Ambrisentan | Cipla USA

About Ambrisentan
- About Ambrisentan
- Alone Therapy & In Combination Therapy
Important FAQ
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About Ambrisentan
Alone Therapy & In Combination Therapy

Ambrisentan is indicated specifically for the treatment of pulmonary arterial hypertension.Pulmonary hypertension (PAH) is a condition in which there is increased blood pressure in the arteries in lungs. It is used to improve exercise capacity and delay clinical worsening insubjects with symptoms of PAH.

Ambrisentan is supplied in 2 different strengths for oral administration and can be taken with or without food. Swallow tablet as whole and do not split, crush, or chew tablets. The recommended initial dose of the drug is 5 mg once daily. It may be increased to 10 mg once daily if the 5 mg dose is tolerated.

Storage

Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F)

Ambrisentan is a type-A selective endothelin receptor antagonist. Endothelin is a peptide made by the body in the endothelium and it constricts blood vessels and elevates blood pressure. Endothelin receptor antagonists (ETRAs) are a class of drugs which prevent the constriction or narrowing of blood vessels thereby enhancing blood flow throughout the body.

Ambrisentan can be used alone or in combination therapy.

Ambrisentan when used in combination with tadalafil can do lot more than when used alone. When used in combination therapy it reduces the hospitalization by decreasing the disease worsening, increases ability to exercise and delays the risks of disease.

GSK had performed study named AMBITION: A Randomized, Multicenter Study of First-Line Ambrisentan and Tadalafil Combination Therapy in Subjects with Pulmonary Arterial Hypertension (PAH) ClinicalTrials.gov Identifier: NCT01178073

The study details on the effect of monotherapy with Ambrisentan and Tadalafil and combination therapy with various doses. The results of monotherapy and combination therapy can be summarized as follows.

The number of patients who had disease worsening or hospitalization was decreased in combination therapy Ambrisentan with Tadalafil than when used alone.

Arm/Group Title	Combination Therapy: Ambrisentan + Tadalafil	Monotherapy Pooled: Ambrisentan or Tadalafil	Ambrisentan Monotherapy	Tadalafil Monotherapy
Arm/Group Description:	Participants initially received one tablet of 5 milligrams (mg) ambrisentan (AMB) and one tablet of AMB matching placebo once daily (QD) for the first 8 weeks plus one tablet of 20 mg tadalafil (TAD) and one tablet of TAD matching placebo QD for the first 4 weeks. The TAD dose was uptitrated to 40 mg (two tablets of 20 mg QD) after 4 weeks and the AMB dose may have been uptitrated to 10 mg (two tablets of 5 mg QD) after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg.	Participants initially received one tablet of 5 mg AMB and one tablet of AMB matching placebo QD for the first 8 weeks; or one tablet of 20 mg TAD and one tablet of TAD-matching placebo QD for the first 4 weeks. For participants on TAD, the dose of TAD was uptitrated to 40 mg (two tablets of 20 mg QD) after 4 weeks and for participants on AMB, the dose of AMB may have been uptitrated to 10 mg (two tablets of 5 mg QD) after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg.	Participants initially received one tablet of 5 mg AMB and one tablet of AMB matching placebo QD for the first 8 weeks plus two tablets of TAD matching placebo. The AMB dose may have been uptitrated to 10 mg (two tablets of 5 mg QD) and two tablets of TAD matching placebo after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg.	Participants initially received one tablet of 20 mg TAD and one tablet of TAD matching placebo QD for the first 4 weeks plus two tablets of AMB matching placebo. The TAD dose was uptitrated to 40 mg (two tablets of 20 mg QD) and two tablets of AMB matching placebo after 4 weeks.
Overall Number of Participants Analyzed	253	247	126	121
Measure Type: Number Unit of Measure: Participants
First adjudicated clinical failure event	46	77	43	34
Death (all-cause)	9	8	2	6
Hospitalization for worsening PAH	10	30	18	12
Disease progression	10	16	12	4
Unsatisfactory long-term clinical response	17	23	11	12

The number of meters patients could walk in 6 minutes was increased from 48 meters which is remarkably more than 22 meters when used in combination.

Arm/Group Title	Combination Therapy: Ambrisentan + Tadalafil	Monotherapy Pooled: Ambrisentan or Tadalafil	Ambrisentan Monotherapy	Tadalafil Monotherapy
Arm/Group Description:	Participants initially received one tablet of 5 milligrams (mg) ambrisentan (AMB) and one tablet of AMB matching placebo once daily (QD) for the first 8 weeks plus one tablet of 20 mg tadalafil (TAD) and one tablet of TAD matching placebo QD for the first 4 weeks. The TAD dose was uptitrated to 40 mg (two tablets of 20 mg QD) after 4 weeks and the AMB dose may have been uptitrated to 10 mg (two tablets of 5 mg QD) after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg.	Participants initially received one tablet of 5 mg AMB and one tablet of AMB matching placebo QD for the first 8 weeks; or one tablet of 20 mg TAD and one tablet of TAD-matching placebo QD for the first 4 weeks. For participants on TAD, the dose of TAD was uptitrated to 40 mg (two tablets of 20 mg QD) after 4 weeks and for participants on AMB, the dose of AMB may have been uptitrated to 10 mg (two tablets of 5 mg QD) after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg.	Participants initially received one tablet of 5 mg AMB and one tablet of AMB matching placebo QD for the first 8 weeks plus two tablets of TAD matching placebo. The AMB dose may have been uptitrated to 10 mg (two tablets of 5 mg QD) and two tablets of TAD matching placebo after 8 weeks. The uptitration of AMB to 10 mg was not mandatory if the investigator decided for tolerability reasons the participants should remain on 5 mg.	Participants initially received one tablet of 20 mg TAD and one tablet of TAD matching placebo QD for the first 4 weeks plus two tablets of AMB matching placebo. The TAD dose was uptitrated to 40 mg (two tablets of 20 mg QD) and two tablets of AMB matching placebo after 4 weeks.
Overall Number of Participants Analyzed	248	244	124	120
Median (95% Confidence Interval) Unit of Measure: Meters
	48.98 (39.00 to 57.50)	23.80 (19.00 to 33.50)	27.00 (12.50 to 38.00)	22.70 (16.50 to 35.50)

Important FAQ

Who should not take Ambrisentan?

Do not take Ambrisentan if you are pregnant, plan to become pregnant, or become pregnant. Ambrisentan can cause serious birth defects.

What should I avoid while taking Ambrisentan?

You should avoid becoming pregnant while taking Ambrisentan. You should also not breastfeed while taking Ambrisentan.

What are the side effects of taking Ambrisentan?

The most common side effects of Ambrisentan are swelling of hands, legs, ankles and feet (peripheral edema), stuffy nose (nasal congestion), inflamed nasal passages (sinusitis), hot flashes or getting red in the face (flushing). The more serious side effects are swelling of the whole body (fluid retention), decreased sperm count, and low red blood cell count (Anemia).

What should I tell my doctor before taking Ambrisentan?

Before you take Ambrisentan, tell your doctor if you: have been told that you have a low red blood cell level (anemia) , have liver problems ,have any other medical conditions.Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Ambrisentan and other medicines may affect each other, causing side effects. Do not start any new medicines until you check with your doctor. Especially tell your doctor if you take the medicine cyclosporine (Gengraf, Neoral, Sandimmune). Your doctor may need to change your dose of Ambrisentan.

Is this medication gluten free?

This medication is gluten free.

Can I take this with food?

Ambrisentan can be taken with food

Can I put this medication into a pill container?

You can put this medication into the pill container.

What should I do if I forget to take the medication?

If you miss a dose, take it as soon as you remember that day. Take your next dose at the regular time. Do not take 2 doses at the same time to make up for a missed dose

What should I do if I get pregnant?

Talk to your doctor or pharmacist right away if you have unprotected sex, if you think your birth control has failed, or if you think you may be pregnant. Your doctor may tell you to use emergency birth control. Do not wait until your next appointment to tell your doctor if you miss your menstrual period or if you think you may be pregnant.

How do I enroll?

Female patients must be enrolled in the Ambrisentan REMS to receive ambrisentan, even if you have been previously enrolled in the Letairis REMS. Follow these steps with your doctor: 1. Read and understand the Guide for Female Patients, which can be found on the Ambrisentan REMS website, www.ambrisentan.us.com. 2. Talk with your doctor to ensure the benefits outweigh the risks of ambrisentan. 3. Ask questions. Make sure you understand what you need to do to enroll and take part in the Ambrisentan REMS. Make sure you know how to receive and take ambrisentan. 4. You and your doctor complete the Patient Enrollment and Consent Form. The form may be completed and submitted online via the Ambrisentan REMS website or by printing and faxing a completed form to the REMS Coordinating Center at 1-866-750-9802.

Is this mandatory?

The Ambrisentan REMS is mandatory for female patients.

If I am unable to get pregnant, do I still need to enroll?

All female patients taking ambrisentan are required to enroll in the Ambrisentan REMS. When completing the enrollment form, your doctor will determine your reproductive status. Pre-pubertal females will be educated using the Guide for Female Patients, which can be found on the program's website. Female patients that cannot become pregnant will be regularly evaluated for any change in reproductive status. Any change will be documented by your doctor's completion of the Ambrisentan Change in Reproductive Potential Status and Pre-Pubertal Annual Verification Form.

Is there a patient assistance program?

Yes, Cipla is providing a Co-Pay Assistance program, please click here for further information ______

Why do you need to know who my doctor is?

Prescribers must be certified with the program by enrolling._

As a patient, what am I required to do for this program?

Females Who Can Get Pregnant:

You are considered to be a female who can get pregnant if you have entered puberty, have a uterus, and have not gone through Menopause.

Before starting ambrisentan, you must:

Review this guide.
Get a pregnancy test. Your doctor orders the pregnancy tests for you.
Enroll in the REMS Program by completing the Patient Enrollment and Consent Form.
Receive counseling from your prescriber on the risk of serious birth defects, the need to use highly reliable birth control during treatment and for one month after stopping treatment, and emergency birth control if needed.

Before each prescription while taking ambrisentan, you must:

Receive counseling from the REMS Coordinating Center or the healthcare provider who dispenses ambrisentan on the risk of serious birth defects, the need to use highly reliable birth control during treatment and for one month after stopping treatment, emergency birth control, to get monthly pregnancy tests, and to report a pregnancy immediately.
Get a pregnancy test. Your doctor orders the pregnancy tests for you. The REMS Coordinating Center will contact you to ask if you have taken this test before ambrisentan is refilled. Be sure you take your monthly pregnancy test as ordered by your doctor. If you do not take you pregnancy test every month, you may not receive your ambrisentan on time.

Do not have unprotected sex. Use appropriate birth control during your ambrisentan treatment and for 1 month after stopping your ambrisentan treatment because the medicine may still be in your body.

How do I enroll?

To become certified, a prescriber must complete and submit the Prescriber Enrollment and Agreement Form. The form may be completed and submitted online via the Ambrisentan REMS website, or by printing and faxing a completed form to the REMS Coordinating Center.

How do I get my patients enrolled?

Upon receipt of a completed patient enrollment form, the REMS Coordinating Center will ensure that the prescriber submitting the Patient Enrollment Form is enrolled in the Ambrisentan REMS. Upon confirmation of an enrolled prescriber, the REMS Coordinating Center will enter the information into the Ambrisentan REMS system completing the patient’s enrollment and linking the enrolled patient with the enrolled prescriber. An enrolled prescriber may also enroll female patients through the Ambrisentan REMS website. Both the prescriber and patient (or parent/guardian for minors) must sign the form.

What are the requirements?

Health Care Providers who prescribe ambrisentan must:

To become certified to prescriber

Review the drug’s Prescribing Information.
Review the following: Prescriber Guide.
Enroll in the REMS by completing the Prescriber Enrollment Form and submitting it to the REMS. Enrollment may also be completed online at www.ambrisentanrems.us.com

For all females:

I will determine the reproductive potential status of all female patients using the definitions provided in the Prescriber Guide and document and submit the results to the REMS Program using the Patient Enrollment Form.
I will counsel all female patients that ambrisentan is only available through a restricted distribution program called the Ambrisentan REMS Program
I will enroll all female patients by completing and submitting the Patient Enrollment Form

For females of reproductive potential:

I will counsel Females of Reproductive Potential about the risk of embryo-fetal toxicity, the need to use highly reliable contraception during ambrisentan treatment and for one month following treatment discontinuation, and emergency contraception using the Guide for Female Patients.
I will assess the pregnancy status of Females of Reproductive Potential by ordering and reviewing a pregnancy test before treatment initiation, before writing each prescription, and for one month after treatment discontinuation.
I will counsel Females of Reproductive Potential if they are not complying with the required testing or if they are not using appropriate contraception.

For pre-pubertal females:

I will counsel each Pre-Pubertal Female patient and her parent/guardian about the risk of embryo-fetal toxicity.
I will regularly assess the reproductive status of each Pre-Pubertal Female during their treatment with ambrisentan
I will assess the reproductive status for Pre-Pubertal Females who are 8 years of age and older and will document and submit findings to the REMS Program at least annually using the Change in Reproductive Potential Status and Pre-Pubertal Annual Verification Form.

At all times:

I will report any change or misclassification in pregnancy status to the Ambrisentan REMS Program using the Change in Reproductive Potential Status and Pre-Pubertal Annual Verification Form within 10 business days of becoming aware of the change in reproductive status.
I will report pregnancies to the REMS Program.

How does a patient enroll?

Only female patients are required to enroll in the Ambrisentan REMS. To enroll a female, the prescriber must complete a Patient Enrollment and Consent Form. The form may be completed and submitted online via the Ambrisentan REMS website, or by printing and faxing a completed form to the REMS Coordinating Center.

How should the medication be stored?

Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F)

What are the requirements?

The Ambrisentan REMS requirements for pharmacies depend on the pharmacy type. For specific information on pharmacy requirements, please refer to the Pharmacy Guide.

Is there a patient assistance program?

Yes, Cipla is providing a Co-Pay Assistance program, please click here for further information ______

Can this be taken with food?

Yes

Can the patient crush the tablet?

No.

Patients / Physicians / Pharmacists

For medical emergencies in USA, please call 911. Patients and other consumers should contact their physician with questions about prescription products and their common indications.

For any further medical information, to report an adverse event or product complaint, please call toll-free.

866-604-3268

Important Safety Information

BOXED WARNING: EMBRYO-FETAL TOXICITY

Ambrisentan cannot be administered 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.

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.

Because of the risk of embryo-fetal toxicity, females can only receive Ambrisentan through a restricted program called the Ambrisentan REMS program.

Contraindications

Cannot be used during Pregnancy.

Cannot use in patients with Idiopathic pulmonary fibrosis.

Cautions

Fetal harm when administered during pregnancy and is contraindicated for use in females who are pregnant (see Pregnancy and Black Box Warnings).

Caution with hepatic impairment; may be associated with rare cases of hepatic cirrhosis with prolonged use; not recommended in patients with moderate-to-severe hepatic impairment.

Discontinue in patients with elevated aminotransferases >5x ULN, or if elevations are accompanied by bilirubin >2X ULN, or signs/symptoms of liver dysfunction Reports of decreased hemoglobin concentrations from baseline that persisted for up to 4 yr. of treatment.

Coadministration with cyclosporine or CYP3A4 or CYP2C19 inhibitors.

Peripheral edema is known class effect of endothelin receptor antagonists, and also a clinical consequence of pulmonary arterial hypertension (PAH) and worsening PAH; fluid retention in patients with pulmonary hypertension, occurring within weeks of initiating therapy reported; if clinically significant fluid retention develops, with or without associated weight gain, further evaluate to determine cause, such as Ambrisentan or underlying heart failure, possible need for specific treatment or discontinuation of therapy Risk of fluid retention and peripheral edema; more common in combination with tadalafil, than with Ambrisentan or tadalafil alone.

Decreased sperm counts observed in human and animal studies with another endothelin receptor antagonist and in animal fertility studies with Ambrisentan Development of acute pulmonary edema during therapy initiation may be associated with pulmonary veno-occlusive disease.