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| Product NDC Code | 66215-501 | ||||||
|---|---|---|---|---|---|---|---|
| Drug Name | Opsumit |
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| Type | Brand | ||||||
| Pharm Class | Endothelin Receptor Antagonist [EPC], Endothelin Receptor Antagonists [MoA] |
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| Active Ingredients |
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| Route | ORAL | ||||||
| Dosage Form | TABLET, FILM COATED | ||||||
| RxCUI drug identifier | 1442137, 1442143 |
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| Application Number | NDA204410 | ||||||
| Labeler Name | Actelion Pharmaceuticals US, Inc. | ||||||
| Packages |
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| Check if available Online | Get Medication Prices online with Discount |
Overdosage of OPSUMIT
Information about signs, symptoms, and laboratory findings of acute ovedosage and the general principles of overdose treatment.10 OVERDOSAGE OPSUMIT has been administered as a single dose of up to and including 600 mg to healthy subjects (60 times the approved dosage). Adverse reactions of headache, nausea and vomiting were observed. In the event of an overdose, standard supportive measures should be taken, as required. Dialysis is unlikely to be effective because macitentan is highly protein-bound.
Adverse reactions
Information about undesirable effects, reasonably associated with use of the drug, that may occur as part of the pharmacological action of the drug or may be unpredictable in its occurrence. Adverse reactions include those that occur with the drug, and if applicable, with drugs in the same pharmacologically active and chemically related class. There is considerable variation in the listing of adverse reactions. They may be categorized by organ system, by severity of reaction, by frequency, by toxicological mechanism, or by a combination of these.6 ADVERSE REACTIONS Clinically significant adverse reactions that appear in other sections of the labeling include: Embryo-fetal Toxicity [see Warnings and Precautions (5.1) ] Hepatotoxicity [see Warnings and Precautions (5.3) ] Fluid Retention [see Warnings and Precautions (5.4) ] Decrease in Hemoglobin [see Warnings and Precautions (5.5) ] Most common adverse reactions (more frequent than placebo by ≥3%) are anemia, nasopharyngitis/pharyngitis, bronchitis, headache, influenza, and urinary tract infection ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Janssen at 1-800-526-7736 (1-800-JANSSEN) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Safety data for OPSUMIT were obtained primarily from one placebo-controlled clinical study in 742 patients with PAH (SERAPHIN study) [see Clinical Studies (14) ]. The exposure to OPSUMIT in this trial was up to 3.6 years with a median exposure of about 2 years (N=542 for 1 year; N=429 for 2 years; and N=98 for more than 3 years). The overall incidence of treatment discontinuations because of adverse events was similar across OPSUMIT 10 mg and placebo treatment groups (approximately 11%). Table 2 presents adverse reactions more frequent on OPSUMIT than on placebo by ≥3%. Table 2: Adverse Reactions Adverse Reaction OPSUMIT 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 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of OPSUMIT. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune system disorders: hypersensitivity reactions (angioedema, pruritus and rash) Vascular disorders : flushing Respiratory, thoracic and mediastinal disorders: nasal congestion Gastrointestinal disorders: Elevations of liver aminotransferases (ALT, AST) and liver injury have been reported with OPSUMIT use; in most cases alternative causes could be identified (heart failure, hepatic congestion, autoimmune hepatitis). Endothelin receptor antagonists have been associated with elevations of aminotransferases, hepatotoxicity, and cases of liver failure [see Warnings and Precautions (5.3) ] . General disorders and administration site conditions: edema/fluid retention. Cases of edema and fluid retention occurred within weeks of starting OPSUMIT, some requiring intervention with a diuretic, fluid management or hospitalization for decompensated heart failure. [see Warnings and Precautions (5.4) ]. Cardiac disorders: symptomatic hypotension
| Adverse Reaction | OPSUMIT 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 |
OPSUMIT Drug Interactions
Information about and practical guidance on preventing clinically significant drug/drug and drug/food interactions that may occur in people taking the drug.7 DRUG INTERACTIONS Strong CYP3A4 inducers (rifampin) reduce exposure to macitentan: avoid co-administration with OPSUMIT ( 7.1 , 12.3 ). Strong CYP3A4 inhibitors (ketoconazole, ritonavir) increase exposure to macitentan: avoid co-administration with OPSUMIT ( 7.2 , 12.3 ) . Moderate dual CYP3A4 and CYP2C9 inhibitors (fluconazole, amiodarone) or use of combined CYP3A4 and CYP2C9 inhibitors may increase exposure to macitentan: avoid co-administration with OPSUMIT ( 7.3 , 12.3 ). 7.1 Strong CYP3A4 Inducers Strong inducers of CYP3A4 such as rifampin significantly reduce macitentan exposure. Concomitant use of OPSUMIT with strong CYP3A4 inducers should be avoided [see Clinical Pharmacology (12.3) ] . 7.2 Strong CYP3A4 Inhibitors Concomitant use of strong CYP3A4 inhibitors like ketoconazole approximately double macitentan exposure. Many HIV drugs like ritonavir are strong inhibitors of CYP3A4. Avoid concomitant use of OPSUMIT with strong CYP3A4 inhibitors [see Clinical Pharmacology (12.3) ] . Use other PAH treatment options when strong CYP3A4 inhibitors are needed as part of HIV treatment [see Clinical Pharmacology (12.3) ] . 7.3 Moderate Dual or Combined CYP3A4 and CYP2C9 Inhibitors Concomitant use of moderate dual inhibitors of CYP3A4 and CYP2C9 such as fluconazole is predicted to increase macitentan exposure approximately 4-fold based on physiologically based pharmacokinetic (PBPK) modelling. Avoid concomitant use of OPSUMIT with moderate dual inhibitors of CYP3A4 and CYP2C9 (such as fluconazole and amiodarone) [see Clinical Pharmacology (12.3) ] . Concomitant treatment of both a moderate CYP3A4 inhibitor and moderate CYP2C9 inhibitor with OPSUMIT should also be avoided [see Clinical Pharmacology (12.3) ].
Clinical pharmacology
Information about the clinical pharmacology and actions of the drug in humans.12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Endothelin (ET)-1 and its receptors (ET A and ET B ) mediate a variety of deleterious effects, such as vasoconstriction, fibrosis, proliferation, hypertrophy, and inflammation. In disease conditions such as PAH, the local ET system is upregulated and is involved in vascular hypertrophy and in organ damage. Macitentan is an endothelin receptor antagonist that inhibits the binding of ET-1 to both ET A and ET B receptors. Macitentan displays high affinity and sustained occupancy of the ET receptors in human pulmonary arterial smooth muscle cells. One of the metabolites of macitentan is also pharmacologically active at the ET receptors and is estimated to be about 20% as potent as the parent drug in vitro . The clinical impact of dual endothelin blockage is unknown. 12.2 Pharmacodynamics Pulmonary Hemodynamics The clinical efficacy study in patients with pulmonary arterial hypertension assessed hemodynamic parameters in a subset of patients after 6 months of treatment. Patients treated with OPSUMIT 10 mg (N=57) achieved a median reduction of 37% (95% CI 22–49) in pulmonary vascular resistance and an increase of 0.6 L/min/m 2 (95% CI 0.3–0.9) in cardiac index compared to placebo (N=67). Cardiac Electrophysiology In a randomized, placebo-controlled four-way crossover study with a positive control in healthy subjects, repeated doses of macitentan 10 and 30 mg (3 times the recommended dosage) had no significant effect on the QTc interval. 12.3 Pharmacokinetics The pharmacokinetics of macitentan and its active metabolite have been studied primarily in healthy subjects. The pharmacokinetics of macitentan are dose proportional over a range from 1 mg to 30 mg after once daily administration. A cross study comparison shows that the exposures to macitentan and its active metabolite in patients with PAH are similar to those observed in healthy subjects. Absorption and Distribution The maximum plasma concentration of macitentan is achieved about 8 hours after oral administration. The absolute bioavailability after oral administration is not known. In a study in healthy subjects, the exposure to macitentan and its active metabolite were unchanged after a high fat breakfast. Macitentan may therefore be taken with or without food. Macitentan and its active metabolite are highly bound to plasma proteins (>99%), primarily to albumin and to a lesser extent to alpha-1-acid glycoprotein. The apparent volumes of distribution (Vss/F) of macitentan and its active metabolite were about 50 L and 40 L respectively in healthy subjects. Metabolism and Elimination Following oral administration, the apparent elimination half-lives of macitentan and its active metabolite are approximately 16 hours and 48 hours, respectively. Macitentan is metabolized primarily by oxidative depropylation of the sulfamide to form the pharmacologically active metabolite. This reaction is dependent on the cytochrome P450 (CYP) system, mainly CYP3A4 with minor contributions of CYP2C8, CYP2C9, and CYP2C19. At steady state in PAH patients, the systemic exposure to the active metabolite is 3-times the exposure to macitentan and is expected to contribute approximately 40% of the total pharmacologic activity. In a study in healthy subjects with radiolabeled macitentan, approximately 50% of radioactive drug material was eliminated in urine but none was in the form of unchanged drug or the active metabolite. About 24% of the radioactive drug material was recovered from feces. Special Populations There are no clinically relevant effects of age, sex, or race on the pharmacokinetics of macitentan and its active metabolite. Renal Impairment Exposure to macitentan and its active metabolite in patients with severe renal impairment (CrCl 15–29 mL/min) compared to healthy subjects was increased by 30% and 60%, respectively. This increase is not considered clinically relevant. Hepatic Impairment Exposure to macitentan was decreased by 21%, 34%, and 6% and exposure to the active metabolite was decreased by 20%, 25%, and 25% in subjects with mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, and C), respectively. This decrease is not considered clinically relevant. Drug Interactions In Vitro Studies At plasma levels obtained with dosing at 10 mg once daily, macitentan has no relevant inhibitory or inducing effects on CYP enzymes. Macitentan is not a substrate or inhibitor of multi-drug resistance protein (P-gp, MDR-1). The active metabolite of macitentan also is not an inhibitor of P-gp/MDR-1 at clinically relevant concentrations. Macitentan and its active metabolite are not expected to have significant interaction with drug transporters such as organic anion transporting polypeptide (OATP1B1, OATP1B3), multidrug and toxin extrusion protein (MATE-1, MATE-2K), bile salt export pump (BSEP), sodium-taurocholate co-transporting polypeptide (NTCP), organic cation transporter (OCT-1, OCT-3), organic anion transporter (OAT-1, OAT-3) or BCRP transporter at clinically relevant plasma concentrations. In Vivo Studies Effect of other drugs on macitentan The effect of other drugs on macitentan and its active metabolite are studied in healthy subjects and are shown in Figure 1 below. Figure 1 Effects of other strong CYP3A4 inhibitors such as ritonavir on macitentan were not studied, but are likely to result in an increase in macitentan exposure at steady state similar to that seen with ketoconazole [see Drug Interactions (7.2) ] . PBPK modeling and simulations based analysis showed that a moderate dual inhibitor of CYP3A4 and CYP2C9 such as fluconazole (400 mg once daily) is predicted to increase macitentan exposure approximately 4-fold without relevant effect on the exposure to its active metabolite [see Drug Interactions (7.3) ] . Figure 1 Effect of macitentan on other drugs Warfarin : Macitentan once daily dosing did not alter the exposure to R- and S-warfarin or their effect on international normalized ratio (INR). Sildenafil : At steady-state, the exposure to sildenafil 20 mg t.i.d. increased by 15% during concomitant administration of macitentan 10 mg once daily. This change is not considered clinically relevant. Hormonal contraceptives : Macitentan 10 mg once daily did not affect the pharmacokinetics of an oral contraceptive (norethisterone 1 mg and ethinyl estradiol 35 µg). BCRP Substrate drugs : Macitentan 10 mg once daily did not affect the pharmacokinetics of concomitant use of a BCRP substrate drug (riociguat 1 mg and rosuvastatin 10 mg).
Mechanism of action
Information about the established mechanism(s) of the drugÕs action in humans at various levels (for example receptor, membrane, tissue, organ, whole body). If the mechanism of action is not known, this field contains a statement about the lack of information.12.1 Mechanism of Action Endothelin (ET)-1 and its receptors (ET A and ET B ) mediate a variety of deleterious effects, such as vasoconstriction, fibrosis, proliferation, hypertrophy, and inflammation. In disease conditions such as PAH, the local ET system is upregulated and is involved in vascular hypertrophy and in organ damage. Macitentan is an endothelin receptor antagonist that inhibits the binding of ET-1 to both ET A and ET B receptors. Macitentan displays high affinity and sustained occupancy of the ET receptors in human pulmonary arterial smooth muscle cells. One of the metabolites of macitentan is also pharmacologically active at the ET receptors and is estimated to be about 20% as potent as the parent drug in vitro . The clinical impact of dual endothelin blockage is unknown.
Pharmacodynamics
Information about any biochemical or physiologic pharmacologic effects of the drug or active metabolites related to the drugÕs clinical effect in preventing, diagnosing, mitigating, curing, or treating disease, or those related to adverse effects or toxicity.12.2 Pharmacodynamics Pulmonary Hemodynamics The clinical efficacy study in patients with pulmonary arterial hypertension assessed hemodynamic parameters in a subset of patients after 6 months of treatment. Patients treated with OPSUMIT 10 mg (N=57) achieved a median reduction of 37% (95% CI 22–49) in pulmonary vascular resistance and an increase of 0.6 L/min/m 2 (95% CI 0.3–0.9) in cardiac index compared to placebo (N=67). Cardiac Electrophysiology In a randomized, placebo-controlled four-way crossover study with a positive control in healthy subjects, repeated doses of macitentan 10 and 30 mg (3 times the recommended dosage) had no significant effect on the QTc interval.
Pharmacokinetics
Information about the clinically significant pharmacokinetics of a drug or active metabolites, for instance pertinent absorption, distribution, metabolism, and excretion parameters.12.3 Pharmacokinetics The pharmacokinetics of macitentan and its active metabolite have been studied primarily in healthy subjects. The pharmacokinetics of macitentan are dose proportional over a range from 1 mg to 30 mg after once daily administration. A cross study comparison shows that the exposures to macitentan and its active metabolite in patients with PAH are similar to those observed in healthy subjects. Absorption and Distribution The maximum plasma concentration of macitentan is achieved about 8 hours after oral administration. The absolute bioavailability after oral administration is not known. In a study in healthy subjects, the exposure to macitentan and its active metabolite were unchanged after a high fat breakfast. Macitentan may therefore be taken with or without food. Macitentan and its active metabolite are highly bound to plasma proteins (>99%), primarily to albumin and to a lesser extent to alpha-1-acid glycoprotein. The apparent volumes of distribution (Vss/F) of macitentan and its active metabolite were about 50 L and 40 L respectively in healthy subjects. Metabolism and Elimination Following oral administration, the apparent elimination half-lives of macitentan and its active metabolite are approximately 16 hours and 48 hours, respectively. Macitentan is metabolized primarily by oxidative depropylation of the sulfamide to form the pharmacologically active metabolite. This reaction is dependent on the cytochrome P450 (CYP) system, mainly CYP3A4 with minor contributions of CYP2C8, CYP2C9, and CYP2C19. At steady state in PAH patients, the systemic exposure to the active metabolite is 3-times the exposure to macitentan and is expected to contribute approximately 40% of the total pharmacologic activity. In a study in healthy subjects with radiolabeled macitentan, approximately 50% of radioactive drug material was eliminated in urine but none was in the form of unchanged drug or the active metabolite. About 24% of the radioactive drug material was recovered from feces. Special Populations There are no clinically relevant effects of age, sex, or race on the pharmacokinetics of macitentan and its active metabolite. Renal Impairment Exposure to macitentan and its active metabolite in patients with severe renal impairment (CrCl 15–29 mL/min) compared to healthy subjects was increased by 30% and 60%, respectively. This increase is not considered clinically relevant. Hepatic Impairment Exposure to macitentan was decreased by 21%, 34%, and 6% and exposure to the active metabolite was decreased by 20%, 25%, and 25% in subjects with mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, and C), respectively. This decrease is not considered clinically relevant. Drug Interactions In Vitro Studies At plasma levels obtained with dosing at 10 mg once daily, macitentan has no relevant inhibitory or inducing effects on CYP enzymes. Macitentan is not a substrate or inhibitor of multi-drug resistance protein (P-gp, MDR-1). The active metabolite of macitentan also is not an inhibitor of P-gp/MDR-1 at clinically relevant concentrations. Macitentan and its active metabolite are not expected to have significant interaction with drug transporters such as organic anion transporting polypeptide (OATP1B1, OATP1B3), multidrug and toxin extrusion protein (MATE-1, MATE-2K), bile salt export pump (BSEP), sodium-taurocholate co-transporting polypeptide (NTCP), organic cation transporter (OCT-1, OCT-3), organic anion transporter (OAT-1, OAT-3) or BCRP transporter at clinically relevant plasma concentrations. In Vivo Studies Effect of other drugs on macitentan The effect of other drugs on macitentan and its active metabolite are studied in healthy subjects and are shown in Figure 1 below. Figure 1 Effects of other strong CYP3A4 inhibitors such as ritonavir on macitentan were not studied, but are likely to result in an increase in macitentan exposure at steady state similar to that seen with ketoconazole [see Drug Interactions (7.2) ] . PBPK modeling and simulations based analysis showed that a moderate dual inhibitor of CYP3A4 and CYP2C9 such as fluconazole (400 mg once daily) is predicted to increase macitentan exposure approximately 4-fold without relevant effect on the exposure to its active metabolite [see Drug Interactions (7.3) ] . Figure 1 Effect of macitentan on other drugs Warfarin : Macitentan once daily dosing did not alter the exposure to R- and S-warfarin or their effect on international normalized ratio (INR). Sildenafil : At steady-state, the exposure to sildenafil 20 mg t.i.d. increased by 15% during concomitant administration of macitentan 10 mg once daily. This change is not considered clinically relevant. Hormonal contraceptives : Macitentan 10 mg once daily did not affect the pharmacokinetics of an oral contraceptive (norethisterone 1 mg and ethinyl estradiol 35 µg). BCRP Substrate drugs : Macitentan 10 mg once daily did not affect the pharmacokinetics of concomitant use of a BCRP substrate drug (riociguat 1 mg and rosuvastatin 10 mg).
Contraindications
Information about situations in which the drug product is contraindicated or should not be used because the risk of use clearly outweighs any possible benefit, including the type and nature of reactions that have been reported.4 CONTRAINDICATIONS Pregnancy ( 4.1 ) Hypersensitivity ( 4.2 ) 4.1 Pregnancy OPSUMIT may cause fetal harm when administered to a pregnant woman. OPSUMIT is contraindicated in females who are pregnant. OPSUMIT was consistently shown to have teratogenic effects when administered to animals. If OPSUMIT is used during pregnancy, advise the patient of the potential risk to a fetus [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1) ] . 4.2 Hypersensitivity OPSUMIT is contraindicated in patients with a history of a hypersensitivity reaction to macitentan or any component of the product [see Adverse Reactions (6.2) ] .
Description
General information about the drug product, including the proprietary and established name of the drug, the type of dosage form and route of administration to which the label applies, qualitative and quantitative ingredient information, the pharmacologic or therapeutic class of the drug, and the chemical name and structural formula of the drug.11 DESCRIPTION OPSUMIT ® (macitentan) is an endothelin receptor antagonist. The chemical name of macitentan is N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'-propylsulfamide. It has a molecular formula of C 19 H 20 Br 2 N 6 O 4 S and a molecular weight of 588.27. Macitentan is achiral and has the following structural formula: Macitentan is a crystalline powder that is insoluble in water. In the solid state macitentan is very stable, is not hygroscopic, and is not light sensitive. OPSUMIT is available as a 10 mg film-coated tablet for once daily oral administration. The tablets include the following inactive ingredients: lactose monohydrate, magnesium stearate, microcrystalline cellulose, polysorbate 80, povidone, and sodium starch glycolate Type A. The tablets are film-coated with a coating material containing polyvinyl alcohol, soya lecithin, talc, titanium dioxide, and xanthan gum. Chemical Structure
Dosage and administration
Information about the drug product’s dosage and administration recommendations, including starting dose, dose range, titration regimens, and any other clinically sigificant information that affects dosing recommendations.2 DOSAGE AND ADMINISTRATION 10 mg once daily . Doses higher than 10 mg once daily have not been studied in patients with PAH and are not recommended ( 2.1 ). 2.1 Recommended Dosage The recommended dosage of OPSUMIT is 10 mg once daily for oral administration. Doses higher than 10 mg once daily have not been studied in patients with PAH and are not recommended. 2.2 Pregnancy Testing in Females of Reproductive Potential Obtain a pregnancy test in females of reproductive potential prior to OPSUMIT treatment, monthly during treatment and one month after stopping OPSUMIT. Initiate treatment with OPSUMIT in females of reproductive potential only after a negative pregnancy test. [see Boxed Warning , Contraindications (4.1) , Warnings and Precautions (5.1) , and Use in Specific Populations (8.3) ] .
Dosage forms and strengths
Information about all available dosage forms and strengths for the drug product to which the labeling applies. This field may contain descriptions of product appearance.3 DOSAGE FORMS AND STRENGTHS Tablets: 10 mg, bi-convex film-coated, round, white, and debossed with "10" on both sides. Tablet: 10 mg ( 3 )
Indications and usage
A statement of each of the drug products indications for use, such as for the treatment, prevention, mitigation, cure, or diagnosis of a disease or condition, or of a manifestation of a recognized disease or condition, or for the relief of symptoms associated with a recognized disease or condition. This field may also describe any relevant limitations of use.1 INDICATIONS AND USAGE OPSUMIT is an endothelin receptor antagonist (ERA) indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to reduce the risks of disease progression and hospitalization for PAH ( 1.1 ). 1.1 Pulmonary Arterial Hypertension OPSUMIT is an endothelin receptor antagonist (ERA) indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to reduce the risks of disease progression and hospitalization for PAH. Effectiveness was established in a long-term study in PAH patients with predominantly WHO Functional Class II–III symptoms treated for an average of 2 years. Patients had idiopathic and heritable PAH (57%), PAH caused by connective tissue disorders (31%), and PAH caused by congenital heart disease with repaired shunts (8%) [see Clinical Studies (14.1) ] .
Spl product data elements
Usually a list of ingredients in a drug product.OPSUMIT macitentan LACTOSE MONOHYDRATE MICROCRYSTALLINE CELLULOSE SODIUM STARCH GLYCOLATE TYPE A POTATO POVIDONE, UNSPECIFIED MAGNESIUM STEARATE POLYSORBATE 80 POLYVINYL ALCOHOL, UNSPECIFIED LECITHIN, SOYBEAN TALC TITANIUM DIOXIDE XANTHAN GUM MACITENTAN MACITENTAN 10
Animal pharmacology and or toxicology
Information from studies of the drug in animals, if the data were not relevant to nor included in other parts of the labeling. Most labels do not contain this field.13.2 Animal Toxicology In dogs, macitentan decreased blood pressure at exposures similar to the therapeutic human exposure. Intimal thickening of coronary arteries was observed at 17-fold the human exposure after 4 to 39 weeks of treatment. Due to the species-specific sensitivity and the safety margin, this finding is considered not relevant for humans. There were no adverse liver findings in long-term studies conducted in mice, rats, and dogs at exposures of 12- to 116-fold the human exposure.
Carcinogenesis and mutagenesis and impairment of fertility
Information about carcinogenic, mutagenic, or fertility impairment potential revealed by studies in animals. Information from human data about such potential is part of the warnings field.13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Carcinogenicity studies of 2 years' duration did not reveal any carcinogenic potential at exposures 75-fold and 140-fold the human exposure (based on AUC) in male and female mice, respectively, and 8.3- and 42-fold in male and female rats, respectively. Mutagenesis Macitentan was not genotoxic in a standard battery of in vitro and in vivo assays that included a bacterial reverse mutation assay, an assay for gene mutations in mouse lymphoma cells, a chromosome aberration test in human lymphocytes, and an in vivo micronucleus test in rats. Impairment of Fertility Treatment of juvenile rats from postnatal Day 4 to Day 114 led to reduced body weight gain and testicular tubular atrophy at exposures 7-fold the human exposure. Fertility was not affected. Reversible testicular tubular dilatation was observed in chronic toxicity studies at exposures greater than 7-fold and 23-fold the human exposure in rats and dogs, respectively. After 2 years of treatment, tubular atrophy was seen in rats at 4-fold the human exposure. Macitentan did not affect male or female fertility at exposures ranging from 19- to 44-fold the human exposure, respectively, and had no effect on sperm count, motility, and morphology in male rats. No testicular findings were noted in mice after treatment up to 2 years.
Nonclinical toxicology
Information about toxicology in non-human subjects.13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Carcinogenicity studies of 2 years' duration did not reveal any carcinogenic potential at exposures 75-fold and 140-fold the human exposure (based on AUC) in male and female mice, respectively, and 8.3- and 42-fold in male and female rats, respectively. Mutagenesis Macitentan was not genotoxic in a standard battery of in vitro and in vivo assays that included a bacterial reverse mutation assay, an assay for gene mutations in mouse lymphoma cells, a chromosome aberration test in human lymphocytes, and an in vivo micronucleus test in rats. Impairment of Fertility Treatment of juvenile rats from postnatal Day 4 to Day 114 led to reduced body weight gain and testicular tubular atrophy at exposures 7-fold the human exposure. Fertility was not affected. Reversible testicular tubular dilatation was observed in chronic toxicity studies at exposures greater than 7-fold and 23-fold the human exposure in rats and dogs, respectively. After 2 years of treatment, tubular atrophy was seen in rats at 4-fold the human exposure. Macitentan did not affect male or female fertility at exposures ranging from 19- to 44-fold the human exposure, respectively, and had no effect on sperm count, motility, and morphology in male rats. No testicular findings were noted in mice after treatment up to 2 years. 13.2 Animal Toxicology In dogs, macitentan decreased blood pressure at exposures similar to the therapeutic human exposure. Intimal thickening of coronary arteries was observed at 17-fold the human exposure after 4 to 39 weeks of treatment. Due to the species-specific sensitivity and the safety margin, this finding is considered not relevant for humans. There were no adverse liver findings in long-term studies conducted in mice, rats, and dogs at exposures of 12- to 116-fold the human exposure.
Package label principal display panel
The content of the principal display panel of the product package, usually including the product’s name, dosage forms, and other key information about the drug product.PRINCIPAL DISPLAY PANEL - 10 mg Tablet Bottle Carton NDC 66215-501-30 Opsumit ® (macitentan) tablets 10 mg Dispense the accompanying Medication Guide to each patient Rx only 30 film-coated tablets janssen PRINCIPAL DISPLAY PANEL - 10 mg Tablet Bottle Carton
Spl unclassified section
Information not classified as belonging to one of the other fields. Approximately 40% of labeling with effective_time between June 2009 and August 2014 have information in this field.Manufactured for: Actelion Pharmaceuticals US, Inc., a Janssen Pharmaceutical Company Titusville, NJ 08560, USA For patent information: www.janssenpatents.com © 2013 – 2019 Actelion Pharmaceuticals US, Inc. All rights reserved.
OPSUMIT: Information for patients
Information necessary for patients to use the drug safely and effectively, such as precautions concerning driving or the concomitant use of other substances that may have harmful additive effects.17 PATIENT COUNSELING INFORMATION Advise patient to read FDA-approved patient labeling (Medication Guide). Embryo-Fetal Toxicity Counsel female patients of reproductive potential about the need to use reliable methods of contraception during treatment with OPSUMIT and for one month after treatment discontinuation. Females of reproductive potential must have monthly pregnancy tests and must use reliable methods of contraception while taking OPSUMIT and for one month after discontinuing OPSUMIT [see Use in Specific Populations (8.1) ] . Macitentan-Containing Products REMS For female patients, OPSUMIT is available only through a restricted program called the Macitentan-Containing Products REMS [see Warnings and Precautions (5.2) ] . Male patients are not enrolled in the Macitentan-Containing Products REMS. 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). Patients should be instructed to contact their physician if they suspect they may be pregnant. Patients should seek additional contraceptive advice from a gynecologist or similar expert as needed. Inform female patients (and their guardians, if applicable) of the following notable requirements. Female patients must sign an enrollment form. Female patients of reproductive potential must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.3) ] . 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. Lactation Advise women not to breastfeed during treatment with OPSUMIT [see Use in Specific Population (8.2) ] . Hepatotoxicity Some members of this pharmacological class are hepatotoxic. Educate patients on signs of hepatotoxicity. Advise patients that they should contact their doctor if they have unexplained nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, fever, or itching. Fluid Retention Educate patients on signs of fluid retention. Advise patients that they should contact their doctor if they have unusual weight increase or swelling of the ankles or legs.
Spl medguide
Information about the patient medication guide that accompanies the drug product. Certain drugs must be dispensed with an accompanying medication guide. This field may contain information about when to consult the medication guide and the contents of the medication guide.MEDICATION GUIDE OPSUMIT ® (OP-sum-it) (macitentan) tablets This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 03/2024 Read this Medication Guide for OPSUMIT before you start taking OPSUMIT and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking with your healthcare provider about your medical condition or your treatment. What is the most important information I should know about OPSUMIT? Serious birth defects. OPSUMIT can cause serious birth defects if taken during pregnancy. Females must not be pregnant when they start taking OPSUMIT or become pregnant during treatment with OPSUMIT. Females who are able to get pregnant must have a negative pregnancy test before beginning treatment with OPSUMIT, each month during treatment with OPSUMIT and 1 month after stopping OPSUMIT. Talk to your healthcare provider about your menstrual cycle. Your healthcare provider will decide when to do the pregnancy test, and will order a pregnancy test for you depending on your menstrual cycle. Females who are able to get pregnant are females who: have entered puberty, even if they have not started their menstrual period, and have a uterus, and have not gone through menopause. Menopause means that you have not had a menstrual period for at least 12 months for natural reasons, or that you have had your ovaries removed. Females who are not able to get pregnant are females who: have not yet entered puberty, or do not have a uterus, or have gone through menopause. Menopause means that you have not had a menstrual period for at least 12 months for natural reasons, or that you have had your ovaries removed, or are infertile for other medical reasons and this infertility is permanent and cannot be reversed. Females who are able to get pregnant must use two acceptable forms of birth control during treatment with OPSUMIT, and for one month after stopping OPSUMIT because the medicine may still be in the body. If you have had a tubal sterilization, have a progesterone implant, or have an IUD (intrauterine device), these methods can be used alone and no other form of birth control is needed. Talk with your healthcare provider or gynecologist (a doctor who specializes in female reproduction) to find out about options for acceptable birth control that you may use to prevent pregnancy during treatment with OPSUMIT. If you decide that you want to change the form of birth control that you use, talk with your healthcare provider or gynecologist to be sure that you choose another acceptable form of birth control. See the chart below for Acceptable Birth Control Options during treatment with OPSUMIT. Do not have unprotected sex. Talk to your healthcare provider or pharmacist right away if you have unprotected sex or if you think your birth control has failed. Your healthcare provider may talk with you about using emergency birth control. Tell your healthcare provider right away if you miss a menstrual period or think you may be pregnant. If you are the parent or caregiver of a female child who started taking OPSUMIT before reaching puberty, you should check your child regularly to see if she is developing signs of puberty. Tell your healthcare provider right away if you notice that she is developing breast buds or any pubic hair. Your healthcare provider should decide if your child has reached puberty. Your child may reach puberty before having her first menstrual period. Females can only receive OPSUMIT through a restricted program called the Macitentan-Containing Products Risk Evaluation and Mitigation Strategy (REMS). If you are a female who can get pregnant, you must talk to your healthcare provider, understand the benefits and risks of OPSUMIT, and agree to all of the instructions in the Macitentan-Containing Products REMS. Males can receive OPSUMIT without taking part in the Macitentan-Containing Products REMS. What is OPSUMIT? OPSUMIT is a prescription medicine used to treat pulmonary arterial hypertension (PAH), which is high blood pressure in the arteries of your lungs. OPSUMIT can improve your ability to exercise, improve some of your symptoms, and help slow down the progression of your disease. OPSUMIT can also lower your chance of being hospitalized for PAH. It is not known if OPSUMIT is safe and effective in children. Who should not take OPSUMIT? Do not take OPSUMIT if you are pregnant, plan to become pregnant, or become pregnant during treatment with OPSUMIT. OPSUMIT can cause serious birth defects (see the Medication Guide section above called " What is the most important information I should know about OPSUMIT? "). Do not take OPSUMIT if you are allergic to macitentan or any of the ingredients in OPSUMIT. See the end of this Medication Guide for a complete list of ingredients in OPSUMIT. Tell your healthcare provider about all your medical conditions and all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. OPSUMIT and other medicines may affect each other causing side effects. Do not start any new medicine until you check with your healthcare provider. Especially tell your healthcare provider if you take an HIV medicine. How should I take OPSUMIT? OPSUMIT will be mailed to you by a specialty pharmacy. Your healthcare provider will give you complete details. Take OPSUMIT exactly as your healthcare provider tells you to take it. Do not stop taking OPSUMIT unless your healthcare provider tells you. You can take OPSUMIT with or without food. If you take too much OPSUMIT, call your healthcare provider or go to the nearest hospital emergency room right away. If you miss a dose of OPSUMIT, take it as soon as you remember that day. Take the next dose at your regular time. Do not take 2 doses at the same time to make up for a missed dose. What should I avoid while taking OPSUMIT? Do not get pregnant while taking OPSUMIT. See the serious birth defects section of the Medication Guide above called " What is the most important information I should know about OPSUMIT? " If you miss a menstrual period, or think you might be pregnant, call your healthcare provider right away. It is not known if OPSUMIT passes into your breastmilk. You should not breastfeed if you take OPSUMIT. Talk to your healthcare provider about the best way to feed your baby if you take OPSUMIT. What are the possible side effects of OPSUMIT? OPSUMIT can cause serious side effects, including: Serious birth defects. See " What is the most important information I should know about OPSUMIT? " Some medicines that are like OPSUMIT can cause liver problems. Your healthcare provider should do blood tests to check your liver before you start taking OPSUMIT. Tell your healthcare provider if you have any of the following symptoms of liver problems while taking OPSUMIT. nausea or vomiting pain in the upper right stomach tiredness loss of appetite yellowing of your skin or whites of your eyes dark urine fever itching Fluid retention can happen within weeks after starting OPSUMIT. Tell your healthcare provider right away if you have any unusual weight gain or swelling of your ankles or legs. Your healthcare provider will look for the cause of any fluid retention. Low red blood cell levels (anemia) can occur with OPSUMIT treatment, usually during the first weeks after starting therapy. In some cases a blood transfusion may be needed, but this is not common. Your healthcare provider will do blood tests to check your red blood cells before starting OPSUMIT. Your healthcare provider may also need to do these tests during treatment with OPSUMIT. Decreased sperm count. OPSUMIT, and other medicines like OPSUMIT, may cause decreased sperm counts in men who take these medicines. A decreased sperm count may affect the ability to father a child. Tell your healthcare provider if being able to have children is important to you. The most common side effects of OPSUMIT are: Stuffy nose or sore throat Irritation of the airways (bronchitis) Headache Flu Urinary tract infection Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of OPSUMIT. For more information, ask your healthcare provider or pharmacist. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store OPSUMIT? Store OPSUMIT tablets at room temperature between 68°F and 77°F (20°C and 25°C). Keep OPSUMIT and all medicines out of the reach of children. General information about OPSUMIT Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use OPSUMIT for a condition for which it was not prescribed. Do not give OPSUMIT to other people, even if they have the same symptoms that you have. It may harm them. This Medication Guide summarizes the most important information about OPSUMIT. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about OPSUMIT that is written for health professionals. For more information, call 1-800-526-7736 (1-800-JANSSEN), or visit www.OPSUMIT.com. What are the ingredients in OPSUMIT? Active ingredient: macitentan Inactive ingredients: lactose monohydrate, magnesium stearate, microcrystalline cellulose, polysorbate 80, povidone, and sodium starch glycolate Type A. The tablets are film-coated with a coating material containing polyvinyl alcohol, soya lecithin, talc, titanium dioxide, and xanthan gum. Manufactured for: Actelion Pharmaceuticals US, Inc., a Janssen Pharmaceutical Company Titusville, NJ 08560, USA For patent information: www.janssenpatents.com © 2013 – 2019 Actelion Pharmaceuticals US, Inc. All rights reserved. Figure
| MEDICATION GUIDE OPSUMIT ® (OP-sum-it) (macitentan) tablets | ||
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| This Medication Guide has been approved by the U.S. Food and Drug Administration. | Revised: 03/2024 | |
| Read this Medication Guide for OPSUMIT before you start taking OPSUMIT and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking with your healthcare provider about your medical condition or your treatment. | ||
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| If you are the parent or caregiver of a female child who started taking OPSUMIT before reaching puberty, you should check your child regularly to see if she is developing signs of puberty. Tell your healthcare provider right away if you notice that she is developing breast buds or any pubic hair. Your healthcare provider should decide if your child has reached puberty. | ||
| Females can only receive OPSUMIT through a restricted program called the Macitentan-Containing Products Risk Evaluation and Mitigation Strategy (REMS). If you are a female who can get pregnant, you must talk to your healthcare provider, understand the benefits and risks of OPSUMIT, and agree to all of the instructions in the Macitentan-Containing Products REMS. | ||
| Males can receive OPSUMIT without taking part in the Macitentan-Containing Products REMS. | ||
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| Especially tell your healthcare provider if you take an HIV medicine. | ||
| OPSUMIT will be mailed to you by a specialty pharmacy. Your healthcare provider will give you complete details. | ||
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| The most common side effects of OPSUMIT are: | ||
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| Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of OPSUMIT. For more information, ask your healthcare provider or pharmacist. | ||
| Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. | ||
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| Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use OPSUMIT for a condition for which it was not prescribed. Do not give OPSUMIT to other people, even if they have the same symptoms that you have. It may harm them. | ||
| This Medication Guide summarizes the most important information about OPSUMIT. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about OPSUMIT that is written for health professionals. For more information, call 1-800-526-7736 (1-800-JANSSEN), or visit www.OPSUMIT.com. | ||
| Manufactured for: Actelion Pharmaceuticals US, Inc., a Janssen Pharmaceutical Company Titusville, NJ 08560, USA For patent information: www.janssenpatents.com © 2013 – 2019 Actelion Pharmaceuticals US, Inc. All rights reserved. | ||
Clinical studies
This field may contain references to clinical studies in place of detailed discussion in other sections of the labeling.14 CLINICAL STUDIES 14.1 Pulmonary Arterial Hypertension The effect of macitentan on progression of PAH was demonstrated in a multi-center, long-term (average duration of exposure approximately 2 years), placebo-controlled study in 742 patients with symptomatic [WHO functional class (FC) II–IV] PAH who were randomized to placebo (n=250), 3 mg macitentan (n=250), or 10 mg macitentan (n=242) once daily. Patients were treated with OPSUMIT monotherapy or in combination with phosphodiesterase-5 inhibitors or inhaled prostanoids. The primary study endpoint was time to the first occurrence of death, a significant morbidity event, defined as atrial septostomy, lung transplantation, initiation of IV or subcutaneous (SC) prostanoids, or "other worsening of PAH" during double-blind treatment plus 7 days. Other worsening was defined as all of the following: 1) a sustained ≥15% decrease from baseline in 6 minute walk distance (6MWD), 2) worsening of PAH symptoms (worsening of WHO FC), and 3) need for additional treatment for PAH. All of these other worsening events were confirmed by an independent adjudication committee, blinded to treatment allocation. A critical secondary endpoint was time to PAH death or PAH hospitalization. The mean patient age was 46 years (14% were age 65 or above). Most patients were white (55%) or Asian (29%) and female (77%). Approximately 52%, 46%, and 2% of patients were in WHO FC II, III, and IV, respectively. Idiopathic or heritable PAH was the most common etiology in the study population (57%) followed by PAH caused by connective tissue disorders (31%), PAH caused by congenital heart disease with repaired shunts (8%), and PAH caused by other etiologies [drugs and toxins (3%) and HIV (1%)]. At baseline, the majority of enrolled patients (64%) were being treated with a stable dose of specific therapy for PAH, either oral phosphodiesterase inhibitors (61%) and/or inhaled/oral prostanoids (6%). Study results are described for the placebo and OPSUMIT 10 mg groups. The median treatment durations were 101 and 118 weeks in the placebo and OPSUMIT 10 mg groups, respectively, up to a maximum of 188 weeks. Treatment with OPSUMIT 10 mg resulted in a 45% reduction (HR 0.55, 97.5% CI 0.39–0.76; logrank p<0.0001) in the occurrence of the primary endpoint up to end of double-blind treatment compared to placebo (Table 3 and Figure 2). The beneficial effect of OPSUMIT 10 mg was primarily attributable to a reduction in clinical worsening events (deterioration in 6MWD and worsening of PAH symptoms and need for additional PAH treatment). Figure 2 Kaplan-Meier Estimates of the Occurrence of the Primary Endpoint Event in the SERAPHIN Study Table 3: Summary of Primary Endpoint Events Placebo N=250 n (%) OPSUMIT 10 mg N=242 n (%) Patients with a primary endpoint event No patients experienced an event of lung transplantation or atrial septostomy in the placebo or OPSUMIT 10 mg treatment groups. 116 (46.4) 76 (31.4) Component as first event Worsening PAH 93 (37.2) 59 (24.4) Death 17 (6.8) 16 (6.6) IV/SC prostanoid 6 (2.4) 1 (0.4) Subgroup analyses were performed to examine their influence on outcome as shown in Figure 3. Consistent efficacy of OPSUMIT 10 mg on the primary endpoint was seen across subgroups of age, sex, race, etiology, by monotherapy or in combination with another PAH therapy, baseline 6MWD, and baseline WHO FC. Figure 3 Subgroup Analysis of the SERAPHIN Study Eo = Number of events OPSUMIT 10 mg; No = Number of patients randomized to OPSUMIT 10 mg Ep = Number of events placebo; Np = Number of patients randomized to placebo PAH related death or hospitalization for PAH was assessed as a secondary endpoint. The risk of PAH related death or hospitalization for PAH was reduced by 50% in patients receiving OPSUMIT 10 mg compared to placebo (HR 0.50, 97.5% CI 0.34–0.75; logrank p<0.0001) (Table 4 and Figure 4). Figure 4 Kaplan-Meier Estimates of the Occurrence of Death due to PAH or Hospitalization for PAH in SERAPHIN Table 4: Summary of Death due to PAH and Hospitalization due to PAH Placebo (N=250) n (%) OPSUMIT 10 mg (N=242) n (%) Death due to PAH or hospitalization for PAH 84 (33.6) 50 (20.7) Component as first event Death due to PAH 5 (2.0) 5 (2.1) Hospitalization for PAH 79 (31.6) 45 (18.6) Treatment with OPSUMIT 10 mg resulted in a placebo-corrected mean increase in 6MWD of 22 meters at Month 6 (97.5% CI 3–41; p=0.0078), with significant improvement in 6MWD by Month 3. 6MWD increased more in patients with worse baseline WHO Functional Class (37 meters and 12 meters placebo-corrected mean increase in WHO FC III/IV and FC I/II, respectively). The increase in 6MWD achieved with OPSUMIT was maintained for the duration of the study. Treatment with OPSUMIT 10 mg led to an improvement of at least one WHO Functional Class at Month 6 in 22% of patients compared to 13% of patients treated with placebo. Figure 2 Figure 3 Figure 4 Long-Term Treatment of PAH In long-term follow-up of patients who were treated with OPSUMIT 10 mg in the placebo-controlled study (N=242) and the open-label extension study, Kaplan-Meier estimates of survival at 1, 2, 5, and 7 years were 95%, 89%, 73%, and 63% respectively. The median exposure to OPSUMIT was 4.6 years. These uncontrolled observations do not allow comparison with a group not given OPSUMIT and cannot be used to determine the long term-effect of OPSUMIT on mortality.
| Placebo N=250 n (%) | OPSUMIT 10 mg N=242 n (%) | |
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| Patients with a primary endpoint event | 116 (46.4) | 76 (31.4) |
| Component as first event | ||
| Worsening PAH | 93 (37.2) | 59 (24.4) |
| Death | 17 (6.8) | 16 (6.6) |
| IV/SC prostanoid | 6 (2.4) | 1 (0.4) |
| Placebo (N=250) n (%) | OPSUMIT 10 mg (N=242) n (%) | |
|---|---|---|
| Death due to PAH or hospitalization for PAH | 84 (33.6) | 50 (20.7) |
| Component as first event | ||
| Death due to PAH | 5 (2.0) | 5 (2.1) |
| Hospitalization for PAH | 79 (31.6) | 45 (18.6) |
Geriatric use
Information about any limitations on any geriatric indications, needs for specific monitoring, hazards associated with use of the drug in the geriatric population.8.5 Geriatric Use Of the total number of subjects in the clinical study of OPSUMIT for PAH, 14% were 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.
Pediatric use
Information about any limitations on any pediatric indications, needs for specific monitoring, hazards associated with use of the drug in any subsets of the pediatric population (such as neonates, infants, children, or adolescents), differences between pediatric and adult responses to the drug, and other information related to the safe and effective pediatric use of the drug.8.4 Pediatric Use The safety and efficacy of OPSUMIT in children have not been established.
Pregnancy
Information about effects the drug may have on pregnant women or on a fetus. This field may be ommitted if the drug is not absorbed systemically and the drug is not known to have a potential for indirect harm to the fetus. It may contain information about the established pregnancy category classification for the drug. (That information is nominally listed in the teratogenic_effects field, but may be listed here instead.)8.1 Pregnancy Risk Summary Based on data from animal reproduction studies, OPSUMIT may cause embryo-fetal toxicity, including birth defects and fetal death, when administered to a pregnant female and is contraindicated during pregnancy. There are risks to the mother and the fetus associated with pulmonary arterial hypertension in pregnancy [see Clinical Considerations ] . There are limited data on OPSUMIT use in pregnant women. Macitentan was teratogenic in rabbits and rats at all doses tested. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the risk to a fetus [see Contraindications (4.1) ] . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. Clinical Considerations Disease-associated Maternal and/or Embryo/Fetal Risk In patients with pulmonary arterial hypertension, pregnancy is associated with an increased rate of maternal and fetal morbidity and mortality, including spontaneous abortion, intrauterine growth restriction and premature labor. Data Animal Data In both rabbits and rats, there were cardiovascular and mandibular arch fusion abnormalities. Administration of macitentan to female rats from late pregnancy through lactation caused reduced pup survival and impairment of the male fertility of the offspring at all dose levels tested.
Use in specific populations
Information about use of the drug by patients in specific populations, including pregnant women and nursing mothers, pediatric patients, and geriatric patients.8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed. ( 8.2 ) 8.1 Pregnancy Risk Summary Based on data from animal reproduction studies, OPSUMIT may cause embryo-fetal toxicity, including birth defects and fetal death, when administered to a pregnant female and is contraindicated during pregnancy. There are risks to the mother and the fetus associated with pulmonary arterial hypertension in pregnancy [see Clinical Considerations ] . There are limited data on OPSUMIT use in pregnant women. Macitentan was teratogenic in rabbits and rats at all doses tested. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the risk to a fetus [see Contraindications (4.1) ] . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. Clinical Considerations Disease-associated Maternal and/or Embryo/Fetal Risk In patients with pulmonary arterial hypertension, pregnancy is associated with an increased rate of maternal and fetal morbidity and mortality, including spontaneous abortion, intrauterine growth restriction and premature labor. Data Animal Data In both rabbits and rats, there were cardiovascular and mandibular arch fusion abnormalities. Administration of macitentan to female rats from late pregnancy through lactation caused reduced pup survival and impairment of the male fertility of the offspring at all dose levels tested. 8.2 Lactation Risk Summary There are no data on the presence of macitentan in human milk, the effects on the breastfed infant, or the effect on milk production. Because of the potential for serious adverse reactions in breastfed infants from OPSUMIT advise women not to breastfeed during treatment with OPSUMIT. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating OPSUMIT, monthly during treatment and one month after stopping treatment with OPSUMIT. The patient should contact her physician immediately for pregnancy testing if onset of menses is delayed or pregnancy is suspected. If the pregnancy test is positive, the physician and patient must discuss the risks to her, the pregnancy, and the fetus [see Warnings and Precautions (5.1) , and Dosage and Administration (2.2) and Contraindication (4.1) ] . Contraception Female patients of reproductive potential must use acceptable methods of contraception during treatment with OPSUMIT and for 1 month after treatment with OPSUMIT. 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 Warnings and Precautions (5.1) ] . Infertility Based on findings in animals, OPSUMIT may impair fertility in males of reproductive potential. It is not known whether effects on fertility would be reversible [see Warnings and Precautions (5.7) , Adverse Reactions (6.1) and Nonclinical Toxicology (13.1) ] . 8.4 Pediatric Use The safety and efficacy of OPSUMIT in children have not been established. 8.5 Geriatric Use Of the total number of subjects in the clinical study of OPSUMIT for PAH, 14% were 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.
How supplied
Information about the available dosage forms to which the labeling applies, and for which the manufacturer or distributor is responsible. This field ordinarily includes the strength of the dosage form (in metric units), the units in which the dosage form is available for prescribing, appropriate information to facilitate identification of the dosage forms (such as shape, color, coating, scoring, and National Drug Code), and special handling and storage condition information.16 HOW SUPPLIED/STORAGE AND HANDLING OPSUMIT ® (macitentan) tablets are 10 mg white, film-coated, bi-convex debossed with "10" on both sides and supplied as follows: 15 count /PVC/ PE/PVDC aluminum foil blisters in carton (NDC 66215-501-15) 30 count white high-density polyethylene bottle in carton (NDC 66215-501-30) Store at 20ºC to 25ºC (68ºF to 77ºF). Excursions are permitted between 15°C and 30°C (59°F and 86°F). [See USP Controlled Room Temperature] . Keep out of reach of children.
Storage and handling
Information about safe storage and handling of the drug product.Store at 20ºC to 25ºC (68ºF to 77ºF). Excursions are permitted between 15°C and 30°C (59°F and 86°F). [See USP Controlled Room Temperature] . Keep out of reach of children.
Boxed warning
Information about contraindications or serious warnings, particularly those that may lead to death or serious injury.WARNING: EMBRYO-FETAL TOXICITY Do not administer OPSUMIT to a pregnant female because it may cause fetal harm [see Contraindications (4.1) , Warnings and Precautions (5.1) , Use in Specific Populations (8.1) ]. Females of reproductive potential: Exclude pregnancy before the start of treatment, monthly during treatment, and 1 month after stopping treatment. Prevent pregnancy during treatment and for one month after stopping treatment by using acceptable methods of contraception [see Pregnancy Testing in Females of Reproductive Potential (2.2) , Use in Specific Populations (8.3) ]. For all female patients, OPSUMIT is available only through a restricted program called the Macitentan-Containing Products Risk Evaluation and Mitigation Strategy (REMS) [see Warnings and Precautions (5.2) ] . WARNING: EMBRYO-FETAL TOXICITY See full prescribing information for complete boxed warning. Do not administer OPSUMIT to a pregnant female because it may cause fetal harm ( 4.1 , 5.1 , 8.1 ). Females of reproductive potential: exclude pregnancy before start of treatment, monthly during treatment, and 1 month after stopping treatment. Prevent pregnancy during treatment and for one month after treatment by using acceptable methods of contraception ( 2.2 , 8.3 ). For all female patients, OPSUMIT is available only through a restricted program called the Macitentan - Containing Products Risk Evaluation and Mitigation Strategy (REMS) ( 5.2 ).
Disclaimer: Do not rely on openFDA or Phanrmacy Near Me to make decisions regarding medical care. While we make every effort to ensure that data is accurate, you should assume all results are unvalidated. Source: OpenFDA, Healthporta Drugs API