Normolepsy

Normolepsy 

Normolepsy 

For The Medical Profession Only 

Normolepsy 

Capsules 

Composition: 

Each capsule contains: 

Pregabalin . 

30 - 60 

15 -K 30 

EIPICO 

. 75, 150 mg 

Excipients: microcrystalline cellulose, maize starch, purified talc. 

Therapeutic Indications: 

Neuropathic pain: Normolepsy is indicated for the treatment of peripheral and 

central neuropathic pain in adults. 

Epilepsy: Normolepsy is indicated as adjunctive therapy in adults with partial 

seizures with or without secondary generalisation. 

Generalised Anxiety Disorder: Normolepsy is indicated for the treatment of 

Generalised Anxiety Disorder (GAD) in adults. 

Posology 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: Normolepsy 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: Normolepsy 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 I 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. 

Normolepsy 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 Normolepsy : In accordance with current clinical practice, if 

Normolepsy has to be discontinued, it is recommended this should be done 

gradually over a minimum of I week independent of the indication. 

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, 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: 

((140-age (years)) X weight (kg) 

(X 0.85 for women) 

CLcr (ml/min)— 

72 x serum creatinine (mg/dl) 

Pregabalin is removed effectively from plasma by haemodialysis (50% of drug in 4 hours). 

For patients receiving haemodialysis, the Normolepsy 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. Normolepsy dose adjustment based on renal function 

Creatinine clearance 

(CLcr) (mL/min) 

60 

c: 15 

Total Normolepsy 

daily dose* 

Starting dose Maximum dose 

Dose regimen 

BID or TID 

BID or TID 

Once Daily or BID 

Once Daily 

Single dose* 

(mg/ day) 

150 

75 

25 - 50 

25 

(mg/ day) 

600 

300 

150 

75 

Supplementary dosage following haemodialysis (mg) 

25 

100 

TID Three divided oses. 

BID Two divided doses. 

- Total daily dose mg/day) should be divided as indicated by dose regimen to 

provide mg/dose. 

- Supplementary dbse is a single additional dose. 

Use in patients with hepatic impairment: No dose adjustment is required for 

patients with hepatic impairment. 

Paediatric population: The safety and efficacy of Normolepsy in children below 

the age of 12 years and in adolescents (12-17 years of age) have not been 

established. No data is available. 

Use in the elderly/ (over 65 years of age): Elderly patients may require a dose 

reduction Of Normolepsy due to a decreased renal function (see patients with 

renal impairment). 

Method of administration: 

Normolepsy may be taken with or without food. 

Normolepsy is for oral use only. 

Contraindications: 

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

Special warnings and precautions for use: 

Diabetic patients: 

In accordance with current clinical practice, some diabetic patients who gain weight 

on Normolepsy treatment may need to adjust hypoglycaemjc medicinal products. 

Hypersensitivity reactions: 

There have been reports in the post-marketing experience of hypersensitivity reactions, 

including cases of angioedema. Normolepsy should be discontinued immediately if 

symptoms of angioedema, such as facial, peri-oral, or upper airway swelling occur. 

Dizziness, somnolence, loss of consciousness, confusion, and mental impairment: 

Normolepsy treat1T1ent 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 impairtnent. Therefore, patients should be advised to exercise caution 

until they are familiar with the potential effects of the medicinal product. 

Vision-related effects: 

Patients treated with pregabalin reported blurred Vision, visual acuity reduction, 

visual field changeS and fundoscopic changes. 

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 Normolepsy may result in resolution or 

improvement of th 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, nausea, anxiety, diarrhoea, flu 

syndrome, nervousness, depression, pain, convulsion, hyperhidrosis and 

dizzinessl The patient should be informed about this at the start of the treatment 

With Normolepsy. 

Convulsions, including status epilepticus and grand mal convulsions, may occur 

during Normolepsy use or shortly after discontinuing Normolepsy. 

Concerning discontinuation of long-term treatment of Normolepsy, 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 ih some 

patients receiving pregabalin. These reactions are mostly seen in elderly 

cardiovascular compromised patients during pregabalin treatment for a 

neuropathic indication. Normolepsy should be used with caution in these 

patients. Discontinuation of Normolepsy 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 Normolepsy 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 if signs of suicidal 

ideation or behaviour emerge. 

Reduced lower gastrointestinal tract function: 

There are post-marketing reports of events related to reduced lower gastrointesti- 

nal 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 Normolepsy 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 

Normolepsy abuse. 

Encephalopathy: 

Cases of encephalopathy have been reported, mostly in patients with underlying 

conditions that may precipitate encephalopathy. 

Interaction with other medicinal products: 

Since Normolepsy 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, pharrnacokinetic interactions. 

In vivo studies and population pharmacokinetic analysis: 

Accordingly, In in vivo studies, no clinically relevant pharmacokinetic interactions 

were observed between pregabalin and phenyt0in, carbamazepine, valprojc acid, 

Iamotrigine, 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 Normolepsy With the oral contraceptives norethisterone 

and/or ethinyl oestradiol does not influence the steady-state pharmacokinetics of 

either substance. 

Ethanol, lorazepam, oxycodone: 

Normolepsy may potentiate the effects of ethanol and lorazepam. 

Co-administeration with oxycodone, lorazepam, or ethanol did not result in 

clinically important effects on respiration. In the post-marketing experience, there 

are reports of respiratory failure and coma in patients taking pregabalin and other 

CNS-depressant medicinal products. Normolepsy 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. 

Fertility, 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. 

Pregnancy: 

There are no adequate data from the use of pregabalin in pregnant women. 

Normolepsy 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 Normolepsy. 

Fertility: 

There are no clinical data on the effects of pregabalin on female fertility. 

Pregabalin has no effects on sperm motility. 

Effects on ability to drive and to use machines: 

Normolepsy may have minor or moderate influence on the ability to drive and use 

of machines. Normolepsy may cause dizziness and somnolence and therefore 

may influence the ability to drive or to use machines. 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.
Undesirable effects:
The most commonly reported adverse reactions are dizziness and somnolence.
Adverse reactions were usually mild to moderate in intensity. The most common
adverse reactions resulting in discontinuation from pregabalin treatment groups
were dizziness and somnolence.
The following adverse reactions are listed by class and frequency (very common (2
1/10); common (2 1/100 to •€1/ 10); uncommon (2 1/1,000 to «I/IOO); rare (2
1/10,000 to «I/I,OOO); 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 the list below.
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: Increased appetite.
Uncommon: Anorexia, hypoglycaemia.
Psychiatric disorders:
Common: Euphoric mood, confusion, irritability, decreased libido, disorientation, insomnia.
Uncommon: Hallucination, panic attack, restlessness, agitation, depression, depressed
mood, mood swings, depersonalisation, word finding difficulty, abnormal dreams,
increased libido, 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, headache.
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.
Frequency not known: Loss of consciousness, mental impairment, convulsions, malaise.
Eye disorders:
Common: Vision blurred, diplopia.
Uncommon: Visual disturbance, eye swelling, visual field defect, visual acuity
reduced, eye pain, asthenopia, dry eye, increased lacrimation.
Rare: Peripheral vision loss, oscillopsiä, altered visual depth perception, photopsia,
eye irritation, mydriasis, strabismus, visual brightness.
Frequency not known: Vision loss , keratitis.
Ear and labyrinth disorders:
Common: Vertigo.
Uncommon: Hyperacusis.
Cardiac disorders:
Uncommon: Tachycardia, atrioventricular first degree block.
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.
Rare: Epjstaxis, throat tightness, cough, nasal congestion, rhinitis, snoring.
Frequency not known: Pulmonary oedema.
Gastrointestinal disorders:
Common: Vomiting, dry mouth, constipation, flatulence.
Uncommon: Abdominal distension, gastro-oesophageal reflux disease, salivary
hypersecretion, oral hypoaesthesia
Rare: Ascites, pancreatitis, dysphagia.
Frequency not known: Swollen tongue, diarrhoea, nausea.
Skin and subcutaneous tissue disorders:
Uncommon: Papular rash, 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: Delayed ejaculation, sexual dysfunction.
Rare: Amenorrhoea, breast discharge, breast pain, dysmenorrhoea, breast hypertrophy.
General disorders and administration site conditions:
Common: Abnormal gait, feeling drunk, fatigue, peripherål oedema, oedema.
Uncommon: Fall, chest tightness, asthenia, thirst, pain, feeling abnormal, chills.
Rare: Generalised oedema, pyrexia.
Frequency not known: Face oedema.
Investigations:
Common: Increased weight.
Uncommon: Increased blood creatine phosphokinase, increased alanine aminotrans-
ferase, increased aspartate aminotransferase, decreased platelet count.
Rare: Increased blood glucose, decreased blood potassium, decreased white blood
cell count, increased blood creatinine, decreased weight.
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 duration
of use and dose of pregabalim
Overdose:
In overdose up to 15 g, no unex ed adverse reaction were reported.
In the post-marketing experience,'the most commonly reported adverse reactions
observed when pregabalin was taken in overdose included somnOIence,
confusional state, agitation, and restlessness.
Treatment of pregabalin overdose should include general supportive measures
and may include haemodialysis if necessary (see Table I).
Pharmacological Properties:
Pharmacodynamic properties:
Pharmacotherapeutic group: Anti-epileptics, other anti-epileptics.
The active substance, pregabalin, is a gamma-aminobutyric acid analogue
((S)-3-(aminomethyI)-5-methylhexanoic acid).
Mechanism of action:
Pregabalin binds to an auxiliary subunit (C12-n protein) of voltage-gated calcium
channels in the central nervous system,
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 I hour following both single and multiple
dose administration. Pregabalin oral bioavailability is estimated to be 9096 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
tmax to approximately 2.5 hours. However, administration Of pregabaltn With food
has no clinically significant effect on the extent of pregabalin absorption.
Distribution:
In humans, the apparent volume of distribution of pregabalin following oral
administration is approximately 0.56 1/kg. Pregabalin is not bound to plasma
proteins.