Pregabalin

Registered South African indications:

• Treatment of neuropathic pain due to herpes zoster infection and diabetes

Contraindications

South African recommendations & Recommendations in other jurisdictions

• Hypersensitivity to the active ingredient or any of its excipients 

Cautions

South African recommendations

• Pregnancy
• Women of childbearing potential not on effective contraception
• Breastfeeding
• Renal impairment
• Elderly
• Congestive heart failure
• Diabetic patients
• Suicidal ideation or behaviour
• History of substance abuse
• Underlying conditions that may cause encephalopathy
• Coadministration with opioids
• May impair ability to drive and operate machinery

Recommendations in other jurisdictions

• Pregnancy
• Women of childbearing potential not on effective contraception
• Breastfeeding
• Renal impairment
• Elderly
• Diabetic patients
• Pre-existing visual disturbances
• Congestive heart failure
  - Elderly (cardiovascular compromised patients)
• Central neuropathic pain due to spinal cord injury
• Compromised respiratory function
• Respiratory disease
• Neurological disease
• History of substance abuse
• Suicidal ideation or behaviour
• Underlying conditions that may precipitate encephalopathy
• Withdrawal of concomitant antiepileptic agents
• Coadministration with agents that cause constipation
• Coadministration with opioids
• Coadministration with central nervous system depressants
• Coadministration with anti-spasticity agents
• Galactose intolerance
• Lapp lactase deficiency
• Glucose-galactose malabsorption
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: cap

Dosages below include:

• South African registered indications and dosages
• Indications and dosages registered in other jurisdictions

South African registered indications and dosages

Treatment of neuropathic pain due to herpes zoster infection and diabetes

• Oral (cap): Initial: 75mg, 12hrly; Titrate to 150mg, 12hrly after an interval of 3-7 days based on individual patient response and tolerability

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Pregabalin can be taken with or without food

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In accordance with current clinical practice, if pregabalin must be discontinued, it is recommended this should be done gradually over a minimum of 1 week. See additional prescribing points for instructions on discontinuation of pregabalin

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Indications and dosages registered in other jurisdictions

Neuropathic pain
- Peripheral and central neuropathic pain

• Oral (cap): Initial: 150mg/day, in 2-3 divided doses; Titrate to 300mg/day after an interval of 3-7 days; Titrate to 600mg/day after an additional 7 day interval, if needed based on individual patient response and tolerability; Max: 600mg/24hrs

Epilepsy
- As adjunctive therapy in adults with partial seizures with or without secondary generalisation

• Oral (cap): Initial: 150mg/day, in 2-3 divided doses; Titrate to 300mg/day at an interval of 1 week; Titrate to 600mg/day after an additional week based on individual patient response and tolerability; Max: 600mg/24hrs

Generalised anxiety disorder 

• Oral (cap): Initial: 150mg/day, in 2-3 divided doses; Titrate by 150mg at intervals of 1 week based on individual patient response and tolerability; Max: 600mg/24hrs

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The dose range is 150-600mg per day given in 2-3 divided doses based on individual patient response and tolerability

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Pregabalin can be taken with or without food

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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 additional prescribing points for instructions on discontinuation of pregabalin

Not established for use in children below 18 years

Pregnancy

South African recommendations

• Caution; not recommended
• 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, pregabalin should not be used during pregnancy
• As the potential risk of pregabalin to humans is unknown, effective contraception must be used in women of child-bearing potential

Recommendations in other jurisdictions

• Caution; not recommended
• Studies in animals have shown reproductive toxicity
• Pregabalin has been shown to cross the placenta in rats. Pregabalin may cross the human placenta
• Data from a Nordic observational study of more than 2700 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
• Use in the first trimester of pregnancy may cause major birth defects in the unborn child
• Pregabalin should not be used during pregnancy unless clearly necessary (if the benefit to the mother clearly outweighs the potential risk to the foetus)
• Women of childbearing potential have to use effective contraception during treatment

Breastfeeding

South African recommendations

• Caution; not recommended
• Pregabalin is excreted in the breast milk of humans, however, it was found to be present in the milk of rats. Therefore, breastfeeding is not recommended

Recommendations in other jurisdictions

• Caution; not recommended
• Pregabalin is excreted into human milk. The effect of pregabalin on newborns/infants is unknown. A decision must be made whether to discontinue breastfeeding or to discontinue pregabalin therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman

Fertility 

South African recommendations

• There is no clinical data on the effects of pregabalin on female fertility

Recommendations in other jurisdictions

• 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 600mg/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 in unknown

Renal Impairment

South African recommendations

• Caution; dose adjustment recommended
  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 dosage supplementation following haemodialysis is necessary
  See additional prescribing points for further information

CrCl (ml/min)	Dose
≥60	Initial: 150mg, dly in 2 divided doses; Max: 300mg/24hrs
30-60	Initial: 75mg, dly in 1-2 divided doses; Max: 150mg/24hrs
15-30	Initial: 25mg-50mg, dly in 1-2 divided doses; Max: 75mg/24hrs
<15	Initial: 25mg, dly; Max. 25mg-50mg/24hrs
Haemodialysis  (Supplementary dose)	25mg as a single additional dose after dialysis; Max: 50mg/24hrs

Recommendations in other jurisdictions

• Caution; dose adjustment recommended
  Pregabalin is eliminated from the systemic circulation primarily by renal excretion as unchanged drug. As pregabalin clearance is directly proportional to creatinine clearance, dose reduction in patients with compromised renal function must be individualised according to creatinine clearance. 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 additional prescribing points for further information

CrCl (ml/min)	Dose
≥60	Initial: 150mg dly in 2-3 divided doses; Max. 600mg/24hrs
≥30-<60	Initial: 75mg in 2-3 divided doses; Max. 300mg/24hrs
≥15-<30	Initial: 25-50mg in 1-2 divided doses; Max. 150mg/24hrs
<15	Initial: 25mg every 24hrs; Max. 75mg/24hrs
Haemodialysis  (Supplementary dose)	25mg as a single additional dose after dialysis; Max: 100mg/24hrs

Hepatic Impairment

• No dose adjustment recommended

Elderly

South African recommendations

• Caution; no dose adjustment recommended
• No dosage adjustment is necessary for elderly patients unless their renal function is compromised
• Pregabalin clearance tends to decrease with increasing age. This decrease in pregabalin 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

Recommendations in other jurisdictions

• Caution; no dose adjustment recommended
• Elderly patients may require a dose reduction of pregabalin due to a decreased renal function

Porphyria Information

• Probably not porphyrinogenic (PNP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Euphoric mood
• Confusion
• Irritability
• Disorientation
• Insomnia
• Decreased libido
• Hallucinations
• Panic attacks
• Restlessness
• Agitation
• Depression
• Depressed mood
• Elevated mood
• Aggression
• Mood swings
• Depersonalisation
• Difficulty finding words
• Abnormal dreams
• Increased libido
• Anorgasmia
• Apathy
• Disinhibition
• Dizziness
• Somnolence
• Headaches
• Ataxia
• Abnormal coordination
• Tremor
• Dysarthria
• Amnesia
• Memory impairment
• Attention disturbance
• Sedation
• Balance disorder
• Lethargy
• Syncope
• Stupor
• Myoclonus
• Loss of consciousness
• Psychomotor hyperactivity
• Dyskinesia
• Postural dizziness
• Intention tremor
• Nystagmus
• Cognitive disorder
• Mental impairment
• Speech disorder
• Hyporeflexia
• Malaise
• Seizures
• Hypokinesia
• Dysgraphia
• Parkinsonism
• Abnormal gait
• Feeling drunk
• Feeling abnormal
• Suicidal behaviour
• Suicidal ideation

Cardiovascular Disorders

• Tachycardia
• First degree atrioventricular block 
• Sinus bradycardia
• Congestive heart failure
• QT prolongation
• Sinus tachycardia
• Sinus arrhythmia
• Hypotension
• Hypertension
• Hot flushes
• Flushing
• Peripheral coldness

Respiratory Disorders

• Dyspnoea
• Epistaxis
• Cough
• Nasal congestion
• Rhinitis
• Snoring
• Nasal dryness
• Pulmonary oedema
• Throat tightness
• Respiratory depression
• Nasopharyngitis

Gastrointestinal Disorders

• Nausea and vomiting
• Constipation
• Diarrhoea
• Flatulence
• Abdominal distension
• Dry mouth
• Gastroesophageal reflux disease
• Salivary hypersecretion
• Oral hypoaesthesia
• Ascites
• Pancreatitis
• Swollen tongue
• Dysphagia
• Thirst

Hepatobiliary Disorders

• Elevated liver enzymes
• Jaundice
• Hepatic failure
• Hepatitis

Genitourinary Disorders

• Urinary incontinence
• Dysuria
• Renal failure
• Oliguria
• Urinary retention
• Erectile dysfunction
• Delayed ejaculation
• Dysmenorrhoea
• Amenorrhoea
• Sexual dysfunction

Endocrine and Metabolic Disorders

• Increased appetite
• Anorexia
• Hypoglycaemia
• Breast discharge
• Breast enlargement
• Gynaecomastia
• Breast pain
• Increased weight
• Increased blood glucose
• Decreased weight

Musculoskeletal Disorders

• Muscle cramp
• Arthralgia
• Back pain
• Limb pain
• Cervical spasm
• Joint swelling
• Myalgia
• Muscle twitching
• Neck pain
• Muscle stiffness
• Rhabdomyolysis
• Increased blood creatine phosphokinase

Skin and Subcutaneous Tissue Disorders

• Papular rash
• Urticaria
• Hyperhidrosis
• Pruritis
• Stevens-Johnson syndrome
• Cold sweat

Immune, Blood and Lymphatic System Disorders

• Neutropenia
• Hypersensitivity
• Angioedema
• Allergic reaction
• Fever
• Decreased platelet count
• Increased blood creatinine
• Decreased blood potassium
• Oedema
  - Peripheral oedema
  - Generalised oedema
• Decreased white blood cell count

Sensory Disorders

• Hyperaesthesia
• Ageusia
• Parosmia
• Paraesthesia
• Hypoaesthesia
• Burning sensation
• Blurred vision
• Diplopia
• Peripheral vision loss
• Visual disturbance
• Eye swelling
• Visual field defect
• Reduced visual acuity
• Eye pain
• Asthenopia
• Photopsia
• Dry eye
• Increased lacrimation
• Eye irritation
• Vision loss
• Keratitis
• Oscillopsia
• Altered visual depth perception
• Mydriasis
• Strabismus
• Visual brightness
• Vertigo
• Hyperacusis

Others

• Face oedema
• Chills
• Chest tightness
• Pain
• Fall

• Central nervous system influencing agents
• Lorazepam
• Opioids
• Central nervous system depressants
• Oxycodone

Other interactions

• Ethanol

• Weight gain

Specific cases may require

• Creatine kinase
• Platelet count

Additional observations

• Measures of efficacy (pain intensity/seizure frequency)
• Mental alertness
• Symptoms of respiratory depression and sedation in patients with underlying respiratory disease
• Symptoms of myopathy
• Symptoms of ocular disturbance
• Oedema
• Skin integrity (in patients with diabetes)
• Signs and symptoms of suicidality (eg, suicidal thoughts, anxiety, depression, behavioural changes)
• Symptoms of misuse, abuse or dependence
• Degree of sedation

Dose adjustment in renal impairment

• Pregabalin is eliminated unchanged from the systemic circulation primarily by renal excretion. 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), using the following formula:

• Pregabalin is removed effectively from plasma by haemodialysis (50 % of pregabalin 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

Hypersensitivity reactions

• There have been reports in the post-marketing reports of hypersensitivity reactions in patients shortly after initiation of treatment with pregabalin, including cases of angioedema and urticaria. 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 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 medication

Discontinuation of pregabalin

• 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, seizures, nervousness, depression, pain, hyperhidrosis and dizziness, suggestive of physical dependence. The patient should be informed about this at the start of the treatment
• In accordance with current clinical practice, if pregabalin must be discontinued, it is recommended this should be done gradually over a minimum of 1 week
• Seizures, including status epilepticus and grand mal seizures, may occur during pregabalin use or shortly after discontinuing pregabalin
• Concerning discontinuation of long-term treatment of pregabalin, data suggest that the incidence and severity of withdrawal symptoms may be dose-related

Pregabalin binds to an auxiliary subunit (alpha-2-delta protein) of voltage-gated calcium channels in the central nervous system.

Capsule 25mg

• Avertz 25 (Dr Reddy's Laboratories)
• Lybet 25 (Ranbaxy Pharmaceuticals)
• Lyrica 25mg  (UpJohn) originator
• Myalica 25mg (Pharma Dynamics)
• Nergil 25mg (Aurogen South Africa)
• Nubacap 25 (Forrester Pharma)
• Nurika (Teva Pharmaceuticals)
• Pregabalin 25 Cipla (Cipla Medpro)
• Pregabalin Ivax 25 (Teva Pharmaceuticals)
• Pregabalin Mylan 25mg (Mylan)
• Pylixa 25 (Spear Pharmaceuticals)
• Pregabalin Teva (Teva Pharmaceuticals)
• Timiril 25mg (Strides Pharma)

Capsule 75mg

• Avertz 75 (Dr Reddy's Laboratories)
• Lybet 75 (Ranbaxy Pharmaceuticals)
• Lyrica 75mg (UpJohn) originator
• Myalica 75mg (Pharma Dynamics)
• Nergil 75mg (Aurogen South Africa)
• Nubacap 75 (Forrester Pharma)
• Nurika (Teva Pharmaceuticals)
• Pregabalin 75 Cipla (Cipla Medpro)
• Pregabalin Ivax 75 (Teva Pharmaceuticals)
• Pregabalin Mylan 75mg (Mylan)
• Pylixa 75 (Spear Pharmaceuticals)
• Pregabalin Teva (Teva Pharmaceuticals)
• Timiril 75mg (Strides Pharma)

Capsule 150mg

• Avertz 150 (Dr Reddy's Laboratories)
• Lybet 150 (Ranbaxy Pharmaceuticals)
• Lyrica 150mg (UpJohn) originator
• Myalica 150mg (Pharma Dynamics)
• Nergil 150mg (Aurogen South Africa)
• Nubacap 150 (Forrester Pharma)
• Nurika (Teva Pharmaceuticals)
• Pregabalin 150 Cipla (Cipla Medpro)
• Pregabalin Ivax 150 (Teva Pharmaceuticals)
• Pregabalin Mylan 150mg (Mylan)
• Pylixa 150 (Spear Pharmaceuticals)
• Pregabalin Teva (Teva Pharmaceuticals)
• Timiril 150mg  (Strides Pharma)