How Effective Is Pregabalin for Neuropathic Pain?

Pregabalin capsules are used to treat postherpetic neuralgia.

Pregabalin capsules are used to treat postherpetic neuralgia.

Alias

Lerica

Drug Name

Pregabalin capsules

Drug type

prescription

Pregabalin capsule ingredients

The main ingredient of this product is pregabalin, and its chemical name is (S) -3- (aminomethyl) -5-methylhexanoic acid.
Chemical Structure:

Molecular formula: C ₈ H ₁₇ NO ₂
Molecular weight: 159.23

Properties of Pregabalin Capsules

This product is a hard capsule with a white to off-white powder.

Pregabalin capsule indications

This product is used to treat postherpetic neuralgia.

Pregabalin capsule specifications

25mg, 50mg, 75mg, 100mg, 150mg, 200mg, 300mg

Pregabalin capsules dosage

This product can be taken simultaneously with food or alone.
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, or 50 mg three times daily. It can be increased to 150 mg twice daily based on efficacy and tolerability within a week. Because this product is mainly cleared by renal excretion, patients with renal dysfunction should adjust the dose. The above recommended dosage is suitable for patients with creatinine clearance 60 ml / min.
Patients who take this product at 300 mg / day and whose pain is not sufficiently relieved after 2 to 4 weeks can be increased to 300 mg each time, twice daily, or 200 mg each time, if they can tolerate this product (600 mg / day). Because adverse reactions are dose-dependent and adverse reactions can lead to higher discontinuation rates, doses exceeding 300 mg / day should only be used in patients with persistent pain that tolerate a dose of 300 mg / day (see [Adverse Effects]).
If pregabalin is to be discontinued, it is recommended to gradually reduce it for at least one week.
Medication for patients with renal impairment:
Because the adverse reactions are dose-dependent and the product is mainly eliminated by renal excretion, patients with renal dysfunction should adjust the dose. Patients with renal impairment should adjust the dose according to creatinine clearance (CLcr), as shown in Table 1. When applying this table, the patient's CLcr (ml / min) needs to be estimated. CLcr (in ml / min) can be calculated by measuring the plasma creatinine level (mg / dL) and substituting it into the Cockcroft and Gault equations.
CLcr (ml / min) = 1.23 * [140-age (years)] * weight (kg) / serum creatinine (u mol / L) female patients * 0.85
Or CLcr (ml / min) = [140-age (years)] * weight (kg) / 72 serum creatinine (mg / dl) female patients * 0.85
For patients undergoing hemodialysis, the daily dose of pregabalin should be adjusted based on the patient's renal function. In addition to adjusting the daily dose, every 4 hours of hemodialysis treatment, a supplemental dose of pregabalin should be given immediately (see Table 1).
Table 1. Pregabalin doses adjusted according to renal function <br /> Creatinine clearance (CLcr) Total daily dose of pregabalin Dosing schedule (ml / min) (mg / day) *
60 150 300 450 600 2 times or 3 times daily 30-60 75 150 225 300 2 times or 3 times daily 15-30 25-50 75 100-150 150 once or 2 times daily [15 25 25-50 50-75 75 once daily supplemental dose after hemodialysis (mg) **
Patients taking 25mg once daily: a single supplemental dose of 25mg or 50mg
Patients taking once a day at 25-50mg: a single supplementary dose is 50mg or 75mg
Patients taking 50-75mg once daily: a single supplemental dose of 75mg or 100mg
Patients taking 75 mg once daily: a single supplemental dose of 100 mg or 150 mg
* Divide the total daily dose (mg / day) by the number of daily doses to get each dose (mg / time)
** Supplementary dose is a single additional dose for patients with liver impairment:
Patients with liver impairment do not need to adjust the dosage (see [Pharmacokinetics]).

Adverse effects of pregabalin capsules

Experience in clinical trials:
Because clinical trials are conducted in many different situations, the incidence of adverse reactions in different clinical trials of one drug with another cannot be directly compared, and the incidence may not be representative of the rates observed in clinical practice.
In all pre-marketing controlled and uncontrolled trials of pregabalin, more than 10,000 patients from different populations took this product. About 5,000 people took the medicine for at least 6 months, more than 3,100 people took the medicine for at least 1 year, and more than 1,400 people took the medicine for at least 2 years.
Among the pre-marketing controlled trials, the adverse reactions that most often led to discontinuation were combined with data from all populations in the pre-marketing controlled trials. The proportion of patients who discontinued early due to adverse reactions was 14% and 7% in the pregabalin and placebo groups, respectively. The most common adverse reactions leading to discontinuation of pregabalin were dizziness (4%) and lethargy (3%). 1% of patients in the placebo group discontinued due to dizziness and <1% of patients discontinued due to drowsiness. Compared with the placebo group, other adverse reactions that were more common in the pregabalin group that led to discontinuation included ataxia, blurred consciousness, fatigue, abnormal thinking, blurred vision, dyskinesia, and peripheral edema (1% each).
The most common adverse reactions in all pre-marketing controlled trials. Combining data from all populations in the pre-marketing controlled trials, the pregabalin group reported more than the placebo group (5% and twice the incidence of adverse reactions). Adverse reactions were dizziness, drowsiness, dry mouth, edema, blurred vision, weight gain, and "abnormal thinking" (mainly difficulty in concentration / difficulty in attention).
Controlled study of postherpetic neuralgia in adverse reactions leading to discontinuation of clinical trials Postherpetic neuralgia in clinical trials, the proportion of patients who discontinued early due to adverse reactions was 14% in the pregabalin group and 7 in the placebo group, respectively. %. The most common adverse reactions leading to discontinuation in the pregabalin group were dizziness (4%) and drowsiness (3%); the proportion of patients in the placebo group who discontinued due to dizziness and drowsiness [1%. Compared with the placebo group, other more common adverse reactions leading to discontinuation in the pregabalin group included confusion (2%), peripheral edema, fatigue, ataxia, and abnormal gait (1% each).
The most common adverse reactions Table 2 lists all adverse reactions in the pregabalin group that occurred at a rate of 1% in the postherpetic neuralgia trial and were higher than in the placebo group. However, the causal relationship between the drug and the adverse reactions is uncertain. Among them, the pregabalin 600 mg / day group also included adverse reactions that occurred more than twice as often as the placebo group, even though the adverse reactions were not more common in the pregabalin group than in the placebo group. Most patients in the pregabalin group had mild or moderate adverse reactions in clinical studies.

Other Pregabalin Adverse Reactions Observed in Clinical Studies The following list of adverse reactions that have occurred after taking pregabalin in all clinical trials. The following events do not include events listed in other sections of this specification, do not include events caused by drug-irrelevant causes, do not include events that are too common to determine whether caused by drugs, and do not include acute reports that have been reported only once without substantial possibility Life-threatening event.
Adverse events are categorized by the human body system and ranked in descending order of the incidence. Incidence rates are defined as: common (1 / 100), rare (1 / 1000-1 / 100), and rare ([1/1000). For a description of clinically significant adverse events, see [Precautions].
Whole body-common: abdominal pain, allergic reaction, fever; rare: abscess, cellulitis, chills, discomfort, neck stiffness, overdose, pelvic pain, photosensitivity reaction, suicide attempt; rare: allergic reaction, ascites, granulomatosis, Hangover effect, intentional injury, retroperitoneal fibrosis, shock, suicide.
Cardiovascular system-rare: deep thrombophlebitis, heart failure, hypotension, orthostatic hypotension, retinal vascular abnormalities, syncope; rare: reduced ST segment, ventricular fibrillation.
Digestive system-common: gastroenteritis, increased appetite; rare: cholecystitis, cholelithiasis, colitis, dysphagia, esophagitis, gastritis, gastrointestinal bleeding, melena, oral ulcer formation, pancreatitis, rectal bleeding, Swelling of the tongue; rare: aphthous stomatitis, esophageal ulcer, periodontal abscess.
Blood and lymphatic system-common: petechiae; rare: anemia, eosinophilia, hypochromic anemia, leukocytosis, leukopenia, lymphadenopathy, thrombocytopenia; rare: bone marrow fibrosis, erythrocytosis, prothrombin Reduction, purpura, thrombocytosis.
Metabolic and nutritional disorders-rare: impaired glucose tolerance, uric acid crystal urine.
Skeletal muscle system-common: joint pain, leg pain, cramps, myalgia, muscle weakness; rare: joint disease; rare: cartilage dystrophy, systemic spasm.
Nervous system-common: anxiety, disintegration of personality, increased muscle tone, loss of sensation, decreased libido, nystagmus, paresthesia, stiffness, twitching; rare: abnormal dreams, agitation, apathy, aphasia, paresthesia, Dysphagia, hallucinations, hostility, hyperalgesia, hyperalgesia, increased exercise, decreased motor function, decreased muscle tone, increased libido, myoclonus, neuralgia; rare: addiction, cerebellar syndrome, gear-like rigidity, coma, Delirium, delusion, autonomic dysfunction, dyskinesia, dystonia, encephalopathy, extrapyramidal syndrome, Guillain-Barre syndrome, hypoalgesia, increased intracranial pressure, manic manifestations, paranoid manifestations, peripheral neuritis, Personality disorders, psychotic depression, schizophrenia manifestations, sleep disorders, torticollis, closed teeth.
Respiratory system-rare: apnea, atelectasis, bronchiolitis, hiccups, laryngospasm, pulmonary edema, pulmonary fibrosis, yawning.
Skin and associated tissues-common: itching; rare: hair loss, dry skin, eczema, hairy, skin ulcers, urticaria, vesicular herpes; rare: angioedema, exfoliative dermatitis, lichenoid dermatitis, melanosis, nails Abnormalities, petechiae, purpura, impetigo, skin atrophy, skin necrosis, skin nodules, Stevens-Johnson syndrome, subcutaneous nodules.
Special sensations-common: conjunctivitis, diplopia, otitis media, tinnitus; rare: abnormal regulation, blepharitis, dry eyes, eye bleeding, auditory allergy, photophobia, retinal edema, loss of taste, abnormal taste; rare: pupil Large, blind, corneal ulcer, exophthalmos, extraocular muscle paralysis, iritis, keratitis, keratoconjunctivitis, pupil dilation, pupil dilation, night blindness, ophthalmoplegia, optic atrophy, optic nipple edema, olfactory sense, Droopy eyelids, uveitis.
Genitourinary system-common: loss of sexual pleasure, erectile dysfunction, frequent urination, urinary incontinence; rare: abnormal ejaculation, proteinuria, amenorrhea, dysmenorrhea, dysuria, hematuria, kidney stones, leucorrhea, menstruation, irregular uterus Bleeding, nephritis, oliguria, urinary retention, abnormal urination; rare: acute renal failure, balanitis, bladder neoplasms, cervicitis, dyspareunia, epididymitis, female lactation, glomerulitis, ovarian disorders, pyelonephritis.
Gender and race comparisons The overall adverse events were similar for men and women. There are insufficient data on the distribution of reports of race-related adverse events, which is difficult to determine.
Post-marketing experience < br The following adverse reactions were reported in the post-marketing application of pregabalin. Because these adverse reactions come from spontaneous reports of uncertain population size, it is difficult to reliably estimate the incidence of these adverse reactions and the causal relationship with drug exposure.
Nervous system abnormalities-headache gastrointestinal abnormalities-nausea, diarrhea, reproductive system and breast diseases-male and female breasts with enlarged breasts

Pregabalin capsule contraindications

Those who are allergic to the active ingredients or any excipients contained in this product.

Pregabalin capsules precautions

Angioedema < br In post-marketing reports, some patients developed angioedema after starting or long-term use of pregabalin. Specific symptoms include swelling of the face, mouth (tongue, lips, and gums) and neck (pharyngeal and throat). A case report of angioedema causing respiratory injury that is life-threatening and requires urgent treatment. If patients have these symptoms, this product should be discontinued immediately.
Patients who have previously experienced angioedema should pay attention to relevant symptoms when taking this product. In addition, when taking other drugs that cause angioedema (such as angiotensin-converting enzyme inhibitors [ACEI]), the risk of angioedema may increase.
Hypersensitivity reactions < br In the post-marketing report, some patients started to use pregabalin for a short period of time. Adverse reactions include redness of the skin, blisters, urticaria, rash, dyspnea and wheezing. If patients have these symptoms, this product should be discontinued immediately.
Withdrawal of antiepileptic drugs (AEDs)
As with all antiepileptic drugs, pregabalin should be gradually stopped to minimize the risk of increased seizure frequency in patients with epilepsy. If this product is to be discontinued, it is recommended to gradually reduce it for at least one week.
Peripheral edema <br /> Pregabalin may cause peripheral edema. Short-term clinical trials (no patients with significant clinically significant heart disease or peripheral vascular disease) did not show a clear association between peripheral edema and cardiovascular complications such as hypertension or congestive heart failure. Peripheral edema has nothing to do with changes in laboratory tests that suggest liver and kidney dysfunction.
In controlled clinical trials, the rates of peripheral edema in the pregabalin and placebo groups were 6% and 2%, respectively. The proportion of patients discontinued due to peripheral edema was 0.5% and 0.2% in the pregabalin group and placebo group, respectively.
Patients taking pregabalin and thiazolidinedione antidiabetics at the same time had more frequent weight gain and peripheral edema than those taking either of the two drugs alone. In the overall safety database, the majority of patients taking thiazolidinedione antidiabetics were subjects in a study of diabetic peripheral neuropathy with pain. The proportion of patients with peripheral edema in this population was 3% (2/60), 8% (69/859), and 19% in the thiazolidinedione antidiabetic group, pregabalin group, and the combination of two drugs, respectively. (23/120). Similarly, the proportion of patients who experienced weight gain was 0% (0/60), 4% (35/859), and 7.5 in the thiazolidinedione antidiabetic group, pregabalin group, and the combination of two drugs, respectively. % (9/120).
Because thiazolidinedione antidiabetic drugs can cause weight gain and / or fluid retention, which may worsen or cause heart failure, pregabalin should be used in conjunction with these drugs to pay attention to changes in the condition.
Due to limited data, patients with congestive heart failure in the NYHA Class III or IV heart function should use this product with caution.
Dizziness and drowsiness <br /> Pregabalin may cause dizziness and drowsiness. Patients should be informed that dizziness and drowsiness associated with this product may affect their ability to drive or operate machinery.
In controlled trials, the incidence of dizziness was 31% and 9% in the pregabalin and placebo groups, respectively. The prevalence of somnolence in the pregabalin and placebo groups was 22% and 7%, respectively. Dizziness and drowsiness usually occur within a short period of time when the product is started, and the high-dose group is more frequent. In controlled studies, dizziness and drowsiness were the most common adverse reactions that led to discontinuation (4% each). In the short-term controlled study, the proportion of patients in the pregabalin group who reported these two types of adverse reactions who had dizziness or drowsiness until the last dose was 30% or 42%, respectively.
Weight gain < br Pregabalin may cause weight gain. In controlled clinical trials of up to 14 weeks, patients who gained 7% from baseline gained 9% and 2% in the pregabalin and placebo groups, respectively. Very few patients (0.3%) in the pregabalin group withdrew from the trial due to weight gain. Weight gain in the pregabalin group was related to dose and duration of exposure and was not related to baseline body mass index (BMI), gender, or age. Weight gain is not limited to edema patients. (See [Precautions, Peripheral Edema])
In short-term clinically controlled studies, weight gain did not cause clinically significant changes in blood pressure, however, the long-term effects of weight gain that occur after pregabalin on the cardiovascular system are unknown.
Among patients with diabetes, the pregabalin and placebo groups gained 1.6 Kg (range: -16 to 16 Kg) and 0.3 Kg (range: -10 to 9 Kg), respectively. The group of 333 diabetic patients who have taken this product for at least 2 years has gained an average weight of 5.2 Kg.
No systematic assessment of whether weight gain following pregabalin affects glycemic control has been performed. Long-term, open-label, controlled clinical trials in diabetic patients have shown that taking this product has nothing to do with uncontrolled blood glucose (tested with HbA1C).
Sudden or rapid discontinuation of medicine <br /> After sudden or rapid discontinuation of pregabalin, some patients experience symptoms such as insomnia, nausea, headache, and diarrhea. Apply this product gradually for at least one week, instead of abruptly stopping the drug.
Potential carcinogenicity <br /> Standard lifetime carcinogenicity preclinical animal studies have shown that two different strains of mice have an unexpectedly high incidence of angiosarcoma. (See [Pharmacology and Toxicology]) The clinical significance of the discovery is unknown. Clinical experience during the pre-market development process has no direct significance in assessing the potential carcinogenicity of pregabalin for human applications.
In clinical studies of various populations, the total exposure of patients over 12 years was 6396 patient-years, and a total of 57 cases of new or previous tumors were reported. Because the tumor incidence and recurrence rate of similar populations without this product is unknown, it is unknown whether the tumor incidence of this population is affected by pregabalin.
Ophthalmology effects . <Br The proportion of patients reporting blurred vision in the controlled study was higher in the pregabalin group (7%) than in the placebo group (2%). Symptoms in most patients disappeared with continued medication. Less than 1% of patients discontinued due to vision-related events (mainly blurred vision).
More than 3,600 patients underwent ophthalmic examinations as planned, including vision, visual field, and fundus examination after dilation. The results showed that the proportion of patients with visual impairment in the pregabalin group and the placebo group was 7% and 5%, respectively, and the proportion of patients with visual field changes was 13% and 12%, respectively. Is 2%.
Although the clinical significance of the above ophthalmologic findings is unknown, patients should be informed that they should notify their doctor if there are visual changes. If visual disturbances persist, further evaluation should be considered. Patients who have undergone regular eye examinations should increase their frequency.
Elevated creatine kinase <br /> Elevated creatine kinase can occur after taking pregabalin. The highest difference between creatine kinase and baseline was 60 U / L and 28 U / L in the pregabalin and placebo groups, respectively. In all controlled trials in different patient groups, the proportion of patients whose creatine kinase value exceeded the upper limit of normal by at least 3 times was 1.5% and 0.7% in the pregabalin group and placebo group, respectively. In pre-marketing clinical trials, three patients in the pregabalin group reported rhabdomyolysis. Because of the factors that may cause or contribute to myopathy events in these cases, the relationship between these myopathy events and this product is unclear. Physicians should advise patients to report difficult muscle pain, tenderness, or weakness, especially if these muscle symptoms are accompanied by general discomfort or fever. This product should be discontinued if suspected or diagnosed as myopathy or a significant increase in creatine kinase.
Decrease in platelet counts <br Decrease in platelet counts can occur after taking pregabalin. The pregabalin group had an average platelet reduction of up to 20 × 103 / µL, while the placebo group had an average reduction of up to 11 × 103 / µL. In the overall database of controlled trials, the proportion of patients with potentially clinically significant thrombocytopenia (defined as 20% below baseline and <150 × 103 / µL) in the pregabalin and placebo groups was 3% and 2 respectively. %. Only one patient experienced severe thrombocytopenia after taking this product, with a platelet count below 20 x 103 / µL. In randomized controlled trials, no increase in bleeding-related adverse reactions was observed after taking this product.
PR interval prolongation <br /> Prolonged PR interval may occur after taking pregabalin. Analysis of ECG data in clinical trials showed that the PR interval was prolonged by an average of 3-6 milliseconds at doses of 300 mg / day. This change did not increase the risk of PR interval extension exceeding the baseline by 25%, did not increase the proportion of patients with PR interval longer than 200 milliseconds, and did not increase the risk of second- and third-degree atrioventricular block.
A subgroup analysis of patients with a prolonged PR interval and other medications that led to a prolonged PR interval did not reveal an increased risk of PR interval prolongation. However, due to the limited number of such patients, the results of this analysis are inconclusive.
Drug abuse and dependence <br /> Unknown This product has an active effect on the receptor site for drug abuse. As with any CNS active drug, the physician should carefully evaluate the patient's history of drug abuse and observe if there are signs of misuse or abuse of this product (eg, tolerance, increased doses, drug-seeking behavior).
Abuse < br A study of recreational users of sedative / sleeping drugs (including alcohol) showed that subjective evaluation of pregabalin (450mg, single dose) includes "good efficacy", "high", "favorite" Etc. The degree is similar to that of stability (30 mg, single dose). Overall clinical control studies of more than 5,500 patients showed that the proportion of patients reporting euphoria as an adverse reaction was 4% and 1% in the pregabalin group and placebo group, respectively. The rate of reporting of this adverse reaction was high in some patient groups (1% to 12%).
Dependence This product was quickly or suddenly discontinued in clinical studies. Some patients report symptoms such as insomnia, nausea, headache, and diarrhea (see [Cautions]), suggesting physical dependence.
Suicidal behaviors and ideas < br For patients receiving antiepileptic drugs (AED) for any indication, antiepileptic drugs (including this product) increase the risk of suicidal thoughts or behaviors. During AED treatment, patients should be monitored for symptoms or worsening of symptoms: depression, suicidal thoughts or behavior, and / or any abnormal changes in mood or behavior.
A combined analysis of 199 placebo-controlled clinical trials (monotherapy and adjuvant therapy) involving 11 different AEDs found that the risk of suicidal thoughts or behaviors in patients in the AED group was about twice that of patients in the placebo group (adjusted The relative risk is 1.8, 95% confidence interval: 1.2, 2.7). The median duration of treatment in these clinical trials was 12 weeks. The estimated incidence of suicidal behaviors or thoughts in 27,863 AED-treated patients was 0.43%, while the estimated incidence of 16,029 patients in the placebo group was 0.24%, indicating that every 530 patients About one additional patient was treated with suicidal thoughts or behavior. There were 4 suicide patients in the drug-treated group and no suicide patients in the placebo group; however, the number of cases was too small to draw any conclusions about the effects of the drug on suicide.
One week after the start of AED treatment, it was observed that AED treatment increased the risk of suicidal thoughts or behaviors and persisted throughout the treatment evaluation period. Because most clinical trials included in the analysis did not exceed 24 weeks, the risk of suicidal thoughts or behavior after 24 weeks could not be evaluated.
The risk of suicidal thoughts or behaviors caused by the drugs included in the data analysis was basically the same. The above risks are found in AEDs with different mechanisms of action and multiple indications, indicating that this risk is prevalent in all indications for all AED treatments. No significant change in risk with age (5-100 years) was found in the analyzed clinical trials.
Table 2 shows the absolute and relative risks of the evaluated AEDs for different indications.

The relative risk of suicidal thoughts or behaviors in clinical trials of epilepsy is higher than that of clinical trials of psychosis or other diseases; but the absolute risk difference between the two indications of epilepsy and psychosis is basically similar.
When considering the prescription of this product or any other AED, the risk of suicidal thoughts or behavior must be weighed against the risk of not treating the disease.
Epilepsy and many other AED-applicable diseases are inherently more at risk for suicidal thoughts and behaviors due to the morbidity and mortality of the disease itself. So, if suicidal thoughts and behaviors occur during treatment, the prescribing physician needs to consider whether the patient with these symptoms is related to the disease he is treating.
Patients, caregivers and their family members should be informed that this product and other AEDs are at increased risk for suicidal thoughts and behaviors. They are advised to pay attention to the occurrence or deterioration of depression symptoms and signs, any abnormal mood or behavior changes, or the occurrence of suicidal thoughts and behaviors, or the emergence of self-harm thoughts. Report suspicious behavior to medical staff immediately.

Pregabalin capsules for pregnant and lactating women

Animal studies have shown that this product has reproductive toxicity. (See [Pharmacology and Toxicology]). The possible risks to humans of this product are currently 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 this product at a dose of 600 mg / day. No effect on sperm motility was found 3 months after the administration.
There is insufficient data on the use of pregabalin in pregnant women, and this product should not be taken during pregnancy unless necessary (the benefits of medication for pregnant women are significantly greater than the potential risk to the fetus). Women of childbearing age must apply effective contraception.
It is unclear whether pregabalin is secreted from breast milk; however, this product can be secreted from the milk of rats. Therefore, breastfeeding during pregabalin treatment is not recommended.

Pregabalin capsules for children

Due to insufficient data on safety and efficacy in this population, children and adolescents (12-17 years) under the age of 12 are not recommended to use this product.

Pregabalin capsules for elderly

Elderly patients (over 65 years of age) may need to reduce the amount due to impaired renal function (see [Dosage and Administration] Medication for patients with impaired renal function).

Pregabalin capsule drug interactions

Since pregabalin is excreted mainly in the form of a prototype drug, its metabolism in humans can be ignored (only less than 2% of the drug's metabolites are found in urine). In vitro studies have shown that pregabalin does not inhibit drug metabolism or bind to plasma proteins, and pregabalin has almost no pharmacokinetic interaction with other drugs.
Similarly, no clinically relevant pharmacokinetics were observed between pregabalin and phenytoin, carbamazepine, valproic acid, lamotrigine, gabapentin, lorazepam, oxycodone, or ethanol in animal studies. interaction. Population pharmacokinetic analysis showed that oral antidiabetics, diuretics, insulin, phenobarbital, tiagabine, and topiramate had no significant clinical effect on clearance of pregabalin.
When pregabalin was taken with the oral contraceptives norethisterone and / or ethinyl estradiol, the steady-state pharmacokinetics of both substances were not affected.
Pregabalin may enhance the effects of ethanol and lauracil. In a clinical controlled study, multiple doses of oral pregabalin combined with oxycodone, laurazepam, or ethanol did not have a clinically significant effect on the patient's breathing. Post-marketing reports of pregabalin and central antidepressants have caused respiratory failure and coma. Pregabalin enhances cognitive impairment and overall motor dysfunction caused by oxycodone.
Studies of drug interactions are performed only in adults and not specifically in elderly volunteers.

Pregabalin capsules overdose

Symptoms and signs of acute overdose in humans and laboratory tests have found limited experience with pregabalin overdose. In clinical research and development projects, the highest reported dose of accidental overdose was 8000 mg, with no significant clinical consequences. In clinical studies, some patients overdose up to 2400 mg / day. The type of adverse reactions in patients in the high-dose group (900 mg) was not clinically different from the recommended dose group.
There is no specific antidote for the treatment or treatment of pregabalin overdose. If it is confirmed that the drug is overdose, try gastric lavage or emetic to remove the unabsorbed drug. Usually, care should be taken to keep the airway open. General supportive care includes monitoring vital signs and observing clinical conditions.
Although a few known cases of overdose of this product have not been used for hemodialysis, it may be necessary to decide whether to use hemodialysis depending on the clinical status of the patient or the degree of renal impairment. Standard hemodialysis clears pregabalin (approximately 50% in 4 hours).

Clinical trial of pregabalin capsules

Three multicenter, double-blind, placebo-controlled studies established the efficacy of pregabalin for postherpetic neuralgia (PHN). Patients enrolled in the study had pain lasting for at least 3 months after the shingles rash healed, and the patient's minimum baseline score was 4 points (the digital pain scoring method has a total of 11 scoring points, with a rating scale ranging from 0 to 10, and no pain to severe pain) . 73% of patients completed the study. Baseline pain in these three studies averaged 6-7. In addition to pregabalin, patients can take up to 4 grams of acetaminophen daily for pain relief. The patient records a pain diary daily.
PHN1 study: The 13-week study was divided into pregabalin 75mg, 150mg, 300mg and placebo groups twice daily. Patients with creatinine clearance between 30-60 ml / min were randomly given 75mg, 150mg or placebo twice daily; patients with creatinine clearance above 60 ml / min were randomly given 75mg, 150mg, 300mg Or placebo, 2 times a day. All pregabalin dose groups significantly improved the endpoint mean pain score for patients with creatinine clearance above 60 ml / min, and increased the proportion of patients whose pain score was reduced by at least 50% from baseline. Although the dosage is different according to renal function, patients with creatinine clearance of 30-60 ml / min have a higher rate of discontinuation of adverse reactions, indicating that pregabalin is less tolerated than creatinine clearance Patients above 60 ml / min. Based on the degree of pain improvement from baseline to the end of the study, Figure 1 shows the proportion of patients with different degrees of pain relief. The graph shows cumulative values, for example, a 50% improvement from baseline, which also includes all patients with an improvement of less than 50%. Patients who did not complete the study were summarized as 0% improvement. In some patients, pain is reduced in the first week and maintained throughout the treatment period.
Figure 1: Percentage of patients receiving varying degrees of pain relief-PHN 1 study

PNH 2 study: This study was 8 weeks long and divided into pregabalin 100 mg, 200 mg and placebo groups 3 times a day. The dose was calculated based on the creatinine clearance. Patients with a creatinine clearance of 30-60 ml / min were given 100 mg each time 3 times a day. Patients with creatinine clearance above 60 ml / min were given 200 mg each time, 3 times a day. The pregabalin group significantly improved the endpoint mean pain score and increased the proportion of patients whose pain score was reduced by at least 50% from baseline. Based on the degree of pain improvement from baseline to the end of the study, Figure 2 shows the proportion of patients who achieved different degrees of pain relief. The graph shows cumulative values, for example, a 50% improvement from baseline, which also includes all patients with an improvement of less than 50%. Patients who did not complete the study were summarized as 0% improvement. In some patients, pain is reduced in the first week and maintained throughout the treatment period.
Figure 2: Percentage of patients receiving varying degrees of pain relief PHN 2 study

PHN 3 study: This study lasted 8 weeks and was divided into pregabalin 50 mg, 100 mg and placebo groups 3 times daily, regardless of creatinine clearance. The pregabalin 50 mg and 100 mg 3 times daily group significantly improved the endpoint mean pain score, and increased the proportion of patients whose pain score was reduced by at least 50% from baseline. Patients with a creatinine clearance of 30-60 ml / min had a higher rate of discontinuation of adverse reactions, indicating that this group of patients was less tolerated of pregabalin than patients with a creatinine clearance above 60 ml / min. Based on the degree of pain improvement from baseline to the end of the study, Figure 3 shows the proportion of patients with different degrees of pain relief. The graph shows cumulative values, for example, a 50% improvement from baseline, which also includes all patients with an improvement of less than 50%. Patients who did not complete the study were summarized as 0% improvement. In some patients, pain is reduced in the first week and maintained throughout the treatment period.
Figure 3: Percentage of patients receiving varying degrees of pain relief PHN 3 study

Pharmacology and Toxicology of Pregabalin Capsules

Pharmacological effects Pregabalin has a high affinity for the 2- site (an auxiliary subunit of voltage-gated calcium channels) in the central nervous system. The mechanism of action of pregabalin is not clear, but the results of studies on transgenic mice and structure-related compounds (such as gabapentin) suggest that the analgesic and anticonvulsant effects in animal models may be related to pregabalin and the 2- subunit. Combining related. In vitro studies have shown that pregabalin may reduce calcium-dependent release of some neurotransmitters by regulating calcium channel function.
Although pregabalin is a structural derivative of the inhibitory neurotransmitter g-aminobutyric acid (GABA), it does not directly bind to GABAA, GABAB or benzodiazepine receptors, and does not increase GABAA in cultured neurons in vitro. The response does not change the GABA concentration in the rat brain, and has no acute effect on GABA uptake or degradation. However, studies have found that when neurons cultured in vitro are exposed to pregabalin for a long time, GABA transporter density and functional GABA transport rate increase. Pregabalin does not block sodium channels, has no activity on opioid receptors, does not change cyclooxygenase activity, has no activity on dopamine and serotonin receptors, and does not inhibit the reactivation of dopamine, serotonin or norepinephrine. Ingest.
Toxicological studies for genotoxicity:
In vitro studies have shown that pregabalin has no mutagenic effects on bacteria and mammalian cells. In vivo and in vitro studies have shown that pregabalin does not cause mammalian chromosomal aberrations and does not induce extracellular DNA synthesis in liver cells in rats or mice.
Reproductive toxicity:
Male rats were orally administered pregabalin (50 to 2500 mg / kg) before mating and during mating. Mating with unadministered female rats showed a variety of adverse effects on reproduction and development, including reduced sperm counts and sperm. Motility decreased, abnormal sperm increased, fertility decreased, pre-implantation loss rate increased, litter size decreased, fetal weight decreased and fetal abnormality increased. During the study period (3-4 months), the effects on sperm and fertility parameters were reversible. At a non-influenced dose (100 mg / kg) to male rats, the plasma pregabalin exposure (AUC) was approximately three times the human exposure at the clinical maximum recommended dose (MRD). In addition, in general toxicity studies of 4 weeks or longer, at a dose of 500-1250 mg / kg in male rats, adverse reactions of the reproductive organs (testicles, epididymis) can be seen on histopathological examination, without affecting the dose of 250 mg / kg, about 8 times the human plasma exposure at MRD.
Pregabalin 500, 1250, 2500 mg / kg was orally administered to female rats before mating, during mating, and early pregnancy. The estrous cycle disorder and mating days increased at each dose, and embryo death was seen at high doses. The plasma exposure of pregabalin at low doses is approximately 9 times the human exposure at MRD, and no unaffected dose has been determined.
When pregnant rats and rabbits are exposed to pregabalin plasma exposure (AUC) equal to or greater than 5 times the MRD exposure, the incidence of fetal structure abnormalities and other developmental toxicity can be increased, including fetal death, growth retardation, nerves And impaired reproductive system function.
Pregnant rats were orally administered pregabalin at 500, 1250, or 2500 mg / kg during organogenesis. The plasma pregabalin exposure (AUC) at low doses was approximately 17 times the human exposure at MRD. At doses 1250 mg / kg, the incidence of specific skull abnormalities increased due to abnormal early ossification (premature fusion of the sacrum and nasal suture). Variations in bone and delayed ossification were seen at all doses. Fetal weight loss at high doses. No pre-influenced dose of pregabalin to rat embryo-fetal development has been established.
Rabbits in pregnancy were orally given pregabalin 250, 500, or 1250 mg / kg during organogenesis. At high doses, the decrease in fetal weight, delayed ossification, skeletal deformity, and increased incidence of visceral mutations can be seen. The dose that had no effect on rabbit development was 500 mg / kg, and the plasma exposure was approximately 16 times the human exposure at MRD.
In the perinatal toxicity test, rats were orally administered pregabalin at 50, 100, 250, 1250, or 2500 mg / kg. The growth of the offspring was slower when 100 mg / kg, and the survival rate of the offspring was 250 mg / kg. reduce. 1250 mg / kg had a significant effect on the survival rate of offspring. The highest litter mortality was 100%. Tests of offspring in adulthood show abnormal neurobehavior (reduced auditory panic response) at 250 mg / kg, and impaired reproductive function (reduced fertility, reduced litter size) at 1250 mg / kg. The dose that had no effect on the perinatal development of rats was 50 mg / kg, and the plasma exposure was approximately twice the human exposure at MRD.
Carcinogenicity:
B6C3F1 and CD-1 mice were mixed with pregabalin at 200, 1000, 5000 mg / kg for two consecutive years, and a dose-dependent increase in the incidence of angiogenic malignant tumors (hemangiosarcoma) was seen. At the lowest dose, the plasma pregabalin exposure (AUC) in mice is approximately equivalent to that at MRD, and no unaffected dose induced by mouse angiosarcoma has been determined.
Wistar rats were administered pregabalin for two consecutive years. Male rats received doses of 50, 150, and 450 mg / kg, and female rats received doses of 100, 300, and 900 mg / kg. The highest doses were equivalent to MRD. 14 times and 24 times the human exposure, no increase in tumor incidence was seen.
Other toxic skin toxicity In repeated toxicity tests in rats and monkeys, skin damage can be seen, and the extent of the lesions ranges from erythema to necrosis, and the etiology is not clear. Pregabalin causes skin lesions at twice the dose of MRD. More severe skin lesions, including necrosis, occur when plasma pregabalin exposure (AUC) is 3-8 times the human exposure at MRD. No increase in the incidence of skin lesions was observed in clinical trials.
Ocular lesions Ocular lesions (characterized by retinal atrophy [including loss of photoreceptor cells] and / or corneal inflammation / mineral deposits) are visible in two carcinogenicity trials in Wistar rats, and plasma pregabalin exposure to changes The amount (AUC) is 2 times the human exposure at MRD, and no unaffected dose has been established. No similar lesions were seen in the two-year carcinogenicity test in mice or the one-year carcinogenicity study in monkeys.

Pharmacokinetics of Pregabalin Capsules

The steady-state pharmacokinetic parameters of pregabalin were similar in healthy volunteers, patients with epilepsy treated with antiepileptic drugs, and patients with chronic pain.
absorb:
Pregabalin is administered on an empty stomach and is absorbed quickly, reaching peak plasma concentrations within 1 hour after single or multiple doses. It is estimated that pregabalin has an oral bioavailability of 90% and is independent of dose. After multiple doses, steady state can be reached within 24 to 48 hours. When taken with food, the absorption rate of pregabalin decreases, C _max decreases by 25-30%, and t _{max is} delayed to about 2.5 hours. However, the simultaneous use of pregabalin and food does not have a clinically significant effect on the extent of pregabalin absorption.
distributed:
Preclinical studies have shown that pregabalin can cross the blood-brain barrier of mice, rats and monkeys. Pregabalin can pass through the placenta of rats and can appear in the milk of lactating rats. In humans, the apparent volume of pregabalin after oral administration is approximately 0.56 L / kg. Pregabalin does not bind to plasma proteins.
metabolism:
Pregabalin's metabolism in the human body is negligible. After giving radiolabeled pregabalin, about 98% of pregabalin was recovered in urine as a prototype. N-methylated derivatives of pregabalin, the main metabolite, were also found in urine, accounting for 0.9% of the administered dose. In the preclinical studies, the racemization of pregabalin from S-optical enantiomer to R-optical enantiomer was not found.
excretion:
Pregabalin is primarily cleared from the systemic circulation and excreted through the kidneys in the form of a prototype drug. The mean clearance half-life of pregabalin is 6.3 hours. Pregabalin plasma clearance and renal clearance are directly proportional to creatinine clearance (see [Pharmacokinetics] renal impairment).
For patients with impaired renal function or undergoing hemodialysis treatment, it is necessary to adjust the dose (see [Dosage and Administration] Table 1).
Linear / Nonlinear:
The pharmacokinetics of pregabalin are linear over the recommended daily dosage range. The pharmacokinetic variability of pregabalin was small among individuals (<20%). The pharmacokinetics of multiple administrations can be inferred from the data of a single administration. Therefore, routine monitoring of pregabalin's plasma concentration is not required.

Pregabalin capsule storage

Keep sealed.

Pregabalin capsule packaging

PVC / aluminum blister pack, 8 capsules / box, 16 capsules / box, 56 capsules / box.

Pregabalin capsule expiration date

36 months

Pregabalin capsules

Import drug registration standard JX20080145 ^[1]