Date of approval: 07/13/2010
Date of revision: 08/24/2010; 04/12/2011; 02/01/2012; 11/19/2014; 11/24/2015; 03/25/2016; 05/13/2016; 11/07/2016; 05/26/2017; 06/05/2017; 06/05/2017 October 31, 2018; August 07, 2018
Pregabalin Capsules Instructions
Please read the instructions carefully and use under the guidance of a physician
Drug name].
Generic name: Pregabalin capsules
Trade name: LERICA (LYRICA)
English Name: Pregabalin Capsules
Hanyu Pinyin: Puruibalin Jiaonang
Ingredients
The main ingredient of this product is Pregabalin, the chemical name of which is (S)-3-(aminomethyl)-5-methylhexanoic acid.
Chemical structure formula.
Molecular formula: C8H17NO2
Molecular weight: 159.23
Properties】This product is a capsule with white to off-white powder content.
【Indications】This product is used for the treatment of.
Post-herpetic neuralgia
Fibromyalgia
Specification】75mg, 150mg
Dosage and Administration】This product can be taken with food or alone.
Treatment of post-herpetic neuralgia.
The recommended dose of this product is 75 or 150 mg twice daily; or 50 mg or 100 mg three times daily.
The starting dose may be 75 mg twice daily (150 mg/day) or 50 mg three times daily (150 mg/day). The dose may be increased to 150 mg twice daily (300 mg/day) within one week, depending on efficacy and tolerability. Since this product is primarily cleared by renal excretion, the dose should be adjusted in patients with reduced renal function. The above recommended doses are for patients with creatinine clearance ≥ 60 mL/min.
Patients who do not achieve adequate pain relief after 2 to 4 weeks on 300 mg/day of this product may be increased to 300 mg twice daily (600 mg/day) or 200 mg three times daily (600 mg/day) if the product is tolerated. Because of the dose-dependent nature of adverse reactions and the fact that adverse reactions can lead to higher discontinuation rates, doses above 300 mg/day should only be used in patients with persistent pain who tolerate a dose of 300 mg/day (see [ADVERSE REACTIONS]).
Treatment of fibromyalgia.
The recommended dose of this product for the treatment of fibromyalgia is 300 to 450 mg/day. The starting dose should be 75 mg twice daily (150 mg/day) and may be increased to 150 mg twice daily (300 mg/day) within one week depending on efficacy and tolerability. 225 mg twice daily (450 mg/day) may be increased in patients who do not adequately benefit from 300 mg/day. Although there have been clinical trials with this product at 600 mg/day, there is no evidence of additional significant efficacy benefit at this dose, and the dose is poorly tolerated. In view of the dose-dependent nature of adverse effects, doses above 450 mg/day are not recommended (see [Adverse Effects]). Since this product is primarily excreted by the kidneys, the dose should be adjusted in patients with reduced renal function (see [DOSAGE AND ADMINISTRATION]).
If discontinuation of pregabalin is required, it is recommended that it be tapered over a period of at least 1 week.
Dosing in patients with renal impairment.
Due to the dose-dependent nature of the adverse effects and the fact that the product is primarily cleared by renal excretion, dose adjustments should be made in patients with reduced renal function. Patients with renal impairment should have their dose adjusted based on creatinine clearance (CLcr) as detailed in Table 1. application of this table requires estimation of the patient’s CLcr (in mL/min). the CLcr (in mL/min) can be calculated by measuring plasma creatinine levels (mg/dL) by substituting into the Cockcroft and Gault equation.
CLcr (ml/min) = (female patient × 0.85)
or
CLcr(ml/min)= (female patient × 0.85)
For patients undergoing hemodialysis treatment, the daily dose of pregabalin should be adjusted according to the patient’s renal function. In addition to adjusting the daily dose, a supplemental dose of pregabalin should be given immediately for every 4-hour hemodialysis session (see Table 1).
Table 1. Adjustment of pregabalin dose according to renal function
Creatinine clearance (CLcr) (mL/min) Pregabalin Total daily dose (mg/day)* Dosing regimen ≥ 60150 300 450 600 twice daily or three times daily 30 – 6075 150 225 300 twice daily or three times daily 15 – 3025 – 5075 100 – 150150 once daily or twice daily<15 25 25 – 5050 – 7575 Supplemental dose (mg)† for patients taking 25 mg once daily after hemodialysis: single supplemental Patients with a single supplemental dose of 25 mg or 50 mg at 25 to 50 mg Once-daily dosing: single supplemental dose of 50 mg or 75 mg at 50 to 75 mg Once-daily dosing: single supplemental dose of 75 mg or 100 mg at 75 mg Once-daily dosing: single supplemental dose of 100 mg or 150 mg* Total daily dose (mg/day) divided by the number of daily doses number of doses to obtain the dose per dose (mg/dose)
†
Supplemental dose is a single additional dose for patients with hepatic impairment.
In patients with hepatic impairment, no dose adjustment is required (see [Pharmacokinetics]).
[Adverse Reactions].
Experience from Clinical Trials.
Because clinical trials were conducted under a variety of different circumstances, the incidence of adverse reactions to one drug cannot be directly compared with another drug in different clinical trials, and the incidence may not be representative of the incidence observed in clinical practice.
More than 10,000 patients from various populations took this product in all controlled and uncontrolled trials of premarin prior to marketing. Approximately 5,000 took the drug for at least 6 months, more than 3,100 took it for at least 1 year, and more than 1,400 took it for at least 2 years.
Adverse reactions most frequently leading to discontinuation in all premarketing controlled trials
Integrating data from all populations in the premarketing controlled trials, the proportion of patients who discontinued early due to adverse reactions was 14% in the pregabalin group and 7% in the placebo group. The most common adverse reactions leading to discontinuation of pregabalin were dizziness (4%) and drowsiness (4%). One percent of patients in the placebo group discontinued due to dizziness and <1% due to drowsiness. Other more common adverse reactions leading to discontinuation in the pregabalin group compared with the placebo group in controlled trials included ataxia, confusion, malaise, abnormal thinking, blurred vision, dyskinesia, and peripheral edema (1% each).
Most Common Adverse Reactions in All Premarketing Controlled Trials
Integrating data from all populations in the premarketing controlled trials, more adverse reactions were reported in the pregabalin group than in the placebo group (≥5% and twice the incidence of adverse reactions in the placebo group): dizziness, drowsiness, dry mouth, edema, blurred vision, weight gain, and “abnormal thinking” (primarily difficulty concentrating/attention).
Controlled study of postherpetic neuralgia
Adverse effects leading to drug withdrawal
In the clinical trial of postherpetic neuralgia, the proportion of patients who discontinued the drug early due to adverse reactions was 14% in the pregabalin group and 7% in the placebo group. The most common adverse reactions leading to discontinuation in the pregabalin group were dizziness (4%) and drowsiness (4%); whereas the proportion of patients discontinuing due to dizziness and drowsiness in the placebo group<1%. Other more common adverse reactions leading to discontinuation in the pregabalin group compared with the placebo group in the trial included confusion (2%), peripheral edema, weakness, ataxia, and gait abnormalities (1% each).
Most common adverse reactions
Table 2 lists all adverse reactions in the postherpetic neuralgia trial that occurred in ≥1% of the pregabalin group and were higher than those in the placebo group, but the causal relationship between the drug and the adverse reactions was not determined. In this table, the pregabalin 600 mg/day group also included adverse reactions with an incidence more than twice that of the placebo group, even though the incidence of that adverse reaction was not higher in the overall pregabalin group than in the placebo group. The majority of patients in the pregabalin group in the clinical study had mild or moderate adverse reactions at their most severe level. Overall, 12.4% of patients in the pregabalin group and 9.0% of patients in the placebo group had at least one adverse event, while 8.0% of patients in the pregabalin group and 4.3% of patients in the placebo group had at least one treatment-related serious adverse event.
Table 2 Incidence of adverse reactions after drug administration in controlled trials of postherpetic neuralgia (incidence at least 1% and higher than all adverse events in the placebo group in the pregabalin group) Body System- Preferred Term 75 mg/day [N=84]% 150 mg/day [N=302]% 300 mg/day [N=312]% 600 mg/day [N=154]% All PGB* [N=852]% Placebo [N=398]% Systemic Infection14 8 6 3 7 4 Headache5 9 5 8 7 5 Pain5 4 5 5 5 5 4 Accidental injury4 3 3 5 3 2 Flu-like syndrome1 2 2 2 1 2 1 2 1 Facial puffiness0 2 1 3 2 1 Digestive system Dry mouth7 7 6 15 8 3 Constipation4 5 5 5 5 5 2 Gastrointestinal distention2 1 2 3 2 1 Vomiting1 1 3 3 2 1 Metabolic and nutritional abnormalities Peripheral edema0 8 16 16 12 4 Weight gain1 2 5 7 4 0 Edema0 1 2 6 2 1 Skeletal muscle system muscle weakness1 1 1 1 1 1 1 0 Nervous system Dizziness11 18 31 37 26 9 Drowsiness8 12 18 25 16 5 Ataxia1 2 5 9 5 1 Gait abnormalities0 2 4 8 4 1 Confusion1 2 3 7 3 0 Abnormal thinking†0 2 1 6 2 2 Motor disorders2 2 1 3 2 0 Amnesia0 1 1 4 2 0 Speech Disorders 0 0 1 1 3 1 0 Respiratory system Bronchitis 0 1 1 3 1 1 Special sensations Blurred vision‡1 5 5 9 5 3 Diplopia 0 2 2 4 2 0 Visual abnormalities 0 1 2 5 2 0 Eye discomfort 0 1 1 2 1 0 Genitourinary incontinence 0 1 1 2 1 0 * PGB: Pregabalin
† Thinking abnormalities include mainly concentration/attention difficulties, but also cognitive and language problems and adverse events associated with delayed thinking
‡ Investigator terminology; summary level terminology is amblyopia
Controlled study of fibromyalgia
Adverse events leading to discontinuation of medication
In clinical trials in fibromyalgia, the proportion of patients who discontinued prematurely due to adverse reactions was 19% in the pregabalin group (150-600 mg/day) and 10% in the placebo group. The most common adverse reactions leading to discontinuation in the pregabalin group were dizziness (6%) and drowsiness (3%), while the rate of discontinuation due to each of these reactions in the placebo group<1%. Other adverse reactions with higher discontinuation rates in the pregabalin group than in the placebo group included fatigue, headache, impaired balance, and weight gain. Each of these adverse reactions caused approximately 1% of patients to withdraw from the study.
Most Common Adverse Reactions
Table 3 lists all adverse reactions in the fibromyalgia trial that occurred in ≥2% of all pregabalin groups and were higher than those in the placebo group, regardless of whether a cause-and-effect relationship existed. The majority of patients in the pregabalin group in the clinical trial had mild or moderate adverse reactions at their most severe level.
Table 3 Incidence of adverse reactions following dosing in controlled trials of fibromyalgia (all adverse events with an incidence ≥2% in the pregabalin group and higher than in the placebo group) Organ System Classification- Preferred Term 150 mg/day [N=132]%300 mg/day [N=502]%450 mg/day [N=505]%600 mg/day [N=378]% All PGB* [N =1517]% Placebo [N=505]% Ear and vagus abnormalities Vertigo2 2 2 2 1 2 0 Eye abnormalities Blurred vision8 7 7 7 12 8 1 Gastrointestinal abnormalities Dry mouth7 6 9 9 8 2 Constipation4 4 7 10 7 2 Vomiting2 3 3 2 3 2 Gastrointestinal flatulence1 1 2 2 2 2 1 Abdominal distention2 2 2 2 2 1 Systemic abnormalities and administration site reactions Fatigue5 7 6 8 7 4 Peripheral edema5 5 6 9 6 2 Chest pain2 1 1 1 2 2 1 Sensory abnormalities1 3 2 2 2 2 0 Edema1 2 1 2 2 2 1 Sense of intoxication1 2 1 2 2 2 0 Infection and invasive sinusitis4 5 7 5 5 4 Examination Weight gain8 10 10 10 14 11 2 Metabolic and nutritional abnormalities Increased appetite4 3 5 7 5 1 Fluid retention2 3 3 3 2 2 2 1 Skeletal muscle and connective tissue abnormalities Arthralgia4 3 3 6 4 2 Muscle cramps2 4 4 4 4 4 2 Back pain2 3 4 3 33 Nervous system Abnormal dizziness23 31 43 45 38 9 Drowsiness13 18 22 22 20 4 Headache11 12 14 10 12 12 Attention deficit4 4 6 6 5 1 Balance deficit2 3 6 9 5 0 Memory impairment1 3 4 4 3 0 Coordination abnormalities2 1 2 2 2 2 1 Hypesthesia2 2 3 2 2 1 Drowsiness2 2 1 2 2 0 Tremor0 1 3 2 2 0 Mental abnormal euphoria2 5 6 7 6 1 Blurred state of consciousness 0 2 3 4 3 0 anxiety2 2 2 2 2 21 disorientation1 0 2 1 2 0 depression2 2 2 2 2 2 2 respiratory, thoracic and mediastinal abnormal sore throat2 1 3 3 2 2 2 * PGB: Pregabalin
Other adverse reactions to pregabalin observed in clinical studies
The following is a list of adverse reactions reported in all clinical trials of pregabalin that occurred after administration of the drug. The following events do not include those listed elsewhere in this instruction manual, events due to drug-independent causes, events that are too common to determine whether they were caused by the drug, or acute life-threatening events that have been reported only once and have no substantial likelihood of occurring.
Adverse events were classified by body system and listed in descending order of incidence. The incidence was defined as very common (≥1/10), common (1/100-1/10), occasional (1/1000-1/100), rare (1/10,000-1/1000), and very rare (<1/10000). See [Precautions] for a detailed description of clinically significant adverse events.
Systemic – common: abdominal pain, allergic reaction, fever, peripheral edema, edema, abnormal gait, fall, feeling of intoxication, fatigue; occasional: abscess, cellulitis, chills, malaise, neck stiffness, drug overdose, pelvic pain, photosensitivity reaction, suicide attempt, generalized edema, chest tightness, pain, thirst, malaise; rare: allergic-like reactions, ascites, sarcoidosis, hangover effects, intentional injury, retroperitoneal fibrous degeneration, shock, suicide.
Cardiovascular system – Occasionally: deep thrombophlebitis, heart failure, hypotension, postural hypotension, retinal vascular abnormalities, syncope, tachycardia, first-degree AV block, sinus bradycardia, hypertension, hot flashes, flushing, cold extremities; rarely: ST-segment reduction, ventricular fibrillation, sinus tachycardia, sinus arrhythmias.
Digestive system – common: gastroenteritis, increased appetite, vomiting, constipation, flatulence, bloating, dry mouth; occasional: cholecystitis, cholelithiasis, colitis, dysphagia, esophagitis, gastritis, gastrointestinal bleeding, black stool, oral ulcer formation, pancreatitis, rectal bleeding, tongue edema, gastroesophageal reflux, hypersalivation, oral hypesthesia; rare: stomatitis with mouth sores, esophageal ulcers, periodontal abscesses.
Blood and lymphatic system – common: petechiae; occasional: anemia, eosinophilia, hypochromic anemia, leukocytosis, leukopenia, lymphadenopathy, thrombocytopenia; rare: myelofibrosis, erythrocytosis, prothrombinopenia, purpura, thrombocytosis.
Metabolic and nutritional abnormalities – common: increased appetite; occasional: anorexia, hypoglycemia; rare: decreased glucose tolerance, uric acid crystalluria.
Skeletal muscular system – common: arthralgia, leg cramps, myalgia, muscle weakness, muscle spasms, back pain, limb pain, neck cramps; occasional: arthrosis, joint swelling, muscle tremors, neck pain, muscle ankylosis; rare: cartilage dystrophy, generalized spasticity, rhabdomyolysis.
Neurological – very common: dizziness, drowsiness; common: anxiety, depersonalization, increased muscle tone, hypoesthesia, hypoactive sexuality, nystagmus, sensory abnormalities, sedation, mydriasis, tremors, euphoria, confusion, irritability, depression, disorientation, insomnia, ataxia, coordination abnormalities, tremor, amnesia memory impairment, attention disorder, balance disorder, somnolence; occasionally: abnormal dreams, agitation, emotional indifference, aphasia, perioral sensory abnormalities, dysarthria, hallucinations, hostility, nociceptive hypersensitivity, sensory hypersensitivity, increased locomotion, hypokinesia, decreased muscle tone, increased libido, myoclonus, neuralgia, irritability, depressed mood, elevated mood, unstable state of mind, difficulty evoking words, psychomotor hyperactivity, postural dizziness, intentional tremor, cognitive impairment, speech disorders, hyporeflexia, burning sensation; rare: addiction, cerebellar syndrome, cogwheel-like ankylosis, coma, delirium, paranoia, autonomic dysfunction, movement disorders, dystonia, encephalopathy, extrapyramidal syndrome, Green-Barre syndrome, hyperalgesia, increased intracranial pressure, manic manifestations, paranoid manifestations, peripheral neuritis, personality disorders, the psychotic depression, schizophrenic manifestations, sleep disorders, slanting neck, clenching of teeth, panic attacks, disinhibition, and writing difficulties.
Respiratory system – common: nasopharyngitis; occasional: dyspnea, epistaxis, cough, nasal congestion, rhinitis, snoring; rare: apnea, pulmonary atelectasis, fine bronchitis, eruption, laryngospasm, pulmonary edema, pulmonary fibrosis, yawning, throat tightness, nasal dryness.
Skin and accessory tissues – common: pruritus; occasional: alopecia, dry skin, eczema, hirsutism, skin ulcers, urticaria, blistering maculopapular rash, papular rash, sweating; rare: angioedema, exfoliative dermatitis, lichenoid dermatitis, melanosis, nail abnormalities, petechiae, purpura-like rash, pustular rash, skin atrophy, skin necrosis, skin nodules, Stevens-Johnson syndrome, subcutaneous nodules, cold sweats.
Special sensations – common: conjunctivitis, diplopia, blurred vision, otitis media, tinnitus, vertigo; occasional: abnormal regulation, blepharitis, dry eyes, ocular hemorrhage, auditory hypersensitivity, photophobia, retinal edema, loss of taste, abnormal taste, loss of peripheral vision, visual disturbances, ocular swelling, visual field defects, decreased visual sensitivity, ocular pain , visual fatigue, flash hallucinations, dry eyes, increased tearing, eye irritation; rare: unequal pupils, blindness, corneal ulcers, proptosis, extraocular muscle paralysis, iritis, keratitis, keratoconjunctivitis, reduced pupil size, dilated pupil, night blindness, ocular muscle paralysis, optic nerve atrophy, optic papilla edema, olfactory abnormalities, ptosis, uveitis, vibratory hallucinations, altered visual depth perception, strabismus, visual brightness.
Genitourinary system – common: sexual pleasure deficit, erectile dysfunction, urinary frequency, urinary incontinence; occasional: abnormal ejaculation, proteinuria, amenorrhea, dysmenorrhea, dyspareunia, hematuria, renal calculi, leukorrhea changes, menorrhagia, irregular uterine bleeding, nephritis, oliguria, urinary retention, urinary abnormalities, sexual dysfunction, delayed ejaculation. Rare: acute renal failure, glomerulitis, bladder tumor, cervicitis, dyspareunia, epididymitis, female lactation, glomerulonephritis, ovarian disorders, pyelonephritis, breast pain, breast discharge, breast enlargement.
Examination – common: weight gain; occasional: elevated blood creatine phosphokinase, elevated blood glucose, decreased platelet count, decreased blood potassium, weight loss; rare: decreased white blood cell count, elevated blood creatinine.
Comparison of gender and race
The overall adverse events were similar in males and females. Data on the distribution of race-related adverse event reports are insufficient and inconclusive.
Postmarketing Experience
The following adverse reactions were reported in post-marketing applications of pregabalin. Because these adverse reactions were spontaneously reported from an uncertain population size, it is difficult to reliably estimate the incidence of these adverse reactions and the causal relationship with drug exposure.
Immune system abnormalities: occasional: hypersensitivity; rare: angioedema, allergic reactions
Neurological abnormalities: very common: headache; occasionally: loss of consciousness, psychiatric impairment; rare: convulsions
Psychiatric abnormalities: occasional: aggression
Ocular abnormalities: rare: keratitis, visual loss
Cardiac abnormalities: rare: congestive heart failure, prolonged QT interval
Respiratory, thoracic and mediastinal abnormalities: rare: pulmonary edema
Gastrointestinal abnormalities: common: nausea, diarrhea; rare: tongue swelling
Hepatobiliary abnormalities: occasional: elevated liver enzymes*; rare: jaundice; very rare: liver failure, hepatitis
Skin and subcutaneous tissue abnormalities: Occasionally: facial swelling, pruritus, Stevens-Johnson syndrome
Renal and urinary system abnormalities: rare: urinary retention
Reproductive system and breast abnormalities: Rare: male gynecomastia
Systemic abnormalities and drug site conditions: Occasionally: discomfort, facial edema
* Elevated alanine aminotransferase (ALT) and elevated aspartate aminotransferase (AST)
Withdrawal withdrawal symptoms may occur in some patients after receiving short- and long-term pregabalin therapy. The following reactions have been reported: insomnia, headache, nausea, anxiety, diarrhea, flu-like syndrome, convulsions, hypersensitivity, depression, pain, hyperhidrosis, and dizziness. Patients should be informed of these conditions at the start of treatment.
For discontinuation of long-term treatment with pregabalin, data suggest that the incidence and severity of withdrawal symptoms may be related to the dose of pregabalin.
Reporting of suspected adverse reactions
It is important to report suspected adverse reactions after a drug has received marketing authorization. The benefit/risk balance of the drug can be continuously monitored.
Contraindications】People who are hypersensitive to the active ingredient or any of the excipients contained in this product.
[Precautions].
Diabetic patients
According to current clinical practice, some diabetic patients require adjustment of glucose-lowering medication when they gain weight due to treatment with pregabalin.
Angioedema
Angioedema has been reported in post-marketing reports in some patients after the initiation or long-term use of pregabalin. Atopic symptoms include swelling of the face, mouth (tongue, lips and gums) and neck (pharynx and larynx). There have been isolated reports of angioedema leading to life-threatening respiratory damage requiring emergency management. The product should be discontinued immediately if the patient develops these symptoms.
Patients who have previously experienced angioedema should be aware of the symptoms when taking this product. In addition, the risk of angioedema may be increased with concomitant use of other drugs that cause angioedema (e.g., angiotensin-converting enzyme inhibitors [ACEIs]).
Hypersensitivity reactions
Hypersensitivity reactions have been reported in post-marketing reports in some patients who started pregabalin for a short period of time. Adverse reactions include skin redness, blistering, urticaria, rash, dyspnea, and wheezing. Patients should discontinue the product immediately if these symptoms occur.
Discontinuation of antiepileptic drugs
As with all antiepileptic drugs, pregabalin should be tapered off to minimize the risk of increased seizure frequency in patients with epilepsy. If discontinuation is required, a taper of at least 1 week is recommended.
Peripheral edema
Peripheral edema may be caused by pregabalin. Short-term clinical trials (patients without clinically significant cardiac disease or peripheral vascular disease) have not shown a clear association between peripheral edema and cardiovascular complications such as hypertension or congestive heart failure. Peripheral edema was not associated with changes in laboratory tests suggestive of hepatic or renal hypoperfusion.
In controlled clinical trials, the incidence of peripheral edema was 6% and 2% in the pregabalin and placebo groups, respectively. The proportion of patients discontinuing the drug due to peripheral edema was 0.5% and 0.2% in the pregabalin and placebo groups, respectively.
Patients taking both pregabalin and thiazolidinedione antidiabetics experienced weight gain and peripheral edema more frequently than either of the two drugs alone. The majority of patients taking thiazolidinedione antidiabetics in the overall safety database were subjects in the Diabetic Peripheral Neuropathy with Pain Study. The proportion of patients in this population who developed peripheral edema was 3% (2/60), 8% (69/859), and 19% (23/120) in the thiazolidinedione antidiabetic group, the pregabalin group, and the two-drug combination group, respectively. Similarly, the proportion of patients who showed weight gain was 0% (0/60), 4% (35/859) and 7.5% (9/120) in the thiazolidinedione antidiabetic group, the pregabalin group and the two-drug combination group, respectively.
Because thiazolidinedione antidiabetics can cause weight gain and/or fluid retention that may exacerbate or lead to heart failure, pregabalin should be monitored for changes in condition when combined with this class of drugs.
Due to limited data, this product should be used with caution in patients with congestive heart failure in New York Heart Association (NYHA) Class III or IV cardiac function.
Dizziness, drowsiness, loss of consciousness, confusion, and psychiatric impairment
Pregabalin treatment can be associated with dizziness and drowsiness, which may increase the risk of unintentional injury (falls) in the elderly. Loss of consciousness, confusion, and psychiatric impairment have been reported in some patients after the introduction of pregabalin. Therefore, patients are advised to use caution until they are familiar with the potential effects of the drug.
In controlled trials, the incidence of dizziness in patients in the pregabalin and placebo groups was 30% and 8%, respectively. The incidence of drowsiness was 23% and 8% in the pregabalin and placebo groups, respectively. Dizziness and somnolence usually occurred within a short time of starting the product, with a higher frequency in the high-dose group. In controlled studies, dizziness and somnolence were the most common adverse reactions leading to discontinuation (4% each). In short-term controlled studies, the proportion of patients in the pregabalin group who reported these two types of adverse reactions and who remained dizzy or drowsy until the last dose was 30% or 42%, respectively.
Weight gain
Pregabalin may cause weight gain. In controlled clinical trials of up to 14 weeks, weight gain from baseline was ≥7% in 9% of patients in the pregabalin group and 2% in the placebo group. Very few patients in the pregabalin group (0.3%) withdrew from the trial due to weight gain. The weight gain seen in the pregabalin group was related to dose and duration of exposure and was not related to baseline body mass index (BMI), sex, or age. Weight gain was not limited to patients with edema. (See [Caution])
Weight gain did not cause clinically significant blood pressure changes in short-term controlled clinical studies; however, the long-term effects on the cardiovascular system of weight gain occurring with the application of pregabalin are unknown.
In diabetic patients, weight gain was 1.6 Kg (range: -16 to 16 Kg) and 0.3 Kg (range: -10 to 9 Kg) in the pregabalin and placebo groups, respectively. The mean weight gain was 5.2 Kg in the group of 333 diabetic patients who had been taking this product for at least 2 years.
No systematic assessment was performed to determine whether the weight gain that occurred with the application of pregabalin affected glycemic control. Long-term open clinical controlled trials in patients with diabetes showed that administration of this product was not associated with uncontrolled glycemia (tested with glycosylated hemoglobin [HbA1C]).
Withdrawal symptoms
Withdrawal withdrawal symptoms can occur in some patients after receiving short- and long-term pregabalin therapy. The following events have been reported: insomnia, headache, nausea, anxiety, diarrhea, flu-like syndrome, convulsions, hypersensitivity, depression, pain, hyperhidrosis, and dizziness. Patients should be informed of these conditions at the start of treatment.
Convulsions, including persistent epilepsy and grand mal convulsions, may occur during pregabalin use or shortly after discontinuation.
For discontinuation of long-term treatment with pregabalin, data suggest that the incidence and severity of withdrawal symptoms may be related to the dose of pregabalin.
Potential Carcinogenicity
Preclinical animal studies of standard lifetime carcinogenicity have shown an unintended high incidence of angiosarcoma in two different strains of mice. (See [Pharmacology and Toxicology]) The clinical significance of this finding is unknown. Clinical experience during premarket development is not directly relevant to the assessment of the potential carcinogenicity of pregabalin for human application.
A total of 57 new or prior tumor exacerbations were reported in clinical studies in various different populations, with a total exposure of 6396 patient-years for patients 12 years of age and older. Since the tumor incidence and recurrence rates in a similar population without application of this product are unknown, it is unknown whether the tumor incidence in this population is affected by pregabalin.
Ophthalmic Effects
The proportion of patients reporting blurred vision in the control study was higher in the pregabalin group (7%) than in the placebo group (2%), with the majority of patients experiencing symptoms that resolved with continued use of the drug. Less than 1% of patients discontinued the drug due to vision-related events (mainly blurred vision).
More than 3600 patients underwent eye examinations as scheduled, including visual acuity, visual field and post-dilated fundoscopy. The results showed that the proportion of patients in the pregabalin and placebo groups with decreased visual acuity was 7% and 5%, respectively, the proportion of patients with visual field changes was 13% and 12%, respectively, and the proportion of patients with fundoscopic changes was 2% in both groups.
Although the clinical significance of the above ophthalmic findings is unknown, patients should be advised to notify their physicians if visual changes occur. If visual disorders persist, further evaluation should be considered. Patients who already have regular ophthalmic examinations should be examined more frequently.
Adverse visual reactions, including blindness, blurred vision, or other changes in vision, many of which are transient, have been reported in certain patients in post-marketing experience. These visual symptoms may improve or disappear after discontinuation of pregabalin.
Elevated creatine kinase
Creatine kinase may be elevated after taking pregabalin. The mean difference between the highest creatine kinase value and baseline was 60 U/L in the pregabalin group and 28 U/L in the placebo group, and the proportion of patients with creatine kinase values at least 3 times above the upper limit of normal was 1.5% in the pregabalin group and 0.7% in the placebo group in all controlled trials in different patient populations. Three cases of rhabdomyolysis events were reported in patients in the pre-marketing clinical trials in the pregabalin group. Because of the presence of factors that may have caused or contributed to the myopathic events in these cases, the relationship of these myopathic events to this product is not clear. Physicians should advise patients to report promptly any unexplained muscle pain, tenderness, or weakness, especially if these muscle symptoms are accompanied by general malaise or fever. The product should be discontinued if myopathy or significant elevation of creatine kinase is suspected or confirmed.
Decreased platelet count
Decreased platelet counts may occur after administration of pregabalin. The mean maximum reduction in platelets was 20 × 103/µL in the pregabalin group and 11 × 103/µL in the placebo group. in the overall database of controlled trials, the proportion of patients with potentially clinically significant thrombocytopenia (defined as 20% and <150 × 103/µL below baseline levels) was 3% and 2% in the pregabalin and placebo groups, respectively. Only one patient experienced severe thrombocytopenia with a platelet count below 20 x 103/ µL. No increase in bleeding-related adverse events was observed after administration of this product in the randomized controlled trial.
Prolonged PR interval
Prolongation of the PR interval may occur with the administration of pregabalin. Analysis of ECG data from clinical trials showed a mean prolongation of the PR interval of 3-6 ms at doses of ≥300 mg/day of this product. The change did not increase the risk of PR interval prolongation beyond 25% of baseline, did not increase the proportion of patients with PR intervals greater than 200 ms, and did not increase the risk of second- and third-degree AV block.
A subgroup analysis of patients with prolonged PR intervals at baseline and those taking other medications that cause prolonged PR intervals did not reveal an increased risk of prolonged PR intervals. However, due to the limited number of patients in this category, the results of this analysis are not conclusive.
Gender
Clinical trials have shown no clinically meaningful effect of gender on blood levels of pregabalin.
Renal Failure
Cases of renal failure have been reported, and in some cases this adverse effect was reversed after discontinuation of pregabalin.
Hepatic Impairment
No specific pharmacokinetic studies have been performed in patients with hepatic impairment. Since pregabalin does not undergo significant metabolism and is excreted in the urine primarily as prodrug, hepatic impairment is not expected to significantly alter pregabalin plasma concentrations.
Older adults
Clearance of pregabalin tends to decrease with increasing age. The decrease in clearance following oral pregabalin is consistent with a decrease in creatinine clearance with increasing age. In patients with concomitant age-related renal impairment, it is necessary to reduce the dose of pregabalin.
Nursing Mothers
The pharmacokinetics of pregabalin given at 150 mg every 12 hours (daily dose of 300 mg) were evaluated in 10 lactating women who had delivered for at least 12 weeks. Lactation had little or no effect on the pharmacokinetics of pregabalin. Prevacid is secreted into breast milk, and the mean steady-state concentration in breast milk is approximately 76% of the mean steady-state concentration in maternal plasma. For women receiving a dose of 300 mg/day or a maximum dose of 600 mg/day, the infants received an estimated dose of pregabalin from breast milk of 0.31 or 0.62 mg/kg/day, respectively (assuming an average breast milk consumption of 150 mL/kg/day). On a mg/kg basis, these estimated doses represent approximately 7% of the mother’s total daily dose.
Congestive Heart Failure
Congestive heart failure has been reported in some patients treated with pregabalin since its introduction. These reactions have been seen mostly in elderly patients with cardiovascular impairment during treatment of neurologic indications with pregabalin. Pregabalin should be used with caution in these patients. These reactions may disappear after discontinuation of pregabalin.
Reduced lower gastrointestinal function
According to post-marketing reports, pregabalin may cause events related to lower GI tract dysfunction (e.g., intestinal obstruction, paralytic intestinal obstruction, and constipation) when used in combination with drugs that may cause constipation (e.g., opioid-like analgesics). When pregabalin is combined with opioids, measures to prevent constipation may need to be considered (especially in female patients and elderly patients).
Encephalopathy
Cases of encephalopathy have been reported, mostly in patients with underlying conditions that can cause encephalopathy.
Lactose intolerance
Pregabalin contains lactose monohydrate. It should not be used in patients with rare genetic disorders such as galactose intolerance, primary lactase deficiency, or glucose-galactose malabsorption.
Effects on the ability to drive and operate machinery
Pregabalin may have a mild or moderate effect on the ability to drive and operate machinery. This product may cause dizziness and drowsiness and therefore may affect the ability to drive or operate machinery. Patients are advised not to drive, operate complex machines, or engage in other potentially hazardous activities until it is clear whether this product will affect their ability to perform these activities.
Substance Abuse and Dependence
This product is not known to have an active effect on the receptor sites for substance abuse. Misuse and abuse have been reported in post-marketing experience databases. As with any CNS-active drug, physicians should carefully assess the patient’s history of drug abuse and observe for signs of misuse or abuse (e.g., development of tolerance, dose escalation, foraging behavior).
Abuse
In a study of recreational users of sedative/sleeping drugs (including alcohol), subjective ratings of pregabalin (450 mg, single dose) included “good”, “highly effective”, and “liked” to a similar extent as Valium (30 mg, single dose). were 4% and 1%, respectively. The rate of reporting this adverse reaction was higher in some patient groups (1% to 12%).
Dependence
Rapid or abrupt discontinuation of the product in clinical studies with some patients reporting insomnia, nausea, headache, and diarrhea (see [Precautions]) suggests somatic dependence.
Suicidal behavior and thoughts
Patients receiving antiepileptic drugs (AEDs) for any indication for which antiepileptic drugs (including this product) increase the risk of suicidal thoughts or behaviors should be monitored during AED treatment for the following symptoms or worsening of symptoms: depression, suicidal thoughts or behaviors, and/or any abnormal changes in mood or behavior.
A combined analysis of 199 placebo-controlled clinical trials (monotherapy and adjunctive therapy) that included 11 different AEDs found that patients in the AED treatment group had approximately twice the risk of suicidal thoughts or behaviors as those in the placebo group (adjusted relative risk 1.8, 95% confidence interval: 1.2, 2.7). The median treatment duration in these clinical trials was 12 weeks, and the estimated incidence of suicidal behavior or thoughts was 0.43% in the 27,863 patients in the AED treatment group compared with 0.24% in the 16,029 patients in the placebo group, indicating an increase of approximately 1 patient with suicidal thoughts or behavior per 530 treated patients. There were four suicidal patients in the drug treatment group and no suicidal patients in the placebo group in the trial; however, the number of cases was too small to draw any conclusions about the effect of drugs on suicide.
The increased risk of suicidal thoughts or behaviors with AED treatment was observed one week after the start of AED treatment and persisted throughout the treatment evaluation period. Because most of the clinical trials included in the analysis did not exceed 24 weeks, the risk of suicidal thoughts or behaviors after 24 weeks could not be evaluated.
The risk of suicidal thoughts or behaviors was generally consistent across the drugs included in the data analysis. These risks were found across different mechanisms of action of AEDs and multiple indications, suggesting that this risk is prevalent in all AED treatments for any indication. No significant changes in risk with age (5 to 100 years) were found in the clinical trials analyzed.
Table 4 shows the absolute and relative risks of the evaluated AEDs for the different indications.
Table 4 Combined analysis of the risk of antiepileptic drugs for different indications
Indication Number of events per 1000 patients in the placebo group Number of events per 1000 patients in the drug group Relative risk: incidence of events in patients in the drug group/incidence of events in patients in the placebo group Risk difference: additional events per 1000 patients in the drug group Epilepsy 1.0 3.4 3.5 2.4 Psychosis 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9
The relative risk of suicidal thoughts or behaviors in clinical trials of epilepsy was higher than in clinical trials of psychosis or other disorders; however, the absolute risk difference was essentially similar for both indications of epilepsy and psychosis.
When considering prescribing this or any other AED, the risk of suicidal thoughts or behaviors must be weighed against the risk of not treating the disorder. Epilepsy and many other conditions for which AED treatment is indicated are at an inherently higher risk for suicidal thoughts and behaviors due to the morbidity and mortality of the disease itself. Therefore, if suicidal thoughts and behaviors occur during treatment, the prescriber needs to consider whether the patient presenting with these symptoms is related to the disease for which he or she is being treated.
Patients, caregivers, and their family members should be informed that this and other AEDs carry an increased risk of suicidal thoughts and behaviors. They should also be advised to watch for the onset or worsening of depressive symptoms and signs, any unusual mood or behavioral changes, or the onset of suicidal thoughts and behaviors, or the emergence of self-harm thoughts. Any suspicious behavior should be reported immediately to medical personnel.
For Pregnant and Lactating Women]
Animal studies have shown this product to be reproductively toxic. (See [Pharmacology and Toxicology]). The possible risk of this product in humans is unknown.
There are no clinical data on the effects of this product on female fertility.
In a clinical trial evaluating the effect of this product on sperm motility, healthy male subjects were exposed to a dose of 600 mg/day of this product. After 3 months of administration, no effect on sperm motility was observed.
There are insufficient data on the use of Prevacid in pregnant women and it should not be administered during pregnancy unless necessary (the benefits of taking the drug in pregnant women clearly outweigh the potential risks of the drug to the fetus). Women of childbearing age must apply effective contraception.
Prevacid may be secreted into human milk (see [Precautions]). The effect of pregabalin on the newborn/infant is not known. The benefits of breastfeeding for the child and the benefits of treatment for the mother must be considered to decide whether to discontinue breastfeeding or discontinue pregabalin treatment.
[Pediatric Dosage].
The safety and efficacy of the drug in pediatric and adolescent patients under 18 years of age have not been established and the use of this product is not recommended.
Geriatric Use]
Geriatric patients may require dose reduction due to decreased renal function (see [DOSAGE AND ADMINISTRATION] for patients with renal impairment).
In a controlled clinical study of pregabalin for postherpetic neuralgia, there were 282 patients aged 65 to 74 years and 379 patients aged 75 years and older. No overall differences in safety and efficacy were seen between the older and younger patients described above.
In the clinical controlled study of pregabalin for fibromyalgia, 106 patients aged 65 years and older. Although adverse reactions were similar in both age groups, the incidence of the following neurological adverse reactions was higher in the 65 years and older group: dizziness, blurred vision, impaired balance, tremor, confused state of consciousness, coordination abnormalities, and drowsiness.
Drug Interactions]
Since pregabalin is mainly excreted in the urine as a prototype drug, the metabolism of this product in the body can be ignored (less than 2% of the administered dose of drug metabolites were found in urine). Isolated studies have shown that pregabalin does not inhibit drug metabolism or bind to plasma proteins and that pregabalin has little pharmacokinetic interaction with other drugs.
Similarly, no clinically relevant pharmacokinetic interactions between pregabalin and phenytoin, carbamazepine, valproic acid, lamotrigine, gabapentin, lorazepam, oxycodone, or ethanol were observed in animal studies. Population pharmacokinetic analysis showed no clinically significant effect of oral antidiabetics, diuretics, insulin, phenobarbital, tiagabine, and topiramate on clearance of pregabalin.
When pregabalin was administered with the oral contraceptives norethindrone and/or ethinyl estradiol, the steady-state pharmacokinetics of both substances were not affected.
Pregabalin may potentiate the effects of ethanol and lorazepam. In controlled clinical studies, when multiple doses of oral pregabalin were combined with oxycodone, lorazepam, or ethanol, no clinically meaningful effects on patient respiration were observed. Respiratory failure and coma have been reported in patients taking pregabalin and other CNS depressants after marketing. Pregabalin may potentiate oxycodone-induced cognitive dysfunction and overall motor dysfunction.
Drug interaction studies have only been conducted in adults and not specifically in elderly volunteers.
[Drug Overdose].
After marketing, the most common adverse reactions caused by pregabalin overdose include drowsiness, confused state of consciousness, agitation, and fidgeting.
Seizures have been reported.
In rare cases, cases of coma have been reported.
Signs, symptoms and laboratory findings of acute drug overdose in humans
There is limited experience with pregabalin overdose. The highest dose reported in the clinical development program for incidental drug overdose was 8000 mg, with no clinically significant consequences. Some patients in clinical studies have overdosed up to 2400 mg/day. The types of adverse reactions in patients in the high dose group (≥900 mg) were not clinically different from those in the recommended dose group.
Treatment or management of overdose
There is no specific antidote for pregabalin overdose. If an overdose is confirmed, gastric lavage or emetics may be tried to remove unabsorbed drug, and care should usually be taken to maintain a patent airway. General supportive therapy includes monitoring of vital signs and observation of clinical status.
Although hemodialysis has not been used in the few known cases of overdose, the decision to use hemodialysis may depend on the patient’s clinical condition or degree of renal impairment. Standard hemodialysis can significantly clear pregabalin (approximately 50% clearance in 4 hours).
[Clinical Trials].
Treatment of postherpetic neuralgia
Three multicenter, double-blind, placebo-controlled studies established the efficacy of pregabalin in the treatment of postherpetic neuralgia (PHN). Patients enrolled in the studies were those whose pain persisted for at least 3 months after healing of the herpes zoster rash and who had a minimum baseline score of ≥4 (11 points on a numeric pain scale ranging from 0 to 10, no pain to severe pain). 73% of patients completed the studies. The mean baseline pain score for these three studies was 6 to 7. Patients were allowed to take up to 4 grams of acetaminophen daily for pain relief in addition to pregabalin. Patients kept a daily pain diary.
PHN1 study: The study was conducted over 13 weeks and was divided into pregabalin 75 mg, 150 mg, 300 mg per dose and placebo groups twice daily. Patients with creatinine clearance between 30 and 60 mL/min were randomized to 75 mg per dose, 150 mg per dose, or placebo twice daily; patients with creatinine clearance above 60 mL/min were randomized to 75 mg per dose, 150 mg per dose, 300 mg per dose, or placebo twice daily. All dose groups of pregabalin significantly improved endpoint mean pain scores in patients with creatinine clearance above 60 mL/min and increased the proportion of patients with at least a 50% reduction in pain scores from baseline. Although the doses administered varied according to renal function, discontinuation rates associated with adverse effects were higher in patients with creatinine clearance between 30 and 60 mL/min, indicating that this group of patients did not tolerate pregabalin as well as those with creatinine clearance above 60 mL/min. Figure 1 shows the proportion of patients who achieved different levels of pain relief based on the different levels of pain improvement from baseline to the study endpoint. The graph shows cumulative values, for example, an improvement of 50% relative to baseline, which also includes all patients with an improvement of less than 50%. Patients who did not complete the study were categorized as having 0% improvement. Pain was reduced in some patients in the first week and was maintained throughout the treatment period.
Figure 1: Percentage of patients who achieved different levels of pain relief – PHN 1 study
PHN 2 Study: The study was conducted over a period of 8 weeks and was divided into pregabalin 100 mg per dose, 200 mg per dose and placebo groups 3 times daily. The dose administered was calculated based on creatinine clearance. Patients with creatinine clearance between 30 and 60 ml/min were given 100 mg per dose, 3 times daily. Patients with creatinine clearance above 60 ml/min were given 200 mg per dose, 3 times daily. All of the pregabalin groups significantly improved endpoint mean pain scores and increased the proportion of patients with at least a 50% reduction in pain scores from baseline. Figure 2 shows the proportion of patients who achieved different levels of pain relief based on the different levels of pain improvement from baseline to the study endpoint. The graph shows cumulative values, e.g., a 50% improvement relative to baseline, which also includes all patients with an improvement of less than 50%. Patients who did not complete the study were categorized as having 0% improvement. Pain was reduced in some patients in the first week and was maintained throughout the treatment period.
Figure 2: Percentage of patients who achieved different levels of pain relief – PHN 2 study
PHN 3 Study: The study was conducted for 8 weeks, regardless of creatinine clearance, and was divided into pregabalin 50 mg per dose, 100 mg per dose and placebo groups 3 times daily. Both the pregabalin 50 mg every time and 100 mg 3 times daily groups significantly improved the endpoint mean pain score and increased the proportion of patients with at least 50% reduction in pain score from baseline. Discontinuation rates associated with adverse effects were higher in patients with creatinine clearance of 30 to 60 mL/min, indicating that this group of patients did not tolerate pregabalin as well as those with creatinine clearance above 60 mL/min. Figure 3 shows the proportion of patients who achieved different levels of pain relief based on the different levels of pain improvement from baseline to the study endpoint. The graph shows cumulative values, for example, an improvement of 50% relative to baseline, which also includes all patients with an improvement of less than 50%. Patients who did not complete the study were categorized as having 0% improvement. Pain was reduced in some patients in the first week and was maintained throughout the treatment period.
Figure 3: Percentage of patients who achieved different levels of pain relief – PHN 3 study
Treatment of fibromyalgia
The efficacy of pregabalin for fibromyalgia was established in a 14-week multicenter, double-blind placebo-controlled trial (F1) and another 6-month randomized discontinuation trial (F2). patients recruited for the F1 and F2 trials were those diagnosed with fibromyalgia according to American College of Rheumatology (ACR) criteria (3-month history of widespread pain with pressure pain in at least 11 of 18 specific pressure points). Visual analogue scores showed a reduction in pain. Furthermore, the patient’s overall impression of change (PGIC) and Fibromyalgia Impact Questionnaire (FIQ) results also showed improvement in pain.
Trial F1: This was a 14-week trial in which the total daily dose of pregabalin was 300, 450, and 600 mg compared with the placebo group. patients with a minimum mean baseline score of ≥4 on the 11-point numeric pain rating scale and a minimum mean baseline score of ≥40 mm on the 100 mm pain visual analogue score (VAS) were enrolled in the trial. The mean baseline pain score in this trial was 6.7. Those who responded to placebo during the initial one-week placebo introduction period were not randomized to subsequent trials. 64% of patients randomized to the pregabalin arm completed the trial. There was no evidence of better pain treatment in the 600 mg daily dose group than in the 450 mg daily dose group, but there was evidence of dose-dependent adverse effects (see [Adverse Effects]). Pain was reduced in some patients in the first week and was maintained throughout the treatment period. The results of the trial are shown in Figure 4 and Table 5.
Figure 4 shows the proportion of patients who achieved varying degrees of pain improvement from baseline to the trial endpoint. The graph shows the cumulative values. Patients who did not complete the trial were assigned to the 0% improvement group. Some patients experienced pain relief in the first week and maintained it throughout the treatment period.
Figure 4: Patients Achieving Different Levels of Pain Improvement – Fibromyalgia F1 Trial
Table 5: Overall patient effectiveness in the Fibromyalgia F1 trial Overall patient impression of change in condition Treatment group (mg/day)
Percentage improvement % 95% CI placebo 47.6 (40.0,55.2) PGB 300 68.1 (60.9, 75.3) PGB 450 77.8 (71.5, 84.0) PGB 600 66.1 (59.1, 73.1) PGB = pregabalin
F2 trial: this randomized discontinuation trial compared the efficacy of the pregabalin group with that of the placebo group. Patients titrated to a total daily dose of 300, 450, or 600 mg during a 6-week open dose preference period were considered treatment effective if they had 1) at least a 50% reduction in pain (VAS) and 2) a PGIC score of “significantly improved” or “very significantly improved”. Treatment-effective individuals entered the double-blind trial and were randomized to either the ‘dose achieved in the open trial group’ or the placebo group. Treatment was administered for a maximum of 6 months from randomization. Time to treatment failure was used as the criterion for assessing efficacy, which was defined as 1) less than 30% reduction in pain (VAS) at two consecutive visits during the double-blind period compared to baseline in the open period, or 2) worsening fibromyalgia symptoms forcing a change in treatment regimen. 54% of patients were titrated to an effective and tolerable dose of pregabalin during the 6-week open period. The proportion of patients completing 26 weeks of treatment during the randomized treatment period was 38% and 19% in the pregabalin and placebo groups, respectively.
If pain recurrence or discontinuation due to adverse events was used as the criterion for lapse in therapy (LTR), the time to lapse in therapy was longer in the pregabalin group than in the placebo group. The proportion of patients who remained on the drug and maintained effective treatment until 26 weeks was 53% in the pregabalin group and 33% in the placebo group. The time to treatment failure was also later in the pregabalin group according to the FIQ1 score. The time to no improvement in the overall assessment of impression of patient status according to the PGIC2 score was also later in the pregabalin group.
1 Time to FIQ exacerbation was defined as the time when each subscale of the FIQ was 1 point higher than the double-blind baseline and the total score was 5 points higher than the double-blind baseline.
2 The time to no improvement in PGIC was defined as the time to a score less than “significantly improved”.
Figure 5: Fibromyalgia F2 trial: time to treatment failure (Kaplan-Meier analysis)
Pharmacology and Toxicology
Pharmacological effects
Pregabalin has a high affinity for the α2-δ site (an auxiliary subunit of voltage-gated calcium channels) in the central nervous system. The mechanism of action of pregabalin is unclear, but results from transgenic mice and structurally related compounds (e.g., gabapentin) suggest that the analgesic and anticonvulsant effects in animal models may be related to the binding of pregabalin to the α2-delta subunit. In vitro studies suggest that pregabalin may reduce the calcium-dependent release of some neurotransmitters by modulating calcium channel function.
Although pregabalin is a structural derivative of the inhibitory neurotransmitter g-aminobutyric acid (GABA), it does not bind directly to GABAA, GABAB or benzodiazepine receptors, does not increase the GABAA response in cultured neurons in vitro, does not alter GABA concentrations in rat brain, and has no acute effect on GABA uptake or degradation. However, it was found that prolonged exposure of in vitro cultured neurons to pregabalin increased GABA transporter protein density and functional GABA transport rate. Pregabalin does not block sodium channels, is inactive at opioid receptors, does not alter cyclooxygenase activity, is inactive at dopamine and 5-hydroxytryptamine receptors, and does not inhibit the reuptake of dopamine, 5-hydroxytryptamine, or norepinephrine.
Toxicological studies
Genotoxicity.
In vitro studies have shown that pregabalin is not mutagenic in bacterial and mammalian cells, and both in vivo and in vitro studies have shown that pregabalin does not cause chromosomal aberrations in mammals and does not induce extra-programmed DNA synthesis in hepatocytes in rats or mice.
Reproductive toxicity.
Oral administration of pregabalin (50 to 2500 mg/kg) to male rats mated with unadministered females prior to to and during mating was associated with a variety of adverse reproductive and developmental effects, including decreased sperm counts, decreased sperm motility, increased sperm abnormalities, decreased fertility, increased rate of loss before implantation, decreased litter size, decreased litter weight, and increased incidence of litter abnormalities. The effects on sperm and fertility parameters were reversible during the study period (3-4 months). At the no-effect dose (100 mg/kg) for male rat reproduction, plasma pregabalin exposure (AUC) was approximately three times the human exposure at the maximum recommended clinical dose (MRD). In addition, in a general toxicity study of 4 weeks or longer, histopathological examination of the reproductive organs (testes, epididymis) in male rats at doses of 500 ~ 1250 mg/kg showed adverse effects at a no-effect dose of 250 mg/kg, approximately 8 times the human plasma exposure at MRD.
In female rats, oral administration of pregabalin at 500, 1250 and 2500 mg/kg before and during mating and early gestation was associated with disturbed estrous cycle and increased number of mating days at all doses, and embryonic death at higher doses. Plasma exposure to pregabalin at low doses was approximately 9 times the exposure at human MRD, and no no effect dose was determined.
Increased incidence of fetal structural malformations and other developmental toxicities, including fetal death, growth retardation, and neurological and reproductive impairment, were seen in pregnant rats and rabbits at plasma exposure (AUC) to pregabalin equivalent to ≥5 times the exposure at MRD.
Plasma pregabalin exposure (AUC) in pregnant rats given orally at 500, 1250, or 2500 mg/kg during the organogenesis period was approximately 17 times the human exposure at MRD at low doses. The incidence of specific cranial abnormalities due to abnormal premature ossification (premature fusion of the zygomatic and nasal interosseous sutures) was increased at doses ≥1250 mg/kg. Skeletal variation and delayed ossification were seen at all doses. The body weight of fetuses was reduced at high doses. A no-effect dose of pregabalin on embryo-fetal development in rats has not been established.
Pregabalin 250, 500 or 1250 mg/kg was administered orally to pregnant rabbits during the organogenesis period. decreased fetal body weight, delayed ossification, increased incidence of skeletal malformations and visceral variation were observed at high doses. The no-effect dose for development in rabbits was 500 mg/kg, and plasma exposure was approximately 16 times that of human exposure at MRD.
In a perinatal toxicity test, rats were given pregabalin orally at 50, 100, 250, 1250, or 2500 mg/kg, and offspring growth was slowed at ≥100 mg/kg and offspring survival was reduced at ≥250 mg/kg. Significant effects on offspring survival were observed at ≥1250 mg/kg, with 100% litter mortality at the highest dose. Neurobehavioral abnormalities (reduced auditory startle response) were observed in offspring tested as adults at ≥250 mg/kg, and reproductive impairment (reduced fertility and litter size) was seen at 1250 mg/kg. The no-effect dose for perinatal development in rats was 50 mg/kg, and plasma exposure was approximately twice the human exposure at MRD.
Carcinogenicity.
A dose-dependent increase in the incidence of malignant tumors of vascular origin (angiosarcoma) was seen in B6C3F1 and CD-1 mice given pregabalin at 200, 1000, and 5000 mg/kg by adulteration for 2 years. Plasma pregabalin exposure (AUC) in mice at the lowest dose was approximately equivalent to that at MRD, and a no-effect dose for angiosarcoma induction in mice has not been determined.
Wistar rats given pregabalin by adulteration for 2 years at doses of 50, 150, and 450 mg/kg in males and 100, 300, and 900 mg/kg in females, the highest doses being equivalent to 14 and 24 times the human exposure at MRD, respectively, did not show an increase in tumor incidence.
Other toxicity.
Skin toxicity
Skin lesions ranging from erythema to necrosis were seen in repeated administration toxicity tests in rats and monkeys, the etiology of which is unclear. Prevacid caused skin lesions at doses twice as high as MRD. More severe skin lesions, including necrosis, occurred at plasma pregabalin exposure (AUC) 3 – 8 times the human exposure at MRD. No increase in the incidence of skin lesions was seen in clinical trials.
Ocular lesions
Ocular lesions (characterized by retinal atrophy [including photoreceptor cell loss] and/or corneal inflammation/mineral deposits) were seen in two Wistar rat carcinogenicity assays, with plasma pregabalin exposure (AUC) ≥2 times the human exposure at MRD at the time of alteration, and no no no-effect dose was established. No similar lesions were seen in a 2-year carcinogenicity test in two strains of mice or a 1-year carcinogenicity study with monkey administration.
[Pharmacokinetics].
Steady-state pharmacokinetic parameters of pregabalin were similar in healthy volunteers, epileptic patients treated with antiepileptic drugs, and patients with chronic pain.
Absorption.
When pregabalin was administered on an empty stomach, it was rapidly absorbed, reaching peak plasma concentrations within 1 hour after single or multiple dose administration. The oral bioavailability of pregabalin was estimated to be ≥90% and was dose-independent. Steady state is achieved within 24 to 48 hours after multiple dose administration. When administered with food, the absorption rate of pregabalin decreases, with a 25-30% reduction in Cmax and a delay in tmax to approximately 2.5 hours. However, concomitant administration of pregabalin with food does not affect the degree of absorption of pregabalin in a clinically meaningful way.
Distribution.
Preclinical studies have shown that pregabalin can cross the blood-brain barrier in mice, rats and monkeys. Prevacid crosses the placenta of rats and can appear in the milk of lactating rats. In humans, the apparent volume of distribution of pregabalin after oral administration is approximately 0.56 L/kg. pregabalin is not bound to plasma proteins.
Metabolism.
The metabolism of pregabalin in humans is negligible. Following administration of radiolabeled pregabalin, approximately 98% of pregabalin is recovered in the urine as a prototype. The major metabolite of pregabalin, the N-methylated derivative, was also found in the urine at 0.9% of the administered dose. In preclinical studies, no racemization of pregabalin from the S- to R-spin enantiomer was detected.
Excretion.
Pregabalin is primarily cleared from the body circulation and excreted as a prototype drug via the kidneys. The mean clearance half-life of pregabalin is 6.3 hours. Both plasma clearance and renal clearance of pregabalin are directly proportional to creatinine clearance.
Dose adjustment is necessary in patients with concomitant renal decompensation or who are on hemodialysis therapy (see [DOSAGE AND ADMINISTRATION] Table 1).
Linear/non-linear.
The pharmacokinetics of pregabalin are linear over the recommended daily dosing range. Interindividual pharmacokinetic variability of pregabalin is small (<20%). The pharmacokinetics of multiple doses can be inferred from the data of a single dose. Therefore, routine monitoring of plasma concentrations of pregabalin is not required.
Storage】Seal and store.
Package】Packaged in PVC/aluminum plastic blister pack, 14 capsules/box, 56 capsules/box.
Expiration date】36 months
Standard】Imported drug registration standard JX20170038.
【Approval number】Imported drug registration no.
75mg: H20150619
150mg: H20150622
【Manufacturing enterprise
Company name: Pfizer Manufacturing Deutschland GmbH, Betriebsstatte Freiburg
Business Address: Mooswaldallee 1, D-79090 Freiburg, Germany
Domestic Contact Address
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Postal code: 100010
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