|
新型口服血管舒张药riociguat获准用于肺动脉高压
7 DRUG INTERACTIONS 7.1 Pharmacodynamic Interactions with Adempas Nitrates: Co-administration of Adempas with nitrates or nitric oxide donors (such as amyl nitrite) in any form is contraindicated because of hypotension [see Contraindications (4.2) and Clinical Pharmacology (12.2)]. PDE Inhibitors: Co-administration of Adempas with specific PDE-5 inhibitors (such as sildenafil, tadalafil, or vardenafil) and nonspecific PDE inhibitors (such as dipyridamole or theophylline), is contraindicated because of hypotension [see Contraindications (4.3) and Clinical Pharmacology (12.2)]. Clinical experience with co-administration of Adempas and other phosphodiesterase inhibitors (for example, milrinone, cilostazole, roflumilast) is limited. 7.2 Pharmacokinetic Interactions with Adempas Smoking: Plasma concentrations in smokers are reduced by 50-60% compared to nonsmokers. Based on pharmacokinetic modeling, for patients who are smokers, doses higher than 2.5 mg three times a day may be considered in order to match exposure seen in nonsmoking patients. Safety and effectiveness of Adempas doses higher than 2.5 mg three times a day have not been established. A dose reduction should be considered in patients who stop smoking [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)]. Strong CYP and P-gp/BCRP inhibitors: Concomitant use of riociguat with strong cytochrome CYP inhibitors and P-gp/BCRP inhibitors such as azole antimycotics (for example, ketoconazole, itraconazole) or HIV protease inhibitors (such as ritonavir) increase riociguat exposure and may result in hypotension. Consider a starting dose of 0.5 mg 3 times a day when initiating Adempas in patients receiving strong CYP and P-gp/BCRP inhibitors. Monitor for signs and symptoms of hypotension on initiation and on treatment with strong CYP and P-gp/BCRP inhibitors. A dose reduction should be considered in patients who may not tolerate the hypotensive effect of riociguat [see Dosage and Administration (2.5), Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)]. Strong CYP3A inducers: Strong inducers of CYP3A (for example, rifampin, phenytoin, carbamazepine, phenobarbital or St. John’s Wort) may significantly reduce riociguat exposure. Data are not available to guide dosing of riociguat when strong CYP3A inducers are co-administered. [see Clinical Pharmacology (12.3)]. Antacids: Antacids such as aluminum hydroxide/magnesium hydroxide decrease riociguat absorption and should not be taken within 1 hour of taking Adempas [see Clinical Pharmacology (12.3)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category X Risk Summary Adempas may cause fetal harm when administered to a pregnant woman and is contraindicated during pregnancy. Adempas was teratogenic and embryotoxic in rats at doses with exposures to unbound drug that were approximately 8 times and 2 times, respectively, the human exposure. In rabbits, riociguat led to abortions at 4 times the human exposure and fetal toxicity with exposures approximately 13 times the human exposure. If Adempas is used in pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus [see Boxed Warning and Contraindications (4.1)]. Animal Data In rats administered riociguat orally (1, 5, and 25 mg/kg/day) throughout organogenesis, an increased rate of cardiac ventricular-septal defect was observed at the highest dose tested. The highest dose produced evidence of maternal toxicity (reduced body weight). Post-implantation loss was statistically significantly increased from the mid-dose of 5 mg/kg/day. Plasma exposure at the lowest dose in which no adverse effects were observed is approximately 0.4 times that in humans at the maximally recommended human dose (MRHD) of 2.5 mg three times a day based on area under the time-concentration curve (AUC) for unbound drug in rat and humans. Plasma exposure at the highest dose (25 mg/kg/day) is approximately 8 times that in humans at the MRHD while exposure at the mid-dose (5 mg/kg/day) is approximately 2 times that in humans at the MRHD. In rabbits given doses of 0.5, 1.5 and 5 mg/kg/day, an increase in spontaneous abortions was observed starting at the middle dose of 1.5 mg/kg, and an increase in resorptions was observed at 5 mg/kg/day. Plasma exposures at these doses were 4 times and 13 times, respectively, the human exposure at the MRHD. 8.3 Nursing Mothers It is not known if Adempas is present in human milk. Riociguat or its metabolites were present in the milk of rats. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants from riociguat, discontinue nursing or Adempas. 8.4 Pediatric Use Safety and effectiveness of Adempas in pediatric patients have not been established [see Nonclinical Toxicology (13.2)]. 8.5 Geriatric Use Of the total number of subjects in clinical studies of Adempas, 23% were 65 and over, and 6% were 75 and over [see Clinical Studies (14)]. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Elderly patients showed a higher exposure to Adempas [see Clinical Pharmacology (12.3)]. 8.6 Females and Males of Reproductive Potential Pregnancy Testing: Female patients of reproductive potential must have a negative pregnancy test prior to starting treatment with Adempas, monthly during treatment, and one month after discontinuation of treatment with Adempas. Advise patients to contact their healthcare provider if they become pregnant or suspect they may be pregnant. Counsel patients on the risk to the fetus [see Boxed Warning, Dosage and Administration (2.3)] and Use in Specific Populations (8.1)]. Contraception: Female patients of reproductive potential must use acceptable methods of contraception during treatment with Adempas and for 1 month after treatment with Adempas. Patients may choose one highly effective form of contraception (intrauterine devices [IUD], contraceptive implants or tubal sterilization) or a combination of methods (hormone method with a barrier method or two barrier methods). If a partner’s vasectomy is the chosen method of contraception, a hormone or barrier method must be used along with this method. Counsel patients on pregnancy planning and prevention, including emergency contraception, or designate counseling by another healthcare provider trained in contraceptive counseling. [See Boxed Warning.] 8.7 Renal Impairment Safety and efficacy have not been demonstrated in patients with creatinine clearance <15 mL/min or on dialysis [see Clinical Pharmacology (12.3).] 8.8 Hepatic Impairment Safety and efficacy have not been demonstrated in patients with severe hepatic impairment (Child Pugh C) [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE In cases of overdose, blood pressure should be closely monitored and supported as appropriate. Based on extensive plasma protein binding, riociguat is not expected to be dialyzable. 11 DESCRIPTION Adempas (riociguat) is a tablet for oral administration. Riociguat is methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo [3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate with the following structural formula: C20H19FN8O2
A statistically significant reduction of PVR (-226 dyn*sec*cm-5) was shown in the Adempas individual titration group (to maximum dose of 2.5 mg three times a day) vs. placebo. Improvement in other relevant hemodynamic parameters (not pre-specified as endpoints) for the individual dose titration group versus placebo are displayed in Table 3. Table 3: PATENT-1, Change in Hemodynamic Parameters from Baseline to Last Visit: (Individual Dose Titration to Maximum 2.5 mg Three Times a Day versus Placebo
In the CHEST-1 study, Adempas significantly reduced N-terminal prohormone of brain natriuretic peptide (NT-proBNP), placebo-corrected mean change from baseline -444 ng/L, 95% CI -843 to -45. In the PATENT-1 study Adempas demonstrated a statistically significant reduction of NT-proBNP, placebo‑corrected mean change from baseline: -432 ng/L, 95% CI –782 to –82. Pharmacodynamic interactions Nitrates: Riociguat 2.5 mg tablets potentiated the blood pressure lowering effect of sublingual nitroglycerin (0.4 mg) taken 4 and 8 hours after riociguat. Syncope was reported in some patients [see Contraindications (4.2)]. Phosphodiesterase-5 inhibitors: In an exploratory interaction study in 7 patients with PAH on stable sildenafil treatment (20 mg three times a day), single doses of riociguat (0.5 mg and 1 mg sequentially) showed additive hemodynamic effects. Among patients with PAH on stable sildenafil treatment (20 mg, three times a day) and riociguat (1 to 2.5 mg, three times a day) there was one death, possibly related to the combination of these drugs, and a high rate of discontinuation for hypotension [see Contraindications (4.3)]. Warfarin: Concomitant administration of riociguat and warfarin did not alter prothrombin time. Acetylsalicylic Acid: Concomitant use of riociguat and aspirin did not affect bleeding time or platelet aggregation 12.3 Pharmacokinetics Riociguat pharmacokinetics are dose proportional from 0.5 to 2.5 mg. Inter-individual variability of riociguat exposure (AUC) across all doses is approximately 60%, and within-subject variability is approximately 30%. Absorption and distribution The absolute bioavailability of riociguat is about 94%. Peak plasma riociguat concentrations were observed within 1.5 hours after tablet intake. Food does not affect the bioavailability of riociguat. The volume of distribution at steady state is approximately 30 L. Plasma protein binding in humans is approximately 95%, with serum albumin and α1–acidic glycoprotein being the main binding components. Riociguat is a substrate of P-gp and BCRP. Metabolism and excretion Riociguat is mainly cleared by metabolism by CYP1A1, CYP3A, CYP2C8 and CYP2J2. Formation of the major active metabolite, M1, is catalyzed by CYP1A1, which is inducible by polycyclic aromatic hydrocarbons such as those present in cigarette smoke. M1 is further metabolized to the inactive N-glucuronide. Plasma concentrations of M1 in patients with PAH are about half those for riociguat. Following oral administration of radiolabeled riociguat in healthy individuals, about 40 and 53% of the total radioactivity was recovered in urine and feces, respectively. There appears to be considerable variability in the proportion of metabolites and unchanged riociguat excreted, but metabolites were the major components of the dose excreted in most individuals. Average systemic clearance of riociguat was about 1.8 L/h in patients with PAH and about 3.4 L/h in healthy subjects. The terminal elimination half-life is about 12 hours in patients and 7 hours in healthy subjects. Specific Populations: The effect of intrinsic factors on riociguat and M1 are shown below in Figure 1. There are no clinically relevant effects of age, sex, weight, or race/ethnicity on the pharmacokinetics of riociguat or M1. No dose adjustment is warranted. Figure 1: Effect of Intrinsic Factors on Riociguat and M1 Pharmacokinetics Drug interactions: The effect of other extrinsic factors on riociguat and M1 were studied in healthy subjects and are shown in Figure 2 Figure 2: Effect of Extrinsic Factors on Riociguat and M1 Pharmacokinetics *HIV protease inhibitors are strong CYP3A inhibitors and may increase riociguat plasma concentrations to levels similar to those seen with ketoconazole. ** AUC only, estimated using population pharmacokinetics methods *** AUC only for metabolite, estimated using population pharmacokinetics methods. **** Monitor for signs and symptoms of hypotension on initiation and on treatment with strong CYP and P-gp/BCRP inhibitors [see Dosage and Administration (2.4, 2.5), Warnings and Precautions (5.3) and Drug Interactions (7.2)]. Strong CYP3A inducers: Data are not available to inform dosing of riociguat when strong CYP3A inducers are co-administered [see Drug Interactions (7.2)]. Effects of Riociguat on other Drugs: Riociguat did not affect the pharmacokinetics of midazolam, warfarin, or sildenafil [see Contraindications (4.3) and Clinical Pharmacology (12.2)]. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis: Carcinogenicity studies of riociguat were conducted in mice and rats. In mice, oral administration of riociguat (up to 25 mg/kg/day in males and 32 mg/kg/day in females) for up to two years did not demonstrate evidence of carcinogenesis. Plasma exposure (AUC) of unbound riociguat at the highest dose was 6 times the human’s exposure. In rats, oral administration of riociguat (up to 20 mg/kg/day) for up to two years did not demonstrate evidence of carcinogenesis. Plasma exposure (AUC) of unbound riociguat at the highest dose was 7 times the human exposure Mutagenesis: Riociguat and M1 did not show genotoxic potential in the in vitro bacterial reverse mutation (Ames) assay, the in vitro chromosomal aberration assay in Chinese hamster V79 cells, or the in vivo micronucleus assay in the mouse. Impairment of fertility: In rats, no effects on male or female fertility were observed. In male rats, oral administration of riociguat (up to 30 mg/kg/day) prior to and throughout the mating period had no effect on fertility. The no-effect dose for adverse effects is 37 times the human exposure when based on body surface area. In female rats, oral administration of riociguat (up to 30 mg/kg/day) prior to and during mating and continuing to gestation Day 7 had no effect on fertility. The no-effect dose for adverse effects is 37 times the human exposure when based on body surface area. 13.2 Animal Toxicology In growing rats, effects on bone formation were observed, including thickening of the growth plates, disorganized trabecular bone, and diffuse hyperostosis [see Use in Specific Populations (8.4)]. 14 CLINICAL STUDIES 14.1 Chronic-Thromboembolic Pulmonary Hypertension A double-blind, multi-national, multi-center, study (CHEST-1) was conducted in 261 patients with CTEPH. Patients were included if they: • were technically inoperable for pulmonary endarterectomy, with PVR >300 dyn*sec*cm -5 and mean pulmonary artery pressure >25 mmHg measured at least 90 days after the start of full anticoagulation, or • had recurrent or persisting pulmonary hypertension defined as PVR > 300 dyn*sec*cm -5 measured at least 180 days following pulmonary endarterectomy. Patients were randomized to Adempas titrated up to 2.5 mg three times a day (n=173) or placebo (n=88). All patients were initiated at 1 mg three times a day. Patients with systolic blood pressure < 95 mmHg were excluded from the study. The dose of riociguat was titrated every 2 weeks based on the patient’s systolic blood pressure and signs or symptoms of hypotension. Stable dosages of oral anticoagulants, diuretics, digitalis, calcium channel blockers and oxygen were allowed, but not concomitant therapy with NO donors, endothelin receptor antagonists, prostacyclin analogues (PCA), specific PDE-5 inhibitors (such as, sildenafil, tadalafil, or vardenafil), and nonspecific phosphodiesterase inhibitors (for example, dipyridamole or theophylline). The primary endpoint of the study was change from baseline in six minute walking distance (6MWD) after 16 weeks. The mean age of the patients enrolled was 59 years (range 18–80 years). In the study, 72% of patients had inoperable CTEPH, 28% had recurrent or persisting pulmonary hypertension following pulmonary endarterectomy. The majority of patients had a World Health Organization (WHO) Functional Class II (31%) or III (64%) at baseline. The mean baseline 6MWD was 347 meters. In the study, 77% of patients were titrated to the maximum dose of 2.5 mg three times a day; 13%, 6%, 4%, and 1% of patients were titrated to riociguat doses of 2, 1.5, 1, and 0.5 mg three times a day, respectively. Results of the 6MWD over 16 weeks for the CHEST-1 study are shown in Figure 3. Figure 3: CHEST-1 Mean Change from Baseline in the 6-Minute Walk Distance The pre-specified primary endpoint of the study was the change in 6MWD from baseline to week 16 and was based on imputed values. The imputation for missing values included last observed value, not including follow-up for patients who completed the study or withdrew. For deaths or clinical worsening without a termination visit or a measurement at that visit, the imputed worst value (zero) was used. Improvements in walking distance were apparent from Week 2 onward. At Week 16, the placebo adjusted mean increase in 6MWD within the Adempas group was 46 m (95% confidence interval [CI]: 25 m to 67 m; p<0.0001). For CHEST-1, the median difference (Hodges-Lehmann non-parametric estimate) in 6MWD was 39 m (95% CI, 25 m to 54 m). Figure 4 illustrates the results of the Adempas and placebo treatment groups displayed as a histogram summarizing the treatment effect on the 6MWD. The patients are grouped by change in 20 meters from baseline. Overall this figure shows that patients treated with Adempas benefit compared to those treated with placebo. As demonstrated in Figure 4, 143 patients receiving Adempas (83%) experienced an improvement in 6MWD compared to 50 patients (57%) on placebo. Figure 4: CHEST-1 Distribution of Patients by Change from Baseline in 6-Minute Walk Distance Placebo-adjusted changes in 6MWD at 16 weeks were evaluated in subgroups (see Figure 5). Figure 5: Mean Treatment Difference in Change from Baseline to Last Visit in 6-Minute Walk Distance (meters) by Prespecified Subgroups WHO Functional Class improvements in the CHEST-1 trial are shown in Table 4. Table 4: Effects of Adempas on the Change in WHO Functional Class in CHEST-1 from Baseline to Week 16
An open-label extension study (CHEST-2) included 237 patients who had completed CHEST-1. At the cut-off date in the CHEST-2 study, the mean treatment duration for the total population was 582 days (± 317). The probability of survival at 1 year and 2 years were 97% and 94%, respectively. Additionally, 6MWD and WHO Functional Class status appeared to further improve in patients taking Adempas. Without a control group, however, these data must be interpreted cautiously. 14.2 Pulmonary Arterial Hypertension A double-blind, multi-national, multi-center study (PATENT-1) was conducted in 443 patients with PAH as defined by PVR >300 dyn*sec*cm-5 and a PAP mean >25 mmHg. Patients were randomized to one of three treatment groups: Adempas titrated up to 1.5 mg (n=63), 2.5 mg (n=254) or placebo (n=126) three times a day. Patients with systolic blood pressure < 95 mmHg were excluded from the study. Patients assigned to Adempas were initiated at 1.0 mg three times a day. The dose of Adempas was up-titrated every 2 weeks based on the patient’s systolic blood pressure and signs or symptoms of hypotension. Oral anticoagulants, diuretics, digitalis, calcium channel blockers, and oxygen were allowed. In this study, 50% of the patients were treatment-naive with respect to PAH therapy, 44% were pre-treated with an endothelin receptor antagonist (ERA) and 6% were pre-treated with a PCA (inhaled, oral or subcutaneous). Pre-treated patients were defined as patients on stable treatment for 3 months with either an ERA or PCA; Adempas was added in combination to these background therapies. The primary endpoint of the study was change from baseline and placebo in 6MWD after 12 weeks in the 2.5 mg group. The mean age of all patients was 51 years and approximately 80% were female. PAH etiologies were either idiopathic (61%) or familial PAH (2%), PAH associated with connective tissue disease (25%), congenital heart disease (8%), portal hypertension (3%), or anorexigen or amphetamine use (1%). The majority of patients had a WHO Functional Class II (42%) or III (54%) at baseline. The overall mean baseline 6MWD was 363 meters. Approximately 75% of patients were up-titrated to receive the maximum dose of 2.5 mg three times a day by week 12; 15%, 6%, 3%, and 2% were titrated to doses of 2 mg, 1.5 mg, 1 mg, and 0.5 mg 3 times a day, respectively. Results of the 6MWD over 12 weeks for the PATENT-1 study are shown in Figure 6. Figure 6: PATENT-1 Mean Change from Baseline in the 6-Minute Walk Distance The pre-specified primary endpoint of the study was the change in 6MWD from baseline to week 12 and was based on imputed values. The imputation for missing values included last observed value, not including follow-up for patients who completed the study or withdrew. In case of death or clinical worsening without a termination visit or a measurement at that termination visit, the imputed worst value (zero) was used. Figure 7 illustrates the results of the Adempas and placebo treatment groups displayed as a histogram summarizing the treatment effect on the 6MWD. The patients are grouped by change in 20 meters from baseline. Overall this figure shows that patients treated with Adempas benefit compared to those treated with placebo. As demonstrated in Figure 7, 193 patients receiving Adempas (76%) experienced an improvement in 6MWD compared to 74 patients (59%) on placebo. Figure 7: PATENT-1 Distribution of Patients by Change from Baseline in 6-Minute Walk Distance Improvements 6MWD were apparent from Week 2 onward. At Week 12, the placebo-adjusted mean increase in 6MWD within the Adempas group was 36 m (95% CI: 20 m to 52 m; p<0.0001). For PATENT-1, the median difference (Hodges-Lehmann non-parametric estimate) in 6MWD was 29 m (95% CI, 17 m to 40 m).There was an exploratory 1.5 mg capped titration arm (n = 63). The data did not suggest incremental benefit from escalating dose from 1.5 mg three times a day to 2.5 mg three times a day. Placebo-adjusted changes in 6MWD at 12 weeks were evaluated in subgroups (see Figure 8). Figure 8: PATENT-1 Mean Treatment Difference in Change from Baseline to Last Visit in 6-Minute Walk Distance (meter) by Prespecified Subgroups WHO Functional Class improvements in the IDT (individual dose titration) arm of the PATENT-1 trial are shown in Table 5 Table 5: Effects of Adempas on the Change in WHO Functional Class in PATENT-1 from Baseline to Week 12
Effects of Adempas in PATENT-1 on events of clinical worsening are shown in Table 6. Table 6: Effects of Adempas in PATENT-1 on Events of Clinical Worsening (ITT analysis set)
Note: Patients may have had more than one event of clinical worsening Adempas-treated patients experienced a significant delay in time to clinical worsening versus placebo-treated patients (p=0.0046; Stratified log-rank test). Significantly fewer events of clinical worsening up to week 12 (last visit) were observed in patients treated with Adempas (1.2%) compared to placebo (6.3%) (p=0.0285, Mantel-Haenszel estimate). The Kaplan-Meier plot of time to clinical worsening is presented in Figure 9. Figure 9: PATENT-1 Time (in Days) to Clinical Worsening (ITT analysis set) Long Term Treatment of PAH An open label extension study (PATENT-2) included 363 patients who had completed PATENT-1. At the cut-off date in the PATENT-2 study, the mean treatment duration for the total population was 663 days (± 319). The probabilities of survival at 1 and 2 years were 97% and 93%, respectively. Without a control group, these data must be interpreted cautiously. 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Adempas (riociguat) tablets are film-coated, round, and debossed with the “Bayer cross” on one side.
Store at 25°C (77°F); excursions are permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide). Embryo-Fetal ToxicityInstruct patients on the risk of fetal harm when Adempas is used during pregnancy [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]. Instruct females of reproductive potential to use effective contraception and to contact her physician immediately if they suspect they may be pregnant. Female patients must enroll in the Adempas REMS Program. Adempas REMS ProgramFor female patients, Adempas is available only through a restricted program called the Adempas REMS Program [see Warnings and Precautions (5.2)]. Male patients are not enrolled in the Adempas REMS Program. Inform female patients (and their guardians, if applicable) of the following important requirements: • All female patients must sign an enrollment form. • Advise female patients of reproductive potential that she must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.6)]. • Educate and counsel females of reproductive potential on the use of emergency contraception in the event of unprotected sex or contraceptive failure. • Advise pre-pubertal females to report any changes in their reproductive status immediately to her prescriber. Review the Medication Guide and REMS educational materials with female patients. Other Risks Associated with Adempas • Inform patients of the contraindication of Adempas with nitrates or nitric oxide donors or PDE-5 inhibitors. • Advise patients about the potential risks/signs of hemoptysis and to report any potential signs of hemoptysis to their physicians. • Instruct patients on the dosing, titration, and maintenance of Adempas. • Advise patients regarding activities that may impact the pharmacology of Adempas (strong multi pathway CYP inhibitors and P-gp/BCRP inhibitors and smoking). Patients should report all current medications and new medications to their physician. • Advise patients that antacids should not be taken within 1 hour of taking Adempas. • Inform patients that Adempas can cause dizziness, which can affect the ability to drive and use machines [see Adverse Reactions (6.1)]. They should be aware of how they react to Adempas, before driving or operating machinery and if needed, consult their physician. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
