Summary Of Exposure |
A) USES: Endothelin receptor antagonists are used for the treatment of pulmonary arterial hypertension (WHO group I) to improve exercise ability and decrease the rate of clinical worsening (primarily evaluated in patients with NYHA class II to IV symptoms).
B) PHARMACOLOGY: Endothelin-1, a neurohormone, is a vasoconstrictor peptide that is produced in the endothelium of blood vessels. Endothelin-1 acts on two receptors, endothelin receptor-A and endothelin receptor-B. The endothelin receptor-A primarily acts on vascular smooth muscle cells and causes vasoconstriction in both large and small blood vessels. Endothelin receptor-B is primarily found in endothelial and vascular smooth muscle cells of the brain, lung, kidney, and aorta, and modulates vasoconstriction by producing vasodilator substances including prostacyclin and nitric oxide.
C) TOXICOLOGY: Overdose causes excessive vasodilation and systemic hypotension.
D) EPIDEMIOLOGY: Overdose is rare.
E) WITH THERAPEUTIC USE
1) ADVERSE EFFECTS: COMMON: AMBRISENTAN: Peripheral edema, nasal congestion, sinusitis, flushing, palpitations, nasopharyngitis, abdominal pain, and constipation. BOSENTAN: Respiratory tract infections, anemia. MACITENTAN: Anemia, nasopharyngitis, bronchitis, headache, influenza, and urinary tract infections.
2) LESS COMMON: Transient hypotension and elevated liver enzymes.
F) WITH POISONING/EXPOSURE
1) TOXICITY: BOSENTAN: An adolescent male experienced nausea, vomiting, hypotension, dizziness, sweating, and blurred vision after an overdose of bosentan 10 g. MACITENTAN: Headaches, nausea, and vomiting were reported following single dose ingestions up to 600 mg (60 times the recommended dose) in healthy subjects.
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Heent |
3.4.5) NOSE
A) WITH THERAPEUTIC USE 1) MACITENTAN: During a placebo-controlled clinical trial of patients with pulmonary arterial hypertension, nasopharyngitis/pharyngitis was reported in 20% of 242 patients receiving macitentan 10 mg orally once daily compared to 13% of 249 patients receiving placebo (Prod Info OPSUMIT(R) oral tablets, 2016).
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Cardiovascular |
3.5.2) CLINICAL EFFECTS
A) HYPOTENSIVE EPISODE 1) WITH THERAPEUTIC USE a) BOSENTAN: Hypotension has been reported in up to 4% of patients with therapeutic use of bosentan (Prod Info TRACLEER(R) oral tablets, 2015).
2) WITH POISONING/EXPOSURE a) BOSENTAN: An adolescent male experienced nausea, vomiting, hypotension, dizziness, sweating, and blurred vision after an overdose of bosentan 10 g (Prod Info TRACLEER(R) oral tablets, 2015). In the cyclosporine A interaction study, concurrent administration of cyclosporine A and bosentan (500 and 1000 mg twice daily) increased bosentan trough plasma levels by about 30-fold; mild decreases in blood pressure, increases in heart rate, severe headache, nausea, and vomiting were reported (Prod Info TRACLEER(R) oral tablets, 2015).
B) ANGINA 1) WITH THERAPEUTIC USE a) BOSENTAN: Angina has been rarely reported in patients receiving bosentan therapy (Galie et al, 2006; Anon, 1999).
C) SINUS TACHYCARDIA 1) WITH POISONING/EXPOSURE a) BOSENTAN: In the cyclosporine A interaction study, concurrent administration of cyclosporine A and bosentan (500 and 1000 mg twice daily) increased bosentan trough plasma levels by about 30-fold; mild decreases in blood pressure, increases in heart rate, severe headache, nausea, and vomiting were reported (Prod Info TRACLEER(R) oral tablets, 2015; Galie et al, 2006).
D) PALPITATIONS 1) WITH THERAPEUTIC USE a) AMBRISENTAN: In two 12-week placebo-controlled trials in patients with pulmonary arterial hypertension (ARIES-1 and ARIES-2), patients were randomized to receive ambrisentan (n=261) 2.5 mg to 10 mg once daily or placebo (n=132). Palpitations occurred in 5% (12 of 261) of patients receiving ambrisentan compared to 2% (3 of 132) of patients receiving placebo (Prod Info LETAIRIS(R) oral tablets, 2010).
b) BOSENTAN: Palpitations were reported in 4% (n=258) of pulmonary arterial hypertension patients receiving bosentan 125 to 250 mg twice daily, compared with 2% (n=172) of placebo-treated patients (Prod Info TRACLEER(R) oral tablets, 2015).
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Respiratory |
3.6.2) CLINICAL EFFECTS
A) BRONCHITIS 1) WITH THERAPEUTIC USE a) MACITENTAN: During a placebo-controlled clinical trial of patients with pulmonary arterial hypertension, bronchitis was reported in 12% of 242 patients receiving macitentan 10 mg orally once daily compared to 6% of 249 patients receiving placebo (Prod Info OPSUMIT(R) oral tablets, 2016).
B) INFLUENZA 1) WITH THERAPEUTIC USE a) MACITENTAN: During a placebo-controlled clinical trial of patients with pulmonary arterial hypertension, influenza was reported in 6% of 242 patients receiving macitentan 10 mg orally once daily compared to 2% of 249 patients receiving placebo (Prod Info OPSUMIT(R) oral tablets, 2016).
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Neurologic |
3.7.2) CLINICAL EFFECTS
A) HEADACHE 1) WITH THERAPEUTIC USE a) AMBRISENTAN 1) In two 12-week placebo-controlled trials in patients with pulmonary arterial hypertension (ARIES-1 and ARIES-2), patients were randomized to receive ambrisentan (n=261) 2.5 mg to 10 mg once daily or placebo (n=132). Headache occurred in 15% (38 of 261) of patients receiving ambrisentan compared with 14% (18 of 132) of patients receiving placebo (Prod Info LETAIRIS(R) oral tablets, 2010).
b) BOSENTAN 1) Headache has been frequently reported with bosentan therapy, particularly with oral doses greater than 300 mg and intravenous doses greater than 250 mg (Binet et al, 2000; Anon, 1999; Weber et al, 1999a; Sutsch et al, 1998; Weber et al, 1996).
2) INCIDENCE: During a bosentan clinical efficacy trial, headache occurred in 24% of patients who received bosentan orally at a dose of 2000 mg daily (n=50) as compared to 18% of patients (n=49) who received placebo (Krum et al, 1998). In a multicentric, double-blind, randomized, placebo-controlled study, 14% of bosentan group experienced headache compared with 12% of the placebo group (Galie et al, 2006).
c) MACITENTAN 1) During a placebo-controlled clinical trial of patients with pulmonary arterial hypertension, headache was reported in 14% of 242 patients receiving macitentan 10 mg orally once daily compared to 9% of 249 patients receiving placebo (Prod Info OPSUMIT(R) oral tablets, 2016).
d) SITAXSENTAN 1) Headache was reported in 45% of sitaxsentan 100 mg/day treated patients, 46% of sitaxsentan 300 mg/day treated patients, and 34% of placebo-treated patients, in a double-blind, multicenter, randomized, 12-week trial in patients with symptomatic pulmonary arterial hypertension (n=178) (Barst et al, 2004).
2) WITH POISONING/EXPOSURE a) BOSENTAN 1) An adolescent male experienced nausea, vomiting, hypotension, dizziness, sweating, and blurred vision after an overdose of bosentan 10 g (Prod Info TRACLEER(R) oral tablets, 2015). In studies, no major adverse events were reported when normal volunteers were given a single dose of up to 2400 mg of bosentan or patients were given up to 2000 mg/day for 2 months. Mild to moderate headache was the most common side effect (Prod Info TRACLEER(R) oral tablets, 2015).
2) In the cyclosporine A interaction study, concurrent administration of cyclosporine A and bosentan (500 and 1000 mg twice daily) increased bosentan trough plasma levels by about 30-fold; mild decreases in blood pressure, increases in heart rate, severe headache, nausea, and vomiting were reported in patients (Prod Info TRACLEER(R) oral tablets, 2015).
b) MACITENTAN 1) Headaches, nausea, and vomiting were reported following single dose ingestions up to 600 mg (60 times the recommended dose) in healthy subjects (Prod Info OPSUMIT(R) oral tablets, 2016).
B) DIZZINESS 1) WITH THERAPEUTIC USE a) BOSENTAN 1) Dizziness was reported in several patients who received bosentan during a randomized placebo-controlled clinical trial (Galie et al, 2006; Anon, 1999; Sutsch et al, 1998).
b) SITAXSENTAN 1) Dizziness was reported in 14% of sitaxsentan 100 mg/day treated patients, 10% of sitaxsentan 300 mg/day treated patients, and 10% of placebo-treated patients, in a double-blind, multicenter, randomized, 12-week, trial in patients with symptomatic pulmonary arterial hypertension (n=178) (Barst et al, 2004).
2) WITH POISONING/EXPOSURE a) BOSENTAN: An adolescent male experienced nausea, vomiting, hypotension, dizziness, sweating, and blurred vision after an overdose of bosentan 10 g (Prod Info TRACLEER(R) oral tablets, 2015).
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Gastrointestinal |
3.8.2) CLINICAL EFFECTS
A) NAUSEA AND VOMITING 1) WITH THERAPEUTIC USE a) BOSENTAN 1) Nausea and vomiting were reported with oral bosentan administration of 1000 mg daily (Binet et al, 2000) and with intravenous administration of bosentan at doses of 500 mg and 750 mg (Anon, 1999; Weber et al, 1996).
b) SITAXSENTAN 1) Nausea was reported in 23% of sitaxsentan 100 mg/day treated patients, 18% of sitaxsentan 300 mg/day treated patients, and 19% of placebo-treated patients, in a double-blind, multicenter, randomized, 12-week trial in patients with symptomatic pulmonary arterial hypertension (n=178) (Barst et al, 2004).
2) WITH POISONING/EXPOSURE a) BOSENTAN: An adolescent male experienced nausea, vomiting, hypotension, dizziness, sweating, and blurred vision after an overdose of bosentan 10 g (Prod Info TRACLEER(R) oral tablets, 2015). In the cyclosporine A interaction study, concurrent administration of cyclosporine A and bosentan (500 and 1000 mg twice daily) increased bosentan trough plasma levels by about 30-fold; mild decreases in blood pressure, increases in heart rate, severe headache, nausea, and vomiting were reported (Prod Info TRACLEER(R) oral tablets, 2015).
b) MACITENTAN: Headaches, nausea, and vomiting were reported following single dose ingestions up to 600 mg (60 times the recommended dose) in healthy subjects (Prod Info OPSUMIT(R) oral tablets, 2016).
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Hepatic |
3.9.2) CLINICAL EFFECTS
A) ABNORMAL LIVER FUNCTION 1) WITH THERAPEUTIC USE a) AMBRISENTAN 1) INCIDENCE: Elevations in aminotransferases by more than 3 times the upper limit of normal (ULN) occurred in 0.8% of ambrisentan-treated patients and by more than 8 times the ULN in 0.2% of ambrisentan-treated patients in two 12-week placebo-controlled trials, compared with 2.3% and 0% in patients receiving placebo, respectively. Aminotransferase levels increased by more than 3 times ULN and 8 times ULN in 2.8% and 0.5% of patients in long-term open-label trials (1 year), respectively. Serious hepatotoxicity has been reported with related drugs (Prod Info LETAIRIS(R) oral tablets, 2010).
b) BOSENTAN 1) Asymptomatic elevations of hepatic enzymes have been reported following therapeutic administration of bosentan (Anon, 1999; Krum et al, 1998) and were reversible upon cessation of therapy.
2) Bosentan caused elevations of liver aminotransferases (ALT and AST) of more than 3 times the upper limit of normal (ULN) in 11% of patients (n=658) and in 2% of placebo patients (n=280). An elevation of bilirubin of more than 3 times the ULN occurred in 0.3% (2 of 658) bosentan-treated patients. Unexplained hepatic cirrhosis has been reported rarely during postmarketing after more than 12 months of bosentan use by patients who had multiple comorbidities and drug therapies. Elevations of liver enzymes during bosentan therapy are dose-dependent, occur both early and later in treatment, usually progress slowly, are typically asymptomatic, and usually are reversible after treatment interruption or cessation. Elevations in aminotransferases and bilirubin levels with nonspecific symptoms were observed in at least one case after longer than 20 months of treatment; all symptoms resolved slowly over time after the cessation of bosentan treatment (Prod Info TRACLEER(R) oral tablets, 2015).
c) SITAXSENTAN 1) Reversible, dose-related increases in aspartate aminotransferase and alanine aminotransferase sometimes accompanied with elevated bilirubin have been associated with sitaxsentan use, especially in patients receiving doses greater than 100 mg once daily (Encysive Pharmaceuticals, 2007).
2) A greater than 3 times the upper limit of normal (ULN) of aminotransferase was reported in 0% of sitaxsentan 100 mg/day treated patients, 10% of sitaxsentan 300 mg/day treated patients, and 3% of placebo-treated patients, in a double-blind, multicenter, randomized, 12-week trial in patients with symptomatic pulmonary arterial hypertension (n=178). All cases resolved. At 6 months, the cumulative risk of an aminotransferase value more than 3 times the ULN was 8% for the 100 mg group, 26% for the 300 mg group. At 9 months, the risk was 8% and 32%, respectively (Barst et al, 2004). There were no liver function abnormalities in 10 patients who received sitaxsentan 100 mg/day for 1 year in an open-label study (Langleben et al, 2004).
B) TOXIC HEPATITIS 1) WITH THERAPEUTIC USE a) SITAXSENTAN 1) Four cases of mild to severe hepatitis, with one case resulting in hepatic failure and death, has been associated with sitaxsentan use. Doses of 300 mg or more once daily may have been a contributing factor along with multiple comorbidities (Encysive Pharmaceuticals, 2007). 2) There were 2 cases of acute hepatitis, which was fatal in one patient, during an open-label pilot study after 12 to 18 weeks of oral sitaxsentan 500 mg twice daily (n=20) (Barst et al, 2002). a) For one of the patients, at week 6, the following hepatic enzyme levels were noted: AST 58 units/liter (U/L), ALT 28 U/L, GGTP 60 U/L, alk phos 72 U/L, total bilirubin 0.5 U/L. At week 12, the dose was reduced but transaminases continued to rise. At week 19, the transaminase levels peaked (AST 1306 U/L, ALT 1041 U/L) and sitaxsentan was discontinued. Acute fulminant hepatitis with central-to-bridging necrosis was demonstrated on liver biopsy. The patient subsequently died.
b) In the other patient who experienced transient and mildly elevated transaminases the following values were noted AST, 50 U/L; ALT, 17 U/L; GGTP, 58 U/L; alk phos, 96 U/L; total bilirubin 0.3 mg/dL, at week 6. The values continued to rise and were highest at week 18 (AST, 1080 U/L; ALT, 37 U/L; GGTP, not determined; alk phos, 620 U/L; and total bilirubin, 7 mg/dL) at which time sitaxsentan was discontinued. Acute hepatitis was demonstrated on liver biopsy. The values gradually decreased and were within normal limits 12 weeks after discontinuation of sitaxsentan.
C) CIRRHOSIS OF LIVER 1) WITH THERAPEUTIC USE a) BOSENTAN/CHRONIC: Postmarketing surveillance has reported the rare occurrence of hepatic cirrhosis following prolonged (longer than 12 months) bosentan therapy in patients with multiple comorbidities and on multiple drug therapies (Prod Info TRACLEER(R) oral tablets, 2015).
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Genitourinary |
3.10.2) CLINICAL EFFECTS
A) URINARY TRACT INFECTIOUS DISEASE 1) WITH THERAPEUTIC USE a) MACITENTAN: During a placebo-controlled clinical trial of patients with pulmonary arterial hypertension, urinary tract infection was reported in 9% of 242 patients receiving macitentan 10 mg orally once daily compared to 6% of 249 patients receiving placebo (Prod Info OPSUMIT(R) oral tablets, 2016).
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Hematologic |
3.13.2) CLINICAL EFFECTS
A) DECREASED HEMOGLOBIN 1) WITH THERAPEUTIC USE a) AMBRISENTAN: In patients with pulmonary arterial hypertension, marked decreases in hemoglobin (greater than 15% decrease from baseline) occurred in 7% of ambrisentan-treated subjects (10% of patients receiving 10 mg) compared with 4% of placebo-treated subjects. In 12-week placebo-controlled studies, decreases in hemoglobin were observed within the first few weeks of treatment (Prod Info ambrisentan oral tablets, 2015).
B) ANEMIA 1) WITH THERAPEUTIC USE a) MACITENTAN: During a placebo-controlled clinical trial of patients with pulmonary arterial hypertension, anemia was reported in 13% of 242 patients receiving macitentan 10 mg orally once daily compared to 3% of 249 patients receiving placebo (Prod Info OPSUMIT(R) oral tablets, 2016).
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Dermatologic |
3.14.2) CLINICAL EFFECTS
A) FLUSHING 1) WITH THERAPEUTIC USE a) BOSENTAN/INCIDENCE: In a clinical efficacy trial, flushing was reported in 18% of patients who received 2000 mg daily of bosentan (n=50), as compared with 4% of patients who received placebo (n=49) (Krum et al, 1998).
b) AMBRISENTAN: In two 12-week placebo-controlled trials in patients with pulmonary arterial hypertension (ARIES-1 and ARIES-2), patients were randomized to receive ambrisentan (n=261) 2.5 mg to 10 mg once daily or placebo (n=132). Flushing occurred in 4% (10 of 261) of patients receiving ambrisentan compared with 1% (1 of 132) of patients receiving placebo (Prod Info ambrisentan oral tablets, 2015).
B) PERIPHERAL EDEMA 1) WITH THERAPEUTIC USE a) AMBRISENTAN 1) In two 12-week placebo-controlled trials in patients with pulmonary arterial hypertension (ARIES-1 and ARIES-2), patients were randomized to receive ambrisentan (n=261) 2.5 mg to 10 mg once daily or placebo (n=132). Peripheral edema occurred in 17% (45 of 261) of patients receiving ambrisentan compared with 11% (14 of 132) of patients receiving placebo (Prod Info ambrisentan oral tablets, 2015).
b) BOSENTAN 1) INCIDENCE: In a clinical efficacy trial, leg edema was reported in 14% of patients who received 2000 mg daily of bosentan (n=50), as compared with 0% of patients who received placebo (n=49) (Krum et al, 1998). In a multicentric, double-blind, randomized, placebo-controlled study, 19% of the bosentan group experienced peripheral edema compared with 9% of the placebo group (Galie et al, 2006).
c) SITAXSENTAN 1) Peripheral edema was reported in 16% of sitaxsentan 100 mg/day treated patients, 25% of sitaxsentan 300 mg/day treated patients, and 17% of placebo-treated patients, in a double-blind, multicenter, randomized, 12-week trial in patients with symptomatic pulmonary arterial hypertension (n=178) (Barst et al, 2004).
C) ANGIOEDEMA 1) WITH THERAPEUTIC USE a) BOSENTAN: Postmarketing surveillance has reported the occurrence of angioneurotic edema with bosentan therapy. Onset of symptoms occurred within 8 hours to 21 days after initiating therapy. In some patients, resolution of the angioedema occurred following treatment with an antihistamine and without discontinuing bosentan therapy (Prod Info TRACLEER(R) oral tablets, 2015).
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Reproductive |
3.20.1) SUMMARY
A) Ambrisentan, bosentan, macitentan, and sitaxentan are classified as FDA pregnancy category X. Teratogenicity is considered a class effect of endothelin receptor antagonists because similar malformations have been observed in animals treated with these drugs. Lactation studies have not been conducted in humans; however, animal lactation studies with ambrisentan and sitaxentan have resulted in reduced numbers of implantations, reduced pup survival, testicular tubular aplasia or atrophy, and delayed postnatal development. Testicular tubular atrophy and impaired fertility that appear to be irreversible have been associated with chronic administration of endothelin receptor antagonists in rodents.
3.20.2) TERATOGENICITY
A) LACK OF INFORMATION 1) At the time of this review no data were available to assess the potential effects of exposure to endothelin receptor antagonists during pregnancy in humans (Prod Info OPSUMIT(R) oral tablets, 2013; Prod Info LETAIRIS(R) oral tablets, 2012; Prod Info TRACLEER(R) film-coated oral tablets, 2007; Prod Info THELIN(R) Australia oral tablets, 2008).
B) ANIMAL STUDIES 1) Because similar malformations have been observed in animals treated with endothelin receptor antagonists, teratogenicity is considered a class effect of these drugs (Prod Info OPSUMIT(R) oral tablets, 2013; Prod Info LETAIRIS(R) oral tablets, 2012; Prod Info TRACLEER(R) film-coated oral tablets, 2007; Prod Info THELIN(R) Australia oral tablets, 2008).
2) AMBRISENTAN: In animal studies, ambrisentan was teratogenic at oral doses of 7 mg/kg/day or higher in rabbits and 15 mg/kg/day or higher in rats (1.7 and 3.5 times the human dose of 10 mg/day, respectively). Fetal effects included abnormalities of the lower jaw and hard and soft palate, malformation of the heart and great vessels, and failure of formation of the thymus and thyroid (Prod Info Letairis(R) oral tablets, 2013).
3) BOSENTAN: During animal studies, teratogenic effects, including malformation of the head, mouth, face, and large blood vessels, were reported with administration of oral bosentan at doses 2 times the maximum recommended human dose (MRHD). Increases in stillbirth and offspring mortality were reported with bosentan doses up to 10 times the MRHD (Prod Info TRACLEER(R) oral tablets, 2015).
4) MACITENTAN: In animal studies, macitentan was embryotoxic, resulting in reduced pup survival and impaired male fertility of the offspring at all doses tested in female rats administered macitentan from late pregnancy through lactation. Teratogenic effects, including cardiovascular and mandibular arch fusion abnormalities, were observed in rats and rabbits at all doses tested. A no-effect dose level was not determined for either species (Prod Info OPSUMIT(R) oral tablets, 2013).
5) SITAXENTAN: In a rat embryo-fetal development study, teratogenicity was observed with twice-daily doses of 40 and 80 mg/kg and once-daily doses of 120 mg/kg of sitaxentan. These doses approximated exposures that were greater than 90 times the human exposure in patients with pulmonary arterial hypertension treated with 100 mg/day. Major fetal effects included craniofacial, heart (septal defects), and large vessel (retroesophageal aortic arch) malformations. Based on these data, sitaxentan is likely to cause birth defects when administered to pregnant women (Prod Info THELIN(R) Australia oral tablets, 2008).
3.20.3) EFFECTS IN PREGNANCY
A) PREGNANCY CATEGORY 1) The manufacturer has classified AMBRISENTAN, BOSENTAN, MACITENTAN, AND SITAXENTAN as FDA pregnancy category X (Prod Info TRACLEER(R) oral tablets, 2015; Prod Info OPSUMIT(R) oral tablets, 2013; Prod Info LETAIRIS(R) oral tablets, 2012; Prod Info THELIN(R) Australia oral tablets, 2008).
2) AMBRISENTAN: Ambrisentan use is contraindicated in women who are or may become pregnant. Although there are no data in pregnant women, as teratogenicity is a class effect with endothelin receptor antagonists, ambrisentan use during pregnancy may cause fetal harm. Access to ambrisentan is restricted under a risk evaluation and mitigation strategy (REMS) to prescribers, patients, and pharmacies enrolled in the LETAIRIS REMS. Prior to initiation of ambrisentan, pregnancy must be excluded. Pregnancy must be prevented with the use of highly reliable methods of contraception after initiation of therapy until for one month after treatment discontinuation. Certified pharmacies must confirm each time that ambrisentan is dispensed that monthly pregnancy tests have been completed in women of childbearing potential. However, if ambrisentan is used during pregnancy or if a patient becomes pregnant while receiving therapy or within 30 days of treatment discontinuation, apprise the patient of the potential hazard to the fetus. More information about LEAP is available at 1-866-664-5327 or www.letairisrems.com (Prod Info Letairis(R) oral tablets, 2013).
3) MACITENTAN is contraindicated during pregnancy. While there are no adequate and well-controlled studies of macitentan in pregnant women, animal studies indicate that macitentan causes fetal harm when administered during pregnancy. Teratogenic effects were consistently observed with administration in pregnant rats and rabbits at all doses tested. Therefore, if the drug is used during pregnancy or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus. Pregnancy should be excluded before starting treatment, monthly during treatment, and 1 month after discontinuing treatment. Additionally, women of childbearing potential are advised to use effective contraceptive measures to avoid becoming pregnant while undergoing treatment with macitentan and for 1 month after treatment (Prod Info OPSUMIT(R) oral tablets, 2013).
B) PREGNANCY TESTING 1) BOSENTAN a) Female patients of reproductive potential must have a negative pregnancy test prior to initiation of treatment. Obtain a pregnancy test during the first 5 days of a normal menstrual period and at least 11 days after the last unprotected act of sexual intercourse (Prod Info TRACLEER(R) oral tablets, 2015).
b) Obtain follow-up serum or urine pregnancy tests monthly (Prod Info TRACLEER(R) oral tablets, 2015).
C) CONTRACEPTION 1) BOSENTAN a) Hormonal contraceptives may be less effective at preventing pregnancy and should not be used as the only contraceptive method (Prod Info TRACLEER(R) oral tablets, 2015).
b) Female patients of reproductive potential must use adequate contraceptive measures, including intrauterine devices, tubal sterilization, or a combination of methods (eg, hormonal contraceptive with a barrier method, 2 barrier methods), during treatment and for at least one month after discontinuation (Prod Info TRACLEER(R) oral tablets, 2015).
D) ANIMAL STUDIES 1) AMBRISENTAN: A preclinical study showed decreased survival of newborn rat pups, and effects on testicle size and fertility of pups, at mid and high doses, following treatment with ambrisentan at doses up to 170 times the maximum oral human dose from late gestation through weaning (Prod Info Letairis(R) oral tablets, 2013).
3.20.4) EFFECTS DURING BREAST-FEEDING
A) LACK OF INFORMATION 1) At the time of this review, no data were available to assess the potential effects of exposure to endothelin receptor antagonists during lactation in humans (Prod Info TRACLEER(R) oral tablets, 2015; Prod Info Letairis(R) oral tablets, 2013; Prod Info OPSUMIT(R) oral tablets, 2013; Prod Info THELIN(R) Australia oral tablets, 2008).
B) BREAST MILK 1) BOSENTAN a) Discontinue treatment or discontinue nursing taking into account the importance of the drug to the mother (Prod Info TRACLEER(R) oral tablets, 2015).
C) ANIMAL STUDIES 1) AMBRISENTAN: In a preclinical study in rats, maternal administration of mid to high doses (51 times and 171 times, respectively, the maximum recommended oral human dose of 10 mg) of ambrisentan from late gestation through weaning resulted in decreased survival of newborn pups. Additionally, effects on testicle size and fertility of pups were evident at the high maternal ambrisentan dose (Prod Info LETAIRIS(R) oral tablets, 2012).
2) BOSENTAN: Lactation studies of bosentan exposure in animals have not been conducted (Prod Info THELIN(R) Australia oral tablets, 2008).
3) MACITENTAN: Macitentan and its metabolites are excreted in the milk of lactating rats. Because many drugs are excreted into human milk and because the potential for serious toxicity from macitentan in a nursing infant exists, it is recommended to either discontinue nursing or the drug (Prod Info OPSUMIT(R) oral tablets, 2013).
4) SITAXENTAN: In rat studies, doses of sitaxentan 20 mg/kg twice daily (ie, maternal exposure greater than 90 times the human exposure with a 100 mg/day dose) given from late pregnancy until the end of lactation led to reduced numbers of implantations, reduced pup survival, testicular tubular aplasia or atrophy, and delayed postnatal development (Prod Info THELIN(R) Australia oral tablets, 2008).
3.20.5) FERTILITY
A) LACK OF INFORMATION 1) At the time of this review no human data were available to assess the potential effects on fertility from exposure to ambrisentan, bosentan, or macitentan (Prod Info Letairis(R) oral tablets, 2013; Prod Info OPSUMIT(R) oral tablets, 2013; Prod Info TRACLEER(R) film-coated oral tablets, 2007).
B) LACK OF EFFECT 1) SITAXENTAN: In clinical trials of a limited number of patients treated with sitaxentan for pulmonary arterial hypertension, there was no effect on male reproductive hormones (FSH, LH, testosterone, and inhibin) or on sperm morphology, concentration or motility (Prod Info THELIN(R) Australia oral tablets, 2008).
C) ANIMAL STUDIES 1) Testicular tubular atrophy and impaired fertility have been associated with chronic administration of endothelin receptor antagonists in animals (Prod Info TRACLEER(R) oral tablets, 2015; Prod Info OPSUMIT(R) oral tablets, 2013; Prod Info LETAIRIS(R) oral tablets, 2012; Prod Info THELIN(R) Australia oral tablets, 2008).
2) AMBRISENTAN: Testicular tubular degeneration was observed in rats exposed to ambrisentan doses of 10 mg/kg/day or greater (8-fold the maximum recommended human dose (MRHD)). Testicular findings were also reported with increased frequency in mice exposed to 50 mg/kg/day or greater (28-fold the MRHD). In male rat fertility studies, effects on sperm count, sperm morphology, mating performance, and fertility were observed in fertility studies when male rats were treated with oral ambrisentan doses of 300 mg/kg/day (236-fold the MRHD). Testicular histopathology in the absence of fertility and sperm effects were observed at doses of greater than or equal to 10 mg/kg/day (Prod Info Letairis(R) oral tablets, 2013).
3) BOSENTAN: No effects on sperm count, sperm motility, mating performance, or fertility were reported in animals administered bosentan at doses up to 50 times the maximum recommended human dose (MRHD). An increased incidence of testicular tubular atrophy was reported with oral bosentan doses as low as 4 times the MRHD (Prod Info TRACLEER(R) oral tablets, 2015).
4) MACITENTAN: Testicular tubular atrophy was observed in juvenile rats administered macitentan from postnatal Day 4 to Day 114 at exposures 7-fold the human exposure; however, fertility was not affected. Reversible testicular tubular dilatation was noted in chronic toxicity studies of rats and dogs at exposures greater than 7-fold and 23-fold, respectively, the human exposure. Tubular atrophy was seen in rats after 2 years of treatment at 4-fold the human exposure. No effect on female or male fertility, including sperm count, motility, or morphology, was observed in rats at exposures ranging from 19-fold (in males) to 44-fold (in females) the human exposure. No testicular findings were noted in mice following 2 years of treatment (Prod Info OPSUMIT(R) oral tablets, 2013).
5) SITAXENTAN: Testicular atrophy was observed at increased frequency in rats; no increased frequency was evident in mice or dogs. However, rat sperm morphology was not effected, and rat fertility was not affected by sitaxentan doses up to 124 times in males or 198 times in females the human dose of 100 mg/day (Prod Info THELIN(R) Australia oral tablets, 2008).
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Carcinogenicity |
3.21.2) SUMMARY/HUMAN
A) At the time of this review, the manufacturer does not report any carcinogenic potential in humans for ambrisentan, bosentan, macitentan, or sitaxentan.
3.21.4) ANIMAL STUDIES
A) AMBRISENTAN 1) A positive trend for the combined incidence of benign basal cell tumor and basal cell carcinoma of skin/subcutis in the mid-dose group, as well as the occurrence of mammary fibroadenomas at the highest dose of 60 mg/kg/day (48 times the maximum recommended human dose on a mg/m(2) basis), were observed in male rats administered oral ambrisentan in a 2-year carcinogenicity study. Due to effects on survival, the highest dose was reduced to 40 mg/kg/day in week 51 and was completely discontinued in week 69 for males and week 93 for females in this study (Prod Info Letairis(R) oral tablets, 2013).
B) BOSENTAN 1) An increased incidence of hepatocellular adenomas and carcinomas was observed in male mice administered bosentan at doses of 450 mg/kg/day (about 8 times the maximum recommended human dose (MRHD) of 125 mg twice daily on a mg/m(2) basis) or greater and increased incidence of colon adenomas was observed in male and female mice given doses greater than 2000 mg/kg/day (about 32 times the MRHD) in a 2-year dietary study. An increased incidence of brain astrocytomas was seen in male rats administered doses of 500 mg/kg/day (about 16 times the MRHD) or greater for 2 years in the diet (Prod Info TRACLEER(R) oral tablets, 2012).
C) LACK OF EFFECT 1) AMBRISENTAN a) Ambrisentan was not associated with excess tumors in mice administered oral doses of 50, 150, and 250 mg/kg/day (28 to 140 times the maximum recommended human dose on a mg/m(2) basis) in a 2-year carcinogenicity study. The highest dose was reduced to 150 mg/kg/day in week 39 and was completely discontinued in week 96 for males and week 76 for females in mice administered the highest dose in this study (Prod Info Letairis(R) oral tablets, 2013).
2) MACITENTAN a) No carcinogenic potential was observed in male and female mice administered macitentan doses resulting in exposures of 75- and 140-fold, respectively, the human exposure based on AUC in a 2-year carcinogenicity study. Likewise, there was no carcinogenic potential for male and female rats given doses resulting in 8.3- and 42-fold, respectively, the human exposure based on AUC in a 2-year carcinogenicity study (Prod Info OPSUMIT(R) oral tablets, 2013).
3) SITAXENTAN a) No carcinogenic potential was observed in rats administered sitaxentan for 91 to 95 weeks at doses resulting in exposures (AUC) that were greater than 90 times the exposure at the recommended human dose for pulmonary arterial hypertension of 100 mg once daily. Likewise, there was no carcinogenic potential for p53(+/-) transgenic mice administered doses for 6 months that were approximately 70 times the exposure at the recommended human dose (Prod Info THELIN(R) Australia oral tablets, 2008).
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Genotoxicity |
A) AMBRISENTAN: Positive results were observed for clastogenicity of ambrisentan at drug concentrations resulting in moderate to high toxicity in the chromosome aberration assay using cultured human lymphocytes. There was no evidence of genotoxicity in the following tests: in vitro bacterial (Ames) test, in vivo micronucleus assay in rats, or in vivo unscheduled DNA synthesis assay in rats (Prod Info Letairis(R) oral tablets, 2013).
B) BOSENTAN: There was no evidence of clastogenicity or mutagenicity for bosentan in the following tests: the in vitro microbial mutagenesis assay, the in vitro unscheduled DNA synthesis assay, the in vitro V-79 mammalian cell mutagenesis assay, the in vitro human lymphocyte assay, and the in vivo mouse micronucleus assay (Prod Info TRACLEER(R) oral tablets, 2012).
C) MACITENTAN: There was no evidence of genotoxicity or mutagenicity for macitentan in the following tests: 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 (Prod Info OPSUMIT(R) oral tablets, 2013).
D) SITAXENTAN: Positive results were observed for clastogenicity of sitaxentan at high concentrations (greater than 158 mcg/mL) in the in vitro chromosome aberration assay. An equivocal response was observed in an in vitro gene mutation assay in mouse L5178Y cells. There was no evidence of genotoxicity or mutagenicity in the following tests: in vivo micronucleus assay in mice at up to a lethal dose and the in vitro bacterial assay for gene mutation (Prod Info THELIN(R) Australia oral tablets, 2008).
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