state pharmacokinetics are similar in healthy volunteers, patients
  with epilepsy receiving
  Anticonvulsant drugs and patients with chronic pain.
  Absori,1iQn;
  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 Cmax 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.
  .Dls1rib..ution
  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 I/kg.
  Pregabalin is not bound to plasma proteins.

• Biotransformation:

  Pregabalin undergoes negligible metabolism in humans. Following a dose of radio-labelled
  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.
  .EJiminalion;
  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.

• Linearity I 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.
  Therefo re, there is no need for routine monitoring of plasma concentrations of pregabalin. Pharmacokinetics
  in special patient groups 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.

• 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.
  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 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 reproductvi e 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.

INDICATIONS

• Neuropathic pain

  Pregabalin is indicated for the treatment of peripheral and central neuropathic pain in adults

• Epilepsy

  Pregabalin is indicated as adjunctive therapy in adults with partial seizures with or
  without secondary generalisation.

• Generalised Anxiety Disorder

  Pregabalin is indicated for the treatment of Generalised Anxiety Disorder (GAD) in
  adults.

CONTRAINDICATIONS
Hypersensitivity to the active substance or to any of the excipients.

WARNINGS AND PRECAUTIONS

• 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.
  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 Anticonvulsant medicinal products

  There are insufficient data for the withdrawal of
  concomitant Anticonvulsant 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, 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
  Anticonvulsant agents in several
  indications. A meta-analysis of randomised placebo controlled studies of Anticonvulsant 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

  Pregabalin 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

DRUG INTERACTIONS
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.

• 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 oxycodooe

  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.

ADVERSE EFFECTS
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 Additional reactions reported from
post-marketing experience are included as Frequency not known in italics in the list below.

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.

DOSE AND METHOD OF ADMINISTRATION

• 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.

• 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.

• Discontinuationof 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
  Special populations

• Special populations

  Pregabalin is eliminated from the systemic circulation primarily by renal excretion as
  unchanged drug. As pregabalin clearance is directly proportional to creatinine clearance, dose reduction in
  patients with
  compromised renal function must be individualised according to creatinine clearance (Cler), as indicated in
  Table 1 determined using the following formula:
  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).

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). Table1 .
Pregabalin dose adjustment based on renal function

TIO = 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).

• Paediatric population

  The safety and efficacy of Pregabalin 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 yearsof age)

  Elderly patients may require a dose reduction of pregabalin due to a decreased renal function (see patients with
  renal impairment).

• Method of administration

  Pregabalin may be taken with or without food.
  PREGABALIN is for oral use only.

PREGNANCY AND LACTATION
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.
Eregnancy
There are no adequate data from the use of pregabalin in pregnant women.
Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown.
Pregabalin 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.
  Earlilil),
  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.

OVERDOSAGE
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.

EXPIRY DATE
Do not use after the date of expiry.

STORAGE
Store below 30°C. Protect from light and moisture.

CATEGORY OF DISTRIBUTION
pp 10

PHARMACOLOGICAL CLASSIFICATION
Anticonvulsants

HOW SUPPLIED/ PRESENTATION
Pregabalin capsules 75 mg are supplied in 1O’s blister pack. Such 3 blisters are packed in to carton with pack insert.