Wednesday, March 22, 2017

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.