Lyrica^® (Capsules) Instructions for Use

Marketing Authorization Holder

Upjohn US 1, LLC (USA)

Manufactured By

Pfizer Manufacturing Deutschland, GmbH (Germany)

ATC Code

N02BF02 (Pregabalin)

Active Substance

Pregabalin (Rec.INN registered by WHO)

Dosage Forms

	Lyrica^®	Capsules 25 mg: 14, 56, 84 or 100 pcs.
		Capsules 50 mg: 14, 56, 84 or 100 pcs.
		Capsules 75 mg: 14, 56, 84 or 100 pcs.
		Capsules 100 mg: 14, 56, 84 or 100 pcs.
		Capsules 150 mg: 14, 56, 84 or 100 pcs.
		Capsules 200 mg: 14, 56, 84 or 100 pcs.
		Capsules 300 mg: 14, 56, 84 or 100 pcs.

Dosage Form, Packaging, and Composition

Capsules hard gelatin, size No. 4, with a white cap and a white body, the dosage and product code “PGN 25” are printed in black ink on the body, “Pfizer” is printed on the cap; capsule contents – white or almost white powder.

	1 caps.
Pregabalin	25 mg

Excipients: lactose monohydrate – 35 mg, corn starch – 20 mg, talc – 20 mg.

Capsule body composition titanium dioxide – 0.557 mg (1.47%), sodium lauryl sulfate – 0.046 mg (0.12%) (max), water – 3.306 mg (8.7%), gelatin – 18.892 mg (49.72%) qsp to 100%.
Capsule cap composition titanium dioxide – 0.371 mg (0.98%), sodium lauryl sulfate – 0.03 mg (0.08%) (max), water – 2.204 mg (5.8%), gelatin – 12.594 mg (33.14%) qsp to 100%.
Ink composition shellac (24-27%), ethanol (23-26%), isopropanol (0.5-3%), butanol (0.5-3%), propylene glycol (3-7%), concentrated ammonia solution (1-2%), potassium hydroxide (0.05-0.1%), purified water (15-18%), black iron oxide dye (24-28%).

10 pcs. – blisters (10) – cardboard packs with first opening control.
14 pcs. – blisters (1) – cardboard packs with first opening control.
14 pcs. – blisters (4) – cardboard packs with first opening control.
21 pcs. – blisters (4) – cardboard packs with first opening control.

Capsules hard gelatin, size No. 3, with a white cap and a white body with a black band; the dosage and product code “PGN 50” are printed in black ink on the body, “Pfizer” is printed on the cap; capsule contents – white or almost white powder.

	1 caps.
Pregabalin	50 mg

Excipients: lactose monohydrate – 70 mg, corn starch – 40 mg, talc – 40 mg.

Capsule body composition titanium dioxide – 0.703 mg (1.46%), sodium lauryl sulfate – 0.058 mg (0.12%) (max), water – 4.176 mg (8.7%), gelatin – 23.863 mg (49.71%) qsp to 100%.
Capsule cap composition titanium dioxide – 0.469 mg (0.98%), sodium lauryl sulfate – 0.038 mg (0.08%) (max), water – 2.784 mg (5.8%), gelatin – 15.909 mg (33.14%) qsp to 100%.
Ink composition shellac (24-27%), ethanol (23-26%), isopropanol (0.5-3%), butanol (0.5-3%), propylene glycol (3-7%), concentrated ammonia solution (1-2%), potassium hydroxide (0.05-0.1%), purified water (15-18%), black iron oxide dye (24-28%).

Capsules hard gelatin, size No. 4, with a cap from reddish-brown to dark reddish-brown* and a white body; the dosage and product code “PGN 75” are printed in black ink on the body, “Pfizer” is printed on the cap; capsule contents – white or almost white powder.

	1 caps.
Pregabalin	75 mg

Excipients: lactose monohydrate – 8.25 mg, corn starch – 8.375 mg, talc – 8.375 mg.

Capsule body composition titanium dioxide – 0.557 mg (1.47%), sodium lauryl sulfate – 0.046 mg (0.12%) (max), water – 3.306 mg (8.7%), gelatin – 18.892 mg (49.72%) qsp to 100%.
Capsule cap composition red iron oxide dye – 0.264 mg (0.69%), titanium dioxide – 0.062 mg (0.16%), sodium lauryl sulfate – 0.03 mg (0.08%) (max), water – 2.204 mg (5.8%), gelatin – 12.64 mg (33.26%) qsp to 100%.
Ink composition shellac (24-27%), ethanol (23-26%), isopropanol (0.5-3%), butanol (0.5-3%), propylene glycol (3-7%), concentrated ammonia solution (1-2%), potassium hydroxide (0.05-0.1%), purified water (15-18%), black iron oxide dye (24-28%).

* in the original manufacturer’s certificates, these colors are described as follows: “from reddish-brown to dark reddish-brown” – “orange”, “from light reddish-brown to reddish-brown” – “light orange”, which corresponds to the color of the comparison pantones used in the European Union for this type of analysis.

Capsules hard gelatin, size No. 3, with a cap and body from reddish-brown to dark reddish-brown*; the dosage and product code “PGN 100” are printed in black ink on the body, “Pfizer” is printed on the cap; capsule contents – white or almost white powder.

	1 caps.
Pregabalin	100 mg

Excipients: lactose monohydrate – 11 mg, corn starch – 11.17 mg, talc – 11.17 mg.

Capsule body composition red iron oxide dye – 0.5 mg (1.04%), titanium dioxide – 0.118 mg (0.25%), sodium lauryl sulfate – 0.058 mg (0.12%) (max), water – 4.176 mg (8.7%), gelatin – 23.949 mg (49.89%) qsp to 100%.
Capsule cap composition red iron oxide dye – 0.333 mg (0.69%), titanium dioxide – 0.079 mg (0.16%), sodium lauryl sulfate – 0.038 mg (0.08%) (max), water – 2.784 mg (5.8%), gelatin – 15.966 mg (33.26%) qsp to 100%.
Ink composition shellac (24-27%), ethanol (23-26%), isopropanol (0.5-3%), butanol (0.5-3%), propylene glycol (3-7%), concentrated ammonia solution (1-2%), potassium hydroxide (0.05-0.1%), purified water (15-18%), black iron oxide dye (24-28%).

Capsules hard gelatin, size No. 2, with a white cap and a white body; the dosage and product code “PGN 150” are printed in black ink on the body, “Pfizer” is printed on the cap; capsule contents – white or almost white powder.

	1 caps.
Pregabalin	150 mg

Excipients: lactose monohydrate – 16.5 mg, corn starch – 16.75 mg, talc – 16.75 mg.

Capsule body composition titanium dioxide – 0.894 mg (1.47%), sodium lauryl sulfate – 0.073 mg (0.12%) (max), water – 5.307 mg (8.7%), gelatin – 30.326 mg (49.71%) qsp to 100%.
Capsule cap composition titanium dioxide – 0.596 mg (0.98%), sodium lauryl sulfate – 0.049 mg (0.08%) (max), water – 3.538 mg (5.8%), gelatin – 20.217 mg (33.14%) qsp to 100%.
Ink composition shellac (24-27%), ethanol (23-26%), isopropanol (0.5-3%), butanol (0.5-3%), propylene glycol (3-7%), concentrated ammonia solution (1-2%), potassium hydroxide (0.05-0.1%), purified water (15-18%), black iron oxide dye (24-28%).

Capsules hard gelatin, size No. 1, with a cap and body from light reddish-brown to reddish-brown*; the dosage and product code “PGN 200” are printed in black ink on the body, “Pfizer” is printed on the cap; capsule contents – white or almost white powder.

	1 caps.
Pregabalin	200 mg

Excipients: lactose monohydrate – 22 mg, corn starch – 22.34 mg, talc – 22.34 mg.

Capsule body composition red iron oxide dye – 0.201 mg (0.26%), titanium dioxide – 0.189 mg (0.25%), sodium lauryl sulfate – 0.091 mg (0.12%) (max), water – 6.612 mg (8.7%), gelatin – 38.507 mg (50.67%) qsp to 100%.
Capsule cap composition red iron oxide dye – 0.134 mg (0.18%), titanium dioxide – 0.126 mg (0.17%), sodium lauryl sulfate – 0.061 mg (0.08%) (max), water – 4.408 mg (5.8%), gelatin – 25.672 mg (33.78%) qsp to 100%.
Ink composition shellac (24-27%), ethanol (23-26%), isopropanol (0.5-3%), butanol (0.5-3%), propylene glycol (3-7%), concentrated ammonia solution (1-2%), potassium hydroxide (0.05-0.1%), purified water (15-18%), black iron oxide dye (24-28%).

Capsules hard gelatin, size No. 0, with a cap from reddish-brown to dark reddish-brown* and a white body, the dosage and product code “PGN 300” are printed in black ink on the capsule body, “Pfizer” is printed on the cap; capsule contents – white or almost white powder.

	1 caps.
Pregabalin	300 mg

Excipients: lactose monohydrate – 33 mg, corn starch – 33.5 mg, talc – 33.5 mg.

Capsule body composition titanium dioxide – 1.407 mg (1.47%), sodium lauryl sulfate – 0.115 mg (0.12%) (max), water – 8.352 mg (8.7%), gelatin – 47.726 mg (49.71%) qsp to 100%.
Capsule cap composition red iron oxide dye – 0.667 mg (0.69%), titanium dioxide – 0.157 mg (0.16%), sodium lauryl sulfate – 0.077 mg (0.08%) (max), water – 5.568 mg (5.8%), gelatin – 31.931 mg (33.26%) qsp to 100%.
Ink composition shellac (24-27%), ethanol (23-26%), isopropanol (0.5-3%), butanol (0.5-3%), propylene glycol (3-7%), concentrated ammonia solution (1-2%), potassium hydroxide (0.05-0.1%), purified water (15-18%), black iron oxide dye (24-28%).

Clinical-Pharmacological Group

Anticonvulsant drug

Pharmacotherapeutic Group

Antiepileptic agent

Pharmacological Action

Pregabalin is an analogue of gamma-aminobutyric acid ((S)-3-(aminomethyl)-5-methylhexanoic acid).

Mechanism of action

Pregabalin has been found to bind to an auxiliary subunit (α2-delta protein) of voltage-gated calcium channels in the CNS, irreversibly displacing [3H]-gabapentin. It is suggested that this binding may contribute to its analgesic and anticonvulsant effects.

Neuropathic pain

Efficacy of pregabalin has been noted in patients with diabetic neuropathy and postherpetic neuralgia.

It has been established that when taken in courses of up to 13 weeks twice daily and up to 8 weeks three times daily, the overall risk of adverse effects and the drug’s efficacy are similar for both twice-daily and three-times-daily regimens.

When taken in a course lasting up to 13 weeks, pain decreased during the first week, and the effect persisted until the end of treatment.

A 50% reduction in the pain index was observed in 35% of patients receiving Pregabalin and 18% of patients receiving placebo. Among patients who did not experience drowsiness, this pain reduction effect was noted in 33% of patients in the pregabalin group and 18% of patients in the placebo group. Drowsiness occurred in 48% of patients taking Pregabalin and 16% of patients taking placebo.

Fibromyalgia

Significant reduction in pain symptoms associated with fibromyalgia is noted with the use of pregabalin at doses from 300 mg to 600 mg/day. The efficacy of doses of 450 and 600 mg/day is comparable, but the tolerability of 600 mg/day is usually worse.

The use of pregabalin is also associated with a noticeable improvement in patients’ functional activity and a reduction in the severity of sleep disturbances. The use of pregabalin at a dose of 600 mg/day led to a more pronounced improvement in sleep compared to the dose of 300-450 mg/day.

Epilepsy

When pregabalin was taken for 12 weeks twice or three times daily, the noted risk of adverse effects and the drug’s efficacy were similar for these dosing regimens. The reduction in seizure frequency began within the first week.

Generalized anxiety disorder

A reduction in symptoms of generalized anxiety disorder is noted in the first week of treatment. When pregabalin was used for 8 weeks, 52% of patients receiving Pregabalin and 38% of patients receiving placebo showed a 50% reduction in symptoms on the Hamilton Anxiety Scale (HAM-A).

In clinical studies, adverse reactions related to the organ of vision (such as blurred vision, decreased visual acuity, visual field changes) were observed more frequently in patients continuously receiving Pregabalin (with the exception of fundus changes) than in patients receiving placebo.

Pharmacokinetics

The pharmacokinetic parameters of pregabalin at steady state were similar in healthy volunteers, in patients with epilepsy receiving antiepileptic therapy, and in patients receiving it for chronic pain syndromes.

Absorption

Pregabalin is rapidly absorbed on an empty stomach. C_max of pregabalin in plasma is reached within 1 hour after both single and repeated administration. The bioavailability of pregabalin after oral administration is ≥90% and is not dose-dependent. With repeated administration, C_ss is reached within 24-48 hours. When taken after a meal, C_max is reduced by approximately 25-30%, and T_max is increased to approximately 2.5 hours. However, food intake does not have a clinically significant effect on the overall absorption of pregabalin.

Distribution

The apparent V_d of pregabalin after oral administration is approximately 0.56 L/kg. Pregabalin does not bind to plasma proteins.

In animal studies of pregabalin, it was noted that it crosses the BBB in mice, rats, and monkeys. It has also been shown that Pregabalin can cross the placental barrier and is found in the milk of rats during lactation.

Metabolism

Pregabalin undergoes practically no metabolism. After administration of labeled pregabalin, approximately 98% of the radioactive label was determined unchanged in the urine. The proportion of the N-methylated derivative of pregabalin, which is the main metabolite found in urine, was 0.9% of the dose. Preclinical studies showed no signs of racemization of the S-enantiomer of pregabalin to the R-enantiomer.

Elimination

Pregabalin is eliminated mainly by the kidneys unchanged.

The mean T_1/2 is 6.3 hours. Plasma clearance of pregabalin and renal clearance are directly proportional to CrCl. In patients with impaired renal function and patients on hemodialysis, dose adjustment is necessary (see section “Dosage and Administration”).

Linearity/non-linearity

The pharmacokinetics of pregabalin in the range of recommended daily doses is linear, with low interindividual variability (<20%). The pharmacokinetics of pregabalin upon repeated administration can be predicted from single-dose data. Therefore, there is no need for regular monitoring of pregabalin concentrations.

Pharmacokinetics in special patient groups

Gender. The patient’s gender does not have a clinically significant effect on pregabalin plasma concentrations.

Renal impairment. Pregabalin clearance is directly proportional to CrCl. Since Pregabalin is primarily eliminated by the kidneys, a reduction in the pregabalin dose is recommended in patients with impaired renal function. Furthermore, Pregabalin is effectively removed from plasma by hemodialysis (after a 4-hour hemodialysis session, pregabalin plasma concentrations are reduced by approximately 50%), an additional dose of pregabalin should be administered following hemodialysis.

Hepatic impairment. The pharmacokinetics of pregabalin in patients with impaired hepatic function has not been specifically studied. Since pregabalin undergoes negligible metabolism and is eliminated primarily unchanged in the urine, impaired hepatic function should not significantly alter pregabalin plasma concentrations.

Elderly patients (over 65 years). Pregabalin clearance tends to decrease with age, reflecting the age-related decrease in CrCl. Elderly patients with impaired renal function may require a reduction in the pregabalin dose.

Indications

Neuropathic pain

Treatment of neuropathic pain in adults.

Epilepsy

As adjunctive therapy in adults with partial seizures, with or without secondary generalization.

Generalized anxiety disorder

Treatment of generalized anxiety disorder in adults.

Fibromyalgia

Treatment of fibromyalgia in adults.

ICD codes

Open the list of ICD codes

ICD-10 code	Indication
B02.2	Herpes zoster with other complications of the nervous system
F41.1	Generalized anxiety disorder
G40	Epilepsy
G53.0	Postherpetic neuralgia (B02.2)
G63.2	Diabetic polyneuropathy
M79.7	Fibromyalgia (including fibromyositis, fibrosis)
R52.2	Other chronic pain

ICD-11 code	Indication
1E91.3	Herpes zoster with involvement of the central nervous system
1E91.40	Acute trigeminal neuropathy due to herpes zoster
1E91.41	Acute herpetic geniculate ganglionitis
1E91.4Y	Other specified acute cranial nerve neuropathy due to herpes zoster
1E91.4Z	Acute cranial nerve neuropathy due to herpes zoster, unspecified
1E91.5	Postherpetic polyneuropathy
1E91.Z	Herpes zoster, unspecified
6B00	Generalized anxiety disorder
8A6Z	Epilepsy or epileptic seizures, unspecified
8C03.0	Diabetic polyneuropathy
MG30.01	Chronic widespread pain
MG30.Z	Chronic pain syndrome, unspecified
1E91.3	Herpes zoster with involvement of the central nervous system
1D02.1	Viral myelitis

Dosage Regimen

The method of application and dosage regimen for a specific drug depend on its form of release and other factors. The optimal dosage regimen is determined by the doctor. It is necessary to strictly adhere to the compliance of the dosage form of a specific drug with the indications for use and dosage regimen.

It is taken orally in a daily dose of 150 to 600 mg in 2 or 3 doses.

For neuropathic pain, treatment is started at a dose of 150 mg/day. Depending on the achieved effect and tolerability, after 3-7 days the dose can be increased to 300 mg/day, and if necessary, after another 7 days – to the maximum dose of 600 mg/day.

For epilepsy, treatment is started at a dose of 150 mg/day. Taking into account the achieved effect and tolerability, after 1 week the dose can be increased to 300 mg/day, and after another week – to the maximum dose of 600 mg/day.

For fibromyalgia, treatment is started at a dose of 75 mg twice a day (150 mg/day). Depending on the achieved effect and tolerability, after 7 days the dose can be increased to 300 mg/day (150 mg twice a day). In the absence of a positive effect, the dose is increased to 450 mg/day (225 mg twice a day), and if necessary, after another 7 days – to the maximum dose of 600 mg/day. It should be taken into account that the 600 mg/day dose does not provide additional benefits but is less well tolerated.

For generalized anxiety disorder, treatment is started at a dose of 150 mg/day. Depending on the achieved effect and tolerability, after 7 days the dose can be increased to 300 mg/day. In the absence of a positive effect, the dose is increased to 450 mg/day, and if necessary, after another 7 days – to the maximum dose of 600 mg/day.

The need for continued therapy should be regularly assessed.

Discontinuation of pregabalin

If treatment needs to be discontinued, it is recommended to do so gradually over a minimum of 1 week.

In patients with impaired renal function, the dose should be individually selected taking into account CC (Table 1).

In patients on hemodialysis, the daily dose of pregabalin is selected taking into account renal function. After a 4-hour hemodialysis session, plasma pregabalin concentrations decrease by approximately 50%. An additional dose should be administered immediately after each 4-hour hemodialysis session (see Table 1).

Table 1. Pregabalin dose selection based on renal function

CC (ml/min)	Starting dose (mg/day)	Maximum dose (mg/day)	Frequency of administration Per day
CC (ml/min)	Starting dose (mg/day)	Maximum dose (mg/day)	Frequency of administration Per day
≥60	150	600	2-3
≥30-<60	75	300	2-3
≥15-<30	25-50	150	1-2
<15	25	75	1
Additional dose after dialysis (mg)
	25	100	Single dose

In patients with impaired hepatic function, no dose adjustment is required.

Elderly patients (over 65 years) may require a dose reduction of pregabalin due to decreased renal function.

Use in children under 12 years and adolescents (12-17 years, inclusive) – the safety and efficacy of pregabalin have not been established. Use in children is not recommended.

Adverse Reactions

Based on the available clinical experience with pregabalin in more than 12,000 patients, the most common adverse events were dizziness and somnolence. The observed events were usually mild or moderate. The frequency of pregabalin and placebo discontinuation due to adverse reactions was 14% and 7%, respectively. The main adverse effects requiring treatment discontinuation were dizziness (4%) and somnolence (3%), depending on their subjective tolerability. Other side effects that also led to drug discontinuation: ataxia, confusion, asthenia, attention disturbance, blurred vision, coordination abnormal, peripheral edema.

Adverse reactions occurring after pregabalin discontinuation have also been noted: insomnia, headache, nausea, anxiety, influenza-like syndrome, convulsions, hyperexcitability, depression, pain, hyperhidrosis, and diarrhea.

During therapy for central neuropathic pain associated with spinal cord injury, an increase in the frequency of adverse reactions in general, as well as CNS adverse reactions, especially somnolence, is observed.

The table lists all adverse events with a frequency exceeding that in the placebo group (observed in more than 1 person). They are distributed by system-organ class. The frequency of adverse reactions was determined based on the number of adverse events in the clinical trial database regardless of causality assessment: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100) and rare (<1/1000). Reactions observed during post-marketing use of the drug are highlighted in italics.

The listed adverse events may also be related to the underlying disease and/or concomitant therapy.

Frequency	Adverse Reactions
Infections and infestations
Common	Nasopharyngitis
Blood and lymphatic system disorders
Uncommon	Neutropenia
Metabolism and nutrition disorders
Common	Increased appetite
Uncommon	Anorexia, hypoglycemia
Psychiatric disorders
Common	Euphoric mood, confusion, insomnia, irritability, depression, disorientation, decreased libido, panic attack, apathy
Uncommon	Hallucinations, restlessness, agitation, depressed mood, elevated mood, mood swings, aggression, depersonalization, anxiety dreams, word-finding difficulty, increased libido, anorgasmia, increased insomnia
Rare	Disinhibition
Nervous system disorders
Very common	Dizziness, somnolence, headache
Common	Ataxia, coordination abnormal, tremor, dysarthria, amnesia, memory impairment, attention disturbance, paresthesia, hypesthesia, sedation, balance disorder, lethargy, ageusia
Uncommon	Syncope, myoclonus, psychomotor hyperactivity, dyskinesia, orthostatic dizziness, intention tremor, nystagmus, speech disorder, hyporeflexia, burning sensation on skin and mucous membranes, hyperesthesia, loss of consciousness, cognitive impairment
Rare	Pathological stupor, parosmia, hypokinesia, dysgraphia, convulsions
Eye disorders
Common	Blurred vision, diplopia
Uncommon	Visual field loss, visual disturbance, eye swelling, visual field defect, visual acuity reduced, eye pain, asthenopia, photopsia, dry eye, lacrimation increased, eye irritation
Rare	Oscillopsia (visual object oscillation), depth perception altered, mydriasis, strabismus, visual brightness enhanced, keratitis, vision loss
Ear and labyrinth disorders
Common	Vertigo
Uncommon	Hyperacusis
Cardiac disorders
Uncommon	Tachycardia, first-degree atrioventricular block, sinus bradycardia, chronic heart failure
Rare	Sinus tachycardia, sinus arrhythmia, QT interval prolonged
Vascular disorders
Uncommon	Hypotension, hypertension, skin hyperemia, flushing, cold extremities
Respiratory, thoracic and mediastinal disorders
Common	Dryness of the nasal mucosa
Uncommon	Dyspnea, epistaxis, cough, nasal congestion, rhinitis, snoring
Rare	Throat tightness, pulmonary edema
Gastrointestinal disorders
Common	Vomiting, constipation, flatulence, abdominal distension, dry mouth, nausea, diarrhea
Uncommon	Gastroesophageal reflux, salivary hypersecretion, oral mucosa decreased sensitivity
Rare	Ascites, pancreatitis, dysphagia, tongue edema
Skin and subcutaneous tissue disorders
Uncommon	Papular rash, urticaria, increased sweating, face edema, pruritus
Rare	Stevens-Johnson syndrome, cold sweat
Musculoskeletal and connective tissue disorders
Common	Muscle cramps, arthralgia, back pain, limb pain, neck muscle spasm
Uncommon	Joint swelling, myalgia, muscle cramp, 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	Breast pain, erectile dysfunction
Uncommon	Sexual dysfunction, delayed ejaculation, dysmenorrhea
Rare	Amenorrhea, breast discharge, breast enlargement, gynecomastia
Immune system disorders
Uncommon	hypersensitivity reactions
Rare	angioedema, allergic reactions
Investigations
Common	Weight increased, blood creatinine increased
Uncommon	Creatine phosphokinase increased, alanine aminotransferase increased, aspartate aminotransferase increased, blood glucose increased, platelet count decreased, blood potassium decreased, weight decreased
Rare	White blood cell count decreased
General disorders and administration site conditions
Common	Peripheral edema, gait disturbance, fall, feeling drunk, malaise, fatigue
Uncommon	Generalized edema, chest tightness, pain, pyrexia, thirst, chills, asthenia, malaise

Contraindications

Hypersensitivity to pregabalin;
Childhood and adolescent age up to 17 years inclusive (no data on use).

With caution

Renal failure, chronic heart failure, concomitant use with opioids.

Due to reported isolated cases of uncontrolled use of pregabalin, this agent should be used with caution in patients with a history of drug dependence (such patients require close medical supervision during treatment).

Use in Pregnancy and Lactation

Pregnancy

There are limited data on the use of pregabalin in pregnant women.

Data from an observational study that included more than 2700 pregnancies with exposure to pregabalin, based on data regularly collected from administrative and medical registries in Denmark, Finland, Norway, and Sweden, do not indicate a substantial increase in the risk of major congenital malformations, adverse birth outcomes, or pathological neurodevelopmental outcomes for pregnancies with pregabalin exposure.

Major congenital malformations

The adjusted prevalence ratios and 95% confidence intervals (CI) in a standard meta-analysis for exposure to pregabalin monotherapy in the first trimester compared to no exposure to antiepileptic drugs were 1.13 (0.96-1.33).

Birth outcomes and postnatal neurodevelopmental outcomes

There were no statistically significant data for stillbirth, low birth weight, preterm birth, small for gestational age, low Apgar score, and microcephaly.

For the pediatric population exposed in utero, the study did not identify an increased risk of developing attention deficit hyperactivity disorder (ADHD), autism spectrum disorders (ASD), and intellectual disability.

In animal studies, Pregabalin showed toxic effects on reproduction. Pregabalin should not be used during pregnancy unless the benefit to the mother clearly outweighs the potential risk to the fetus. When treating with pregabalin, women of reproductive age should use adequate contraceptive methods.

Breastfeeding period

Pregabalin is excreted in breast milk. Since the safety of pregabalin use in newborns is unknown, breastfeeding is not recommended during pregabalin treatment. Breastfeeding should be discontinued or pregabalin therapy should be withdrawn, taking into account the need for therapy for the mother and breastfeeding for the newborn.

Fertility

There are no clinical data on the effect of pregabalin on fertility in women of childbearing potential.

Use in Hepatic Impairment

In patients with impaired hepatic function, no dose adjustment is required.

Use in Renal Impairment

Should be used with caution in renal failure. In patients with impaired renal function, the dose should be individually selected taking into account CC.

Pediatric Use

Contraindicated for use under the age of 17 years inclusive (no data on use).

Geriatric Use

Elderly patients (over 65 years) may require a dose reduction of pregabalin due to decreased renal function.

Special Precautions

Patients with diabetes mellitus

In some patients with diabetes mellitus, if weight gain occurs during pregabalin treatment, adjustment of hypoglycemic drug doses may be required.

Hypersensitivity reactions

Pregabalin should be discontinued if symptoms of angioedema (such as facial edema, perioral edema, or swelling of the upper respiratory tract tissues) develop.

Suicidal thoughts and behavior

Antiepileptic drugs, including Pregabalin, may increase the risk of suicidal thoughts or behavior. Therefore, patients receiving these drugs should be closely monitored for the emergence or worsening of depression, and the appearance of suicidal thoughts or behavior.

Reduced gastrointestinal function

When pregabalin and opioids are used concomitantly, the need for preventive measures to prevent constipation should be considered (especially in elderly patients and women).

Dizziness, somnolence, loss of consciousness, confusion, and cognitive impairment

Treatment with pregabalin has been associated with dizziness and somnolence, which increase the risk of accidental injuries (falls) in the elderly. Cases of loss of consciousness, confusion, and cognitive impairment have also been reported during post-marketing use of the drug. Therefore, until patients have assessed the potential effects of the drug, they should exercise caution.

Discontinuation of concomitant anticonvulsant therapy

Information on the possibility of discontinuing other anticonvulsant drugs when seizures are suppressed by pregabalin and the advisability of monotherapy with this drug is insufficient.

There are reports of seizures, including status epilepticus and petit mal seizures, during pregabalin use or immediately after the end of therapy.

Effect of pregabalin on vision

In clinical studies, the side effect of blurred vision was reported more frequently in patients continuously receiving Pregabalin than in patients receiving placebo. This side effect resolved with continued treatment. In clinical studies where ophthalmological examination of patients was performed, reduced visual acuity and visual field changes were observed more frequently in patients receiving Pregabalin than in those receiving placebo. The frequency of fundus changes was higher in patients receiving placebo.

Although the clinical significance of these disorders has not been established, patients should report any vision changes during pregabalin therapy to their doctor. If visual impairment symptoms persist, follow-up observation should be continued. More frequent vision checks should be performed in patients who are already under regular ophthalmological supervision. If adverse reactions such as vision loss, blurred vision, or other visual disturbances occur in response to pregabalin use, discontinuation of the drug may lead to the disappearance of these symptoms.

Renal Failure

Cases of renal failure have also been noted; in some cases, renal function recovered following pregabalin discontinuation.

Pregabalin Withdrawal Symptoms

The following adverse events were observed following pregabalin withdrawal after long-term or short-term therapy: insomnia, headache, nausea, diarrhea, flu-like syndrome, depression, sweating, dizziness, convulsions, and anxiety. Available data suggest that the frequency and severity of withdrawal symptoms may be dose-dependent.

Pregabalin Abuse

There is no data indicating that pregabalin is active at receptors responsible for drug abuse in patients. Post-marketing studies have reported cases of deviation from the recommended dosage regimen, abuse, and dependence on pregabalin. As with any centrally acting medicinal product, a patient’s history of drug abuse and/or mental disorders should be carefully assessed. Patients should be monitored for signs of deviation from the recommended dosage regimen, abuse, and dependence on pregabalin (e.g., development of tolerance to pregabalin therapy, unjustified dose escalation, addictive behavior).

Chronic Heart Failure

Although no clear relationship with pregabalin plasma concentration and the development of heart failure was noted, cases of chronic heart failure during pregabalin therapy have been reported during post-marketing use in some patients. In patients without clinically significant pre-existing cardiovascular conditions, no association was found between peripheral edema and cardiovascular complications such as hypertension or chronic heart failure. These reactions were predominantly observed in elderly patients with pre-existing cardiac impairment receiving the drug for neuropathy. Therefore, Pregabalin should be used with caution in this patient population. Manifestations of such reactions may resolve following pregabalin discontinuation.

Concomitant Use with Opioids

Caution is recommended when prescribing pregabalin concomitantly with opioids due to the risk of CNS depression. In an observational study of opioid users, patients who received pregabalin therapy concomitantly with an opioid had an increased risk of opioid-related mortality compared to those taking opioids alone (adjusted odds ratio, 1.68 [95% CI, 1.19-2.36]).

Therapy for Central Neuropathic Pain Associated with Spinal Cord Injury

The frequency of CNS adverse events, particularly somnolence, is increased when treating central neuropathic pain due to spinal cord injury, which may, however, be a consequence of the additive effects of pregabalin and other concomitantly administered medications (e.g., antispastic agents). This circumstance should be taken into account when prescribing pregabalin for this indication.

Encephalopathy

Cases of encephalopathy have been reported, especially in patients with pre-existing conditions that may predispose them to this condition.

Women of Childbearing Potential/Contraception

Use of pregabalin during the first trimester of pregnancy may cause major birth defects in the unborn child. Pregabalin should not be used during pregnancy unless the benefit to the mother clearly outweighs the potential risk to the fetus. Women of childbearing potential should use adequate contraception during treatment (see section “Pregnancy and lactation”).

Effect on Ability to Drive and Use Machines

Pregabalin may cause dizziness and somnolence and thereby may affect the ability to drive and operate complex machinery. Patients should not drive, operate complex machinery, or engage in other potentially hazardous activities until it is known whether this drug affects their ability to perform these tasks.

Drug Interactions

Pregabalin is excreted renally primarily as unchanged drug, undergoes minimal metabolism in humans (less than 2% of a dose is excreted in urine as metabolites), does not inhibit the metabolism of other drugs in vitro, and is not bound to plasma proteins; therefore, it is unlikely to be involved in pharmacokinetic interactions.

In Vivo Studies and Population Pharmacokinetic Analysis

No evidence of clinically significant pharmacokinetic interaction of pregabalin with phenytoin, carbamazepine, valproic acid, lamotrigine, gabapentin, lorazepam, oxycodone, or ethanol was found. Oral hypoglycemic agents, diuretics, insulin, phenobarbital, tiagabine, and topiramate were found to have no clinically significant effect on pregabalin clearance.

Oral Contraceptives, Norethisterone and/or Ethinyl Estradiol

Co-administration of oral contraceptives containing norethisterone and/or ethinyl estradiol with pregabalin did not affect the steady-state pharmacokinetics of either agent.

CNS-Affecting Drugs

Cases of respiratory depression, coma, and death have been reported with the concomitant use of pregabalin with other CNS depressants, including in patients with a history of substance abuse.

Repeated oral administration of pregabalin with oxycodone, lorazepam, or ethanol had no clinically significant effect on respiration. Pregabalin appears to potentiate the cognitive and motor impairments caused by oxycodone. Pregabalin may potentiate the effects of ethanol and lorazepam.

Effect on the Gastrointestinal Tract

Negative effects of pregabalin on gastrointestinal function (including development of intestinal obstruction, paralytic ileus, constipation) have also been reported when used concomitantly with medications that cause constipation (such as opioids).

Drug Interactions in Elderly Patients

Special pharmacodynamic interaction studies with other drugs in elderly patients have not been conducted.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.

Medical Disclaimer