Neuropathic pain:

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

Epilepsy:

Nervax is indicated as adjunctive therapy in adults with partial seizures with or without secondary generalization.

Generalised Anxiety Disorder:

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

The dose range is 150 to 600 mg per day given in either two or three divided doses. Nervax may be taken with or without food.

Neuropathic pain

Pregabalin treatment can be started at a dose of 150 mg per day. Based on individual patient response and tolerability, the dosage 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. Based on individual patient response and tolerability, the dosage may be increased to 300 mg per day after 1 week. The maximum dosage 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.

Discontinuation of pregabalin
In accordance with current clinical practice, if pregabalin has to be discontinued either in neuropathic pain or epilepsy, it is recommended this should be done gradually over a minimum of 1 week.

Patients with renal impairment
As pregabalin clearance is directly proportional to creatinine clearance, dosage reduction in patients with compromised renal function must be individualised according to creatinine clearance (CLcr).
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.

TID = Three divided doses

BID = Two divided doses

QD = Single daily dose

* 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 dosage adjustment is required for patients with hepatic impairment.

Use in children and adolescents (12 to 17 years of age)

The safety and effectiveness of pregabalin in pediatric patients below the age of 12 years and adolescents has not been established.

The use in children is not recommended.

Use in the elderly (over 65 years of age)

Elderly patients may require a dose reduction of pregabalin due to a decreased renal function.

Angioedema: There have been postmarketing reports of angioedema in patients during initial and chronic treatment with pregabalin. Specific symptoms included swelling of the face, mouth (tongue, lips, and gums), and neck (throat and larynx). There were reports of life-threatening angioedema with respiratory compromise requiring emergency treatment. Discontinue pregabalin immediately in patients with these symptoms.

Exercise caution when prescribing pregabalin to patients who have had a previous episode of angioedema. In addition, patients who are taking other drugs associated with angioedema (e.g., angiotensin converting enzyme inhibitors [ACE-inhibitors]) may be at increased risk

of developing angioedema.

Hypersensitivity: There have been postmarketing reports of hypersensitivity in patients shortly after initiation of treatment with pregabalin. Adverse reactions included skin redness, blisters, hives, rash, dyspnea, and wheezing. Discontinue pregabalin immediately in patients with these symptoms.

Withdrawal of Antiepileptic Drugs (AEDs): As with all AEDs, withdraw pregabalin gradually to minimize the potential of increased seizure frequency in patients with seizure disorders. If pregabalin is discontinued, taper the drug gradually over a minimum of 1 week.

Suicidal Behavior and Ideation: Antiepileptic drugs (AEDs), including pregabalin, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Monitor patients treated with any AED for any indication for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Peripheral Edema: Pregabalin treatment may cause peripheral edema. In short-term trials of patients without clinically significant heart or peripheral vascular disease, there was no apparent association between peripheral edema and cardiovascular complications such as

hypertension or congestive heart failure. Peripheral edema was not associated with laboratory changes suggestive of deterioration in renal or hepatic function.

In controlled clinical trials the incidence of peripheral edema was 6% in the pregabalin group compared with 2% in the placebo group. In controlled clinical trials, 0.5% of pregabalin patients and 0.2% placebo patients withdrew due to peripheral edema.

Higher frequencies of weight gain and peripheral edema were observed in patients taking both pregabalin and a thiazolidinedione antidiabetic agent compared to patients taking either drug alone. The majority of patients using thiazolidinedione antidiabetic agents in the  overall safety database were participants in studies of pain associated with diabetic peripheral neuropathy. In this population, peripheral edema was reported in 3% (2/60) of patients who were using thiazolidinedione antidiabetic agents only, 8% (69/859) of patients who were treated with pregabalin only, and 19% (23/120) of patients who were on both pregabalin and thiazolidinedione antidiabetic agents. Similarly, weight gain was reported in 0% (0/60) of patients on thiazolidinediones only; 4% (35/859) of patients on pregabalin only; and 7.5% (9/120) of patients on both drugs.

As the thiazolidinedione class of antidiabetic drugs can cause weight gain and/or fluid retention, possibly exacerbating or leading to heart failure, exercise caution when coadministering pregabalin and these agents.

Because there are limited data on congestive heart failure patients with New York Heart Association (NYHA) Class III or IV cardiac status, exercise caution when using pregabalin in these patients.

Dizziness and Somnolence: Pregabalin may cause dizziness and somnolence. Inform patients that pregabalin -related dizziness and somnolence may impair their ability to perform tasks such as driving or operating machinery.

Weight Gain: Pregabalin treatment may cause weight gain. In pregabalin controlled clinical trials of up to 14 weeks, a gain of 7% or more over baseline weight was observed in 9% of pregabalin -treated patients and 2% of placebo-treated patients. Few patients treated with pregabalin (0.3%) withdrew from controlled trials due to weight gain. Pregabalin associated weight gain was related to dose and duration of exposure, but did not appear to be associated with baseline BMI, gender, or age. Weight gain was not limited to patients with edema. Although weight gain was not associated with clinically important changes in blood pressure in short-term controlled studies, the long-term cardiovascular effects of pregabalin - associated weight gain are unknown.

Among diabetic patients, pregabalin -treated patients gained an average of 1.6 kg (range: - 16 to 16 kg), compared to an average 0.3 kg (range: -10 to 9 kg) weight gain in placebo patients. In a cohort of 333 diabetic patients who received pregabalin for at least 2 years, the

average weight gain was 5.2 kg.

While the effects of pregabalin -associated weight gain on glycemic control have not been systematically assessed, in controlled and longer-term open label clinical trials with diabetic patients, pregabalin treatment did not appear to be associated with loss of glycemic control (as measured by HbA1C).

Abrupt or Rapid Discontinuation: Following abrupt or rapid discontinuation of pregabalin, some patients reported symptoms including insomnia, nausea, headache, and diarrhea. Taper pregabalin gradually over a minimum of 1 week rather than discontinuing the drug abruptly.

Tumorigenic Potential: In standard preclinical in vivo lifetime carcinogenicity studies of pregabalin, an unexpectedly high incidence of hemangiosarcoma was identified in two different strains of mice. The clinical significance of this finding is unknown. Clinical experience during pregabalin premarketing development provides no direct means to assess its potential for inducing tumors in humans.

In clinical studies across various patient populations, comprising 6396 patient-years of exposure in patients >12 years of age, new or worsening-preexisting tumors were reported in 57 patients. Without knowledge of the background incidence and recurrence in similar populations not treated with pregabalin, it is impossible to know whether the incidence seen in these cohorts is or is not affected by treatment.

Ophthalmological Effects: In controlled studies, a higher proportion of patients treated with pregabalin reported blurred vision (7%) than did patients treated with placebo (2%), which resolved in a majority of cases with continued dosing. Less than 1% of patients discontinued pregabalin treatment due to vision-related events (primarily blurred vision).

Prospectively planned ophthalmologic testing, including visual acuity testing, formal visual field testing and dilated funduscopic examination, was performed in over 3600 patients. In these patients, visual acuity was reduced in 7% of patients treated with pregabalin, and 5% of placebo-treated patients. Visual field changes were detected in 13% of pregabalin - treated, and 12% of placebo-treated patients. Funduscopic changes were observed in 2% of pregabalin -treated and 2% of placebo-treated patients.

Although the clinical significance of the ophthalmologic findings is unknown, inform patients to notify their physician if changes in vision occur. If visual disturbance persists, consider further assessment. Consider more frequent assessment for patients who are already routinely monitored for ocular conditions.

Creatine Kinase Elevations: Pregabalin treatment was associated with creatine kinase elevations. Mean changes in creatine kinase from baseline to the maximum value were 60 U/L for pregabalin -treated patients and 28 U/L for the placebo patients. In all controlled trials across multiple patient populations, 1.5% of patients on pregabalin and 0.7% of placebo patients had a value of creatine kinase at least three times the upper limit of normal. Three pregabalin treated subjects had events reported as rhabdomyolysis in premarketing clinical trials. The relationship between these myopathy events and pregabalin is not completely understood because the cases had documented factors that may have caused or contributed to these events. Instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if these muscle symptoms are accompanied by malaise or fever. Discontinue treatment with pregabalin if myopathy is diagnosed or suspected or if markedly elevated creatine kinase levels occur.

Decreased Platelet Count: Pregabalin treatment was associated with a decrease in platelet count. Pregabalin -treated subjects experienced a mean maximal decrease in platelet count of 20 Å~ 103/μL, compared to 11 Å~ 103/μL in placebo patients. In the overall database of controlled trials, 2% of placebo patients and 3% of pregabalin patients experienced a potentially clinically significant decrease in platelets, defined as 20% below baseline value and <150 Å~ 103/μL. A single pregabalin treated subject developed severe thrombocytopenia with a platelet count less than 20 Å~ 103/ μL. In randomized controlled trials, pregabalin A was not associated with an increase in bleeding-related adverse reactions.

PR Interval Prolongation: Pregabalin treatment was associated with PR interval prolongation. In analyses of clinical trial ECG data, the mean PR interval increase was 3–6 msec at pregabalin doses ≥300 mg/day. This mean change difference was not associated with an increased risk of PR increa≥s2e5 % from baseline, an increased percentage of subjects with on-treatment PR >200 msec, or an increased risk of adverse reactions of second or third degree AV block.

Subgroup analyses did not identify an increased risk of PR prolongation in patients with baseline PR prolongation or in patients taking other PR prolonging medications. However, these analyses cannot be considered definitive because of the limited number of patients in these categories.

Respiratory Depression: Pregabalin has been associated with serious, life-threatening, and fatal respiratory depression. The risk may be increased with the concomitant use of opioids and other central nervous system (CNS) depressants, and with conditions such as chronic
obstructive pulmonary disease. The elderly are also at higher risk. Health care providers should start pregabalin at the lowest dose and monitor patients for symptoms of respiratory depression and sedation when co-prescribing pregabalin with an opioid or other CNS
depressants (eg, benzodiazepines). Patients with underlying respiratory disease and elderly patients are also at increased risk and should be managed similarly.

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.

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

Opioids and CNS depressants
Serious respiratory depression may occur with pregabalin when co-administered with opioids and CNS depressants such as benzodiazepine. Therefore, monitor for symptoms of respiratory depression and sedation in patients who require concomitant treatment with opioids or CNS depressants.

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

Studies in animals have shown reproductive toxicity. The potential risk to humans is unknown. Therefore, Nervax should not be used during pregnancy unless the benefit to the mother clearly outweighs the potential risk to the foetus. Effective contraception must be

used in women of child bearing potential.

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.

Nervax 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 medication affects their ability to perform these activities.

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 13 % for patients receiving pregabalin and 7 % for patients receiving placebo. The most common adverse reactions resulting in discontinuation from pregabalin treatment groups were dizziness and somnolence.

Mentioned below all the side effects listed by class and frequency

(Very common >1/10, common > 1/100, < 1/10) , rare <1/100) 

Blood and lymphatic system disorders

Rare, Neutropenia.

Metabolism and nutrition disorders

Common: Appetite increased, Uncommon: Anorexia, Rare: Hypoglycaemia

Psychiatric disorders

Common: Euphoric mood, confusion, libido decreased, irritability, Uncommon: Depersonalisation, anorgasmia, restlessness, depression, agitation, mood swings, insomnia exacerbated, depressed mood, word finding difficulty, hallucination, abnormal dreams, libido increased, panic attack, apathy, Rare: Disinhibition, elevated mood

Nervous system disorders

Very Common: Dizziness, somnolence, Common: Ataxia, disturbance in attention, coordination abnormal, memory impairment, tremor, dysarthria, paraesthesia, Uncommon: Cognitive disorder, hypoaesthesia,visual field defect, nystagmus, speech disorder, myoclonus, hyporeflexia, dyskinesia, psychomotor hyperactivity, dizziness postural, hyperaesthesia, ageusia, burning sensation, intention tremor, stupor, syncope.

Rare: Hypokinesia,parosmia,dysgraphia

Eye disorders

Common: Vision blurred, diplopia, Uncommon: Visual disturbance, dry eye, eye swelling, visual acuity reduced, eye pain, asthenopia, lacrimation increased, Rare: Photopsia, eye irritation, mydriasis, oscillopsia, altered visual depth perception, peripheral vision loss, strabismus, visual brightness

Ear and labyrinth disorders

Common: Vertigo, Rare: Hyperacusis

Cardiac disorders

Uncommon: Tachycardia, Rare: Atrioventricular block first degree, sinus tachycardia, sinus arrhythmia, sinus bradycardia.

Vascular disorders

Uncommon: Flushing, hot flushes, Rare: Hypotension, peripheral coldness, hypertension

Respiratory ,thoracic and mediastinal disorders

Uncommon: Dyspnoea, nasal dryness. Rare: Nasopharyngitis, cough, nasal congestion, epistaxis, rhinitis, snoring, throat tightness

Gastrointestinal disorders

Common: Dry mouth, constipation, vomiting, flatulence, Uncommon: Abdominal distension, salivary hypersecretion, gastrooesophageal reflux disease, hypoaesthesia oral.

Rare: Ascites, dysphagia, pancreatitis.

Skin and subcutaneous tissue disorders

Uncommon: Sweating, rash popular, Rare: Cold sweat, urticaria

Musculoskeletal and connective tissue disorders

Uncommon: Muscle twitching, joint swelling, muscle cramp, myalgia, arthralgia, back pain, pain in limb, muscle stiffness,

Rare: Cervical spasm, neck pain, rhabdomyolysis.

Renal and urinary disorders

Uncommon: Dysuria, urinary incontinence, Rare: Oliguria, renal failure

Reproductive system and breast disorders

Common: Erectile dysfunction, Uncommon: Ejaculation delayed, sexual dysfunction, Rare: Amenorrhoea, breast pain, breast discharge, dysmenorrhoea, hypertrophy breast.

General disorders and administration site conditions

Common : Fatigue, oedema peripheral, feeling drunk, oedema, gait abnormal, Uncommon: Asthenia, fall, thirst, chest tightness,

Rare: Pain exacerbated anasarca, pyrexia, rigors.

Investigations

Common: Weight increased, Uncommon: Alanine aminotransferase increased, blood creatine phosphokinase increased, aspartate aminotransferase increased, platelet count decreased, Rare: Blood glucose increased, blood creatinine increased, blood potassium decreased, weight decreased, white blood cell count decreased.

Please report adverse drug events to:
The National Pharmacovigilance Centre (NPC):
Fax: +966-11-205-7662
SFDA Call Center: 19999
E-mail: npc.drug@sfda.gov.sa
Website: https://ade.sfda.gov.sa

In overdoses up to 15 g, no unexpected adverse reactions were reported. Treatment of pregabalin overdose should include general supportive measures and may include haemodialysis if necessary.

Pharmacotherapeutic group: Antiepileptics.

ATC code: N03AX16

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

Mechanism of action

Pregabalin binds to an auxiliary subunit (α2-δ protein) of voltage-gated calcium channels in the central nervous system, potently displacing [3H]-gabapentin.

Clinical experience:

Neuropathic pain

Efficacy has been shown in studies 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 studies of up to 13 weeks with twice a day dosing (BID) and up to 8 weeks with three times a day (TID) dosing. Overall, the safety and efficacy profiles for BID and 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 week 1 and was maintained throughout the treatment period.

In controlled clinical trials in peripheral neuropathic pain 35% of the pregabalin treated patients and 18% of the patients on placebo had a 50% improvement in pain score. For 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

Pregabalin has been studied in 3 controlled clinical studies 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.

Generalised Anxiety Disorder

Pregabalin has been studied in 6 controlled studies 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 (HAMA) was observed by Week 1.

In controlled clinical trials (4-8 week duration) 52% of the pregabalin treated patients and 38% of the patients on placebo had at least a 50% improvement in HAM-A total score from baseline to endpoint.

In controlled studies, a higher proportion of patients treated with pregabalin reported blurred vision than did patients treated with placebo which resolved in a majority of cases with continued dosing. Ophthamologic testing (including visual acuity testing, formal visual field testing and dilated funduscopic examination) was conducted in over 3600 patients within controlled clinical trials. In these patients, visual acuity was reduced in 6.5% of patients treated with pregabalin, and 4.8% of placebo-treated patients. Visual field changes were detected in 12.4% of pregabalin-treated, and 11.7% of placebo-treated patients. Funduscopic changes were observed in 1.7% of pregabalin-treated and 2.1% of placebo-treated patients.

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 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 C_max 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:

The apparent volume of distribution of pregabalin following oral administration is approximately 0.56 l/kg. Pregabalin is not bound to plasma proteins.

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. Dosage adjustment in patients with reduced renal function or undergoing haemodialysis is necessary.

In conventional safety pharmacology studies in animals, pregabalin was well-tolerated at clinically relevant doses. In repeated dose toxicity studies in rats and monkeys CNS effects were observed, including hypoactivity, hyperactivity and ataxia. An increased incidence of retinal atrophy commonly observed in aged albino rats was seen after long term exposure to pregabalin at exposures 5 times the mean human exposure at the maximum recommended clinical dose.

Pregabalin was not teratogenic in mice, rats or rabbits. Foetal toxicity in rats and rabbits occurred only at exposures sufficiently above human exposure. In prenatal/postnatal toxicity studies, pregabalin induced offspring developmental toxicity in rats at exposures>2 times the maximum recommended human exposure.

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. 

Store below 30°C.

Do not use beyond the expiry date or if the product shows any sign of deterioration.

Two Aluminum-PVC/PVDC blisters of 10 capsules each, packed in a printed carton with folded leaflet.

Six Aluminum-PVC/PVDC blisters of 10 capsules each, packed in a printed carton with folded leaflet.

No special requirements.