AMBRISENTAN tablet, film coated

Country: United States

Language: English

Source: NLM (National Library of Medicine)

Active ingredient:

AMBRISENTAN (UNII: HW6NV07QEC) (AMBRISENTAN - UNII:HW6NV07QEC)

Available from:

Sun Pharmaceutical Industries, Inc.

Administration route:

ORAL

Prescription type:

PRESCRIPTION DRUG

Therapeutic indications:

Ambrisentan is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1): • To improve exercise ability and delay clinical worsening. Studies establishing effectiveness included predominantly patients with WHO Functional Class II–III symptoms and etiologies of idiopathic or heritable PAH (60%) or PAH associated with connective tissue diseases (34%). Ambrisentan may cause fetal harm when administered to a pregnant female. Ambrisentan is contraindicated in females who are pregnant. Ambrisentan was consistently shown to have teratogenic effects when administered to animals. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Warnings and Precautions (5.1, 5.2) and Use in Specific Populations (8.1)] . Ambrisentan is contraindicated in patients with Idiopathic Pulmonary Fibrosis (IPF), including IPF patients with pulmonary hypertension (WHO Group 3) [see Clinical Studies (14.4)]. Risk Summary Based on data from animal reproduction studies, ambrisentan may cause fetal harm when administered to a pregnant woman and is contraindicated during pregnancy. There are limited data on ambrisentan use in pregnant women. In animal reproduction studies, ambrisentan was teratogenic in rats and rabbits at doses which resulted in exposures of 3.5 and 1.7 times, respectively, the human dose of 10 mg per day [see Animal Data] . If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential hazard to a fetus [see Contraindications (4.1), Warnings and Precautions (5.1)] . 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 to 4% and 15 to 20%, respectively. Data Animal Data Ambrisentan was teratogenic at oral dosages of ≥15 mg/kg/day (AUC 51.7 h•mcg/mL) in rats and ≥7 mg/kg/day (24.7 h•mcg/mL) in rabbits; it was not studied at lower dosages. These dosages are of 3.5 and 1.7 times, respectively, the human dose of 10 mg per day (14.8 h•mcg/mL) based on AUC. In both species, there were 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. A preclinical study in rats has shown decreased survival of newborn pups (mid and high dosages) and effects on testicle size and fertility of pups (high dosage) following maternal treatment with ambrisentan from late gestation through weaning. The mid and high dosages were 51 x, and 170 x (on a mg/m2 body surface area basis) the maximum oral human dose of 10 mg and an average adult body weight of 70 kg. These effects were absent at a maternal dosage 17 x the human dose based on mg/m2 . Risk Summary It is not known whether ambrisentan is present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions in breastfed infants from ambrisentan, a decision should be made whether to discontinue breastfeeding or discontinue ambrisentan, taking into account the importance of the drug to the mother. Pregnancy Testing Female patients of reproductive potential must have a negative pregnancy test prior to initiation of treatment, monthly pregnancy test during treatment, and pregnancy test 1 month after stopping treatment with ambrisentan. Advise patients to contact their healthcare provider if they become pregnant or suspect they may be pregnant. Perform a pregnancy test if pregnancy is suspected for any reason. For positive pregnancy tests, counsel patient on the potential risk to the fetus and patient options [see Boxed Warning and Dosage and Administration (2.2)].  Contraception Female patients of reproductive potential must use acceptable methods of contraception during treatment with ambrisentan and for 1 month after stopping treatment with ambrisentan. Patients may choose one highly effective form of contraception (intrauterine device (IUD), contraceptive implant, 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 In a 6-month study of another endothelin receptor antagonist, bosentan, 25 male patients with WHO functional class III and IV PAH and normal baseline sperm count were evaluated for effects on testicular function. There was a decline in sperm count of at least 50% in 25% of the patients after 3 or 6 months of treatment with bosentan. One patient developed marked oligospermia at 3 months, and the sperm count remained low with 2 follow-up measurements over the subsequent 6 weeks. Bosentan was discontinued and after 2 months the sperm count had returned to baseline levels. In 22 patients who completed 6 months of treatment, sperm count remained within the normal range and no changes in sperm morphology, sperm motility, or hormone levels were observed. Based on these findings and preclinical data [see Nonclinical Toxicology (13.1)] from endothelin receptor antagonists, it cannot be excluded that endothelin receptor antagonists such as ambrisentan have an adverse effect on spermatogenesis. Counsel patients about the potential effects on fertility [see Warnings and Precautions (5.5)] . Safety and effectiveness of ambrisentan in pediatric patients have not been established. Juvenile Animal Data In juvenile rats administered ambrisentan orally once daily during postnatal day 7 to 26, 36, or 62, a decrease in brain weight (−3% to −8%) with no morphologic or neurobehavioral changes occurred after breathing sounds, apnea, and hypoxia were observed, at exposures approximately 1.8 to 7.0 times human pediatric exposures at 10 mg, based on AUC. In the two placebo-controlled clinical studies of ambrisentan, 21% of patients were ≥65 years old and 5% were ≥75 years old. The elderly (age ≥65 years) showed less improvement in walk distances with ambrisentan than younger patients did, but the results of such subgroup analyses must be interpreted cautiously. Peripheral edema was more common in the elderly than in younger patients. The impact of renal impairment on the pharmacokinetics of ambrisentan has been examined using a population pharmacokinetic approach in PAH patients with creatinine clearances ranging between 20 and 150 mL/min. There was no significant impact of mild or moderate renal impairment on exposure to ambrisentan [see Clinical Pharmacology (12.3)] . Dose adjustment of ambrisentan in patients with mild or moderate renal impairment is therefore not required. There is no information on the exposure to ambrisentan in patients with severe renal impairment. The impact of hemodialysis on the disposition of ambrisentan has not been investigated. Preexisting Hepatic Impairment The influence of preexisting hepatic impairment on the pharmacokinetics of ambrisentan has not been evaluated. Because there is in vitro and in vivo evidence of significant metabolic and biliary contribution to the elimination of ambrisentan, hepatic impairment might be expected to have significant effects on the pharmacokinetics of ambrisentan [see Clinical Pharmacology (12.3)] . Ambrisentan is not recommended in patients with moderate or severe hepatic impairment. There is no information on the use of ambrisentan in patients with mild preexisting impaired liver function; however, exposure to ambrisentan may be increased in these patients. Elevation of Liver Transaminases Other endothelin receptor antagonists (ERAs) have been associated with aminotransferase (AST, ALT) elevations, hepatotoxicity, and cases of liver failure [see Adverse Reactions (6.1, 6.2)]. In patients who develop hepatic impairment after ambrisentan initiation, the cause of liver injury should be fully investigated. Discontinue ambrisentan if elevations of liver aminotransferases are >5 x ULN or if elevations are accompanied by bilirubin >2 x ULN, or by signs or symptoms of liver dysfunction and other causes are excluded.

Product summary:

Ambrisentan film-coated tablets are supplied as follows: Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F). [See USP Controlled Room Temperature]. Store ambrisentan in its original packaging.

Authorization status:

Abbreviated New Drug Application

Patient Information leaflet

Sun Pharmaceutical Industries, Inc.
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MEDICATION GUIDE
Ambrisentan (am" bri senʹ tan) Tablets
Read this Medication Guide before you start taking ambrisentan tablets
and each time you get a refill.
There may be new information. This Medication Guide does not take the
place of talking with your
doctor about your medical condition or your treatment.
What is the most important information I should know about ambrisentan
tablets?
•
Serious birth defects.
Ambrisentan tablets can cause serious birth defects if taken during
pregnancy.
•
Females must not be pregnant when they start taking ambrisentan
tablets or become
pregnant during treatment with ambrisentan tablets.
•
Females who are able to get pregnant must have a negative pregnancy
test before
beginning treatment with ambrisentan tablets, each month during
treatment with
ambrisentan tablets, and one month after stopping ambrisentan tablets.
Talk to your doctor
about your menstrual cycle. Your doctor will decide when to do a
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 ableto 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
•
who are infertile for any other medical reason 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 ambrisentan tablets, and for one month after stopping ambrisentan
tablets because the me

Summary of Product characteristics

AMBRISENTAN- AMBRISENTAN TABLET, FILM COATED
SUN PHARMACEUTICAL INDUSTRIES, INC.
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HIGHLIGHTS OF PRESCRIBING INFORMATION
THESE HIGHLIGHTS DO NOT INCLUDE ALL THE INFORMATION NEEDED TO USE
AMBRISENTAN TABLETS
SAFELY AND EFFECTIVELY. SEE FULL PRESCRIBING INFORMATION FOR
AMBRISENTAN TABLETS.
AMBRISENTAN TABLETS, FOR ORAL USE
INITIAL U.S. APPROVAL: 2007
WARNING: EMBRYO-FETAL TOXICITY
_SEE FULL PRESCRIBING INFORMATION FOR COMPLETE BOXED WARNING._
DO NOT ADMINISTER AMBRISENTAN TO A PREGNANT FEMALE BECAUSE IT MAY
CAUSE FETAL
HARM (4.1, 5.1, 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 (2.2, 8.3).
BECAUSE OF THE RISK OF EMBRYO-FETAL TOXICITY, FOR ALL FEMALE PATIENTS,
AMBRISENTAN IS
ONLY AVAILABLE THROUGH A RESTRICTED PROGRAM UNDER A RISK EVALUATION
AND MITIGATION
STRATEGY (REMS) CALLED AMBRISENTAN REMS (5.2).
INDICATIONS AND USAGE
(1)
Ambrisentan is an endothelin receptor antagonist indicated for the
treatment of pulmonary arterial
hypertension (PAH) (WHO Group 1): (1)
To improve exercise ability and delay clinical worsening.
Studies establishing effectiveness included trials predominantly in
patients with WHO Functional Class II–III
symptoms and etiologies of idiopathic or heritable PAH (60%) or PAH
associated with connective tissue
diseases (34%). (1)
(1)
DOSAGE AND ADMINISTRATION
• Initiate treatment at 5 mg once daily (2.1).
• Titrate at 4-week intervals as needed and tolerated (2.1).
• Do not split, crush, or chew tablets (2.1). (2)
DOSAGE FORMS AND STRENGTHS
Tablet: 5 mg and 10 mg (3)
CONTRAINDICATIONS
• Pregnancy (4.1)
• Idiopathic Pulmonary Fibrosis (4.2) (4)
WARNINGS AND PRECAUTIONS
Fluid retention may require intervention (5.3).
If patients develop acute pulmonary edema during initiation of therapy
with ambrisentan, consider
underlying pulmonary veno-occlusive dis