4.1. Therapeutic indications

Neuropathic pain

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

Epilepsy

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

Generalised anxiety disorder

Pregabalin Zentiva is indicated for the treatment of generalised anxiety disorder (GAD) in adults.

4.2. Posology and method of administration

Prior to starting treatment with pregabalin, a discussion should be held with patients to put in place a strategy for ending treatment with pregabalin in order to minimise the risk of dependence, addiction and drug withdrawal syndrome (see section 4.4).

Treatment should be given for the shortest possible duration. If this medicine is being used for the treatment of epilepsy this medicine should be used for as long as the prescriber considers it necessary.

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.

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).

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:

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 haemodialysis (mg)

25

100

Single dose +

TID = Three divided doses.BID = Two divided doses.* Total daily dose (mg/day) should be divided as indicated by dose regimen to provide mg/dose.+ Supplementary dose is a single additional dose.

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. Currently available data are described in sections 4.8, 5.1 and 5.2 but no recommendation on a posology can be made.

Elderly

Elderly patients may require a dose reduction of pregabalin due to a decreased renal function (see section 5.2).

Method of administration

Pregabalin Zentiva may be taken with or without food.

Pregabalin Zentiva is for oral use only.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

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.

Severe cutaneous adverse reactions (SCARs)

SCARs including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which can be life-threatening or fatal, have been reported rarely in association with pregabalin treatment. At the time of prescription patients should be advised of the signs and symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of these reactions appear, pregabalin should be withdrawn immediately and an alternative treatment considered (as appropriate).

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 anti-epileptic medicinal products

There are insufficient data for the withdrawal of concomitant anti-epileptic medicinal products, once seizure control with pregabalin in the add-on situation has been reached, in order to reach monotherapy on 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.

Respiratory depression

There have been reports of severe respiratory depression in relation to pregabalin use. Patients with compromised respiratory function, respiratory or neurological disease, renal impairment, concomitant use of CNS depressants and the elderly may be at higher risk of experiencing this severe adverse reaction. Dose adjustments may be necessary in these patients (see section 4.2).

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. Cases of suicidal ideation and behaviour have been observed in patients treated with pregabalin in the post-marketing experience (see section 4.8). An epidemiological study using a self-controlled study design (comparing treatment periods with non-treatment periods within an individual) showed evidence of an increased risk of new onset of suicidal behaviour and death by suicide in patients treated with pregabalin.

Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge. Patients should be monitored for signs of suicidal ideation and behaviour and appropriate treatment should be considered. Discontinuation of pregabalin treatment should be considered in case of suicidal ideation and behaviour.

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).

Concomitant use with opioids

Caution is advised when prescribing pregabalin concomitantly with opioids due to risk of CNS depression (see section 4.5). In a case-control study of opioid users, those patients who took pregabalin concomitantly with an opioid had an increased risk for opioid-related death compared to opioid use alone (adjusted odds ratio [aOR], 1.68 [95% CI, 1.19 – 2.36]). This increased risk was observed at low doses of pregabalin (≤ 300 mg, aOR 1.52 [95% CI, 1.04 – 2.22]) and there was a trend for a greater risk at high doses of pregabalin (> 300 mg, aOR 2.51 [95% CI 1.24 – 5.06]).

Drug dependence, tolerance and potential for abuse

Drug addiction comprises behavioural, cognitive and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use and possible tolerance or physical dependence. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, which manifests as withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Addiction and dependence are related but distinct presentations and in discussing these themes, terminology that apportion blame to the individual should be avoided.

For all patients, prolonged use of this product may lead to drug dependence and addiction but can occur with short-term use at recommended therapeutic doses. The risks are increased in individuals with current or past history of substance misuse disorder (including alcohol misuse) or mental health disorder (e.g., major depression).

Additional support and monitoring may be necessary when prescribing for patients at risk of drug misuse.

A comprehensive patient history should be taken to document concomitant medications, including over-the-counter medicines and medicines obtained on-line, and past and present medical and psychiatric conditions.

Patients may find that treatment is less effective with chronic use and express a need to increase the dose to obtain the same level of symptom control as initially experienced. Patients may also supplement their treatment with additional medications to achieve the same effect. These could be signs that the patient is developing tolerance. The risks of developing tolerance should be explained to the patient.

Overuse or misuse may result in overdose and/or death. It is important that patients only use medicines that are prescribed for them at the dose they have been prescribed and do not give this medicine to anyone else.

Patients should be closely monitored for signs of misuse, abuse, or addiction.

The clinical need for treatment with pregabalin should be reviewed regularly, with frequent assessments of patients being undertaken during the course of their treatment.

Drug withdrawal syndrome

Prior to starting treatment with pregabalin, a discussion should be held with patients to explain the risk of dependence, addiction, and drug withdrawal syndrome. A withdrawal strategy for ending treatment with pregabalin should also be put in place with the patient before starting treatment (there may be exceptions to this in specific clinical situations such as symptom management in end of life palliative care, and for use in epilepsy).

Drug withdrawal syndrome may occur upon abrupt cessation of therapy or dose reduction. When a patient no longer requires therapy, it is advisable to taper the dose gradually to minimise symptoms of withdrawal. Tapering from a high dose may take in excess of weeks or months. Patients should be informed of this when the medication is first prescribed.

The reduction schedule for a patient should be tailored to the individual and should be modified to allow intolerable withdrawal symptoms to improve before making the next reduction. If using a published withdrawal schedule, apply it flexibly to accommodate the person's preferences, changes to their circumstances and the response to dose reductions.

Reduce the dose by a fixed amount at each decrement, unless clinical risk is such that rapid withdrawal is needed.

If a patient develops withdrawal reactions, consider pausing the taper or increasing the dosage to the previous tapered dosage level.

If women take this drug during pregnancy, there is a risk that their newborn infants will experience neonatal withdrawal syndrome.

Encephalopathy

Cases of encephalopathy have been reported, mostly in patients with underlying conditions that may precipitate encephalopathy.

Women of childbearing potential/Contraception

Pregabalin Zentiva use in the first‑trimester of pregnancy may cause major birth defects in the unborn child. Pregabalin should not be used during pregnancy unless the benefit to the mother clearly outweighs the potential risk to the foetus. Women of childbearing potential have to use effective contraception during treatment (see section 4.6).

Lactose

Pregabalin Zentiva contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total 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 oestradiol

Co-administration of pregabalin with the oral contraceptives norethisterone and/or ethinyl oestradiol does not influence the steady-state pharmacokinetics of either substance.

Central nervous system influencing medical products

Pregabalin may potentiate the effects of ethanol and lorazepam. In the post-marketing experience, there are reports of respiratory failure, coma and deaths in patients taking pregabalin and opioids and/or other central nervous system (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 childbearing potential/Contraception

Women of childbearing potential have to use effective contraception during treatment (see section 4.4).

Pregnancy

Studies in animals have shown reproductive toxicity (see section 5.3).

Pregabalin has been shown to cross the placenta in rats (see section 5.2). Pregabalin may cross the human placenta.

Major congenital malformations

Data from a Nordic observational study of more than 2,700 pregnancies exposed to pregabalin in the first trimester showed a higher prevalence of major congenital malformations (MCM) among the paediatric population (live or stillborn) exposed to pregabalin compared to the unexposed population (5.9% vs. 4.1%).

The risk of MCM among the paediatric population exposed to pregabalin in the first trimester was slightly higher compared to unexposed population (adjusted prevalence ratio and 95% confidence interval: 1.14 (0.96-1.35)), and compared to population exposed to lamotrigine (1.29 (1.01–1.65)) or to duloxetine (1.39 (1.07–1.82)).

The analyses on specific malformations showed higher risks for malformations of the nervous system, the eye, orofacial clefts, urinary malformations and genital malformations, but numbers were small and estimates imprecise.

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

Pregabalin is excreted into human milk (see section 5.2). The effect of pregabalin on newborns/infants is unknown. A decision must be made whether to discontinue breast-feeding or to discontinue pregabalin therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

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

Pregabalin may have minor or moderate influence on the ability to drive and use machines. Pregabalin 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 8,900 patients exposed to pregabalin, of whom over 5,600 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 Table 2 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 section 4.4).

Additional reactions reported from post-marketing experience are included in italics in the list below.

Table 2: Pregabalin Adverse Drug Reactions

System Organ Class

Adverse drug reactions

Infections and infestations

Common

Nasopharyngitis

Blood and lymphatic system disorders

Uncommon

Neutropaenia

Immune system disorders

Uncommon

Hypersensitivity

Rare

Angioedema, allergic reaction

Metabolism and nutrition disorders

Common

Appetite increased

Uncommon

Anorexia, hypoglycaemia

Psychiatric disorders

Common

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

Uncommon

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

Rare

Disinhibition, suicidal behaviour, suicidal ideation

Not known

Drug dependence (see section 4.4)

Nervous system disorders

Very common

Dizziness, somnolence, headache

Common

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

Uncommon

Syncope, stupor, myoclonus, loss of consciousness, psychomotor hyperactivity, dyskinesia, dizziness postural, intention tremor, nystagmus, cognitive disorder, mental impairment, speech disorder, hyporeflexia, hyperaesthesia, burning sensation, ageusia, malaise

Rare

Convulsions, parosmia, hypokinesia, dysgraphia, parkinsonism

Eye disorders

Common

Vision blurred, diplopia

Uncommon

Peripheral vision loss, visual disturbance, eye swelling, visual field defect, visual acuity reduced, eye pain, asthenopia, photopsia, dry eye, lacrimation increased, eye irritation

Rare

Vision loss, keratitis, oscillopsia, altered visual depth perception, mydriasis, strabismus, visual brightness

Ear and labyrinth disorders

Common

Vertigo

Uncommon

Hyperacusis

Cardiac disorders

Uncommon

Tachycardia, atrioventricular block first degree, sinus bradycardia, congestive heart failure

Rare

QT prolongation, sinus tachycardia, sinus arrhythmia

Vascular disorders

Uncommon

Hypotension, hypertension, hot flushes, flushing, peripheral coldness

Respiratory, thoracic and mediastinal disorders

Uncommon

Dyspnoea, epistaxis, cough, nasal congestion, rhinitis, snoring, nasal dryness

Rare

Pulmonary oedema, throat tightness

Not known

Respiratory depression

Gastrointestinal disorders

Common

Vomiting, nausea, constipation, diarrhoea, flatulence, abdominal distension, dry mouth

Uncommon

Gastrooesophageal reflux disease, salivary hypersecretion, hypoaesthesia oral

Rare

Ascites, pancreatitis, swollen tongue, dysphagia

Hepatobiliary disorders

Uncommon

Elevated liver enzymes*

Rare

Jaundice

Very rare

Hepatic failure, hepatitis

Skin and subcutaneous tissue disorders

Uncommon

Rash papular, urticaria, hyperhidrosis, pruritus

Rare

Toxic epidermal necrolysis, Stevens-Johnson syndrome, cold sweat

Musculoskeletal and connective tissue disorders

Common

Muscle cramp, arthralgia, back pain, pain in limb, cervical spasm

Uncommon

Joint swelling, myalgia, muscle twitching, neck pain, muscle stiffness

Rare

Rhabdomyolysis

Renal and urinary disorders

Uncommon

Urinary incontinence, dysuria

Rare

Renal failure, oliguria, urinary retention

Reproductive system and breast disorders

Common

Erectile dysfunction

Uncommon

Sexual dysfunction, ejaculation delayed, dysmenorrhoea, breast pain

Rare

Amenorrhoea, breast discharge, breast enlargement, gynaecomastia

General disorders and administration site conditions

Common

Oedema peripheral, oedema, gait abnormal, fall, feeling drunk, feeling abnormal, fatigue

Uncommon

Generalised oedema, face oedema, chest tightness, pain, pyrexia, thirst, chills, asthenia

Investigations

Common

Weight increased

Uncommon

Blood creatine phosphokinase increased, blood glucose increased, platelet count decreased, blood creatinine increased, blood potassium decreased, weight decreased

Rare

White blood cell count decreased

* Alanine aminotransferase increased (ALT) and aspartate aminotransferase increased (AST).

After discontinuation of short-term and long-term treatment with pregabalin withdrawal symptoms have been observed. The following symptoms have been reported: insomnia, headache, nausea, anxiety, diarrhoea, flu syndrome, convulsions, nervousness, depression, suicidal ideation, pain, hyperhidrosis and dizziness. These symptoms may indicate drug dependence. The patient should be informed about this at the start of the treatment.

Concerning discontinuation of long-term treatment of pregabalin, data suggest that the incidence and severity of withdrawal symptoms may be dose-related (see sections 4.2 and 4.4).

Paediatric population

The pregabalin safety profile observed in five paediatric studies in patients with partial seizures with or without secondary generalisation (12-week efficacy and safety study in patients 4 to 16 years of age, n = 295; 14-day efficacy and safety study in patients 1 month to younger than 4 years of age, n = 175; pharmacokinetic and tolerability study, n = 65; and two 1 year open label follow on safety studies, n = 54 and n = 431) was similar to that observed in the adult studies of patients with epilepsy. The most common adverse events observed in the 12-week study with pregabalin treatment were somnolence, pyrexia, upper respiratory tract infection, increased appetite, weight increased, and nasopharyngitis. The most common adverse events observed in the 14-day study with pregabalin treatment were somnolence, upper respiratory tract infection, and pyrexia (see sections 4.2, 5.1 and 5.2).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Patients should be informed of the signs and symptoms of overdose and to ensure that family and friends are also aware of these signs and to seek immediate medical help if they occur.

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. Seizures were also reported.

In rare occasions, cases of coma have been reported.

Treatment of pregabalin overdose should include general supportive measures and may include haemodialysis if necessary (see section 4.2 Table 1).