BOSENTAN tablet, film coated

Երկիր: Ամերիկայի Միացյալ Նահանգներ

Լեզու: անգլերեն

Աղբյուրը: NLM (National Library of Medicine)

Ակտիվ բաղադրիչ:

BOSENTAN (UNII: Q326023R30) (BOSENTAN ANHYDROUS - UNII:XUL93R30K2)

Հասանելի է:

Actavis Pharma, Inc.

Կառավարման երթուղին:

ORAL

Ռեկվիզորի տեսակը:

PRESCRIPTION DRUG

Թերապեւտիկ ցուցումներ:

Bosentan tablets are indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1): - in adults to improve exercise ability and to decrease clinical worsening. Studies establishing effectiveness included predominantly patients with WHO Functional Class II-IV symptoms and etiologies of idiopathic or heritable PAH (60%), PAH associated with connective tissue diseases (21%), and PAH associated with congenital heart disease with left-to-right shunts (18%) [see Clinical Studies (14.1)] . - in pediatric patients aged 3 years and older with idiopathic or congenital PAH to improve pulmonary vascular resistance (PVR), which is expected to result in an improvement in exercise ability. Use of bosentan is contraindicated in females who are or may become pregnant. To prevent pregnancy, females of reproductive potential must use two reliable forms of contraception during treatment and for one month after stopping bosentan [see Boxed Warning, Warnings and Precautions (5.2), Drug Interactions (7.2), Use in Specific Populations (8.1)] . Coadministration of cyclosporine A and bosentan resulted in markedly increased plasma concentrations of bosentan. Therefore, concomitant use of bosentan and cyclosporine A is contraindicated [see Cytochrome P450  Drug Interactions (7.1)] . An increased risk of liver enzyme elevations was observed in patients receiving glyburide concomitantly with bosentan. Therefore coadministration of glyburide and bosentan is contraindicated [see Cytochrome P450  Drug Interactions (7.1)] . Bosentan is contraindicated in patients who are hypersensitive to bosentan or any component of the product. Observed reactions include Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), anaphylaxis, rash, and angioedema [see Adverse Reactions (6.2), Description (11)] . Risk Summary Based on data from animal reproduction studies, bosentan may cause fetal harm, including birth defects and fetal death, when administered to a pregnant female and is contraindicated during pregnancy [see Contraindications (4.1)] . There are limited data on bosentan use in pregnant women. In animal reproduction studies, oral administration of bosentan to pregnant rats at 2-times the maximum recommended human dose (MRHD) on a mg/m2 basis caused teratogenic effects in rats, including malformations of the head, mouth, face, and large blood vessels [see Animal Data] . Advise pregnant women of the potential risk to a fetus. 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% to 4% and 15% to 20%, respectively. Data Animal Data Bosentan was teratogenic in rats given oral doses two times the MRHD (on a mg/m2 basis). In an embryo-fetal toxicity study in rats, bosentan showed dose-dependent teratogenic effects, including malformations of the head, mouth, face and large blood vessels. Bosentan increased stillbirths and pup mortality at oral doses 2 and 10 times the MRHD (on a mg/m2 basis). Although birth defects were not observed in rabbits given oral doses of up to the equivalent of 10.5 g/day in a 70 kg person, plasma concentrations of bosentan in rabbits were lower than those reached in the rat. The similarity of malformations induced by bosentan and those observed in endothelin-1 knockout mice and in animals treated with other endothelin receptor antagonists indicates that embryo-fetal toxicity is a class effect of these drugs. Risk Summary Data from a case report describe the presence of bosentan in human milk. There is insufficient information about the effects of bosentan on the breastfed infant and no information on the effects of bosentan on milk production. Because of the potential for serious adverse reactions, such as fluid retention and hepatotoxicity, in breastfed infants from bosentan, advise women not to breastfeed during treatment with bosentan. Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating bosentan, monthly during treatment and one month after stopping treatment with bosentan. 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. Contraception Drug interaction studies show that bosentan reduces serum levels of the estrogen and progestin in oral contraceptives. Based on these findings, hormonal contraceptives (including oral, injectable, transdermal, and implantable contraceptives) may be less effective for preventing pregnancy in patients using bosentan and should not be used as a patient’s only contraceptive method [see Drug Interactions (7.2)] . Females of reproductive potential using bosentan must use two acceptable methods of contraception during treatment and for 1 month after treatment with bosentan. Patients may choose one highly effective form of contraception (intrauterine devices (IUD) or tubal sterilization) or a combination of methods (hormone method with a barrier method or two barrier methods). If a partner’s vasectomy is the chosen method of contraception, a hormone or barrier method must be used along with this method. Counsel patients on pregnancy planning and prevention, including emergency contraception, or designate counseling by another healthcare provider trained in contraceptive counseling [see Boxed Warning] . Infertility Males Decreased sperm counts have been observed in patients receiving bosentan. Based on these findings and findings in animals, bosentan may impair fertility in males of reproductive potential. It is not known whether effects on fertility would be reversible [see Warnings and Precautions (5.6), Adverse Reactions (6.1), Nonclinical Toxicology (13.1)] . The efficacy of bosentan in patients <18 years is supported by data from an uncontrolled trial in which 19 pediatric patients were treated with bosentan. In this study, cardiopulmonary hemodynamic improvements were similar to those seen in adults treated with bosentan [see Pulmonary Arterial Hypertension (14.1)] . Safety in pediatric patients is supported by data from 100 pediatric patients treated with bosentan for a median of 17 months [see Clinical Studies Experience (6.1), Pulmonary Arterial Hypertension (14.1)] . Juvenile Animal Toxicity Data In a juvenile rat toxicity study, rats were treated from Day 4 postpartum to adulthood (Day 69 postpartum). Decreased body weights, absolute weights of testes and epididymides, and reduced number of sperm in epididymides were observed after weaning. No effect on testis histology or sperm morphology and function was seen. The NOAEL was 4 times (at Day 4 postpartum) and 2 times (Day 69 postpartum) the human therapeutic exposure, respectively. No effects on general development, sensory, cognitive function and reproductive performance were detected at the highest dose tested in juvenile rats, 7 times the therapeutic exposure in children with PAH. Clinical studies of bosentan did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. Because there is in vitro and in vivo evidence that the main route of excretion of bosentan is biliary, liver impairment could be expected to increase exposure (Cmax and AUC) of bosentan. The pharmacokinetics of bosentan have not been evaluated in patients with severe liver impairment (Child-Pugh Class C). In patients with moderate hepatic impairment (Child-Pugh Class B), the systemic exposures to bosentan and its active metabolite increased significantly. Bosentan should generally be avoided in patients with moderate or severe liver impairment. Pharmacokinetics of bosentan were not altered in patients with mild impairment of hepatic function (Child-Pugh Class A) [see Dosage and Administration (2.6), Warnings and Precautions (5.1), Pharmacokinetics (12.3)] . The effect of renal impairment on the pharmacokinetics of bosentan is small and does not require dosing adjustment [see Pharmacokinetics (12.3)] .

Ապրանքի ամփոփագիր:

Bosentan Tablets are available as follows: 62.5 mg – Light orange, round, biconvex, film-coated tablets, debossed with ‘WPI’ on one side and ‘62.5’ on the other side contains 64.541 mg of bosentan monohydrate, equivalent to 62.5 mg of bosentan base. Tablets are supplied in bottles of 60 (NDC 0591-2511-60) with a child-resistant closure. 125 mg – Light orange, oval, biconvex, film-coated tablets, debossed with ‘WPI’ on one side and ‘125’ on the other side contains 129.082 mg of bosentan monohydrate, equivalent to 125 mg of bosentan base. Tablets are supplied in bottles of 60 (NDC 0591-2512-60) with a child-resistant closure. Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP. Keep this and all medications out of the reach of children.

Լիազորման կարգավիճակը:

Abbreviated New Drug Application

Տեղեկատվական թերթիկ

Actavis Pharma, Inc.
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MEDICATION GUIDE
Bosentan (boe sen' tan) Tablets
Read the Medication Guide that comes with bosentan tablets before you
start taking it 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 bosentan
tablets?
Bosentan tablets are only available through the Bosentan REMS Program.
Before you begin taking bosentan tablets, you must read and agree to
all of the
instructions in the Bosentan REMS Program.
Bosentan tablets can cause serious side effects including:
Liver damage.
•
Liver damage may not cause symptoms at first. Only a blood test can
show if you have early liver damage. You must have your blood tested
to
check your liver function before you start bosentan tablets and each
month after that. Your healthcare provider will order these tests.
Regular
blood tests are important because they will help your healthcare
provider adjust or stop your treatment before there is permanent
damage.
•
Tell your healthcare provider if you have had liver problems,
including liver problems while taking other medicines. Call your
healthcare provider
right away if you have any of these symptoms of liver problems while
taking bosentan tablets:
•
nausea
•
vomiting
•
fever
•
unusual tiredness
•
stomach area (abdominal) pain
•
yellowing of the skin or the whites of your eyes (jaundice)
Serious birth defects.
•
Bosentan tablets can cause serious birth defects if taken during
pregnancy. You must not be pregnant when you start taking bosentan
tablets or
during bosentan tablet treatment. Serious birth defects from bosentan
tablets can happen early in pregnancy. Females who are able to get
pregnant
must have a negative pregnancy test before starting treatment with
bosentan tablets, each month during treatment with bosentan tablets,
and 1
month after stopping treatment with bosentan tablets.
•

Ապրանքի հատկությունները

BOSENTAN- BOSENTAN TABLET, FILM COATED
ACTAVIS PHARMA, INC.
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HIGHLIGHTS OF PRESCRIBING INFORMATION
THESE HIGHLIGHTS DO NOT INCLUDE ALL THE INFORMATION NEEDED TO USE
BOSENTAN TABLETS
SAFELY AND EFFECTIVELY. SEE FULL PRESCRIBING INFORMATION FOR BOSENTAN
TABLETS.
BOSENTAN TABLETS, FOR ORAL USE
INITIAL U.S. APPROVAL: 2001
WARNING: RISKS OF HEPATOTOXICITY AND EMBRYO-FETAL TOXICITY
_SEE FULL PRESCRIBING INFORMATION FOR COMPLETE BOXED WARNING._
BOSENTAN TABLETS ARE AVAILABLE ONLY THROUGH A RESTRICTED DISTRIBUTION
PROGRAM CALLED
THE BOSENTAN REMS PROGRAM BECAUSE OF THESE RISKS (5.3):
ELEVATIONS OF LIVER AMINOTRANSFERASES (ALT, AST) AND LIVER FAILURE
HAVE BEEN REPORTED
WITH BOSENTAN (5.1).
MEASURE LIVER AMINOTRANSFERASES PRIOR TO INITIATION OF TREATMENT AND
THEN MONTHLY
(2.1, 5.1).
DISCONTINUE BOSENTAN IF AMINOTRANSFERASE ELEVATIONS ARE ACCOMPANIED BY
SIGNS OR
SYMPTOMS OF LIVER DYSFUNCTION OR INJURY OR INCREASES IN BILIRUBIN
≥2XULN (2.4, 5.1).
BASED ON ANIMAL DATA, BOSENTAN IS LIKELY TO CAUSE MAJOR BIRTH DEFECTS
IF USED DURING
PREGNANCY (4.1, 5.2, 8.1).
MUST EXCLUDE PREGNANCY BEFORE AND DURING TREATMENT (2.1, 4.1, 8.1).
TO PREVENT PREGNANCY, FEMALES OF REPRODUCTIVE POTENTIAL MUST USE TWO
RELIABLE
FORMS OF CONTRACEPTION DURING TREATMENT AND FOR ONE MONTH AFTER
STOPPING
BOSENTAN (4.1, 5.2, 8.1).
INDICATIONS AND USAGE
Bosentan is an endothelin receptor antagonist indicated for the
treatment of pulmonary arterial
hypertension (PAH) (WHO Group 1):
in adults to improve exercise ability and to decrease clinical
worsening. Studies establishing
effectiveness included predominantly patients with WHO Functional
Class II-IV symptoms and etiologies
of idiopathic or heritable PAH (60%), PAH associated with connective
tissue diseases (21%), and PAH
associated with congenital heart disease with left-to-right shunts
(18%) (1).
in pediatric patients aged 3 years and older with idiopathic or
congenital PAH to improve pulmonary
vascular resistance (PVR), which is expected to result in an
improvement in exercise ability (1).
DOSAG