Pregabalin 1A Farma 100 mg Kapsel, hård

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

Bipacksedel Bipacksedel (PIL)

22-04-2018

Produktens egenskaper Produktens egenskaper (SPC)

22-04-2018

Aktiva substanser:
pregabalin
Tillgänglig från:
Billev Pharma ApS,
ATC-kod:
N03AX16
INN (International namn):
pregabalin
Dos:
100 mg
Läkemedelsform:
Kapsel, hård
Sammansättning:
propylenglykol Hjälpämne; pregabalin 100 mg Aktiv substans; mannitol Hjälpämne
Receptbelagda typ:
Receptbelagt
Produktsammanfattning:
Förpacknings: Burk, 60 kapslar; Blister, 56 kapslar; Blister, 14 kapslar; Blister, 7 kapslar; Blister, 84 kapslar; Blister, 100 kapslar; Blister, 112 kapslar; Blister, 100 x 1 kapslar (endos)
Bemyndigande status:
Godkänd
Godkännandenummer:
54334
Tillstånd datum:
2016-06-22

Dokument på andra språk

Bipacksedel Bipacksedel - engelska

11-03-2021

Produktens egenskaper Produktens egenskaper - engelska

11-03-2021

Offentlig bedömningsrapport Offentlig bedömningsrapport - engelska

22-08-2019

Läs hela dokumentet

Package Leaflet: Information for the user

Pregabalin 1A Farma 25 mg hard capsules,

Pregabalin 1A Farma 50 mg hard capsules,

Pregabalin 1A Farma 75 mg hard capsules,

Pregabalin 1A Farma 100 mg hard capsules,

Pregabalin 1A Farma 150mg hard capsules,

Pregabalin 1A Farma 200 mg hard capsules,

Pregabalin 1A Farma 225 mg hard capsules,

Pregabalin 1A Farma 300 mg hard capsules

Pregabalin

Read all of this leaflet carefully before you start taking this medicine because it contains

important information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or pharmacist.

This medicine has been prescribed for you only. Do not pass it on to others. It may harm

them, even if their signs of illness are the same as yours.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible

side effects not listed in this leaflet.

See section 4.

What is in this leaflet:

1. What [Invented name] is and what it is used for

2. What you need to know before you take [Invented name]

3. How to take [Invented name]

4. Possible side effects

5. How to store [Invented name]

6. Contents of the pack and other information

1. What [Invented name] is and what it is used for

[Invented name] belongs to a group of medicines used to treat epilepsy, neuropathic pain and

Generalised Anxiety Disorder (GAD) in adults.

Peripheral and central neuropathic pain:

[Invented name] is used to treat long lasting pain

caused by damage to the nerves. A variety of diseases can cause peripheral neuropathic pain,

such as diabetes or shingles.

Pain sensations may be described as hot, burning, throbbing, shooting, stabbing, sharp,

cramping, aching, tingling, numbness, pins and needles. Peripheral and central neuropathic

pain may also be associated with mood changes, sleep disturbance, fatigue (tiredness), and

can have an impact on physical and social functioning and overall quality of life.

Epilepsy:

[Invented name] is used to treat a certain form of epilepsy (partial seizures with or

without secondary generalisation) in adults. Your doctor will prescribe [Invented name] for

you to help treat your epilepsy when your current treatment is not controlling your condition.

You should take [Invented name] in addition to your current treatment. [Invented name] is not

intended to be used alone, but should always be used in combination with other anti-epileptic

treatment.

Generalised Anxiety Disorder:

[Invented name] is used to treat Generalised Anxiety

Disorder (GAD). The symptoms of GAD are prolonged excessive anxiety and worry that are

difficult to control. GAD can also cause restlessness or feeling keyed up or on edge, being

easily fatigued (tired), having difficulty concentrating or mind going blank, feeling irritable,

having muscle tension or sleep disturbance. This is different to the stresses and strains of

everyday life.

2. What you need to know before you take [Invented name]

Do not take [Invented name]

If you are allergic to pregabalin or any of the other ingredients of this medicine (listed in

section 6).

Warnings and Precautions

Talk to your doctor, pharmacist or nurse before taking [Invented name].

Some patients taking pregabalin have reported symptoms suggesting an allergic reaction.

These symptoms include swelling of the face, lips, tongue, and throat, as well as diffuse

skin rash. Should you experience any of these reactions, you should contact your

physician immediately.

[Invented name] has been associated with dizziness and somnolence, which could

increase the occurrence of accidental injury (fall) in elderly patients. Therefore, you

should be careful until you are used to any effect the medicine might have.

[Invented name] may cause blurring or loss of vision, or other changes in eyesight, many

of which are temporary. You should immediately tell your doctor if you experience any

changes in your vision.

Some patients with diabetes who gain weight while taking pregabalin may need an

alteration in their diabetic medicines.

Certain side effects may be more common, such as sleepiness, because patients with

spinal cord injury may be taking other medicines to treat, for example, pain or spasticity,

that have similar side effects to pregabalin and the severity of these effects may be

increased when taken together.

There have been reports of heart failure in some patients when taking pregabalin; these

patients were mostly elderly with cardiovascular conditions.

Before taking this medicine

you should tell your doctor if you have a history of heart disease

There have been reports of kidney failure in some patients when taking pregabalin. If

while taking [Invented name] you notice decreased urination, you should tell your doctor

as stopping the medicine may improve this.

A small number of people being treated with anti-epileptics such as pregabalin have had

thoughts of harming or killing themselves. If at any time you have these thoughts,

immediately contact your doctor.

When [Invented name] is taken with other medicines that may cause constipation (such as

some types of pain medicines) it is possible that gastrointestinal problems may occur (e.g.

constipation, blocked or paralysed bowel). Tell your doctor if you experience

constipation, especially if you are prone to this problem.

Before taking this medicine you should tell your doctor if you have a history of

alcoholism or any drug abuse or dependence. Do not take more medicine than prescribed.

There have been reports of convulsions when taking pregabalin or shortly after stopping

pregabalin. If you experience a convulsion, contact your doctor immediately.

There have been reports of reduction in brain function (encephalopathy) in some patients

taking pregabalin when they have other conditions. Tell your doctor if you have a history

of any serious medical conditions, including liver or kidney disease.

There have been reports of breathing difficulties. If you have nervous system disorders,

respiratory disorders, renal impairment, or you are older than 65, your doctor may

prescribe you a different dosing regimen. Contact your doctor if you experience trouble

breathing or shallow breaths.

Children and adolescents

The safety and efficacy in children and adolescents (under 18 years of age) has not been

established and therefore, pregabalin should not be used in this age group.

Other medicines and [Invented name]

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other

medicines.

[Invented name] and certain other medicines may influence each other (interaction). When

taken with certain other medicines which have sedative effects (including opioids), [Invented

name] may potentiate these effects, and could lead to respiratory failure, coma and death. The

degree of dizziness, sleepiness and decreased concentration may be increased if [Invented

name] is taken together with medicines containing:

Oxycodone – (used as a pain-killer)

Lorazepam – (used for treating anxiety)

Alcohol

[Invented name] may be taken with oral contraceptives.

[Invented name] with food, drink and alcohol

[Invented name] capsules may be taken with or without food.

It is advised not to drink alcohol while taking [Invented name].

Pregnancy and breast-feeding

[Invented name] should not be taken during pregnancy or when breast-feeding, unless you are

told otherwise by your doctor. Effective contraception must be used by women of child-

bearing potential. If you are pregnant or breast-feeding, think you may be pregnant or are

planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Driving and using machines

[Invented name] may produce dizziness, sleepiness and decreased concentration. You should

not drive, operate complex machinery or engage in other potentially hazardous activities until

you know whether this medicine affects your ability to perform these activities.

3. How to take [Invented name]

Always take this medicine exactly as your doctor has told you. Check with your doctor or

pharmacist if you are not sure.

Your doctor will determine what dose is appropriate for you.

[Invented name] is for oral use only.

Peripheral and central neuropathic pain, epilepsy or Generalised Anxiety Disorder:

Take the number of capsules as instructed by your doctor.

The dose, which has been adjusted for you and your condition, will generally be between

150 mg and 600 mg each day.

Your doctor will tell you to take [Invented name] either twice or three times a day. For

twice a day take [Invented name] once in the morning and once in the evening, at about

the same time each day. For three times a day take [Invented name] once in the morning,

once in the afternoon and once in the evening, at about the same time each day.

If you have the impression that the effect of [Invented name] is too strong or too weak, talk to

your doctor or pharmacist.

If you are an elderly patient (over 65 years of age), you should take [Invented name] normally

except if you have problems with your kidneys.

Your doctor may prescribe a different dosing schedule and/or dose if you have problems with

your kidneys.

Swallow the capsule whole with water.

Continue taking [Invented name] until your doctor tells you to stop.

If you take more [Invented name] than you should

Call your doctor or go to the nearest hospital emergency unit immediately. Take your box or

bottle of [Invented name] capsules with you. You may feel sleepy, confused, agitated, or

restless as a result of taking more [Invented name] than you should. Fits have also been

reported.

If you forget to take [Invented name]

It is important to take your [Invented name] capsules regularly at the same time each day. If

you forget to take a dose, take it as soon as you remember unless it is time for your next dose.

In that case, just carry on with the next dose as normal. Do not take a double dose to make up

for a forgotten dose.

If you stop taking [Invented name]

Do not stop taking [Invented name] unless your doctor tells you to. If your treatment is

stopped it should be done gradually over a minimum of 1 week.

After stopping long and short-term [Invented name] treatment, you need to know that you

may experience certain side effects. These include, trouble sleeping, headache, nausea,

feeling anxious, diarrhoea, flulike symptoms, convulsions, nervousness, depression, pain,

sweating, and dizziness. These symptoms may occur more commonly or severely if you have

been taking [Invented name] for a longer period of time.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Very common

(may affect more than 1 in 10 people)

Dizziness

Drowsiness

Headache

Common

(may affect up to 1 in 10 people)

Increased appetite

Feeling of extreme joy (elation), confusion, disorientation, decrease in sexual interest,

irritability

Disturbance in attention, clumsiness, memory impairment, loss of memory, tremor,

difficulty with speaking, tingling feeling, numbness, sedation, lack of energy and

enthusiasm (lethargy), insomnia, fatigue, feeling abnormal.

Blurred vision, double vision.

Vertigo, problems with balance, fall.

Dry mouth, constipation, vomiting, flatulence, diarrhoea, nausea, swollen abdomen

Difficulties with erection

Swelling of the body including extremities.

Feeling drunk, abnormal style of walking.

Weight gain.

Muscle cramp, joint pain, back pain, pain in limb

Sore throat

Uncommon

(may affect up to 1 in 100 people)

Loss of appetite, weight loss, low blood sugar,

high blood sugar.

Change in perception of self, restlessness, depression, agitation, mood swings, difficulty

finding words, hallucinations (seeing or hearing things which are not there), abnormal

dreams, panic attacks, apathy, aggression, elevated mood, mental impairment, difficulty

with thinking, increase in sexual interest, problems with sexual functioning including

inability to achieve a sexual climax, delayed ejaculation.

Changes in eyesight, unusual eye movement, changes in vision including tunnel vision,

flashes of light, jerky movements, reduced reflexes, increased activity, dizziness on

standing, sensitive skin, loss of taste, burning sensation, tremor on movement, decreased

consciousness, loss of consciousness, fainting, increased sensitivity to noise, feeling

unwell.

Dry eyes, eye swelling, eye pain, weak eyes, watery eyes, eye irritation.

Heart rhythm disturbances, increased heart rate, low blood pressure, high blood pressure,

changes in heartbeat, heart failure.

Flushing, hot flushes.

Difficulty breathing, dry nose, nasal congestion.

Increased saliva production, heartburn, numb around mouth

Sweating, rash, chills,

fever.

Muscle twitching, joint swelling, muscle stiffness, pain including muscle pain, neck pain.

Breast pain.

Difficulty with or painful urination, incontinence.

Weakness, thirst, chest tightness.

Changes in blood and liver test results (blood creatinine phosphokinase increased, alanine

amino transferase increased, aspartate aminotransferase increased, platelet count

decreased, neutropenia, increase in blood creatinine, decrease in blood potassium).

Hypersensitivity, swollen face, itchiness, hives, runny nose, nose bleed, cough, snoring.

Painful menstrual periods.

Coldness of hands and feet.

Rare

(may affect up to 1 in 1,000 people)

Abnormal sense of smell, swinging vision, altered perception of depth, visual brightness,

vision loss.

Dilated pupils, cross eyes.

Cold sweat, tightness of the throat, swollen tongue.

Inflammation of the pancreas.

Difficulty in swallowing.

Slow or reduced movement of the body.

Difficulty with writing properly.

Increased fluid in the abdomen.

Fluid in the lungs

Convulsions

Changes in the recording of electrical changes (ECG) in the heart which correspond to

heart rhythm disturbances

Muscle damage.

Breast discharge, abnormal breast growth,

breast growth in males.

Interrupted menstrual periods.

Kidney failure, reduced urine volume, urinary retention.

Decrease in white blood cell count.

Inappropriate behaviour.

Allergic reactions (which may include difficulty breathing, inflammation of the eyes

(keratitis) and a serious skin reaction characterized by rash, blisters, peeling skin and

pain).

Jaundice (yellowing of the skin and eyes).

Very rare

(may affect up to 1 in 10,000 people)

Liver failure.

Hepatitis (inflammation of the liver).

If you experience swollen face or tongue or if your skin turns red and starts to blister or

peel you should seek immediate medical advice.

Certain side effects may be more common, such as sleepiness, because patients with spinal

cord injury may be taking other medicines to treat, for example, pain or spasticity, that have

similar side effects to pregabalin and the severity of these effects may be increased when

taken together.

The following adverse reaction has been reported in the post-marketing experience: Trouble

breathing, shallow breaths.

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible

side effects not listed in this leaflet. You can also report side effects directly via the national

reporting system listed in Appendix V. By reporting side effects you can help provide more

information on the safety of this medicine.

5. How to store [Invented name]

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date

which is stated on the carton

‘’EXP’’

. The

expiry date refers to the last day of that month.

This medicine does not require any special storage conditions.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist

how to throw away medicines you no longer use. These measures will help protect the

environment.

6. Contents of the pack and other information

What [Invented name] contains

The active substance is pregabalin. Each hard capsule contains either 25 mg

,

50 mg, 75

mg, 100 mg, 150 mg, 200 mg, 225 mg or 300 mg pregabalin.

The other ingredients are:

Capsule content: pregelatinized starch, mannitol, talc

Capsule shell: gelatin, titanium dioxide (E171), red Iron Oxide (E172) (only for 75 mg,

100 mg, 200 mg, 225 mg, 300 mg) and yellow iron oxide (E172) (only for 200 mg, 225

mg).

Printing Ink: Shellac, black iron oxide (E172), propylene glycol (E1520)

What [Invented name] looks like and contents of the pack

25 mg capsules: White hard capsules, marked

with

"25" on the body. The length of the

capsule cap is 6.97mm-7.97mm and the length of the capsule body is 11.8mm-12.84mm.

50 mg capsules: White hard capsules, marked

with

"50" on the body. The length of the

capsule cap is 7.73mm-8.73mm and the length of the capsule body is 12.98mm-13.98mm.

75 mg capsules: White and Swedish orange hard capsules, marked

with

"75" on the body.

The length of the capsule cap is 7.73mm-8.73mm and the length of the capsule body is

12.98mm-13.98mm.

100 mg capsules: Swedish orange hard capsules, marked with "100" on the body. The length

of the capsule cap is 8.67mm-9.67mm and the length of the capsule body is 14.84mm-

15.84mm.

150 mg capsules: White hard capsules, marked with "150" on the body. The length of the

capsule cap is 9.3mm-10.51mm and the length of the capsule body is 16.1mm-17.22mm.

200 mg capsules: Red hard capsules, marked with "200" on the body. The length of the

capsule cap is 10.68mm-11.68mm and the length of the capsule body is 18.1mm-19.22mm.

225 mg capsules: Red and white hard capsules, marked with "225" on the body. The length of

the capsule cap is 11.53mm-12.45mm and the length of the capsule body is 20.3mm-

21.44mm.

300 mg capsules: White and orange hard capsules, marked with "300" on the body. The

length of the capsule cap is 11.40mm-12.20mm and the length of the capsule body is

19.80mm-20.70mm.

[Invented name] is available in a cardboard box containing the appropriate number of PVC

/aluminium foil blisters containing:

25 mg: 14, 56, 84, 100, 100 x 1 or 112 hard capsules

50 mg: 7, 14, 56, 84, 100, 100 x 1 or 112 hard capsules

75 mg: 14, 56, 84, 100, 100 x 1 or 112 hard capsules

100 mg: 7, 14, 56, 84, 100, 100 x 1 or 112 hard capsules

150 mg: 14, 56, 84, 100, 100 x 1 or 112 hard capsules

200 mg: 14, 56, 84, 100, 100 x 1 or 112 hard capsules

225 mg: 14, 56, 84, 100, 100 x 1 or 112 hard capsules

300 mg: 14, 56, 84, 100, 100 x 1 or 112 hard capsules

HDPE bottle with PP screwcap containing:

25 mg: 60 hard capsules

50 mg: 60 hard capsules

75 mg: 60 hard capsules

100 mg: 60 hard capsules

150 mg: 60 hard capsules

200 mg: 60 hard capsules

225 mg: 60 hard capsules

300 mg: 60 hard capsules

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder

<to be completed nationally>

Manufacturer:

<to be completed nationally>

This leaflet was last revised in:

4 March 2021

Läs hela dokumentet

1. NAME OF THE MEDICINAL PRODUCT

Pregabalin 1A Farma 25 mg hard capsules

Pregabalin 1A Farma 50 mg hard capsules

Pregabalin 1A Farma 75 mg hard capsules

Pregabalin 1A Farma 100 mg hard capsules

Pregabalin 1A Farma 150 mg hard capsules

Pregabalin 1A Farma 200 mg hard capsules

Pregabalin 1A Farma 225 mg hard capsules

Pregabalin 1A Farma 300 mg hard capsules

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each hard capsule of [Invented Name] 25 mg contains 25 mg of pregabalin.

Each hard capsule of [Invented Name] 50 mg contains 50 mg of pregabalin

.

Each hard capsule of [Invented Name] 75 mg contains 75 mg of pregabalin.

Each hard capsule of [Invented Name] 100 mg contains 100 mg of pregabalin

.

Each hard capsule of [Invented Name] 150 mg contains 150 mg of pregabalin.

Each hard capsule of [Invented Name] 200 mg contains 200 mg of pregabalin

.

Each hard capsule of [Invented Name] 225 mg contains 225 mg of pregabalin.

Each hard capsule of [Invented Name] 300 mg contains 300 mg of pregabalin

.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Hard capsules

25 mg: White cap and body capsule, imprinted with "25" on the body with black ink. The

length of the capsule cap is 6.97mm-7.97mm and the length of the capsule body is 11.8mm-

12.84mm.

50 mg: White cap and body capsule, imprinted with "50" on the body with black ink. The

length of the capsule cap is 7.73mm-8.73mm and the length of the capsule body is 12.98mm-

13.98mm.

75 mg: Swedish orange cap and white body, imprinted with "75" on the body with black ink.

The length of the capsule cap is 7.73mm-8.73mm and the length of the capsule body is

12.98mm-13.98mm.

100 mg: Swedish orange cap and body capsule, imprinted with "100" on the body with black

ink. The length of the capsule cap is 8.67mm-9.67mm and the length of the capsule body is

14.84mm-15.84mm.

150 mg: White cap and body capsules, imprinted with "150" on the body with black ink. The

length of the capsule cap is 9.3mm-10.51mm and the length of the capsule body is 16.1mm-

17.22mm.

200 mg: Red cap and body capsule, imprinted with "200" on the body with black ink. The

length of the capsule cap is 10.68mm-11.68mm and the length of the capsule body is

18.1mm-19.22mm.

225 mg: Red cap and white body elongated capsule, imprinted with "225" on the body with

black ink. The length of the capsule cap is 11.53mm-12.45mm and the length of the capsule

body is 20.3mm-21.44mm.

300 mg: Swedish orange cap and white body capsule, imprinted with "300" on the body with

black ink. The length of the capsule cap is 11.40mm-12.20mm and the length of the capsule

body is 19.80mm-20.70mm.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Neuropathic pain

[Invented Name] is indicated for the treatment of peripheral and central neuropathic pain in

adults.

Epilepsy

[Invented Name] is indicated as adjunctive therapy in adults with partial seizures with or

without secondary generalisation.

Generalised Anxiety Disorder

[Invented Name] 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.

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:

(ml/min) =

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

BID or TID

≥30- <60

BID or TID

≥15 - <30

25 – 50

Once Daily or BID

< 15

Once Daily

Supplementary dosage following haemodialysis (mg)

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 [Invented Name] 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

[Invented Name] may be taken with or without food.

[Invented Name] 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 postmarketing 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 pregabalin in the add-on situation has been reached, in

order to reach monotherapy on pregabalin.

Withdrawal symptoms

After discontinuation of short-term and long-term treatment with pregabalin, withdrawal

symptoms have been observed in some patients. The following events have been mentioned:

insomnia, headache, nausea, anxiety, diarrhoea, flu syndrome, nervousness, depression, pain

,

convulsion, hyperhidrosis and dizziness, suggestive of physical dependence. 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, data suggest that the

incidence and severity of withdrawal symptoms may be dose-related.

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 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).

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]).

Misuse, abuse potential or dependence

Cases of misuse, abuse and dependence 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 misuse, abuse or dependence (development of tolerance, dose escalation,

drug-seeking behaviour have been reported).

Encephalopathy

Cases of encephalopathy have been reported, mostly in patients with underlying conditions

that may precipitate encephalopathy.

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 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 section 5.3). The potential risk for

humans is unknown.

[Invented Name] 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

[Invented Name] may have minor or moderate influence on the ability to drive and use

machines. [Invented Name] 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

Neutropenia

System Organ Class

Adverse drug reactions

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

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

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

System Organ Class

Adverse drug reactions

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

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 in some patients. The following reactions have been

mentioned: insomnia, headache, nausea, anxiety, diarrhoea, flu syndrome, convulsions,

nervousness, depression, pain

,

hyperhidrosis and dizziness, suggestive of physical

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.

Paediatric population

The pregabalin safety profile observed in five paediatric studies in patients with partial

seizures with or without secondary generalization (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 national

reporting system listed in Appendix V.

4.9 Overdose

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).

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antiepileptics, other 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 (α

-δ protein) of voltage-gated calcium channels in

the central nervous system.

Clinical efficacy and safety

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 (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

Adjunctive Treatment

Pregabalin has been studied in 3 controlled clinical trials of 12 week duration with either

twice a day (BID) dosing 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.

Paediatric population

The efficacy and safety of pregabalin as adjunctive treatment for epilepsy in paediatric

patients below the age of 12 and adolescents has not been established. The adverse events

observed in a pharmacokinetic and tolerability study that enrolled patients from 3 months to

16 years of age (n=65) with partial onset seizures were similar to those observed in adults.

Results of a 12-week placebo-controlled study of 295 paediatric patients aged 4 to 16 years

and a 14-day placebo-controlled study of 175 paediatric patients aged 1 month to younger

than 4 years of age performed to evaluate the efficacy and safety of pregabalin as adjunctive

therapy for the treatment of partial onset seizures and two 1 year open label safety studies in

54 and 431 paediatric patients respectively, from 3 months to 16 years of age with epilepsy

indicate that the adverse events of pyrexia and upper respiratory infections were observed

more frequently than in adult studies of patients with epilepsy (see sections 4.2, 4.8 and 5.2).

In the 12-week placebo-controlled study, paediatric patients (4 to 16 years of age) were

assigned to pregabalin 2.5 mg/kg/day (maximum, 150 mg/day), pregabalin 10 mg/kg/day

(maximum, 600 mg/day), or placebo. The percentage of subjects with at least a 50% reduction

in partial onset seizures as compared to baseline was 40.6% of subjects treated with

pregabalin 10 mg/kg/day (p=0.0068 versus placebo), 29.1% of subjects treated with

pregabalin 2.5 mg/kg/day (p=0.2600 versus placebo) and 22.6% of those receiving placebo.

In the 14-day placebo-controlled study, paediatric patients (1 month to younger than 4 years

of age) were assigned to pregabalin 7 mg/kg/day, pregabalin 14 mg/kg/day, or placebo.

Median 24-hour seizure frequencies at baseline and at the final visit were 4.7 and 3.8 for

pregabalin 7 mg/kg/day, 5.4 and 1.4 for pregabalin 14 mg/kg/day, and 2.9 and 2.3 for

placebo, respectively. Pregabalin 14 mg/kg/day significantly reduced the log-transformed

partial onset seizure frequency versus placebo (p=0.0223); pregabalin 7 mg/kg/day did not

show improvement relative to placebo.

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 a 50% improvement in 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. Ophthalmologic 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.

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 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

by approximately 25-30% and a delay in t

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 N-methylated 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.

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.

Paediatric population

Pregabalin pharmacokinetics were evaluated in paediatric patients with epilepsy (age groups:

1 to 23 months, 2 to 6 years, 7 to 11 years and 12 to 16 years) at dose levels of 2.5, 5, 10 and

15 mg/kg/day in a pharmacokinetic and tolerability study.

After oral administration of pregabalin in paediatric patients in the fasted state, in general,

time to reach peak plasma concentration was similar across the entire age group and occurred

0.5 hours to 2 hours postdose.

Pregabalin C

and AUC parameters increased in a linear manner with increasing dose

within each age group. The AUC was lower by 30% in paediatric patients below a weight of

30 kg due to an increased body weight adjusted clearance of 43% for these patients in

comparison to patients weighing ≥30 kg.

Pregabalin terminal half-life averaged about 3 to 4 hours in paediatric patients up to 6 years of

age, and 4 to 6 hours in those 7 years of age and older.

Population pharmacokinetic analysis showed that creatinine clearance was a significant

covariate of pregabalin oral clearance, body weight was a significant covariate of pregabalin

apparent oral volume of distribution, and these relationships were similar in paediatric and

adult patients.

Pregabalin pharmacokinetics in patients younger than 3 months old have not been studied (see

sections 4.2, 4.8 and 5.1).

Elderly

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).

Breast-feeding mothers

The pharmacokinetics of 150 mg pregabalin given every 12 hours (300 mg daily dose) was

evaluated in 10 lactating women who were at least 12 weeks postpartum. Lactation had little

to no influence on pregabalin pharmacokinetics. Pregabalin was excreted into breast milk

with average steady-state concentrations approximately 76% of those in maternal plasma. The

estimated infant dose from breast milk (assuming mean milk consumption of 150 ml/kg/day)

of women receiving 300 mg/day or the maximum dose of 600 mg/day would be 0.31 or 0.62

mg/kg/day, respectively. These estimated doses are approximately 7% of the total daily

maternal dose on a mg/kg basis.

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 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.

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

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

Capsules content:

Pregelatinized Starch

Mannitol

Talc

Capsules shell:

Gelatin (for all strengths)

Titanium Dioxide (E171) (for all strengths)

Red Iron Oxide (E172) (only for 75 mg, 100 mg, 300mg)

Red Iron Oxide (E172) and Yellow iron oxide (E172) (only for 200 mg, 225 mg)

Printing Ink:

Shellac

Black Iron Oxide (E172)

Propylene Glycol

E1520)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions

6.5 Nature and contents of container

A cardboard box containing the appropriate number of PVC/Aluminium foil blisters

containing:

25 mg: 14, 56, 84, 100, 100 x 1 or 112 hard capsules

50 mg: 7, 14, 56, 84, 100, 100 x 1 or 112 hard capsules

75 mg: 14, 56, 84, 100, 100 x 1 or 112 hard capsules

100 mg: 7, 14, 56, 84, 100, 100 x 1 or 112 hard capsules

150 mg: 14, 56, 84, 100, 100 x 1 or 112 hard capsules

200 mg: 14, 56, 84, 100, 100 x 1 or 112 hard capsules

225 mg: 14, 56, 84, 100, 100 x 1 or 112 hard capsules

300 mg: 14, 56, 84, 100, 100 x 1 or 112 hard capsules

HDPE bottle containing:

25 mg: 60 hard capsules

50 mg: 60 hard capsules

75 mg: 60 hard capsules

100 mg: 60 hard capsules

150 mg: 60 hard capsules

200 mg: 60 hard capsules

225 mg: 60 hard capsules

300 mg: 60 hard capsules

Not all pack sizes may be marketed

6.6 Special precautions for disposal and other handling

No special requirements for disposal.

7. MARKETING AUTHORISATION HOLDER

<to be completed nationally>

8. MARKETING AUTHORISATION NUMBER(S)

<to be completed nationally>

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

<to be completed nationally>

10. DATE OF REVISION OF THE TEXT

4 March 2021

Läs hela dokumentet

Postadress/Postal address: P.O. Box 26, SE-751 03 Uppsala, SWEDEN

Besöksadress/Visiting address: Dag Hammarskjölds väg 42, Uppsala

Telefon/Phone: +46 (0)18 17 46 00 Fax: +46 (0)18 54 85 66

Internet: www.lakemedelsverket.se E-mail: registrator@lakemedelsverket.se

Public Assessment Report

Scientific discussion

Pregabalin 1A Farma

(pregabalin)

SE/H/1711/01-08/E/01

This module reflects the scientific discussion for the approval of Pregabalin 1A Farma. The Public

Assessment Report was written in August 2016 by the previous RMS DK after initial procedure

DK/H/2596/001-008/MR.

RMS

transfer

from

DK

to

SE

was

completed

2017-12-19.

For

information on changes after this date please refer to the module ‘Update’.

I.

INTRODUCTION

Based on the review of the quality, safety and efficacy data, the Member States have granted a marketing

authorisation for Pregabalin 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 225 mg and 300 mg hard

capsules, from Pharmathen S.A.

The product is indicated for: Neuropathic pain, epilepsy and Generalised Anxiety Disorder.

A comprehensive description of the indications and posology is given in the SmPC.

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

methylhexanoic acid). Pregabalin binds to an auxiliary subunit (α2-δ protein) of voltage-gated calcium

channels in the central nervous system.

This mutual recognition procedure concerns a generic application claiming essential similarity with the

reference product Lyrica hard capsules, which has been registered in Europe by Pfizer ApS since 2004.

The marketing authorisation is granted based on article 10.1 of Directive 2001/83/EC.

II.

QUALITY ASPECTS

II.1

Introduction

Each hard capsule contains 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 225 mg or 300 mg of

pregabalin, respectively.

The 25 mg capsules are white cap and body, imprinted with "25" on the body with black ink. The

length of the capsule cap is 6.97mm-7.97mm and the length of the capsule body is 11.8mm-12.84mm.

The 50 mg capsules are white cap and body, imprinted with "50" on the body with black ink. The

length of the capsule cap is 7.73mm-8.73mm and the length of the capsule body is 12.98mm-

13.98mm.

The 75 mg capsules are swedish orange cap and white body, imprinted with "75" on the body with

black ink. The length of the capsule cap is 7.73mm-8.73mm and the length of the capsule body is

12.98mm-13.98mm.

The 100 mg capsules are swedish orange cap and body, imprinted with "100" on the body with black

ink. The length of the capsule cap is 8.67mm-9.67mm and the length of the capsule body is 14.84mm-

15.84mm.

The 150 mg capsules are white cap and body, imprinted with "150" on the body with black ink. The

length of the capsule cap is 9.3mm-10.51mm and the length of the capsule body is 16.1mm-17.22mm.

The 200 mg capsules are red cap and body, imprinted with "200" on the body with black ink. The

length of the capsule cap is 10.68mm-11.68mm and the length of the capsule body is 18.1mm-

19.22mm.

The 225 mg elongated capsules are red cap and white body, imprinted with "225" on the body with

black ink. The length of the capsule cap is 11.53mm-12.45mm and the length of the capsule body is

20.3mm-21.44mm.

The 300 mg capsules are swedish orange cap and white body, imprinted with "300" on the body with

black ink. The length of the capsule cap is 11.40mm-12.20mm and the length of the capsule body is

19.80mm-20.70mm.

The capsules are packed in PVC/Aluminium foil blisters in a cardboard box in pack sizes of 7 (50 mg

and 100 mg only), 14 and 56 hard capsules. However, not all pack sizes may be marketed.

The capsule content is: Pregelatinized starch; mannitol and talc.

The capsule shell is composed of: Gelatin; titanium dioxide (E171); red iron oxide (E172) (75 mg, 100

mg and 300 mg only); red iron oxide (E172) and yellow iron oxide (E172) (200 mg and 225 mg only).

The printing ink contains: Shellac; black iron oxide (E172) and propylene glycol (E1520).

The RMS has been assured that acceptable standards of GMP (see Directive 2003/94/EC) are in place

for this product type at all sites responsible for the manufacturing of the active substance as well as for

the manufacturing and assembly of this product prior to granting its national authorisation.

II.2

Drug Substance

The active substance, pregabalin, is not described in the European Pharmacopoeia. It is a white or

almost white crystalline powder. It is soluble in 1M sodium hydroxide and sparingly soluble in water.

It is optically active.

Structural formula:

Molecular formula: C

Molecular weight: 159.23

The documentation on the active substance is provided as an ASMF. The proposed starting materials

of the synthesis is acceptable after re-definition of the starting materials was performed.

The active substance is not described in any pharmacopoeia and the specifications have been set based

on in-house requirements. The proposed specifications are acceptable.

Based on the stability data presented, an appropriate re-test period has been set.

The finished product manufacturer’s specification on the drug substance is in line with the ASM’s

specification and is found acceptable.

II.3

Medicinal Product

The finished product is conventional hard capsules to be marketed in PVC/alu blisters. The strengths

applied for are 25, 50, 75, 100, 150, 200, 225 and 300 mg. All strengths are dose proportional.

The development of the product has been adequately described, the choice of excipients is justified

and their functions explained.

Satisfactory validation of the manufacturing process has been carried out on 3 pilot scale batches of

each strength. A process validation scheme is provided in the dossier for further process evaluation on

production scale batches.

The finished product specifications cover appropriate parameters for this dosage form. The proposed

limit for total impurities at shelf-life is considered acceptable. Satisfactory validations of the analytical

methods have been presented. Batch analysis results presented show that the finished products meet the

specifications proposed.

Stability data are provided for 3 pilot scale batches of the strengths 25, 200 and 300 mg packed in

PVC-alu blisters and HDPE bottles under long term, intermediate and accelerated conditions. The

proposed shelf-life of 36 months with no special precautions for storage is supported by the data.

In-use stability studies have been carried out on the lowest (25 mg) and highest (300 mg) strengths and

the finished product has been shown to be stable under the intended use.

III.

NON-CLINICAL ASPECTS

III.1

Introduction

Pharmacodynamic, pharmacokinetic and toxicological properties of pregabalin are well known. As

pregabalin is a widely used, well-known active substance, the MAH has not provided additional

studies and further studies are not required. Overview based on literature review is, thus, appropriate.

The non-clinical overview report refers several publications up to year 2013. The non-clinical

overview on the pre-clinical pharmacology, pharmacokinetics and toxicology is adequate.

III.2

Ecotoxicity/environmental risk assessment (ERA)

Since Pregabalin “Pharmathen” is intended for generic substitution, this will not lead to an increased

exposure to the environment. An environmental risk assessment is therefore not deemed necessary.

IV.

CLINICAL ASPECTS

IV.1

Introduction

Pregabalin is a well-known active substance with established efficacy and tolerability. As pregabalin is

a widely used, well-known active substance, the MAH has not provided additional studies (apart from a

supportive bioequivalence study referenced below) and further studies are not required. Overview

based on literature review is, thus, appropriate.

The clinical report refers several publications up to year 2013. The clinical overview on the clinical

pharmacology, efficacy and safety is adequate.

IV.2

Pharmacokinetics

To support the application the MAH has submitted as report one bioequivalence study with Lyrica 300

mg hard capsules, Pfizer, from the Greek market as the reference product and Pregabalin “Pharmathen”

300 mg hard capsules as the test product.

Biowaiver

The bioequivalence study was conducted using the highest strength 300 mg. The additional strengths

applied for comply with the criteria cf. Guideline on the Investigation of Bioequivalence

(CPMP/EWP/QWP/1401/98 Rev.1/Corr*) section 4.1.6 in order to accept biowaiver. Pregabalin has

shown linearity over dose range (150-600 mg) and as recommended by the guideline, the

bioequivalence study was conducted using the highest strength (300 mg). Similar dissolution profiles

are demonstrated between the biobatch and additional strengths in different media.

Bioequivalence study

The study was an open-label, randomized, two-treatment, two-sequence, two-period, two-way

crossover, single-dose bioavailability study conducted under fasting conditions with a wash out period

of 8 days between the two administrations. 300 mg was administered in each period.

28 healthy subjects participated in the study. 20 subjects completed the study.

Primary variables for the evaluation of bioequivalence were AUC

and C

Bioequivalence of Test Product-T vs. Reference Product-R was concluded, if the 90% confidence

interval fell within the acceptance range 80.00-125.00% for ln-transformed pharmacokinetic

parameters AUC

and C

for pregabalin.

Results

Table 1. Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, t

max

median, range), N=20

90% CI for AUC

and C

are within the criteria (80.00-125.00%) to demonstrate bioequivalence

between the test product and reference product under fasting conditions.

Pharmacokinetic conclusion

Based on the submitted bioequivalence study Pregabalin “Pharmathen” 300 mg hard capsules is

considered bioequivalent with Lyrica 300 mg hard capsules under fasting conditions.

The results of the bioequivalence study can be extrapolated to the other strengths as relevant criteria

for waiving are fulfilled in accordance with current guidance.

The RMS has been assured that the bioequivalence study has been conducted in accordance with

acceptable standards of Good Clinical Practice (GCP, see Directive 2005/28/EC) and Good

Laboratory Practice (GLP, see Directives 2004/9/EC and 2004/10/EC).

IV.3

Risk Management Plan

The MAH has submitted a risk management plan, in accordance with the requirements of Directive

2001/83/EC as amended, describing the pharmacovigilance activities and interventions designed to

identify, characterise, prevent or minimise risks relating to Pregabalin “Pharmathen”.

The following summary list of safety concerns with no additional pharmacovigilance measures or risk

minimisation measures has been agreed:

Table 2. Summary table of safety concerns as approved in RMP

V.

USER CONSULTATION

The package leaflet has been evaluated via a user consultation study in accordance with the

requirements of Articles 59(3) and 61(1) of Directive 2001/83/EC. The language used for the purpose

of user testing the PL was English.

The results show that the package leaflet meets the criteria for readability as set out in the Guideline

on the readability of the label and package leaflet of medicinal products for human use.

The test consisted of: a pilot test with 4 participants, followed by two rounds with 10 participants each.

The questions covered the following areas sufficiently: traceability, comprehensibility and

applicability.

VI.

OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND

RECOMMENDATION

Pregabalin “Pharmathen” 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 225 mg and 300 mg hard

capsules has a proven chemical-pharmaceutical quality and is a generic form of Lyrica hard capsules.

Lyrica is a well-known medicinal product with an established favourable efficacy and safety profile.

Bioequivalence has been shown to be in compliance with the requirements of European guidance

documents.

The MAH has presented a risk management plan summarising the safety concerns. There are no

additional pharmacovigilance or risk minimisation measures.

Agreement between Member States was reached during a written procedure. There was no discussion

in the CMD(h). The Concerned Member States, on the basis of the data submitted, considered that

essential similarity has been demonstrated for Pregabalin “Pharmathen” with the reference product,

and have therefore granted a marketing authorisation. The mutual recognition procedure was finalised

on 18 May 2016.

According to the List of Union reference dates and frequency of submission of periodic safety update

reports (PSURs), no routine PSURs are required for this product.

The date for the first renewal will be: 14 July 2020.

There were no post-approval commitments made during the procedure.

Liknande Produkter

Sök varningar relaterade till denna produkt

Visa dokumenthistorik

Dela den här informationen