Approval date: XXXX XXXX XXXX
Instructions for Macitentan Tablets
Please read the instructions carefully and use under the guidance of a physician
Embryo-fetal toxicity
This product is prohibited for use in pregnant females due to fetotoxicity. Females of childbearing potential need to exclude the possibility of pregnancy before the start of treatment, every month during treatment and 1 month after cessation of treatment, and should use reliable contraception during treatment and 1 month after cessation of treatment.
Drug Name]
Generic name: Macitentan Tablets
Trade name: OPSUMITÒ
English Name: Macitentan Tablets
Chinese Pinyin: Maxitengtan Pian
Ingredients
Active ingredient: Macitentan
Chemical name: N-[5-(4-bromophenyl)-6-[2-[(5-bromopyrimidin-2-yl)oxy]ethoxy]-pyrimidin-4-yl]-N’-propyl sulfonyl diamine
Chemical structure formula.
Molecular formula: C19H20Br2N6O4S
Molecular weight: 588.27
Properties
This product is a white to off-white double-sided raised circular film-coated tablet with the word “10” engraved on one side.
Indications
This product is an endothelin receptor antagonist (ERA) for the treatment of pulmonary arterial hypertension (PAH, WHO Group 1) to slow disease progression. Disease progression includes death, intravenous (IV) or subcutaneous administration of prostaglandin analogs, or clinical worsening of PAH (decreased 6-minute walk distance, worsening PAH symptoms and need for additional PAH therapy). This product also reduced hospitalization of patients with PAH.
The effectiveness study of this product was a long-term study in patients with PAH in WHO functional class II-III for a mean of 2 years of treatment. Patients were treated with this product as monotherapy or in combination with phosphodiesterase-5 inhibitors and inhaled prostaglandin analogs. Patients included those with idiopathic or hereditary PAH (57%), PAH associated with connective tissue disease (31%), and PAH associated with congenital heart disease with repair of shunts (8%).
【Specifications】.
10mg
【Dosage】
Treatment should be initiated and monitored by a physician experienced in the treatment of pulmonary arterial hypertension.
Dosage
The recommended dose of this product is 10mg, taken orally once daily. It can be taken with meals or on an empty stomach. Patients are not advised to break the tablet in half, crush it or chew it. Studies higher than 10 mg, once daily dose have not been conducted in patients with PAH and are therefore not recommended.
Missed Doses
This product should be taken at a regular time each day. If a dose is missed, it should be made up as soon as possible and the next dose should be taken at the regular time, and the patient needs to be informed not to take a double dose to make up for the missed one.
Pregnancy test for women of childbearing age
Women of childbearing age should only begin treatment with this product if a pregnancy test is negative. Pregnancy tests should be performed monthly during treatment (see section [Pregnancy and Lactation]).
Patients with hepatic insufficiency
Based on pharmacokinetic data, no dose adjustment is required in patients with mild, moderate, or severe hepatic impairment (see [Pharmacokinetics] section). However, there is no clinical experience with the use of this product in patients with PAH with moderate or severe hepatic impairment. This product is not recommended for use in patients with moderate hepatic impairment. It should not be initiated in patients with severe liver injury or in patients with clinically significant increases in hepatic transaminases (> 3 times the upper limit of normal (> 3 x ULN)). Liver enzyme tests should be performed prior to initiation of this product and reviewed during treatment as clinically indicated. (See [Precautions] section).
Patients with Renal Insufficiency
Based on pharmacokinetic data, no dose adjustment is required in patients with renal impairment. There is no clinical experience with the use of this product in patients with severe renal impairment PAH and caution is advised for use in this population. The risk of hypotension and anemia during treatment with this product may be higher in patients with renal insufficiency; therefore, monitoring of blood pressure and hemoglobin should be considered. The use of this product is not recommended in patients receiving dialysis (see [Pharmacokinetics] section).
[Adverse Reactions].
Clinically significant adverse reactions include.
Embryo-fetal toxicity (see [Precautions] section)
Hepatotoxicity (see [Precautions] section)
Fluid retention (see [Precautions] section)
Hemoglobin reduction (see [Precautions] section)
Clinical trial experience
Because clinical trials are conducted under widely varying conditions, the incidence of adverse reactions observed in clinical trials for one drug cannot be directly compared with the incidence observed in clinical trials for another drug, nor does it reflect the incidence observed in clinical practice.
Safety data for this product were obtained primarily from a placebo-controlled clinical study (SERAPHIN study) in 742 patients with pulmonary hypertension (see [Clinical Trials] section). In this trial, exposure to this product was up to 3.6 years, with a median exposure time of approximately 2 years (1 year: N=542; 2 years: N=429; >3 years: N=98). The overall incidence of treatment discontinuation due to adverse events was similar between the group receiving macitentan 10 mg and the placebo group (approximately 11%). Table 1 shows the adverse reactions that occurred more frequently in the group receiving macitentan than in the placebo group (3%).
Table 1 Adverse reactions
Adverse reactions Macitentan 10 mg
(N=242)
(%) Placebo
(N=249)
(%) Anemia 13 3 Nasopharyngitis/pharyngitis 20 13 Bronchitis 12 6 Headache 14 9 Influenza 6 2 Urinary tract infection 9 6 Postmarketing experience
The following adverse reactions were identified during post-approval use of this product. Because these reactions were spontaneously reported from populations with unknown sample sizes, it was not always possible to reliably estimate their frequency or to determine their causal relationship with drug exposure.
Various immune system disorders: hypersensitivity reactions (angioedema, pruritus and rash)
Respiratory, thoracic and mediastinal disorders: nasal congestion
Gastrointestinal disorders: elevated hepatic transaminases (ALT, AST) and liver injury have been reported during administration of this drug; alternative etiologies (heart failure, hepatic stasis, autoimmune hepatitis) can be identified in most cases. Elevated aminotransferases, hepatotoxicity, and cases of hepatic failure are known to be associated with endothelin receptor antagonists (ERA) (see [Precautions] section).
Systemic disease and various reactions at the site of administration: edema/fluid retention. Adverse reactions of edema and fluid retention occur within a few weeks of administration, and some require treatment of decompensated heart failure with diuretics, fluid management, or hospitalization (see [Precautions] section).
Cardiac disease: symptomatic hypotension
[Contraindication
Pregnancy
The use of this product in pregnant women may result in fetal damage. This product is contraindicated in pregnant women. In animal studies, Macitentan has shown teratogenic effects. If the drug is applied during pregnancy, the patient should be informed of the possible fetal harm. (See the sections [Precautions] and [Use in Pregnant and Lactating Women]).
Precautions]
Embryo-fetal toxicity
This product is contraindicated in pregnant women because of fetal harm associated with its use during pregnancy. In women of childbearing age, exclude pregnancy before starting treatment, ensure that they are using reliable contraception and perform monthly pregnancy tests during treatment (see [Dosage and Administration] and [Use in Pregnant and Lactating Women] sections).
Hepatotoxicity
Increased hepatic transaminases (AST, ALT) have been associated with PAH and endothelin receptor antagonists (ERA). Application of endothelin receptor antagonists (ERAs) can cause elevated transaminases, hepatotoxicity, and liver failure. The incidence of transaminase elevation in patients in the study of macitentan for pulmonary hypertension is shown in Table 2.
Table 2 Incidence of aminotransferase elevations in the SERAPHIN study
Macitentan 10 mg
(N=242) Placebo
(N=249)> 3 x upper limit of normal 3.4% 4.5% > 8 x upper limit of normal 2.1% 0.4% In the placebo-controlled study of macitentan, 3.3% of the macitentan 10 mg group discontinued due to hepatic adverse events compared to 1.6% in the placebo group. Liver enzyme tests should be performed prior to initiation of this product and reviewed during treatment based on clinical conditions (see [Adverse Reactions] section).
This product should not be initiated in patients with severe hepatic impairment or elevated hepatic transaminases (3 times above the upper limit of normal) and is not recommended for use in patients with moderate hepatic impairment. It is recommended that liver enzyme testing should be performed prior to initiating treatment with this product.
Patients need to be advised that symptoms suggestive of liver injury (nausea, vomiting, right upper abdominal pain, fatigue, anorexia, jaundice, dark urine, fever, or pruritus) should be reported. The product should be discontinued if clinically relevant transaminase elevations occur, or if transaminase elevations are accompanied by bilirubin elevations greater than 2 times the upper limit of normal, or if clinical signs of liver injury are present. Consider starting this product again when liver enzyme levels return to normal in patients who have not experienced clinical signs of liver injury.
Fluid retention
Peripheral edema and fluid retention are known clinical consequences of PAH and are also known adverse effects of endothelin receptor antagonists (ERA). In a placebo-controlled study of macitentan conducted in patients with PAH, the incidence of edema was 21.9% in the macitentan 10 mg group and 20.5% in the placebo group.
Patients with underlying left ventricular dysfunction are at specific risk for significant fluid retention after initiation of endothelin receptor antagonist (ERA) therapy. A small study in patients with pulmonary hypertension due to left ventricular dysfunction showed that more patients in the macitentan group experienced significant fluid retention and were hospitalized for worsening heart failure compared to those in the placebo group. Post-marketing reports of edema and fluid retention within a few weeks of starting macitentan therapy have been reported, and some patients required diuretic intervention or hospitalization for decompensated heart failure (see [Adverse Reactions] section).
Signs of fluid retention should be monitored after starting macitentan therapy. If a clinically significant fluid retention event occurs, the patient should be evaluated to determine the etiology, such as whether it is attributable to this product or to underlying heart failure, and whether discontinuation of this product is warranted.
Decreased hemoglobin
Decreases in hemoglobin concentration and erythrocyte specific volume occur with the application of other endothelin receptor antagonists (ERAs) and were similarly observed in studies with Macitentan. These decreases occurred early in the course of drug administration and subsequently stabilized. In a placebo-controlled study in patients with pulmonary hypertension, hemoglobin decreased by a mean of approximately 1.0 g/dL from baseline to 18 months in the macitentan 10 mg-treated group, with no change in the placebo group. Hemoglobin decreased to less than 10.0 g/dL in 8.7% of patients in the macitentan 10 mg treatment group and 3.4% of patients in the placebo group. These patients with reduced hemoglobin rarely required blood transfusions. Initiation of this product is not recommended for patients with severe anemia. Hemoglobin should be tested prior to initiation of this product and repeated during treatment as clinically indicated (see [Adverse Reactions] section).
Pulmonary edema in the setting of pulmonary veno-occlusive disease (PVOD)
If signs of pulmonary edema occur with the use of this product, the possibility of associated PVOD should be considered. If confirmed, the product should be discontinued.
Decreased sperm count
Other endothelin receptor antagonists (ERAs) can have adverse effects on spermatogenesis. Male patients should be informed of the potential effects of this product on fertility (see [Pregnancy and Lactation] and [Pharmacology and Toxicology] sections).
Pregnant women and nursing mothers
Pregnancy
This product is contraindicated during pregnancy because it may cause fetal damage in pregnant women. Macitentan was teratogenic in rabbits and rats at all doses tested, and no no no-effect dose was determined in either species. If the drug is used during pregnancy, or if pregnancy occurs while taking the drug, the patient should be informed of the potential hazard of the drug to the fetus (see [Contraindications] section).
Lactating women
It is not known whether this product is secreted into human breast milk. Macitentan and its metabolites appear in the milk of lactating rats. Because many drugs can be secreted into breast milk and because infants may have serious adverse reactions to macitentan, lactating women are advised to discontinue breast-feeding or discontinue use of this product.
Females and males of childbearing age
Females
Pregnancy test: Female patients of childbearing potential must have a negative pregnancy test prior to initiation of treatment with this drug, and a monthly pregnancy test while taking this drug. Patients should be advised to contact their health care provider if pregnancy or suspected pregnancy occurs. If pregnancy is suspected for any reason, a pregnancy test should be performed. Patients with a positive pregnancy test result should be informed of the potential risk of the drug to the fetus (see [Precautions] and [Dosage] sections).
Contraception: Female patients of childbearing age should use reliable contraception during and one month after treatment with this product. Patients may choose one highly effective form of contraception (intrauterine device (IUD), subcutaneous implant, or tubal sterilization) or a combination (hormonal method with one or both barrier methods). If the partner chooses vasectomy as a contraceptive, one hormonal or barrier method must be used at the same time. Counseling should be provided for the planning and prevention of the patient’s pregnancy, including emergency contraception, or other health care providers trained in contraceptive counseling should be designated (see [Precautions] section).
Male
Testicular effects: As with other endothelin receptor antagonists (ERAs), this product may have adverse effects on sperm production (see [Precautions] and [Pharmacology and Toxicology] sections).
Pediatric Use
The safety and efficacy of this product have not been established in pediatric patients.
Geriatric use
In clinical studies of this product for the treatment of pulmonary hypertension, 14% of the subjects were 65 years of age or older, and no overall differences in safety and efficacy were observed in these subjects compared to younger subjects. Clinical experience with the use of this product in patients >75 years of age is limited, and caution should be exercised in its use in this population.
[Drug Interactions].
CYP3A4 potent inducer
CYP3A4 potent inducers, such as rifampin, can significantly reduce exposure to Macitentan. Combination of this product with CYP3A4 potent inducers (e.g., rifampin, St. John’s wort, carbamazepine, phenytoin) should be avoided.
CYP3A4 potent inhibitors
Combination with CYP3A4 potent inhibitors, such as ketoconazole almost doubles the exposure to Macitentan. Many HIV drugs, such as ritonavir, are potent inhibitors of CYP3A4. Combination of this product with CYP3A4 potent inhibitors such as itraconazole, ketoconazole, voriconazole, clarithromycin, telithromycin, nefazodone, ritonavir, and saquinavir should be avoided. When the use of CYP3A4 potent inhibitors is necessary for HIV treatment, other pulmonary hypertension therapeutic agents should be selected.
In vitro studies
At plasma concentrations obtained with macitentan 10 mg administered once daily, macitentan has no relevant inhibitory or inducing effects on CYP enzymes and is neither a substrate nor an inhibitor of multidrug resistance proteins (P-gp, MDR-1). Macitentan and its active metabolites are neither substrates nor inhibitors of organic anion transporting polypeptides (OATP1B1 and OATP1B3), and there are no significant interactions with proteins involved in hepatic bile salt transport, namely bile salt export pump (BSEP) and sodium-dependent taurocholic acid cotransporting polypeptide (NTCP)).
In vivo studies
Effects of other drugs on macitentan: The effects of other drugs studied in healthy subjects on macitentan and its metabolites are shown in Figure 1.
Figure 1 Effects of other drugs on macitentan and its metabolites studied in healthy subjects
The effects of other potent CYP3A4 inhibitors, such as ritonavir, on macitentan have not been studied, but are similar to those observed in ketoconazole and may result in increased exposure as macitentan reaches steady state.
Effects of Macitentan on other drugs
Warfarin: Macitentan once daily did not alter R-warfarin and S-warfarin exposure or their effect on the international normalized ratio (INR).
Sildenafil: The combination of macitentan 10 mg once daily with sildenafil 20 mg three times daily increased sildenafil exposure by 15% at steady state. This change was not considered to be clinically significant.
[Drug overdose].
Healthy subjects have received single doses of up to 600 mg (60 times the approved dose) and adverse effects were observed as headache, nausea and vomiting. In the event of drug overdose, routine supportive therapy should be administered as needed. Because of the high protein binding rate of Macitentan, dialysis may not be effective.
Clinical trials]
Pulmonary arterial hypertension (PAH)
A long-term (mean exposure duration of approximately 2 years), multicenter, placebo-controlled study confirmed the effect of macitentan on disease progression in pulmonary arterial hypertension. 742 patients with symptomatic (WHO functional class (FC) II-IV) pulmonary arterial hypertension were randomly assigned to the placebo group (n=250), the macitentan once-daily 3 mg group (n=250), or the macitentan once-daily 10 mg group (n=242). group (n=242).
The primary study endpoint was the time to first mortality, significant morbidity event (defined as double-blind treatment + 7 days for atrial septotomy, lung transplantation, intravenous or subcutaneous prostaglandin analogs, or “other worsening of pulmonary arterial hypertension”). Other worsening was defined as 1) a sustained decrease in 6-minute walk distance (6MWD) of ≥15% from baseline, 2) worsening of symptoms of pulmonary hypertension (WHO functional class worsening), and 3) the need for other treatment of pulmonary hypertension. All of these other worsening events were subject to confirmation by an independent adjudication committee blinded to the treatment subgroup. The key secondary endpoint was the time to death or hospitalization for pulmonary hypertension.
The mean age of patients was 46 years (14% were 65 years or older). The majority of patients were Caucasian (55%) or Asian (29%) and female (77%). Approximately 52%, 46%, and 2% of patients were WHO functional class II, III, and IV, respectively.
In the study population, idiopathic or hereditary pulmonary hypertension was the most common cause (57%), followed by pulmonary hypertension associated with connective tissue disease (31%), pulmonary hypertension associated with congenital heart disease with repair of shunts (8%), and pulmonary hypertension due to other etiologies (drugs and toxins (3%) and HIV (1%)).
At baseline, the majority of enrolled patients (64%) were receiving stable doses of PAH-specific therapy with oral phosphodiesterase inhibitors (61%) and/or inhaled/oral prostaglandin analogs (6%).
The median duration of treatment in the placebo and macitentan 10 mg groups was 101 and 118 weeks, respectively, with a maximum duration of 188 weeks. The occurrence of the primary endpoint event by the end of double-blind treatment was reduced by 45% in the macitentan 10 mg group compared with the placebo group (HR 0.55, 97.5% CI 0.39-0.76; log rank p< 0.0001) (Table 3 and Figure 2). The benefit in the macitentan 10 mg group was mainly a reduction in clinical worsening events (6MWD reduction, worsening PAH symptoms and need for other PAH treatments).
Figure 2 Kaplan-Meier risk estimates for the primary endpoint events in the SERAPHIN study
Number at risk Macitentan 10 mg 242208 187171 155 91 41 Placebo 250188 160135 122 64 23 Table 3 Summary of primary endpoint events
Placebo
N=250
n (%) Macitentan 10 mg
N=242
n (%) Patients with primary endpoint event* 116 (46.4) 76 (31.4) Composition of first event
Worsening of pulmonary hypertension
Death
Intravenous/subcutaneous administration of prostaglandin analogs
93 (37.2)
17 (6.8)
6 (2.4)
59 (24.4)
16 (6.6)
1 (0.4) *No patients in the placebo and macitentan 10 mg groups underwent lung transplantation or atrial septotomy.
As shown in Figure 3, subgroup analysis was performed to examine the effect of each factor on the outcome. The definitive effectiveness of 10 mg macitentan was demonstrated by subgroup analyses for age, gender, race, etiology, monotherapy or combination with other PAH treatments, 6MWD baseline, and WHO functional class baseline.
Figure 3 Subgroup analysis of the SERAPHIN study
* 6 patients in the macitentan group and 7 patients in the placebo group were younger than 18 years
**Including 1 patient in the macitentan group with WHO functional class I at baseline
Eo=number of events in the macitentan 10 mg group; No=number of patients randomly assigned to the macitentan 10 mg group
Ep=number of events in the placebo group; Np=number of patients randomly assigned to the placebo group
Death due to PAH or hospitalization for PAH was defined as a secondary endpoint. The risk of PAH-related death or hospitalization was reduced by 50% in patients receiving 10 mg of macitentan compared with placebo (HR 0.50, 97.5% CI 0.34-0.75; log rank p< 0.0001) (Table 4 and Figure 4).
Figure 4 Kaplan-Meier risk estimates for death or hospitalization due to PAH in the SERAPHIN study
Number at risk Macitentan 10 mg2422031831661528639 Placebo 2501881551321196222 Table 4 Summary of deaths due to PAH and hospitalizations for PAH
Placebo
(N=250)
n (%) Macitentan 10 mg
(N=242)
n (%) Death due to PAH or hospitalization for PAH84 (33.6) 50 (20.7) Composition of first event
Death due to PAH
Hospitalization due to PAH
5 (2.0)
79 (31.6)
5 (2.1)
45 (18.6)
The correction for 6-minute walk distance (6MWD) in the macitentan 10 mg group increased by a mean of 22 m (97.5% CI 3-41; p=0.0078) relative to the placebo group at 6 months of treatment, a significant improvement over 6MWD at month 3. 6MWD increased more in patients with poor WHO functional class at baseline (WHO functional class III/IV and functional class I/II). /II classes increased by a mean of 37 m and 12 m, respectively, relative to the placebo group). The increase in 6MWD obtained in the macitentan treatment group persisted over the study period.
WHO functional class improved by at least 1 grade in 22% of patients in the macitentan 10 mg group at 6 months of treatment, compared to 13% of patients treated with placebo.
Pharmacology and Toxicology]
Pharmacological effects
Endothelin-1 (ET-1) and its receptors (ETA and ETB) mediate a variety of adverse effects such as vasoconstriction, fibrosis, hyperplasia, hypertrophy and inflammation, and in disease states such as pulmonary arterial hypertension (PAH), upregulation of the local ET system is seen and is involved in vascular hypertrophy and organ damage.
Macitentan is an endothelin receptor antagonist (ERAs) that blocks ET-1 binding to ETA and ETB receptors. In human pulmonary artery smooth muscle cells, macitentan has a high affinity for ET receptors and binds persistently. A metabolite of macitentan also exhibits pharmacological activity against ET receptors, and in vitro assays estimate its potency to be approximately 20% of that of the parent drug.
Pulmonary hemodynamics: A clinical efficacy study in patients with pulmonary hypertension evaluated hemodynamic parameters after 6 months of treatment in a subgroup of patients. There was a 37% (median) reduction in pulmonary vascular resistance (95% CI 22-49) and a 0.6 L/min/m2 (95% CI 0.3-0.9) increase in cardiac index in the macitentan 10 mg treatment group (N=57) compared to the placebo group (N=67).
Cardiac electrophysiology: In a randomized, placebo-controlled, four-phase crossover study in healthy subjects, multiple administrations of macitentan 10 mg and 30 mg (three times the recommended dose) did not significantly affect the QTc interval.
Toxicological studies
General Toxicity: A decrease in blood pressure was seen in dogs given macitentan orally when the exposure (based on AUC) was similar to that seen at therapeutic doses in humans. Coronary artery intima thickening was seen in dogs administered for 4 to 39 weeks when the exposure was 17 times the human exposure. Based on the species-specific sensitivity and safety window, the above results are not considered relevant in humans. No abnormal liver changes were seen in repeated dosing trials in mice, rats and dogs given macitentan when the exposure was 12 to 116 times the human exposure.
Genotoxicity: The results of the Macitentan Ames test, the mouse lymphoma cell mutation test, the human lymphocyte chromosome aberration test, and the rat micronucleus test were all negative.
Reproductive toxicity.
Repeated dosing toxicity tests in rats and dogs showed recovery with testicular tubule dilation seen at 7 and 23 times the human exposure to macitentan, respectively. In rats administered orally with macitentan for 2 years, testicular tubule atrophy was seen when the exposure was 4 times the human exposure. No significant effects on fertility were seen in male and female rats given orally macitentan when the exposure was 19 to 44 times the human exposure, and no significant effects on sperm count, viability and morphology were seen in males. No significant effects on the testes were seen in mice given mahicetentan orally for 2 years.
In rabbits and rats, at all doses tested, macitentan was toxic to offspring growth and development; no no effect dose was determined, and cardiovascular abnormalities and abnormal mandibular arch fusion were observed in fetuses.
In female rats given macitentan during late gestation to lactation, reduced pup survival and impaired fertility in male offspring were seen when maternal exposure was 5 times the human exposure.
In juvenile rats given macitentan from postnatal day 4 to day 114, when exposure was 7 times the human exposure, slow body weight gain and testicular tubule atrophy were seen, and no significant effects on fertility were observed.
Carcinogenicity: No administration-related carcinogenicity was observed in mice and rats given oral macitentan for 2 years when the exposure was 75 and 140 times the human exposure for male and female mice, respectively, and 8.3 and 42 times the human exposure for male and female rats, respectively.
[Pharmacokinetics].
Pharmacokinetic studies of macitentan and its active metabolites were conducted primarily in healthy subjects. The pharmacokinetics of macitentan administered once daily showed a proportional dose-response relationship in the range of 1 mg-30 mg.
A crossover study comparison showed that exposure to macitentan and its active metabolite in patients with pulmonary hypertension was similar to that observed in healthy subjects.
Absorption and Distribution
Peak concentrations of macitentan are reached approximately 8 hours after oral administration. The absolute bioavailability of macitentan is not known. In a study in healthy subjects, exposure to macitentan and its active metabolites was not altered after a high-fat breakfast. Therefore, macitentan may or may not be taken with or without food.
Macitentan and its active metabolites are highly bound to plasma proteins (>99%), primarily to albumin and, to a lesser extent, to alpha-1-acidic glycoprotein. The apparent volume of distribution (Vss/F) of macitentan and its active metabolites in healthy subjects is approximately 50 L and 40 L, respectively.
Metabolism and clearance
After oral administration, the apparent elimination half-lives of macitentan and its active metabolites were 16 and 48 hours, respectively. Macitentan undergoes mainly oxidative deprotonation by sulfonamide to form pharmacologically active metabolites. This reaction is dependent on the cytochrome P450 system (CYP), primarily CYP3A4, with CYP2C19 also playing a partial role. In patients with pulmonary hypertension, the systemic exposure to the active metabolites of macitentan is three times greater than the macitentan exposure at steady-state blood levels and is expected to constitute 40% of the total pharmacological activity. In a study employing radiolabeled macitentan for use in healthy subjects, approximately 50% of the radiologically active drug was eliminated by urine, but not as a prototype drug or as an active metabolite. Approximately 24% of the radioactive drug was found in the feces.
Special Populations
There are no clinically relevant effects of age, gender or race on the pharmacokinetics of Macitentan and its active metabolites.
Renal impairment: Exposure to macitentan and its active metabolites was increased by 30% and 60%, respectively, in patients with severe renal impairment (creatinine clearance (CrCl) 15-29 mL/min) compared to healthy subjects. This increase is not considered to be clinically relevant.
Hepatic impairment: Exposure to macitentan was reduced by 21%, 34%, and 6% in subjects with mild, moderate, and severe hepatic impairment (Child-Pugh categories A, B, and C), respectively, and exposure to its active metabolite was reduced by 20%, 25%, and 25%, respectively. This reduction was not considered to be clinically relevant.
[Storage].
Store below 30°C.
Package】
Aluminum-plastic package, 30 tablets/box.
[Expiration date
60 months
Execution Standard
Imported drug registration standard JX20160140
[Imported drug registration certificate number
XXXXXXXX
【Manufacturing Company
Company Name: Actelion Pharmaceuticals Ltd.
Company Address: Gewerbestrasse 16, 4123 Allschwil, Switzerland
Factory name: Patheon Italia S.P.A.
Plant address: Viale G.B. Stucchi 110, 20900 Monza (MB), Italy
Domestic Contact Name: Acetelon Pharmaceutical Trading (Shanghai) Co.
Tel: 800-8196-500
Fax: 021-80258310