Date of approval: Year Month
Instructions for Anrisentan Tablets
Please read the instructions carefully and use under the guidance of a physician
Warning: Contraindicated in pregnancy.
The use of aniracetam in pregnant women is likely to result in serious birth defects, an effect frequently observed when this drug is applied in animals (see [Contraindications] section). Pregnancy must therefore be excluded before starting treatment. Contraception should be performed using a suitable contraceptive method during treatment and for 1 month after discontinuation of the drug. Pregnancy tests are performed every month.
[Drug Name].
Generic name: Ambrisentan Tablets
English Name: Ambrisentan Tablets
Hanyu Pinyin: Anlishengtan Pian
Ingredients
The main ingredient of this product is Ambrisentan.
Chemical name: (+)-(2S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropionic acid
Chemical structure formula.
Molecular formula: C22H22N2O4
Molecular weight: 378.42
Properties
This product is a yellow film-coated tablet, which appears white or off-white after removing the film coating.
Indications
This product is indicated for the treatment of patients with WHO class II or III pulmonary hypertension (WHO group 1) to improve exercise capacity and delay clinical deterioration. Studies supporting the effectiveness of aniracetam have mainly included patients with idiopathic or hereditary PAH (64%) or connective tissue disease-associated PAH (32%) aetiological features.
Specification
5mg
Dosage]
The decision to initiate treatment with this drug must be made by a physician experienced in the treatment of pulmonary arterial hypertension and the course of treatment must be monitored.
Adult Dose
The starting dose is 5 mg orally once daily on an empty stomach or after a meal; if tolerated, an adjustment to 10 mg once daily may be considered.
Tablets may be taken on an empty stomach or with a meal. Tablets should not be broken in half, crushed, or chewed. No studies have been conducted in patients with pulmonary hypertension at doses higher than 10 mg once daily. Monitor liver function prior to and during initiation of treatment with aniracetam (see [Precautions] section).
Women of childbearing potential
Women should only receive treatment if they have a negative pregnancy test and are using a suitable contraceptive method for birth control. Women of childbearing potential treated with aniracetam should undergo monthly pregnancy tests (see [Contraindications] and [Precautions] sections).
Pre-existing liver damage
There are no studies on the effect of pre-existing liver damage on the pharmacokinetics of aniracetam. Because both in vivo and in vitro evidence suggests that clearance of amritsentan is heavily dependent on hepatic metabolism and biliary excretion, hepatic impairment is expected to have a significant effect on the pharmacokinetics of amritsentan. Anrisentan is not recommended for use in patients with moderate or severe hepatic impairment. There is no information on the use of aniracetam in patients with preexisting mild hepatic impairment; however, exposure to aniracetam may be elevated in such patients.
Elevated hepatic transaminases
Other endothelin receptor antagonists (ERAs) have been associated with elevated transaminases (AST, ALT), hepatotoxicity, and cases of liver failure. Patients who develop liver injury after initiation of aniracetam should be thoroughly investigated for the causative factors of liver injury. Discontinue aniracetam if transaminase is elevated >5x ULN or if transaminase elevation is accompanied by bilirubin >2x ULN, or if signs or symptoms of hepatic insufficiency are present and other causes can be excluded.
Combination with cyclosporine A
When used in combination with cyclosporine A, the dose of aniracetam should be limited to 5 mg once daily (see [Drug Interactions], [Pharmacokinetics] section).
[Adverse reactions].
Experience from key clinical studies
Clinical trials conducted in more than 480 patients with PAH evaluated the safety of aniracetam. The adverse drug reactions (ADRs) obtained from clinical trial data are summarized below by system organ classification and frequency of occurrence. The frequency of occurrence has been placebo corrected and defined as common (≥1/100, <1/10) and uncommon (≥1/1000, <1/100). The frequency of adverse reactions is based on the empirical classification of clinical trials and does not necessarily reflect the frequency of adverse events in normal clinical practice.
Hematologic and lymphatic system abnormalities
Common: anemia (decreased hemoglobin and/or erythrocyte pressure volume)
Immune system abnormalities
Uncommon: allergies (e.g., angioedema, rash)
Neurological abnormalities
Common: Headache
Cardiac abnormalities
Common: palpitations
Abnormal vascular function
Common: Flushing
Respiratory, thoracic and mediastinal abnormalities
Common: Nasal congestion, sinusitis, rhinopharyngitis
Dose-related incidence of nasal congestion during treatment with aniracetam
Abnormalities of the gastrointestinal system
Common: abdominal pain, constipation
Systemic disease and various reactions at the site of administration
Common: fluid retention, peripheral edema
Experience from long-term clinical studies
The long-term safety of aniracetam was evaluated in more than 500 patients with PAH (> 3 months). The following adverse drug reactions were identified based on data from non-placebo controlled clinical trials. Reaction frequency was defined as very common (≥1/10) and common (≥1/100, <1/10).
Blood and lymphatic system abnormalities
Very common: anemia (decreased hemoglobin and/or erythrocyte pressure volume)
Immune system abnormalities
Common: allergies (including drug allergies)
Nervous system abnormalities
Very common: vertigo, headache
Cardiac abnormalities
Very common: palpitations
Abnormal vascular function
Very common: flushing (including hot flashes)
Respiratory, thoracic and mediastinal abnormalities
Very common: nasal congestion, sinusitis, rhinopharyngitis, dyspnea (difficulty breathing with activity)
Abnormalities of the gastrointestinal system
Very common: abdominal pain (including upper and lower abdominal pain), nausea
Common: vomiting, constipation
Skin and subcutaneous tissue type abnormalities
Common: rash (erythematous eruption, circumscribed rash, maculopapular rash, papulopapular rash, pruritic rash)
Systemic diseases and various reactions at the site of drug administration
Very common: fatigue, fluid retention (including fluid overload), peripheral edema
Common: weakness
Ocular organ abnormalities
Common: visual impairment (including blurred vision)
Post-marketing experience
In addition to the adverse reactions identified in the clinical studies, the following adverse reactions were identified during the post-approval use phase. Because these events were spontaneously reported from populations of unknown size, it is not possible to estimate their frequency.
Hematologic and lymphatic system abnormalities
Unknown: Anemia requiring blood transfusion
Cardiac abnormalities
Unknown: heart failure (associated with fluid retention)
Hepatobiliary abnormalities
Common: elevated liver transferase
Unknown: liver injury, autoimmune hepatitis
Autoimmune hepatitis (including exacerbation of autoimmune hepatitis) and causes have been reported during treatment with aniracetam
unknown liver injury.
Vascular abnormalities
Unknown: Hypotension
[Contraindicated].
The use of aniracetam in pregnant women may result in fetal damage. Anrisentan is teratogenic at oral doses of ≥15 mg/kg/day in rats and ≥7 mg/kg/day in rabbits; no studies are available for lower doses. Malformations of the lower jaw, hard and soft palate, and heart and great vessels, as well as impaired thymus and thyroid formation, were observed in both species of animals. Teratogenicity is a class of effects of endothelin receptor antagonists. There are no data on the use of aniracetam in pregnant women.
Enrisentan is contraindicated in women who do or may become pregnant. If the drug is applied during pregnancy, or if pregnancy occurs during the application of the drug, the patient should be informed of the possible risks to the fetus.
For women of childbearing potential, pregnancy must be ruled out before starting treatment and appropriate contraceptive methods should be used for contraception both during and for 1 month after treatment, and it is recommended that pregnancy tests be repeated every month while on the drug until 4 weeks after stopping treatment.
Idiopathic pulmonary fibrosis (IPF)
Aniracetam is contraindicated in patients with idiopathic pulmonary fibrosis (IPF) with or without secondary pulmonary hypertension.
Severe hepatic impairment
Contraindicated in patients with hypersensitivity to aniracetam, soy or any of the excipients in aniracetam tablets.
Precautions]
The decision to initiate treatment with this drug should be made by a physician with extensive experience in the treatment of pulmonary hypertension, and the course of treatment should be strictly monitored. The medical information leaflet for this product should be read before prescribing this product and the patient should be informed of the precautions to take this product. Patients should read the medical information leaflet for this product (given to the patient section) before starting treatment with this product.
Studies have not been conducted in a sufficient number of patients to weigh the benefits and risks of this product for the treatment of WHO Class I pulmonary arterial hypertension. The efficacy of this product as monotherapy has not been established in patients with WHO Class IV pulmonary hypertension.
Women of childbearing potential: Pregnancy must be excluded prior to initiation of therapy. Perform pregnancy testing prior to first treatment with this product and monthly during treatment. Confirm completion of pregnancy testing prior to drug administration. A suitable method of contraception should be used during treatment and for 1 month after treatment. Contact your prescribing physician if you become pregnant while taking this product or within 30 days of stopping it.
Potential Liver Damage
Elevated liver enzymes have been seen with the application of endothelin receptor antagonists (ERAs).
Liver function should be evaluated prior to initiation of therapy with aniracetam, which is not recommended if transaminases (glutathione aminotransferase, ALT, or glutathione aminotransferase, AST) are greater than 3 times the upper limit of normal.
For patients with clinically significant right heart failure, prior liver disease, elevated prior transaminases, or combined medications that can cause transaminase elevation, the risk of transaminase elevation may occur during treatment with aniracetam and monitoring of transaminases according to clinical indications.
Monitoring of patients for signs of liver injury and, if necessary, monthly monitoring of ALT and AST is recommended. if patients develop persistent, unexplained and clinically significant elevations of ALT and/or AST, or if elevations of ALT and/or AST are accompanied by signs or symptoms of liver injury (e.g., jaundice), treatment with aniracetam should be discontinued.
If the patient has no signs or symptoms of liver injury or jaundice, consider reintroducing aniracetam after the liver enzyme abnormalities have subsided.
Patients with pulmonary arterial hypertension (PAH) are known to develop liver injury and autoimmune hepatitis, and patients with idiopathic pulmonary arterial hypertension (IPAH) frequently develop autoantibodies. Several cases of autoimmune hepatitis (including possible exacerbation of the underlying autoimmune hepatitis) and liver injury have been reported with the use of aniracetam, and the role of aniracetam in these events is not known.
Therefore, when using aniracetam alone or in combination with other drugs known to be associated with liver injury, symptoms of liver injury should be observed clinically and used with caution, as it is not known whether aniracetam has a superimposed effect with these drugs. Management of autoimmune hepatitis in patients with pulmonary arterial hypertension (PAH) should be optimized prior to and during initiation of therapy with aniracetam. If a patient develops signs or symptoms of hepatitis, or has worsening autoimmune hepatitis, aniracetam should be discontinued.
Hematologic alterations
Decreases in hemoglobin concentration and erythrocyte pressure have been observed following the administration of endothelin receptor antagonists, including aniracetam, and some have resulted in anemia, sometimes requiring blood transfusions. These decreases occurred in the first few weeks after initiation of aniracetam treatment and remained stable thereafter. In the 12-week placebo-controlled study, patients treated with aniracetam had a mean decrease in hemoglobin of 0.8 g/dL at the end of treatment compared to baseline, and in the long-term open extension study of the phase 3 pivotal clinical study, hemoglobin concentrations decreased by a mean of 0.9 to 1.2 g/dL compared to baseline over the 4-year aniracetam treatment period.
Seven percent of patients treated with aniracetam (10% of whom were treated with a daily dose of 10 mg) experienced a significant decrease in hemoglobin (a decrease of >15% from baseline and below the low limit of normal in absolute terms), compared with only 4% of patients in the placebo group. The cause of the decrease in hemoglobin is not known, but it does not appear to be due to bleeding or hemolysis.
Hemoglobin should be tested before starting aniracetam treatment, during the first month after starting treatment, and periodically thereafter.
Treatment with aniracetam is not recommended if the patient is associated with clinically significant anemia. If a patient develops clinically significant anemia during the course of therapy and other contributing factors are excluded, discontinuation of aniracetam therapy should be considered.
Fluid retention
Peripheral edema is a known effect of endothelin receptor antagonists and a clinical consequence of worsening pulmonary hypertension and pulmonary arterial hypertension. In placebo-controlled studies, the incidence of peripheral edema was higher in patients treated with 5 or 10 mg of aniracetam compared to the placebo group (see [Adverse Reactions] section). Most of the edema was mild to moderate in severity.
In addition, there are post-marketing reports of fluid retention occurring in patients with pulmonary hypertension in the weeks following treatment with aniracetam. Patients require diuretics, restriction of fluid intake, or, in some cases, hospitalization due to cardiac failure failure failure. If a patient has previously experienced fluid overload, appropriate clinical management should be performed prior to the use of aniracetam.
If clinically significant fluid retention develops further (with or without weight gain), further evaluation should be undertaken to clarify the etiology (e.g., aniracetam or underlying heart failure) and specific treatment or interruption of aniracetam therapy should be instituted if necessary.
Decreased sperm count
Another 6-month study of an endothelin receptor antagonist (bosentan) evaluated the effect of the drug on testicular function in 25 men with WHO functional class III and IV pulmonary hypertension and normal baseline sperm counts. After 3 or 6 months of treatment with bosentan, 25% of the patients had a decrease in sperm count of at least 50%. One of the patients experienced significant sperm reduction at 3 months and the sperm count tested remained low at the two subsequent 6-week follow-up visits. Two months after discontinuation of bosentan treatment, sperm counts returned to baseline levels. In the 22 patients who completed 6 months of treatment, sperm counts remained within the normal range and no changes in sperm morphology, sperm motility, or hormone levels were observed. Based on these findings and preclinical data on endothelin receptor antagonists (see [Pharmacology and Toxicology] section), it cannot be ruled out that endothelin receptor antagonists such as the aniracetam class can have adverse effects on spermatogenesis.
Pulmonary veno-occlusive disease
If a patient develops acute pulmonary edema during the initial phase of treatment with a vasodilator (e.g., endothelin receptor antagonist), the possibility of pulmonary veno-occlusive disease should be considered and, if confirmed, the product should be discontinued.
Excipients.
This product contains lactose. There are rare genetic problems with galactose tolerance. Do not take this drug in patients with lactase deficiency or impaired glucose-galactose absorption.
[For pregnant and lactating women].
Pregnant patients
Anrisentan is contraindicated in women who do or may become pregnant. If the drug is applied during pregnancy or if pregnancy occurs during the application of the drug, the patient should be informed of the possible hazards to the fetus. (See [Contraindications] section).
Nursing Mothers
It is not known whether or not aniracetam is secreted with breast milk. Breast-feeding while taking aniracetam is not recommended. A preclinical study in rats showed that the administration of aniracetam to mothers from late gestation to weaning resulted in decreased survival in neonatal mice (medium to high doses) and affected testicular size and maturation in mice (high doses). The doses detected were 17, 51 and 170 times the maximum oral dose (10 mg) in humans (low, medium and high doses, respectively) in mg/mm2.
[Pediatric Use].
The safety and efficacy of this product in pediatric patients have not been established.
[Geriatric use].
In two placebo-controlled clinical studies of aniracetam, 21% of patients were ≥65 years of age, while 5% were ≥75 years of age. Older patients (≥65 years of age) treated with aniracetam showed less improvement in walking distance than younger patients, but the results of such subgroup analyses must be interpreted with caution. Peripheral edema was more common in older patients than in younger patients.
Drug Interactions]
In vitro studies
Studies using human liver tissues have shown that aniracetam is metabolized by CYP3A, CYP2C19, 5′-diphosphoglucosyltransferases (UGTs), 1A9S, 2B7S, and 1A3S. In vitro experiments suggest that anrisentan is a substrate of organic anion transport protein (OATP) and also a substrate (not an inhibitor) of P-gp.
In vivo studies
The combination of aniracetam with the following drugs does not result in clinically meaningful changes in aniracetam exposure.
Ketoconazole
Omeprazole
Cetorphine
Sildenafil or tadalafil
Rifampin
Combined application of aniracetam does not result in altered exposure to
Warfarin
Digoxin
Cetorphine
Sildenafil or tadalafil
Ethinyl estradiol/norethindrone
Cyclosporine A
A clinical trial in healthy subjects showed that a steady-state dose of 10 mg of aniracetam did not significantly affect the single-dose pharmacokinetics of the ethinyl estradiol or norethindrone components of the combination oral contraceptive (Ortho-Novum 1/35). Based on this pharmacokinetic study, aniracetam is not expected to have an effect on estrogen or progesterone-based contraceptive exposure.
In combination with cyclosporine A (an inhibitor of P-gp and OATP), the steady-state blood levels of aniracetam were increased 2-fold in healthy volunteers. Therefore, if co-administered with cyclosporine A, the dose of aniracetam should be limited to 5 mg once daily (see [Dosage] section).
section). No clinically significant effects of aniracetam on cyclosporine A exposure have been observed (see [Pharmacokinetics] section).
After the first combined administration of aniracetam and rifampin (inhibitors of OATP, strong inducers of CYP3A and 2C19, and inducers of P-gp and UGTs) in healthy volunteers, exposure to aniracetam increased transiently (approximately 2-fold). However, stable administration of rifampicin had no clinically relevant effect on aniracetam exposure at day 7 after dosing. Therefore, no dose adjustment of aniracetam is required when administered in combination with rifampin (see [Pharmacokinetics] section).
Overdose]
There is no experience with overdose of aniracetam. The highest single dose of aniracetam applied in healthy volunteers is 100 mg, while in patients with pulmonary hypertension it is 10 mg once daily. In healthy volunteers, single doses of 50 mg and 100 mg (5 to 10 times the maximum recommended dose) were associated with headache, facial flushing, dizziness, nausea, and nasal congestion. Severe overdose may result in hypotension requiring therapeutic intervention.
Pharmacology and Toxicology
Pharmacological effects
Endothelin-1 (ET-1) is a potent autocrine and paracrine peptide. The two receptor subtypes (ETA and ETB) jointly regulate the action of ET-1 in vascular smooth muscle and endothelial cells; the main effects of ETA are vasoconstriction and cell proliferation, while the main effects of ETB are vasodilation, inhibition of proliferation, and clearance of ET-1.
In patients with pulmonary hypertension, plasma ET-1 concentrations were increased 10-fold and correlated with increased mean right atrial pressure and disease severity. ET-1 and ET-1 mRNA concentrations were increased 9-fold in lung tissue of patients with pulmonary hypertension, mainly concentrated in pulmonary artery endothelial cells. These findings suggest that ET-1 may play an important role in the pathogenesis and progression of pulmonary hypertension.
Anrisentan is a receptor antagonist that binds highly to ETA (Ki=0.011 nM) and is highly selective (>4000-fold) for ETA compared to ETB, and the clinical implications regarding the high selectivity for ETA are unknown.
In a randomized, positive and placebo-controlled, parallel-group study, healthy subjects were divided into three groups, with the first group receiving aniracetam 10 mg once daily and then increasing to 40 mg once daily; the second group receiving placebo and then changing to 400 mg moxifloxacin once daily; and the third group receiving placebo only. No significant effect on the QTc interval was seen with aniracetam 10mg once daily. Anritasentan 40 mg prolonged the mean QTc with a Tmax of 5 ms and an upper 95% confidence interval of 9 ms. No significant QTc prolongation is expected in patients who take anritasentan 5-10 mg daily and are not on concomitant metabolic inhibitors.
Toxicological studies
Genotoxicity.
The human lymphocyte chromosomal aberration test for amritsentan was positive, and the Ames test and the rat in vivo micronucleus test (DNA synthesis assay) were negative.
Reproductive toxicity.
Chronic administration of endothelin receptor antagonists in rodents may result in testicular tubular atrophy and impaired fertility.
Testicular tubule degeneration was seen in rats given orally aniracetam ≥10 mg/kg/day [8 times the maximum recommended human dose (MRHD)] for two years, and an increased incidence of testicular damage was seen in mice given orally aniracetam ≥50 mg/kg/day (28 times the MRHD) for two years. In the fertility test, effects on sperm count, sperm morphology, mating ability and fertility were seen in male rats given orally aniracetam ≥50 mg/kg/day (236 times MRHD); no significant effects on fertility were seen at aniracetam>10 mg/kg/day, and effects on sperm and histopathological changes in the testis were seen.
Perinatal oral administration of aniracetam to rats resulted in decreased neonatal survival (medium to high dose) and affected neonatal testicular size and maturation (high dose), with the low, medium and high doses being 17, 51 and 170 times the maximum clinical oral dose (10 mg), respectively, as extrapolated from body surface area.
Carcinogenicity.
In a two-year oral carcinogenicity test, initial doses of 10, 30, and 60 mg/kg/day in rats were 8-48 times the MRHD, extrapolated by body surface area, and initial doses of 50, 150, and 250 mg/kg/day in mice were 28-140 times the MRHD. In rats, the dose was reduced to 20 and 40 mg/kg/day at week 51 for the medium and high doses due to its effect on survival, and was discontinued at weeks 69 and 93 for males and females in the high dose group, respectively. The combined incidence of benign cutaneous/subcutaneous basal cell tumors and basal cell carcinomas in male rats in the mid-dose group (the high-dose group was not included in the analysis), and the incidence of mammary fibroadenomas in males in the high-dose group were elevated. In mice, the dose was reduced to 150 mg/kg/day at week 39 in the high-dose group and discontinued at week 96 (males) or week 76 (females). No increase in the incidence of tumors associated with dosing was seen in any of the dosing groups in mice.
Pharmacokinetics]
Pharmacokinetics
The pharmacokinetics of aniracetam (S-aniracetam) in healthy subjects is proportional to the dose. The absolute bioavailability of aniracetam is not known. The absorption of aniracetam is rapid, with peak concentrations occurring about 2 hours after oral administration in both healthy subjects and patients with pulmonary hypertension. Eating does not affect the bioavailability of the drug. In vitro studies have shown that aniracetam is a substrate for P-gp. Anrisentan binds very tightly (99%) to plasma proteins. The clearance of aniracetam is mainly via non-renal routes, but the relative contribution of metabolic and biliary clearance is not well defined. In plasma, the AUC of 4-hydroxymethyl-anrisentan accounts for approximately 4% of the parent AUC. In vivo conversion of S-aniracetam to R-aniracetam is negligible. The mean oral clearance of aniracetam in healthy subjects and in patients with pulmonary hypertension was 38 mL/min and 19 mL/min, respectively. although the terminal half-life of aniracetam is 15 hours, the mean trough concentration of aniracetam at steady state is approximately 15% of the mean peak concentration, and the cumulative factor after long-term daily administration is approximately 1.2, suggesting an effective half-life of approximately 9 hours for aniracetam .
In vitro data suggest that concentrations up to 300 µM of aniracetam do not significantly inhibit the activity of UGT1A1, UGT1A6, UGT1A9, UGT2B7 and cytochrome P450 enzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4. In addition, in vitro studies have shown that aniracetam does not inhibit P-glycoprotein (P-gp), breast cancer receptor protein (BCRP), multidrug resistance protein isoform-2 (MRP2) or bile salt export pump (BSEP) at concentrations up to 100 µM, and weakly inhibits OATP1B3 and sodium taurocholate cotransporter (NTCP) in vitro, with IC50 values of 47 µM. Furthermore, anrisentan did not induce MRP2, P-gp and BESP.
Based on data from in vitro studies, the expected clinically relevant concentrations of aniracetam had little effect on in vitro transport via BSEP, BCRP, P-gp, MRP2, OATP1B1/3, or NTCP.
The effects of repeated cyclosporine A dosing (100 – 150 mg twice daily) on the steady-state pharmacokinetics of aniracetam (5 mg once daily), and the effects of repeated aniracetam dosing (5 mg once daily) on the steady-state pharmacokinetics of cyclosporine A (100 – 150 mg twice daily) were studied in healthy subjects The Cmax and Cmax of aniracetam were determined. The Cmax and AUC (0-τ) of aniracetam increased after repeated cyclosporine A administration (48% and 121%, respectively). Based on these changes, when cyclosporine A is administered in combination with aniracetam, the dose of aniracetam should be limited to 5 mg once daily (see [Dosage] section). However, repeated administration of amritsentan has no clinically relevant effect on cyclosporine A exposure, and therefore no dose adjustment of cyclosporine A is required for co-administration.
The effects of acute and repeated administration of rifampicin (600 mg once daily) on the steady-state pharmacokinetics of aniracetam (10 mg once daily) were studied in healthy subjects. During the initial administration phase of rifampicin, a transient increase in the AUC (0- τ) of aniracetam was observed (87% and 79% increase after the first and second administration of rifampicin, respectively). However, there was no longer any clinically relevant effect on the exposure to aniracetam after 7 days of rifampicin administration. Therefore, no dose adjustment is required for the combination of aniracetam and rifampicin.
Special Populations
Renal Impairment
Effect of renal impairment on the pharmacokinetics of aniracetam: A population pharmacokinetic approach has been validated in patients with pulmonary hypertension with creatinine clearance between 20 and 150 mL/min. Mild to moderate renal impairment does not have a significant effect on the exposure to aniracetam. Therefore, no aniracetam dose adjustment is required in patients with mild to moderate renal impairment. There are no data on the use of aniracetam in patients with severe renal impairment, and it should be used with caution in patients with severe renal impairment (creatinine clearance <30 mL/min).
There are no studies on the distribution of aniracetam by hemodialysis.
Liver damage
There are no studies on the effect of pre-existing hepatic impairment on the pharmacokinetics of aniracetam. Because both in vivo and in vitro evidence suggests that clearance of aniracetam is heavily dependent on hepatic metabolism and biliary excretion, hepatic impairment is expected to have a significant effect on the pharmacokinetics of aniracetam. Anrisentan is not recommended for use in patients with moderate or severe hepatic impairment. There is no information on the use of aniracetam in patients with preexisting mild hepatic impairment; however, exposure to aniracetam may be elevated in such patients.
Elevated hepatic transaminases
Other endothelin receptor antagonists (ERAs) have been associated with elevated transaminases (AST, ALT), hepatotoxicity, and cases of liver failure. Patients who develop liver injury after initiation of aniracetam should be thoroughly investigated for the causative factors of liver injury. Discontinue aniracetam if transaminase is elevated >5x ULN or if transaminase elevation is accompanied by bilirubin >2x ULN, or if signs or symptoms of hepatic insufficiency are present and other causes can be excluded.
Based on a final population pharmacokinetic model using data from patients treated with aniracetam in clinical trials, a significant relationship between aniracetam CL/F and liver function could be found by evaluating total bilirubin. However, the amount of change in total bilirubin was relatively small.
Storage]
Store under 30℃ under shade and seal.
Package
Aluminum-plastic package, 10 tablets/plate×1 plate/box.
Expiration date
24 months
Execution Standard
Approval number】
【Manufacturer】
Enterprise name: Jiangsu Haosen Pharmaceutical Group Co.
Address: No. 8 Lushan Road, Lianyungang Economic and Technological Development Zone
Postal Code: 222047
Customer Service Tel: 4008285227
Web
Address: http://www.hansoh.cn