Ambrisentan

AMBRISENTAN- ambrisentan tablet, film coated
Actavis Pharma, Inc.

WARNING: EMBRYO-FETAL TOXICITY

Do not administer ambrisentan to a pregnant female because it may cause fetal harm. Ambrisentan is very likely to produce serious birth defects if used by pregnant females, as this effect has been seen consistently when it is administered to animals [see Contraindications (4.1), Warnings and Precautions (5.1), and Use in Specific Populations (8.1)].

Exclude pregnancy before the initiation of treatment with ambrisentan. Females of reproductive potential must use acceptable methods of contraception during treatment with ambrisentan and for one month after treatment. Obtain monthly pregnancy tests during treatment and 1 month after discontinuation of treatment [see Dosage and Administration (2.2) and Use in Specific Populations (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 the Ambrisentan REMS [see Warnings and Precautions (5.2)].

1 INDICATIONS AND USAGE

Ambrisentan tablets are indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1):

  • To improve exercise ability and delay clinical worsening.
  • In combination with tadalafil to reduce the risks of disease progression and hospitalization for worsening PAH, and to improve exercise ability [see Clinical Studies (14.2)].

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%).

2 DOSAGE AND ADMINISTRATION

2.1 Adult Dosage

Initiate treatment at 5 mg once daily, with or without tadalafil 20 mg once daily. At 4-week intervals, either the dose of ambrisentan or tadalafil can be increased, as needed and tolerated, to ambrisentan 10 mg or tadalafil 40 mg.

Do not split, crush, or chew tablets.

2.2 Pregnancy Testing in Females of Reproductive Potential

Initiate treatment with ambrisentan in females of reproductive potential only after a negative pregnancy test. Obtain monthly pregnancy tests during treatment [see Use in Specific Populations (8.3)].

3 DOSAGE FORMS AND STRENGTHS

5 mg and 10 mg film coated tablets for oral administration

  • Each 5 mg tablet is white to off-white, capsule shaped, film-coated, and debossed with “5” on one side and “405” on the other side.
  • Each 10 mg tablet is white to off-white, capsule shaped, film-coated, and debossed with “10 ” on one side and “406” on the other side.

4 CONTRAINDICATIONS

4.1 Pregnancy

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)].

4.2 Idiopathic Pulmonary Fibrosis

Ambrisentan is contraindicated in patients with Idiopathic Pulmonary Fibrosis (IPF), including IPF patients with pulmonary hypertension (WHO Group 3) [see Clinical Studies (14.4)].

5 WARNINGS AND PRECAUTIONS

5.1 Embryo-fetal Toxicity

Ambrisentan may cause fetal harm when administered during pregnancy and is contraindicated for use in females who are pregnant. In females of reproductive potential, exclude pregnancy prior to initiation of therapy, ensure use of acceptable contraceptive methods, and obtain monthly pregnancy tests [see Dosage and Administration (2.2), and Use in Specific Populations (8.1, 8.3)].

Ambrisentan is only available for females through a restricted program under a REMS [see Warnings and Precautions (5.2)].

5.2 Ambrisentan Risk Evaluation and Mitigation Strategy (REMS)

For all females, ambrisentan is available only through a restricted program under a REMS called the Ambrisentan REMS because of the risk of embryo-fetal toxicity [see Contraindications (4.1), Warnings and Precautions (5.1), and Use in Specific Populations (8.1, 8.3)].

Important requirements of the Ambrisentan REMS include the following:

  • Prescribers must be certified with the Ambrisentan REMS by enrolling and completing training.
  • All females, regardless of reproductive potential, must enroll in the Ambrisentan REMS prior to initiating ambrisentan. Male patients are not enrolled in the REMS.
    • Females of reproductive potential must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.3)].
  • Pharmacies that dispense ambrisentan must be certified with the Ambrisentan REMS and must dispense to female patients who are authorized to receive ambrisentan.

Further information is available at www. ambrisentanrems.us .com or Phone (1-888-417-3172) and Fax (1-866-750-9802) .

5.3 Fluid Retention

Peripheral edema is a known class effect of endothelin receptor antagonists, and is also a clinical consequence of PAH and worsening PAH. In the placebo-controlled studies, there was an increased incidence of peripheral edema in patients treated with doses of 5 or 10 mg ambrisentan compared to placebo [see Adverse Reactions (6.1)]. Most edema was mild to moderate in severity.

In addition, there have been postmarketing reports of fluid retention in patients with pulmonary hypertension, occurring within weeks after starting ambrisentan. Patients required intervention with a diuretic, fluid management, or, in some cases, hospitalization for decompensating heart failure.

If clinically significant fluid retention develops, with or without associated weight gain, further evaluation should be undertaken to determine the cause, such as ambrisentan or underlying heart failure, and the possible need for specific treatment or discontinuation of ambrisentan therapy.

Peripheral edema/fluid retention is more common with ambrisentan plus tadalafil than with ambrisentan or tadalafil alone.

5.4 Pulmonary Edema with Pulmonary Veno-occlusive Disease (PVOD)

If patients develop acute pulmonary edema during initiation of therapy with vasodilating agents such as ambrisentan, the possibility of PVOD should be considered, and if confirmed ambrisentan should be discontinued.

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