Ambrisentan

Ambrisentan tablets are 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%).

Adult Dosage

Initiate treatment at 5 mg once daily. At 4-week intervals, the dose of ambrisentan can be increased, as needed and tolerated, to ambrisentan10 mg.

Do not split, crush, or chew tablets.

Pregnancy Testing in Females of Reproductive Potential

Initiate treatment with ambrisentan tablets in females of reproductive potential only after a negative pregnancy test. Obtain monthly pregnancy tests during treatment [see Use in Specific Populations ].

5 mg and 10 mg film-coated tablets for oral administration

• Each 5 mg tablet is pale pink square shaped biconvex film coated tablets debossed with 'C' on one side and '386' on other side
• Each 10 mg tablet is deep pink oval shaped biconvex film coated tablets debossed with 'C' on one side and '387' on other side.

Pregnancy

Risk Summary

Based on data from animal reproduction studies, ambrisentan tablets may cause fetal harm when administered to a pregnant woman and is contraindicated during pregnancy. There are limited data on ambrisentan tablets 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 , Warnings and Precautions ].

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.

Data

Animal Data

Ambrisentan was teratogenic at oral dosages of ≥15 mg/kg/day (AUC 51.7 h•μg/mL) in rats and ≥7 mg/kg/day (24.7 h•μg/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•μg/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/m2body 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.

Lactation

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 tablets, a decision should be made whether to discontinue breastfeeding or discontinue ambrisentan tablets, taking into account the importance of the drug to the mother.

Females and Males of Reproductive Potential

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 tablets. 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 ].

Contraception

Female patients of reproductive potential must use acceptable methods of contraception during treatment with ambrisentan tablets and for 1 month after stopping treatment with ambrisentan tablets. 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 ] from endothelin receptor antagonists, it cannot be excluded that endothelin receptor antagonists such as ambrisentan tablets have an adverse effect on spermatogenesis. Counsel patients about the potential effects on fertility [see Warnings and Precautions ].

Pediatric Use

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.

Geriatric Use

In the two placebo-controlled clinical studies of ambrisentan tablets, 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 tablets 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.

Renal Impairment

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 ]. Dose adjustment of ambrisentan tablets 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.

Hepatic Impairment

Pre-existing Hepatic Impairment

The influence of pre-existing 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 ]. Ambrisentan tablets are not recommended in patients with moderate or severe hepatic impairment. There is no information on the use of ambrisentan tablets in patients with mild pre-existing 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 ]. In patients who develop hepatic impairment after ambrisentan tablet initiation, the cause of liver injury should be fully investigated. Discontinue ambrisentan tablets 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.