Drugs Details

Drugs Info of Letairis
Drugs Details
  • Drugs Type  : FDA
  • Date : 3rd Jan 2015 03:24 am
  • Brand Name : Letairis
  • Generic Name : ambrisentan (Pronunciation: am bri SEN tan)
Descriptions

Letairis is the brand name for ambrisentan, an endothelin receptor antagonist that is selective for the endothelin type-A (ETA) receptor. The chemical name of ambrisentan is (+)-(2S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropanoic acid. It has a molecular formula of C22H22N2O4 and a molecular weight of 378.42. It contains a single chiral center determined to be the (S) configuration and has the following structural formula:

Figure 1 : Ambrisentan Structural Formula

Letairis (ambrisentan) Structural Formula Illustration

Ambrisentan is a white to off-white, crystalline solid. It is a carboxylic acid with a pKa of 4.0. Ambrisentan is practically insoluble in water and in aqueous solutions at low pH. Solubility increases in aqueous solutions at higher pH. In the solid state ambrisentan is very stable, is not hygroscopic, and is not light sensitive.

Letairis is available as 5 mg and 10 mg film-coated tablets for once daily oral administration. The tablets include the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate and microcrystalline cellulose. The tablets are film-coated with a coating material containing FD&C Red #40 aluminum lake, lecithin, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. Each square, pale pink Letairis tablet contains 5 mg of ambrisentan. Each oval, deep pink Letairis tablet contains 10 mg of ambrisentan. Letairis tablets are unscored.

What are the possible side effects of ambrisentan (Letairis)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have a serious side effect such as:

  • anxiety, sweating, pale skin, severe shortness of breath, wheezing, gasping for breath, cough with foamy mucus, chest pain, fast or uneven heart rate;
  • swelling of the feet, ankles, or legs;
  • pounding heartbeats or fluttering in your chest; or
  • nausea, upper stomach pain, itching, loss of appetite, dark urine, clay-colored...

Read All Potential Side Effects and See Pictures of Letairis »

What are the precautions when taking ambrisentan tablets (Letairis)?

Before taking ambrisentan, tell your doctor or pharmacist if you are allergic to it; or to other endothelin receptor blockers (e.g., bosentan); or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: liver disease, certain lung conditions (pulmonary fibrosis), anemia.

Older adults may be at greater risk for swelling ankles/feet while using this drug.

This medication must not be used during pregnancy. It may harm an unborn baby. If you are planning pregnancy, become pregnant, or think you may be pregnant, tell your doctor immediately. Women who may...

Read All Potential Precautions of Letairis »


This monograph has been modified to include the generic and brand name in many instances.

Indications

Letairis 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 (64%) or PAH associated with connective tissue diseases (32%).

Dosage Administration

Adult Dosage

Initiate treatment at 5 mg once daily, and consider increasing the dose to 10 mg once daily if 5 mg is tolerated.

Tablets may be administered with or without food. Tablets should not be split, crushed, or chewed. Doses higher than 10 mg once daily have not been studied in patients with pulmonary arterial hypertension (PAH).

Pregnancy Testing In Females Of Reproductive Potential

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

How Supplied

Dosage Forms And Strengths

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

  • Each 5 mg tablet is square convex, pale pink, with “5” on one side and “GSI” on the other side.
  • Each 10 mg tablet is oval convex, deep pink, with “10” on one side and “GSI” on the other side.

Storage And Handling

Letairis film-coated tablets are supplied as follows:

 

Tablet Strength Package Configuration NDC No. Description of Tablet; Debossed on Tablet; Size
5 mg 30 count blister 61958-0801-2 Square convex; pale pink; “5” on side 1 and “GSI” on side 2; 6.6 mm Square
30 count bottle 61958-0801-1
10 count blister 61958-0801-3
10 count bottle 61958-0801-5
10 mg 30 count blister 61958-0802-2 Oval convex; deep pink; “10” on side 1 and “GSI” on side 2; 9.8 mm x 4.9 mm Oval
30 count bottle 61958-0802-1
10 count blister 61958-0802-3
10 count bottle 61958-0802-5

Store at 25° C (77° F); excursions permitted to 15–30° C (59–86° F) [see USP controlled room temperature]. Store Letairis in its original packaging.

Gilead Sciences, Inc., Foster City, CA 94404. Revised: May 2014


This monograph has been modified to include the generic and brand name in many instances.

Side Effects

Clinically significant adverse reactions that appear in other sections of the labeling include:

  • Embryo-fetal Toxicity [see WARNINGS AND PRECAUTIONS, Use In Specific Populations]
  • Fluid Retention [see WARNINGS AND PRECAUTIONS]
  • Pulmonary Edema with PVOD [see WARNINGS AND PRECAUTIONS]
  • Decreased Sperm Count [see WARNINGS AND PRECAUTIONS]
  • Hematologic Changes [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Safety data for Letairis were obtained from two 12-week, placebo-controlled studies in patients with pulmonary arterial hypertension (PAH) (ARIES-1 and ARIES-2) and four nonplacebo-controlled studies in 483 patients with PAH who were treated with doses of 1, 2.5, 5, or 10 mg once daily. The exposure to Letairis in these studies ranged from 1 day to 4 years (N = 418 for at least 6 months and N = 343 for at least 1 year).

In ARIES-1 and ARIES-2, a total of 261 patients received Letairis at doses of 2.5, 5, or 10 mg once daily and 132 patients received placebo. The adverse reactions that occurred in > 3% more patients receiving Letairis than receiving placebo are shown in Table 1.

Table 1 : Adverse Reactions with Placebo-Adjusted Rates > 3%

Adverse Reaction Placebo
(N = 132)
Letairis
(N = 261)
n (%) n (%) Placebo-adjusted (%)
Peripheral edema 14 (11) 45 (17) 6
Nasal congestion 2 (2) 15 (6) 4
Sinusitis 0 (0) 8 (3) 3
Flushing 1 (1) 10 (4) 3

Most adverse drug reactions were mild to moderate and only nasal congestion was dose-dependent.

Few notable differences in the incidence of adverse reactions were observed for patients by age or sex. Peripheral edema was similar in younger patients ( < 65 years) receiving Letairis (14%; 29/205) or placebo (13%; 13/104), and was greater in elderly patients ( ≥ 65 years) receiving Letairis (29%; 16/56) compared to placebo (4%; 1/28). The results of such subgroup analyses must be interpreted cautiously.

The incidence of treatment discontinuations due to adverse events other than those related to PAH during the clinical trials in patients with PAH was similar for Letairis (2%; 5/261 patients) and placebo (2%; 3/132 patients). The incidence of patients with serious adverse events other than those related to PAH during the clinical trials in patients with PAH was similar for placebo (7%; 9/132 patients) and for Letairis (5%; 13/261 patients).

During 12-week controlled clinical trials, the incidence of aminotransferase elevations > 3 x upper limit of normal (ULN) were 0% on Letairis and 2.3% on placebo. In practice, cases of hepatic injury should be carefully evaluated for cause.

Use in Patients with Prior Endothelin Receptor Antagonist (ERA) Related Serum Liver Enzyme Abnormalities

In an uncontrolled, open-label study, 36 patients who had previously discontinued endothelin receptor antagonists (ERAs: bosentan, an investigational drug, or both) due to aminotransferase elevations > 3 x ULN were treated with Letairis. Prior elevations were predominantly moderate, with 64% of the ALT elevations < 5 x ULN, but 9 patients had elevations > 8 x ULN. Eight patients had been re-challenged with bosentan and/or the investigational ERA and all eight had a recurrence of aminotransferase abnormalities that required discontinuation of ERA therapy. All patients had to have normal aminotransferase levels on entry to this study. Twenty-five of the 36 patients were also receiving prostanoid and/or phosphodiesterase type 5 (PDE5) inhibitor therapy. Two patients discontinued early (including one of the patients with a prior 8 x ULN elevation). Of the remaining 34 patients, one patient experienced a mild aminotransferase elevation at 12 weeks on Letairis 5 mg that resolved with decreasing the dosage to 2.5 mg, and that did not recur with later escalations to 10 mg. With a median follow-up of 13 months and with 50% of patients increasing the dose of Letairis to 10 mg, no patients were discontinued for aminotransferase elevations. While the uncontrolled study design does not provide information about what would have occurred with re-administration of previously used ERAs or show that Letairis led to fewer aminotransferase elevations than would have been seen with those drugs, the study indicates that Letairis may be tried in patients who have experienced asymptomatic aminotransferase elevations on other ERAs after aminotransferase levels have returned to normal.

Postmarketing Experience

The following adverse reactions were identified during postapproval use of Letairis. Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to estimate reliably the frequency or to establish a causal relationship to drug exposure: anemia [see WARNINGS AND PRECAUTIONS], asthenia, dizziness, fatigue, fluid retention [see WARNINGS AND PRECAUTIONS], heart failure (associated with fluid retention), hypersensitivity (eg, angioedema, rash), nausea, and vomiting.

Elevations of liver aminotransferases (ALT, AST) have been reported with Letairis use; in most cases alternative causes of the liver injury could be identified (heart failure, hepatic congestion, hepatitis, alcohol use, hepatotoxic medications). Other endothelin receptor antagonists have been associated with elevations of aminotransferases, hepatotoxicity, and cases of liver failure.

Read the Letairis (ambrisentan tablets) Side Effects Center for a complete guide to possible side effects

Interactions

Multiple dose coadministration of ambrisentan and cyclosporine resulted in an approximately 2-fold increase in ambrisentan exposure in healthy volunteers; therefore, limit the dose of ambrisentan to 5 mg once daily when coadministered with cyclosporine [see CLINICAL PHARMACOLOGY].

Read the Letairis Drug Interactions Center for a complete guide to possible interactions

Learn More »


This monograph has been modified to include the generic and brand name in many instances.

Warnings

Included as part of the PRECAUTIONS section.

Precautions

Embryo-Fetal Toxicity

Letairis 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, and Use in Specific Populations].

Letairis is only available for females through a restricted program under a REMS.

Letairis REMS Program

For all females, Letairis is available only through a restricted program called the Letairis REMS, because of the risk of embryo-fetal toxicity [see CONTRAINDICATIONS and Use In Specific Populations].

Notable requirements of the Letairis REMS program include the following:

  • Prescribers must be certified with the program by enrolling and completing training.
  • All females, regardless of reproductive potential, must enroll in the Letairis REMS program prior to initiating Letairis. 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].
    • Pharmacies that dispense Letairis must be certified with the program and must dispense to female patients who are authorized to receive Letairis.

Further information is available at www.letairisrems.com or 1-866-664-5327.

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 Letairis compared to placebo [see ADVERSE REACTIONS]. Most edema was mild to moderate in severity, and it occurred with greater frequency and severity in elderly patients.

In addition, there have been postmarketing reports of fluid retention in patients with pulmonary hypertension, occurring within weeks after starting Letairis. 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 Letairis or underlying heart failure, and the possible need for specific treatment or discontinuation of Letairis therapy.

Pulmonary Edema With Pulmonary Veno-occlusive Disease (PVOD)

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

Decreased Sperm Counts

Decreased sperm counts have been observed in human and animal studies with another endothelin receptor antagonist and in animal fertility studies with ambrisentan. Letairis may have an adverse effect on spermatogenesis. Counsel patients about potential effects on fertility [see Use in Specific Populations and Nonclinical Toxicology].

Hematological Changes

Decreases in hemoglobin concentration and hematocrit have followed administration of other endothelin receptor antagonists and were observed in clinical studies with Letairis. These decreases were observed within the first few weeks of treatment with Letairis, and stabilized thereafter. The mean decrease in hemoglobin from baseline to end of treatment for those patients receiving Letairis in the 12-week placebo-controlled studies was 0.8 g/dL.

Marked decreases in hemoglobin ( > 15% decrease from baseline resulting in a value below the lower limit of normal) were observed in 7% of all patients receiving Letairis (and 10% of patients receiving 10 mg) compared to 4% of patients receiving placebo. The cause of the decrease in hemoglobin is unknown, but it does not appear to result from hemorrhage or hemolysis.

In the long-term open-label extension of the two pivotal clinical studies, mean decreases from baseline (ranging from 0.9 to 1.2 g/dL) in hemoglobin concentrations persisted for up to 4 years of treatment.

There have been postmarketing reports of decreases in hemoglobin concentration and hematocrit that have resulted in anemia requiring transfusion.

Measure hemoglobin prior to initiation of Letairis, at one month, and periodically thereafter. Initiation of Letairis therapy is not recommended for patients with clinically significant anemia. If a clinically significant decrease in hemoglobin is observed and other causes have been excluded, consider discontinuing Letairis.

Patient Counseling Information

See FDA-approved patient labeling (Medication Guide).

Embryo-fetal Toxicity

Instruct patients on the risk of fetal harm when Letairis is used in pregnancy [see WARNINGS AND PRECAUTIONS and Use In Specific Populations]. Female patients must enroll in the Letairis REMS program. Instruct females of reproductive potential to immediately contact their physician if they suspect they may be pregnant.

Letairis REMS Program

For female patients, Letairis is only available through a restricted program called the Letairis REMS [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS]. Male patients are not enrolled in the Letairis REMS.

Inform female patients (and their guardians, if applicable) of the following notable requirements:

  • All female patients must sign an enrollment form.
  • Advise female patients of reproductive potential that they must comply with the pregnancy testing and contraception requirements [see Use In Specific Populations].
  • Educate and counsel females of reproductive potential on the use of emergency contraception in the event of unprotected sex or known or suspected contraceptive failure.
  • Advise pre-pubertal females to report any changes in their reproductive status immediately to their prescriber.

Review the Letairis Medication Guide and REMS educational material with female patients.

A limited number of pharmacies are certified to dispense Letairis. Therefore, provide patients with the telephone number and website for information on how to obtain the product.

Hepatic Effects

Some members of this pharmacological class are hepatotoxic. Patients should be educated on the symptoms of potential liver injury (such as anorexia, nausea, vomiting, fever, malaise, fatigue, right upper quadrant abdominal discomfort, jaundice, dark urine, or itching) and instructed to report any of these symptoms to their physician.

Hematological Change

Patients should be advised of the importance of hemoglobin testing.

Other Risks Associated With Letairis

Instruct patients that the risks associated with Letairis also include the following:

  • Decreases in hemoglobin and hematocrit
  • Decreases in sperm count
  • Fluid overload
Administration

Patients should be advised not to split, crush, or chew tablets.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Oral carcinogenicity studies of up to two years duration were conducted at starting doses of 10, 30, and 60 mg/kg/day in rats (8 to 48 times the maximum recommended human dose [MRHD] on a mg/m² basis) and at 50, 150, and 250 mg/kg/day in mice (28 to 140 times the MRHD). In the rat study, the high-and mid-dose male and female groups had their doses lowered to 40 and 20 mg/kg/day, respectively, in week 51 because of effects on survival. The high-dose males and females were taken off drug completely in weeks 69 and 93, respectively. The only evidence of ambrisentan-related carcinogenicity was a positive trend in male rats, for the combined incidence of benign basal cell tumor and basal cell carcinoma of skin/subcutis in the mid-dose group (high-dose group excluded from analysis), and the occurrence of mammary fibroadenomas in males in the high-dose group. In the mouse study, high-dose male and female groups had their doses lowered to 150 mg/kg/day in week 39 and were taken off drug completely in week 96 (males) or week 76 (females). In mice, ambrisentan was not associated with excess tumors in any dosed group.

Positive findings of clastogenicity were detected, at drug concentrations producing moderate to high toxicity, in the chromosome aberration assay in cultured human lymphocytes. There was no evidence for genetic toxicity of ambrisentan when tested in vitro in bacteria (Ames test) or in vivo in rats (micronucleus assay, unscheduled DNA synthesis assay).

The development of testicular tubular atrophy and impaired fertility has been linked to the chronic administration of endothelin receptor antagonists in rodents. Testicular tubular degeneration was observed in rats treated with ambrisentan for two years at doses ≥ 10 mg/kg/day (8-fold MRHD). Increased incidences of testicular findings were also observed in mice treated for two years at doses ≥ 50 mg/kg/day (28-fold MRHD). Effects on sperm count, sperm morphology, mating performance, and fertility were observed in fertility studies in which male rats were treated with ambrisentan at oral doses of 300 mg/kg/day (236-fold MRHD). At doses of ≥ 10 mg/kg/day, observations of testicular histopathology in the absence of fertility and sperm effects were also present.

Use In Specific Populations

Pregnancy

Pregnancy Category X

Risk Summary

Letairis may cause fetal harm when administered to a pregnant woman and is contraindicated during pregnancy. Letairis 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. 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].

Animal Data

Letairis was teratogenic at oral doses 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 doses. These doses 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 doses) and effects on testicle size and fertility of pups (high dose) following maternal treatment with ambrisentan from late gestation through weaning. Doses tested were 17 x, 51 x, and 170 x (on a mg/kg:mg/m² basis) the maximum oral human dose of 10 mg and an average adult body weight of 70 kg.

Nursing Mothers

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 nursing infants from Letairis, a decision should be made whether to discontinue nursing or discontinue Letairis, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness of Letairis in pediatric patients have not been established.

Geriatric Use

In the two placebo-controlled clinical studies of Letairis, 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 Letairis 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.

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 1 month after stopping treatment with Letairis. 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 Letairis and for 1 month after stopping treatment with Letairis. 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 Letairis have an adverse effect on spermatogenesis. Counsel patients about the potential effects on fertility [see WARNINGS AND PRECAUTIONS].

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 Letairis 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]. Letairis is not recommended in patients with moderate or severe hepatic impairment. There is no information on the use of Letairis 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 Letairis initiation, the cause of liver injury should be fully investigated. Discontinue Letairis 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.


This monograph has been modified to include the generic and brand name in many instances.

OverDose

There is no experience with overdosage of Letairis. The highest single dose of Letairis administered to healthy volunteers was 100 mg, and the highest daily dose administered to patients with PAH was 10 mg once daily. In healthy volunteers, single doses of 50 mg and 100 mg (5 to 10 times the maximum recommended dose) were associated with headache, flushing, dizziness, nausea, and nasal congestion. Massive overdosage could potentially result in hypotension that may require intervention.

ContrainDications

Pregnancy

Letairis may cause fetal harm when administered to a pregnant female. Letairis is contraindicated in females who are pregnant. Letairis 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 and Use in Specific Populations].

Idiopathic Pulmonary Fibrosis

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


This monograph has been modified to include the generic and brand name in many instances.

Clinical Pharamacology

Mechanism Of Action

Endothelin-1 (ET-1) is a potent autocrine and paracrine peptide. Two receptor subtypes, ETA and ETB, mediate the effects of ET-1 in the vascular smooth muscle and endothelium. The primary actions of ETA are vasoconstriction and cell proliferation, while the predominant actions of ETB are vasodilation, antiproliferation, and ET-1 clearance.

In patients with PAH, plasma ET-1 concentrations are increased as much as 10-fold and correlate with increased mean right atrial pressure and disease severity. ET-1 and ET-1 mRNA concentrations are increased as much as 9-fold in the lung tissue of patients with PAH, primarily in the endothelium of pulmonary arteries. These findings suggest that ET-1 may play a critical role in the pathogenesis and progression of PAH.

Ambrisentan is a high-affinity (Ki=0.011 nM) ETA receptor antagonist with a high selectivity for the ETA versus ETB receptor ( > 4000-fold). The clinical impact of high selectivity for ETA is not known.

Pharmacodynamics

Cardiac Electrophysiology

In a randomized, positive-and placebo-controlled, parallel-group study, healthy subjects received either Letairis 10 mg daily followed by a single dose of 40 mg, placebo followed by a single dose of moxifloxacin 400 mg, or placebo alone. Letairis 10 mg daily had no significant effect on the QTc interval. The 40 mg dose of Letairis increased mean QTc at tmax by 5 ms with an upper 95% confidence limit of 9 ms. For patients receiving Letairis 5–10 mg daily and not taking metabolic inhibitors, no significant QT prolongation is expected.

Pharmacokinetics

The pharmacokinetics of ambrisentan (S-ambrisentan) in healthy subjects is dose proportional. The absolute bioavailability of ambrisentan is not known. Ambrisentan is absorbed with peak concentrations occurring approximately 2 hours after oral administration in healthy subjects and PAH patients. Food does not affect its bioavailability. In vitro studies indicate that ambrisentan is a substrate of P-gp. Ambrisentan is highly bound to plasma proteins (99%). The elimination of ambrisentan is predominantly by non-renal pathways, but the relative contributions of metabolism and biliary elimination have not been well characterized. In plasma, the AUC of 4-hydroxymethyl ambrisentan accounts for approximately 4% relative to parent ambrisentan AUC. The in vivo inversion of S-ambrisentan to R-ambrisentan is negligible. The mean oral clearance of ambrisentan is 38 mL/min and 19 mL/min in healthy subjects and in PAH patients, respectively. Although ambrisentan has a 15-hour terminal half-life, the mean trough concentration of ambrisentan at steady-state is about 15% of the mean peak concentration and the accumulation factor is about 1.2 after long-term daily dosing, indicating that the effective half-life of ambrisentan is about 9 hours.

Drug Interactions

In Vitro Studies

Studies with human liver tissue indicate that ambrisentan is metabolized by CYP3A, CYP2C19, and uridine 5'-diphosphate glucuronosyltransferases (UGTs) 1A9S, 2B7S, and 1A3S. In vitro studies suggest that ambrisentan is a substrate of the Organic Anion Transporting Polypeptides OATP1B1 and OATP1B3, and P-glycoprotein (P-gp). Drug interactions might be expected because of these factors; however, a clinically relevant interaction has been demonstrated only with cyclosporine [see DRUG INTERACTIONS]. In vitro studies found ambrisentan to have little to no inhibition of human hepatic transporters. Ambrisentan demonstrated weak dose-dependent inhibition of OATP1B1, OATP1B3, and NTCP (IC50 of 47 μM, 45 μM, and approximately 100 μM, respectively) and no transporter-specific inhibition of BSEP, BRCP, P-gp, or MRP2. Ambrisentan does not inhibit or induce drug metabolizing enzymes at clinically relevant concentrations.

In Vivo Studies

The effects of other drugs on ambrisentan pharmacokinetics and the effects of ambrisentan on the exposure to other drugs are shown in Figure 2 and Figure 3, respectively.

Figure 2 : Effects of Other Drugs on Ambrisentan Pharmacokinetics

View Enlarged Table

* Omeprazole: based on population pharmacokinetic analysis in PAH patients

** Rifampin: AUC and Cmax were measured at steady-state. On Day 3 of coadministration a transient 2-fold increase in AUC was noted that was no longer evident by Day 7. Day 7 results are presented.

Figure 3 : Effects of Ambrisentan on Other Drugs

View Enlarged Table

* Active metabolite of mycophenolate mofetil ** GMR (95% CI) for INR

Clinical Studies

Pulmonary Arterial Hypertension (PAH)

Two 12-week, randomized, double-blind, placebo-controlled, multicenter studies were conducted in 393 patients with PAH (WHO Group 1). The two studies were identical in design except for the doses of Letairis and the geographic region of the investigational sites. ARIES-1 compared once-daily doses of 5 mg and 10 mg Letairis to placebo, while ARIES-2 compared once-daily doses of 2.5 mg and 5 mg Letairis to placebo. In both studies, Letairis or placebo was added to current therapy, which could have included a combination of anticoagulants, diuretics, calcium channel blockers, or digoxin, but not epoprostenol, treprostinil, iloprost, bosentan, or sildenafil. The primary study endpoint was 6-minute walk distance. In addition, clinical worsening, WHO functional class, dyspnea, and SF-36® Health Survey were assessed.

Patients had idiopathic or heritable PAH (64%) or PAH associated with connective tissue diseases (32%), HIV infection (3%), or anorexigen use (1%). There were no patients with PAH associated with congenital heart disease.

Patients had WHO functional class I (2%), II (38%), III (55%), or IV (5%) symptoms at baseline. The mean age of patients was 50 years, 79% of patients were female, and 77% were Caucasian.

Submaximal Exercise Ability

Results of the 6-minute walk distance at 12 weeks for the ARIES-1 and ARIES-2 studies are shown in Table 2 and Figure 4.

Table 2 : Changes from Baseline in 6-Minute Walk Distance (meters)

View Enlarged Table

Figure 4 : Mean Change in 6-Minute Walk Distance

View Enlarged Table

Mean change from baseline in 6-minute walk distance in the placebo and Letairis groups Values are expressed as mean ± standard error of the mean.

In both studies, treatment with Letairis resulted in a significant improvement in 6-minute walk distance for each dose of Letairis and the improvements increased with dose. An increase in 6-minute walk distance was observed after 4 weeks of treatment with Letairis, with a dose-response observed after 12 weeks of treatment. Improvements in walk distance with Letairis were smaller for elderly patients (age ≥ 65) than younger patients and for patients with secondary PAH than for patients with idiopathic or heritable PAH. The results of such subgroup analyses must be interpreted cautiously.

The effects of Letairis on walk distances at trough drug levels are not known. Because only once-daily dosing was studied in the clinical trials, the efficacy and safety of more frequent dosing regimens for Letairis are not known. If exercise ability is not sustained throughout the day in a patient, consider other PAH treatments that have been studied with more-frequent dosing regimens.

Clinical Worsening

Time to clinical worsening of PAH was defined as the first occurrence of death, lung transplantation, hospitalization for PAH, atrial septostomy, study withdrawal due to the addition of other PAH therapeutic agents, or study withdrawal due to early escape. Early escape was defined as meeting two or more of the following criteria: a 20% decrease in the 6-minute walk distance; an increase in WHO functional class; worsening right ventricular failure; rapidly progressing cardiogenic, hepatic, or renal failure; or refractory systolic hypotension. The clinical worsening events during the 12-week treatment period of the Letairis clinical trials are shown in Table 3 and Figure 5.

Table 3 : Time to Clinical Worsening

  ARIES-1 ARIES-2
Placebo
(N = 67)
Letairis
(N = 134)
Placebo
(N = 65)
Letairis
(N = 127)
Clinical worsening, no. (%) 7 (10%) 4 (3%) 13 (22%) 8 (6%)
Hazard ratio - 0.28 - 0.30
p-value, Fisher exact test - 0.044 - 0.006
p-value, Log-rank test - 0.030 - 0.005
Intention-to-treat population
Note: Patients may have had more than one reason for clinical worsening.
Nominal p-values

There was a significant delay in the time to clinical worsening for patients receiving Letairis compared to placebo. Results in subgroups such as the elderly were also favorable.

Figure 5 : Time to Clinical Worsening

View Enlarged Table

Time from randomization to clinical worsening with Kaplan-Meier estimates of the proportions of failures in ARIES-1 and ARIES-2.

p-values shown are the log-rank comparisons of Letairis to placebo stratified by idiopathic or heritable PAH and non-idiopathic, non-heritable PAH patients

Long-term Treatment Of PAH

In long-term follow-up of patients who were treated with Letairis (2.5 mg, 5 mg, or 10 mg once daily) in the two pivotal studies and their open-label extension (N = 383), Kaplan-Meier estimates of survival at 1, 2, and 3 years were 93%, 85%, and 79%, respectively. Of the patients who remained on Letairis for up to 3 years, the majority received no other treatment for PAH. These uncontrolled observations do not allow comparison with a group not given Letairis and cannot be used to determine the long-term effect of Letairis on mortality.

Adverse Effects In Idiopathic Pulmonary Fibrosis (IPF)

A randomized controlled study in patients with IPF, with or without pulmonary hypertension (WHO Group 3), compared Letairis (N = 329) to placebo (N = 163). The study was terminated after 34 weeks for lack of efficacy, and was found to demonstrate a greater risk of disease progression or death on Letairis. More patients taking Letairis died (8% vs. 4%), had a respiratory hospitalization (13% vs. 6%), and had a decrease in FVC/DLCO (17% vs. 12%) [see CONTRAINDICATIONS].


This monograph has been modified to include the generic and brand name in many instances.

Patient Information

No information provided. Please refer to the WARNINGS AND PRECAUTIONS section.


This monograph has been modified to include the generic and brand name in many instances.

Consumer Overview Uses

IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

 

AMBRISENTAN - ORAL

 

(AM-bri-SEN-tan)

 

COMMON BRAND NAME(S): Letairis

 

WARNING: This medication must not be used during pregnancy because it can harm an unborn baby. See also Precautions section.

In the US, ambrisentan is only available to female patients enrolled in the Letairis Risk Evaluation and Mitigation Strategy (REMS) program. Male patients do not need to be enrolled in this program to receive this medication. Only doctors and pharmacies enrolled in this program may prescribe or provide ambrisentan. Consult your doctor or pharmacist for more details about this program and about the risks and benefits of using this medication.

These requirements apply in the US. If you live in Canada or any other country, consult your doctor and pharmacist for your country's regulations.

 

USES: Ambrisentan is used to treat high blood pressure in the lungs (pulmonary arterial hypertension). This condition is thought to be caused by increased levels of a certain natural substance (endothelin-1). This medication blocks the effects of endothelin-1, thereby helping to decrease the blood pressure in the lungs, slow the worsening of symptoms, and improve your ability to exercise.

 

HOW TO USE: This drug is controlled through a special program. A program worker will call you each month to make sure that you have gotten a pregnancy test if you are a woman who may become pregnant. See also Warning and Precautions sections.

Read the Medication Guide provided by your pharmacist before you start using ambrisentan and each time you get a refill. If you have any questions, consult your doctor or pharmacist.

Take this medication by mouth with or without food, usually once daily or as directed by your doctor. Do not crush, chew, or break the tablets.

Dosage is based on your medical condition and response to treatment.

Use this medication regularly to get the most benefit from it. To help you remember, take it at the same times each day.

Do not stop taking this medication without consulting your doctor. Some conditions may become worse when the drug is suddenly stopped. Your dose may need to be gradually decreased.

Women who are pregnant or who may become pregnant should not handle the tablets or breathe the dust from this medication.

Tell your doctor if your condition persists or worsens.

Consumer Overview Side Effect

SIDE EFFECTS: Stuffy nose, runny nose, or flushing may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: fast heartbeat, extreme tiredness, swelling ankles/feet, sudden/unexplained weight gain, trouble breathing.

Other medications that are like ambrisentan may rarely cause very serious liver problems. Tell your doctor immediately if you develop symptoms of liver disease, including: persistent nausea/vomiting, severe stomach/abdominal pain, dark urine, yellowing eyes/skin.

This medication can decrease sperm production in some men, an effect that may lower male fertility. Consult your doctor for more details.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

In the US -

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

 

Read the Letairis (ambrisentan tablets) Side Effects Center for a complete guide to possible side effects

Learn More »

PRECAUTIONS: Before taking ambrisentan, tell your doctor or pharmacist if you are allergic to it; or to other endothelin receptor blockers (e.g., bosentan); or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: liver disease, certain lung conditions (pulmonary fibrosis), anemia.

Older adults may be at greater risk for swelling ankles/feet while using this drug.

This medication must not be used during pregnancy. It may harm an unborn baby. If you are planning pregnancy, become pregnant, or think you may be pregnant, tell your doctor immediately. Women who may become pregnant must have a negative pregnancy test before starting this medication, once a month while taking it, and for 1 month after stopping the medication. Consult your doctor for more details and to discuss reliable forms of birth control. Unless otherwise directed by your doctor, it is recommended that at least 2 reliable forms of birth control (e.g., birth control pills, condoms) be used while taking this medication and for 1 month after stopping the medication. Birth control should still be used, even if your partner had a vasectomy.

It is not known whether this medication passes into breast milk. Because of the possible risk to the infant, breast-feeding while using this medication is not recommended. Consult your doctor before breast-feeding.

Consumer Overview Missed Dose

DRUG INTERACTIONS: Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor's approval.

Some products that may interact with this drug include: cyclosporine.

 

OVERDOSE: If overdose is suspected, contact a poison control center or emergency room immediately. US residents can call their local poison control center at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include: severe dizziness.

 

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (such as liver function test, monthly pregnancy test, hemoglobin level) will be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

 

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

 

STORAGE: Store at room temperature away from light and moisture. Do not store in the bathroom. Keep all medications away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company.

 

Information last revised December 2013. Copyright(c) 2013 First Databank, Inc.

Patient Detailed Side Effect

Brand Names: Letairis

Generic Name: ambrisentan (Pronunciation: am bri SEN tan)

  • What is ambrisentan (Letairis)?
  • What are the possible side effects of ambrisentan (Letairis)?
  • What is the most important information I should know about ambrisentan (Letairis)?
  • What should I discuss with my healthcare provider before taking ambrisentan (Letairis)?
  • How should I take ambrisentan (Letairis)?
  • What happens if I miss a dose (Letairis)?
  • What happens if I overdose (Letairis)?
  • What should I avoid while using ambrisentan (Letairis)?
  • What other drugs will affect ambrisentan (Letairis)?
  • Where can I get more information?

What is ambrisentan (Letairis)?

Ambrisentan prevents thickening of the blood vessels, especially those in the lungs and heart. Ambrisentan also lowers blood pressure in your lungs, helping your heart pump blood more efficiently.

Ambrisentan is used to treat pulmonary arterial hypertension (PAH). It improves your ability to exercise and prevents your condition from getting worse.

Ambrisentan may also be used for purposes not listed in this medication guide.

What are the possible side effects of ambrisentan (Letairis)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have a serious side effect such as:

  • anxiety, sweating, pale skin, severe shortness of breath, wheezing, gasping for breath, cough with foamy mucus, chest pain, fast or uneven heart rate;
  • swelling of the feet, ankles, or legs;
  • pounding heartbeats or fluttering in your chest; or
  • nausea, upper stomach pain, itching, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes).

Less serious side effects may include:

  • headache;
  • stomach pain, vomiting, constipation;
  • stuffy nose, sinus pain, sore throat; or
  • warmth, redness, or tingly feeling under your skin.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Read the Letairis (ambrisentan tablets) Side Effects Center for a complete guide to possible side effects

Learn More »

What is the most important information I should know about ambrisentan (Letairis)?

Ambrisentan can harm an unborn baby or cause birth defects. Do not use if you are pregnant.

If you are a woman of child-bearing potential, you will need to have a negative pregnancy test before you start treatment with ambrisentan. You will also be re-tested each month during your treatment.

You will be required to use two forms of birth control to prevent pregnancy during your treatment, and for at least 1 month after your treatment ends. If you have had a tubal ligation or are using a copper IUD, you will not need to use a second form of birth control.

Do not stop taking ambrisentan without first talking to your doctor. You may need to use less and less before you stop the medication completely.

Ambrisentan is available only under a special program called LEAP (Letairis Education and Access Program). You must be registered in the program and sign agreements to use birth control and undergo pregnancy and blood testing as required by the program. Read all program brochures and agreements carefully.

Side Effects Centers
  • Letairis

Patient Detailed How Take

What should I discuss with my healthcare provider before taking ambrisentan (Letairis)?

Your should not use this medication if you are allergic to ambrisentan, or if you are pregnant.

To make sure you can safely take ambrisentan, tell your doctor if you have any of these other conditions:

  • anemia (low red blood cell counts);
  • a history of liver problems; or
  • if you are pregnant or plan to become pregnant while taking ambrisentan.

FDA pregnancy category X. This medication can harm an unborn baby or cause birth defects. Do not use ambrisentan if you are pregnant. Tell your doctor right away if you become pregnant during treatment.

If you are a woman of child-bearing potential, you will need to have a negative pregnancy test before you start treatment with ambrisentan. You will also be re-tested each month during your treatment.

You will be required to use two forms of birth control to prevent pregnancy during your treatment, and for at least 1 month after your treatment ends. If you have had a tubal ligation or are using a copper IUD (intrauterine device), you will not need to use a second form of birth control.

Recommended combinations of birth control forms include:

  • 1 hormone form (birth control pill, skin patch, implant, vaginal ring, or injection) plus 1 barrier form (condom, diaphragm with spermicide, or cervical cap with spermicide).
  • a condom and a female barrier form together (diaphragm with spermicide, or cervical cap with spermicide).
  • a partner's vasectomy plus 1 hormone form or 1 barrier form.

Talk with your doctor about the use of emergency contraception if you have unprotected sex or if you believe your form of contraception has failed.

It is not known whether ambrisentan passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are using ambrisentan.

Ambrisentan may lower a man's sperm count and could affect fertility (your ability to have children).

How should I take ambrisentan (Letairis)?

Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Ambrisentan is available only under a special program called LEAP (Letairis Education and Access Program). You must be registered in the program and sign agreements to use birth control and undergo pregnancy and blood testing as required by the program. Read all program brochures and agreements carefully.

Before you start treatment with ambrisentan, your doctor may perform blood tests to make sure it is safe for you to take this medication. Your blood will need to be tested often during treatment. Visit your doctor regularly.

Ambrisentan is usually taken once daily. Take the medicine at the same time each day.

Ambrisentan can be taken with or without food.

Do not crush, chew, or split the tablet. Swallow the pill whole.

Do not stop taking ambrisentan without first talking to your doctor. You may need to use less and less before you stop the medication completely.

Store at room temperature away from moisture and heat. Keep this medicine in its original container.

Side Effects Centers
  • Letairis

Patient Detailed Avoid Taking

What happens if I miss a dose (Letairis)?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose (Letairis)?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include feeling like you might pass out.

What should I avoid while using ambrisentan (Letairis)?

Follow your doctor's instructions about any restrictions on food, beverages, or activity.

What other drugs will affect ambrisentan (Letairis)?

Before you take ambrisentan, tell your doctor if you are using cyclosporine (Sandimmune, Neoral, Gengraf).

This list is not complete and other drugs may interact with ambrisentan. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

Where can I get more information?

Your doctor or pharmacist can provide more information about ambrisentan.


Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

Copyright 1996-2013 Cerner Multum, Inc. Version: 6.01. Revision date: 4/16/2012.

Your use of the content provided in this service indicates that you have read,understood and agree to the End-User License Agreement,which can be accessed by clicking on this link.

Healthwise

Side Effects Centers
  • Letairis

Rx Scoops
Featured Topics
Advertisements
Copyrights ©2014: Rx Scoops - Designed & Developed By - GOIGI