Pfizer Lyrica Lactose Monohydrate Capsules

LYRICA®

(Pregabalin Capsules)

 

1. NAME OF THE MEDICINAL PRODUCT

LYRICA 25 mg hard capsules

LYRICA 75 mg hard capsules

LYRICA 150 mg hard capsule

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each hard capsule contains 25 mg of pregabalin.

Each hard capsule contains 75 mg of pregabalin.

Each hard capsule contains 150 mg of pregabalin.

Excipients:

Each hard capsule of Lyrica 25mg also contains 35 mg lactose monohydrate.

Each hard capsule of Lyrica 75mg also contains 8.25 mg lactose monohydrate.

Each hard capsule of Lyrica 150mg also contains 16.50 mg lactose monohydrate.

For a full list of excipients, see section 6.1.

 

3. PHARMACEUTICAL FORM

LYRICA 25 mg Hard capsule

White marked “Pfizer” on the cap and ,”PGN 25” on the body with black ink.

LYRIGA 75 mg Hard capsule

White and orange, marked “Pfizer” on the cap and “PGN 75” on the body with black ink.

LYRICA 150 mg Hard capsules

White marked “Pfizer” on the cap and “PGN 150” on the body with black ink.

 

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

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.

 

4.2 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

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.

Generailsed 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:

CLcr (ml/mm) = [1.23 x[140-age (years)] x weight (kg) / serum creatinine (µmol/l)] (x 0.85 for female patients)

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 (CLcr) (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 haemodialyis (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).

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.

 

4.3 Contraindications

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

 

4.4 Special warnings and precautions for use

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 post marketing 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 pregahalin 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 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.

 

4.5 Interaction with other medicinal products and other forms of interaction

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 oestrpdiol

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 post marketing 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.

 

4.6 Fertility, pregnancy and lactation

Women of child bearing 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).

 

4.7 Effects on ability to drive and use machines

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 activities until it is known whether this medicinal product affects their ability to perform these activities.

 

4.8 Undesirable 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 (See 4.4).

Additional reactions reported from post-marketing experience are included as Frequency not known 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                                                              Appetite increased Anorexia, hypoglycaemia
Psychiatric disorders Common

 

Uncommon

 

 

Rare

Frequency not known

Euphoric mood, confusion, initability, libido decreased, disorientation, insomnia

Hallucination, panic attack, restlessness, agitation, depression, depressed mood, mood swings, depersonalisation, word finding difficulty, abnormal dreams, libido increased, anorgasmia, apathy Disinhibition, elevated mood

Aggression

Nervous system disorders Very common

Common

 

 

Uncommon

 

 

 

Rare

Frequency not known

Dizziness, somnolence

Ataxia, coordination abnormal, tremor, dysarthria, memory impairment, disturbance in attention, paraesthesia, sedation, balance disorder, lethargy, Headache

Syncope, stupor, myoclonus, psychomotor hyperactivity, ageusia, dyskinesia, dizziness postural, intention tremor, nystagmus, cognitive disorder; speech disorder, hyporeflexia, hypo aesthesia, amnesia, hyperaesthesia, burning sensation

Hypokinesia, parosmia, dysgraphia

Loss of consciousness, mental impairment, convulsions, malaise

Eye disorders Common

Uncommon

 

 

Rare

 

Frequency not known

Vision blurred, diplopia

Visual disturbance, eye swelling, visual field defect, visual acuity reduced, eye pain, asthenopia, dry eye, lacrimation increased

Peripheral vision loss, oscillopsia, altered visual depth perception, photopsia, eye irritation, mydriasis, strabismus, visual brightness

Vision loss, keratitis

Ear and labyrinth disorders Common

Uncommon

Vertigo

Hyperacusis

Cardiac disorders Uncommon

 

Rare

Frequency not known

Tachycardia, artrioventricular block first degree

Sinus tachycardia, sinus bradycardia, sinus arrhythmia

Congestive heart failure, QT prolongation

Vascular disorders Uncommon

Rare

Flushing, hot flushes, hypotension, hypertension

Peripheral coldness

Respiratory, thoracic and mediastinal disorders Uncommon

Rare

Frequency not known

Dyspnoea, nasal dryness

Epistaxis, throat tightness, cough, nasal congestion, rhinitis, snoring

Pulmonary oedema

Gastrointestinal disorders Common

 

Uncommon

 

Rare

Frequency not known

Vomiting, dry mouth, constipation, flatulence

Abdominal distension, gastrooesophageal reflux disease, salivary hypersecretion, hypoaesthesia oral

Ascites, pancreatitis, dysphagia

Swollen tongue, diarrhoea, nausea

Skin and subcutaneous tissue disorders Uncommon

Rare

Frequency not known

Rash popular, hyperhidrosis

Urticaria, cold sweat

Steven Johnson syndrome, pruritus

Musculoskeletal and connective tissue disorders Uncommon

 

Rare

Muscle twitching, joint swelling, muscle cramp, myalgia, arthragia, back pain, pain in limb, muscle stiffness

Rhabdomyolysis, cervical spasm, neck pain

Renal and urinary disorders Uncommon

Rare

Frequency not known

Urinary incontinence, dysuria

Renal failure, oliguria

Urinary retention

Reproductive system and breast disorders Common

Uncommon

Rare

Frequency not known

Erectile dysfunction

Ejaculation delayed, sexual dysfunction

Amenorrhoea, breast discharge, breast pain, dysmenorrhoea, breast enlargement

Gynaecomastia

General disorders and administration site conditions Common

Uncommon

Rare

Frequency not known

Gait abnormal, feeling drunk, fatigue, oedema peripheral, oedema

Fall, chest tightness, asthenia, thirst, pain, feeling abnormal, chillis

Generalised oedema, pyrexia

Face oedema

Investigations Common

Uncommon

 

Rare

Weight increased

Blood creatine phosphokinase increased, aspartate amino-transferase increased, platelet court decreased

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.

 

4.9 Overdose

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. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antiepileptics, other anti epileptics ATC code: NO3AX16

The active substance, pregabalin, is a gamma-aminobutyric acid analogue ((S)-3-(aminomethyl)-5methylhexanoic acid).

Mechanism of action

Pregabalin binds to an auxiliary subunit (ᾳ2 — õ 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 (TlD) 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 1 week 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 tied 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.

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 (BID). 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 50% improvementin 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. ln 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 pIasma 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 tmax 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.

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 Nmethylated 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 observed in aged albino rats 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. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Capsule Content Capsule Shell Printing Ink
Lyrica 25mg capsules Lactose
monohydrate
Maize starch
Talc
Gelatin
Titanium Dioxide
(E171)
Sodium
Laurilsulphate
Silica, colloidal
anhydrous
Purified water
Shellac
Black Iron
Oxide (E172)
Propylene
Glycol
Potassium
Hydroxide
Lyrica 75mg capsules Lactose monohydrate Maize starch Talc Gelatin
Titanium Dioxide
(E171)
Sodium
Laurilsulphate
Silica colloidal
anhydrous
Purified water
Red Iron Oxide
(E172)
Shellac
Black Iron
Oxide (E172)
Propylene
Glycol
Potassium
Hydroxide
Lyrica 150mg capsules Lactose
monohydrate
Maize starch
Talc
Gelatin
Titanium Dioxide
(El71)
Sodium
Lauritsulphate
Silica, colloidal
anhydrous ‘
Purified water
Shellac
Black Iron
Oxide (E172)
Propylene
Glycol
Potassium
Hydroxide

 

6.2 Incompatibilities

Not applicable.

 

6.3 Shelf life

This drug should not be used after the expiration date as stated on the package.

 

6.4 Special precautions for storage

Store below 30°C.

 

6.5 Nature and contents of container

Lyrica 25mg, 75mg and 150mg are available in blister packs of 28 capsules.

 

6.6 Special precautions for disposal and other handling

No special requirements for disposal.

 

7. MARKETING AUTHORISATION HOLDER

Pfizer Limited,

Ramsgate Road,

Sandwich,

Kent

CT13 9NJ

UK

8. MANUFACWRER

Pfizer Manufacturing Deutschland GmbH, Betriebsstätte Freiburg,

Mooswaldallee 1, D-79090 Freiburg, Germany.

 

9. DATE OF REVISION OF THE TEXT

November 2011

 

Detailed information on this product is available on the website o the European Medicines Agency http://www.ema.europa.eu/

Roche Lexotan Bromazepam Tablets

LEXOTAN®

Bromazepam

 

1.1 Therapeutic/Pharmacologic Class of Drug

Anxiolytic.

 

1.2 Type of Dosage Form

Tablets.

 

1.3 Route of Administration

Oral.

 

1.4 Qualitative and Quantitative Composition

Active ingredient: bromazepam. Tablets 1.5 mg, 3 mg and 6 mg.

Excipients: Lexotan tablets contain lactose.

For warning related to lactose, see 2.4.1 General (Warnings and Precautions).

 

2. CLINICAL PARTICULARS

2.1 Therapeutic Indication(s)

Anxiety, tension and other somatic or psychiatric complaints associated with the anxiety syndrome.

Adjunctive use for treatment of anxiety or excitation associated with psychological disorders, such as mood disorders or schizophrenia.

Benzodiazepines are only indicated when the disorder is severe, disabling or subjecting the individual to extreme distress.

 

2.2 Dosage and Administration

Standard dosage

Average dosing for outpatient therapy: 1.5 – 3 mg up to three times daily.
Severe cases, especially in hospital: 6 -12 mg two or three times daily.

These amounts are general recommendations, and dosage should be individually determined.

Treatment of outpatients should begin with low doses, gradually increasing to the optimum level. The duration of treatment should be as short as possible. The patient should be reassessed regularly and the need for continued treatment should be evaluated, especially in case the patient is symptom free. The overall treatment generally should not be more than 8 – 12 weeks, including a tapering-off process. In certain cases extension beyond the maximum treatment period may be necessary, if so, it should not take place without re-evaluation of the patient’s status with special expertise.

 

2.2.1 Special Dosage Instructions

Lexotan is usually not indicated in children, but if the physician feels Lexotan treatment is appropriate, then the dose should be adjusted to their low body weight (about 0.1 – 0.3 mg/kg body weight).

Elderly patients (see 3.2.5 Pharmacokinetics in Special Populations) and those with impaired hepatic function require lower doses because of individual variations in sensitivity and pharmacokinetics.

 

2.3 Contraindications

Lexotan must not be administered to patients with known hypersensitivity to benzodiazepines, severe respiratory insufficiency, severe hepatic insufficiency (benzodiazepines are not indicated to treat patients with severe hepatic insufficiency as they may cause encephalopathy) or sleep apnea syndrome.

 

2.4 Warnings and Precautions

2.4.1 General

Amnesia

Benzodiazepines may induce anterograde amnesia. Anterograde amnesia may occur using higher therapeutic dosages (documented at 6 mg), the risk increasing at higher dosages.

Duration of treatment

It may be useful to inform the patient when treatment is started that it will be of limited duration and to explain precisely how the dosage will be progressively decreased. It is important that the patient should be aware of the possibility of rebound phenomena that may occur while the drug is being discontinued (see 2.4.2 Drug Abuse and Dependence).

 

General precautions

Concomitant use of alcohol/CNS depressants

The concomittant use of Lexotan with alcohol or/and CNS depressants should be avoided. Such concomitant use has the potential to increase the clinical effects of Lexotan possibly including severe sedation, clinically relevant respiratory and/or cardiovascular depression (see 2.4.4 Interactions with other Medicinal Products and other Forms of Interaction).

 

Medical history of alcohol or drug abuse

Lexotan should be used with extreme caution in patients with a medical history of alcohol or drug abuse.

The patient should be checked regularly at the start of treatment in order to minimise the dosage and/or the frequency of administration and to prevent overdose due to accumulation.

When benzodiazepines are used, withdrawal symptoms may develop when changing to a benzodiazepine with a considerably shorter elimination half-life (see 2.4.2 Drug Abuse and Dependence).

 

Tolerance

Some loss of response to the effects of Lexotan may develop after repeated use for a prolonged time.

Benzodiazepines should not be used alone to treat depression or anxiety associated with depression (suicide may be precipitated in such patients).

Benzodiazepines are not recommended for the primary treatment of psychotic illness.

 

Specific patient groups

In patients with myasthenia gravis who are prescribed Lexotan, care should be taken on account of pre-existing muscle weakness. Particular care is required in patients with chronic respiratory insufficiency due to the risk of respiratory depression.

If containing lactose, patients with rare hereditary problems of galactose intolerance (the Lapp lactase deficiency or glucose-galactose malabsorption) should not take this medicine.

 

2.4.2 Drug Abuse and Dependence

Dependence

The use of benzodiazepines and benzodiazepine-like agents may lead to the development of physical and psychic dependence upon these products (see 2.6 Undesirable Effects). The risk of dependence increases with dose and duration of treatment; it is also greater in patients with a medical history of alcohol and/or drug abuse.

 

Withdrawal

Once physical dependence has developed, termination of treatment will be accompanied by withdrawal symptoms. These may consist of headaches, muscle pain, extreme anxiety, tension, restlessness, confusion and irritability. In severe cases the following symptoms may occur: derealisation, depersonalisation, hyperacusis, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact, hallucinations or epileptic seizures (see 2.6 Undesirable Effects).

Rebound anxiety, a transient syndrome whereby the symptoms that led to treatment with Lexotan recur in an enhanced form, may occur on withdrawal of treatment. It may be accompanied by other reactions including mood changes; anxiety or sleep disturbances and restlessness.

Since the risk of withdrawal phenomena and rebound phenomena is greater after abrupt discontinuation of treatment, it is recommended that the dosage be decreased gradually.

 

2.4.3 Ability to Drive and Use Machines

Sedation, amnesia and impaired muscular function may adversely affect the ability to drive or to use machinery. This effect is increased if the patient has taken alcohol.

 

2.4.4 Interactions with other Medicinal Products and other Forms of Interaction

Pharmacokinetic Drug-Drug Interaction (DDI)

There is a possibility that compounds, which inhibit certain hepatic enzymes, may influence the activity of those benzodiazepines that are metabolised by these enzymes. Co-administration of cimetidine may prolong the elimination half-life of bromazepam.

Pharmacodynamic Drug-Drug Interaction (DDI) Enhanced effects on sedation, respiration and hemodynamics may occur when Lexotan is co-administered with any centrally acting depressants including alcohol.

Alcohol should be avoided in, patients receiving Lexotan (see 2.4.1 General [Warnings and Precautions]).

See section 2.7 Overdose for warning of other central nervous system depressants, including alcohol.

In the case of narcotic analgesics enhancement of euphoria may also occur, leading to an increase in psychic drug dependence.

 

2.5 Use in Special Populations

2.5.1 Pregnancy

The safety of bromazepam for use in human pregnancy has not been established. A review of spontaneously reported adverse drug events shows no greater incidence than would be anticipated from a similar untreated population. An increased risk of congenital malformations associated with the use of minor tranquilisers (diazepam, meprobamate and chlordiazepoxide) during the first trimester of pregnancy has been suggested in several studies. Bromazepam should be avoided during pregnancy unless there is no safer alternative.

If the product is prescribed to a woman of childbearing potential, she should be warned to contact her physician regarding discontinuance of the product if she intends to become or suspects that she is pregnant.

Administration of bromazepam during the last three months of pregnancy or during labour is allowed only in the event of a strict medical indication as, due to the pharmacological action of the product, effects on the neonate can be expected, such as hypothermia, hypotonia and moderate respiratory depression.

Moreover, infants born to mothers who took benzodiazepines chronically during the latter stages of pregnancy may have developed physical dependence and may be at some risk for developing withdrawal symptoms in the postnatal period.

 

2.5.2 Labour and Delivery

See 2.5.1 Pregnancy.

 

2.5.3 Nursing Mothers

As benzodiazepines pass into breast milk, nursing mothers should not take Lexotan.

 

2.5.4 Pediatric Use

See 2.2.1 Special Dosage Instructions.

 

2.5.5 Geriatric Use

See also 2.2.1 Special Dosage Instructions, 2.6 Undesirable Effects and 3.2.5 Pharmacokinetics in Special Populations.

 

2.5.6 Hepatic Impairment

See 2.2.1 Special Dosage Instructions.

 

2.6 Undesirable Effects

2.6.1 Post Marketing

Lexotan is well tolerated in therapeutic doses.

The following undesirable effects may occur:

Psychiatric Disorders Confusional state, emotional disorder. These phenomena occur predominantly at the start of therapy, and usually disappear with repeated administration. Libido disorders have been reported occasionally.

Depression: Pre-existing depression may be unmasked during benzodiazepine use.

Paradoxical reactions such as restlessness, agitation, irritability, aggression, delusion, anger, nightmares, hallucinations, psychosis, inappropriate behaviour and other adverse behavioural effects are known to occur with benzodiazepines or benzodiazepine-like agents (see 2.4.2 Drug Abuse and Dependence). Should this occur, the use of the drug should be discontinued. They are more likely to occur in children and elderly patients than in other patients.

Dependence: Chronic use (even, at therapeutic doses) may lead to the development of physical and psychic drug dependence: discontinuation of therapy may result in withdrawal or rebound phenomena (see 2.4.1 General [Warnings and Precautions] and 2.4.2 Drug Abuse and Dependence).

Abuse of benzodiazepines has been reported.

Nervous System Disorder: Drowsiness, headache, dizziness, decreased alertness, ataxia. These phenomena occur predominantly at the start of therapy and usually disappear with repeated administration.

Anterograde amnesia may occur using therapeutic dosages, the risk increasing at higher dosages. Amnestic effects may be associated with inappropriate behaviour.

Eye Disorders: Diplopia, this phenomenon occurs predominantly at the start of therapy and usually disappears with repeated administration.

Gastrointestinal Disorders: Gastrointestinal disorders have been reported occasionally.

Skin and Subcutaneous Tissue Disorders: Skin reactions have been reported occasionally.

Musculoskeletal and Connective Tissue Disorders: Muscle weakness, this phenomenon occurs predominantly at the start of therapy and usually disappears with repeated administration.

General Disorders and Administration Site Conditions: Fatigue, this phenomenon occurs predominantly at the start of therapy and usually disappears with repeated administration.

Injury, Poisoning and Procedural Complications: There have been reports of falls and fractures in benzodiazepine users. The risk is increased in those taking concomitant sedatives (including alcoholic beverages) and in the elderly.

Respiratory Disorders: Respiratory depression.

Cardiac Disorders: Cardiac failure including cardiac arrest.

 

2.7 Overdose

Symptoms

Benzodiazepines commonly cause drowsiness, ataxia, dysarthria and nystagmus. Overdose of Lexotan is seldom taken alone but may lead to areflexia, apnea, hypotension, cardiorespirtory depression and coma. Coma, if it occurs, usually lasts a few, hours but it may be more protracted and cyclical, particularly in elderly patients. Benzodiazepine respiratory depressant effects are more serious in patients with respiratory disease.

Benzodiazepines increase the effects of other central nervous system depressants, including alcohol.

 

Treatment

Monitor the patient’s vital signs and institute supportive measures as indicated by the patient’s clinical state In particular, patients may require symptomatic treatment for cadiorespiratory effects or central nervous system effects.

Further absorption should be prevented using an appropriate method e.g. treatment within 1-2 hours with activated charcoal. If activated charcoal is used, airway protection is imperative for drowsy patients. In case of mixed ingestion gastric lavage may be considered however, not as a routine measure.

If CNS depression is severe consider the use of flumazenil (Anexate®), a benzodiazepine antagonist. This should only be administered under closely monitored conditions. It has a short half-life (about an hour), therefore patients administered flumazenil will require monitoring after its effects have worn off. Flumazenil is to be used with extreme caution in the presence of drugs that reduce seizure threshold (e.g. tricyclic antidepressants). Refer to the prescribing information for flumazenil, (Anexate®), for further information on the correct use of this drug.

 

3. PHARMACOLOGICAL PROPERTIES AND EFFECTS

3.1 Pharmacodynamic Properties

3.1.1 Mechanism of Action

In low dosage, Lexotan selectively reduces tension and anxiety. In high dosage, sedative and muscle- relaxant properties appear.

 

3.2 Pharmacokinetic Properties

3.2.1 Absorption

Peak plasma concentrations are reached within 2 hours of oral administration of bromazepam.

The absolute (versus i.v. solution) and relative (versus oral solution) bioavailability of the tablet is 60% and100%, respectively.

 

3.2.2 Distribution

On average, 70% of bromazepam is bound to plasma proteins. The volume of distribution is 50 litres.

 

3.2.3 Metabolism

Bromazepam is metabolised in the liver.
Quantitatively, two metabolite predominate: 3-hydroxy-bromazepam and 2-(2-amino-5-bromo- 3-hydroxybenzoyl)pyridine.

 

3.2.4 Elimination

The urinary recovery of intact bromazepam and the glucuronide conjugates of 3-hydroxy-bromazepam and 2-(-2-amino-5-bromo-3-hydroxybenzoyl) pyridine is 2%, 27% and 40% of the administered dose.

Bromazepam has an elimination half-life of about 20 hours. The clearance is 40 ml/mm.

 

3.2.5 Pharmacokinetics in Special Populations

Elderly

The elimination half-life may be prolonged in elderly patients (see 2.2.1 Special Dosage Instructions).

 

3.3 Preclinical

3.3.1 Carcinogenicity

Carcinogenicity studies conducted in rats did not reveal any evidence of a carcinogenic potential for bromazepam.

 

3.3.2 Mutagenicity

Bromazepam was not genotoxic in in vitro and in vivo tests.

 

3.3.3. Impairment of Fertility

Daily oral administration of bromozepam did not have any effect on the fertility and general reproductive performance of rats.

 

3.3.4 Teratogenicity

Increases in fetal mortality, an increase in the stillbirth rate and a reduction in pup survival have been observed when bromozapem was given to pregnant rats. In studies on embryotoxicity/ teratogenicity no teratogenic effect was detected up to a dosage of 125 mg/kg/day.

Following per os administration with doses of up to 50 mg/kg/day to pregnant rabbits a reduction in maternal weight gain, a reduction in fetal weight and an increase in the incidence of resorptions have been observed.

 

3.5.5 Other

Chronic toxicity

No deviations from normal were observed in long-term toxicology studies except for an increase in liver weight. Hitopathological examination revealed centrolobular hepatocellular hypertrophy which was considered to be indicative of enzyme induction by bromazepam. Adverse effects observed after high doses were slight to moderate sedation, ataxia, isolated brief convulsive seizures, occasional elevation in serum alkaline phosphate and a borderline increase in SGPT (ALT).

 

4. PHARMACEUTICAL PARTICULARS

4.1 Storage

This medicine should not be used after the expiry date (EXP) shown on the pack.

 

4.2 Packs

Tablets (scored) 1.5 mg 30, 100, 1000

Tablets (scored) 3 mg 30, 100, 1000

Tablets (scored) 6 mg 30, 100, 1000

 

Medicine: Keep out of reach of children.

 

Current September 2012.

 

Made for F. Hoffman-La Roche Ltd,

Basel, Switzerland

By Roche S.p.A. Milan, production site

Segrate, Italy.